ASTHELMINT~C QUATERXARY SALTS. IV
September 1969
807
TABLE I ~MINOPENTADIENYLIDENEhMMONIUYSALTS
[It+=CHC=CHCH=CHR]
X-
I
R' Yield, No.
I 2a. 2)) 3 it 3t) 4
.)a 5b
H.
I ll100
11)
.-I
I
>1i100
.ill
2.i
I .i IO0 L',i!l
I
I:!
-ZNTHELMISTIC QUATERSAHT SALTS. 1\' TARLI.: I1 (Continued) .Y.du6ius in miceh C o inpri
1-5
16 17 15
19 20 21 22 23 24 2.5 26 27 25
.icute toxicity in mice" mg'kg------LDsi, IP Oral
10 10 7.50 200 .50
.50 100 >1000 1300
200
NO.
Dose, mg kg
2 .i 2 .i l.)0 .500
--
50 1.io
.iO
,500
.500 50 >I000 10
> 1000
,500
100 >lo00 >1000
1.i ,500 15
10 30 200 .XI
of worms, 70redn
Gastrointestinal nematodes in sheep' Eggslg Dose, of feces, mg/kg "To redn
0 0
0 0 0 0 0 0 0 0
50 200 500 ,500
A . .uum in miced Lung Dose, lesions, mg,'kg 70redn
23
100
0 32 0 37 0
30 100 25 30
0 0 50 91
10 25
100 30 200 .j0
10 10 10 10
J
10 1 1
200
10 10
0
_ _ _ _A . suum in swineP--Dose, % in feed
Liver lesions, redn
Lung larvae, "?c redn
0.013
0
0
40
>
10 0 30 30 20 10 40 20 40 30 30
a The LDho values recorded in the table are estimates based on acnte toxicity studies in which three mice were used per dose level Each of three mice which had been infected with 50 -V. dubius with an average of eight dose levek for each mode of admiiiistration. larvae several weeks earlier was adniinist,ered a dose of I>-50 nig,:kg orally. A similar dose was administered on the following day. On the seventh day the mice were sacrificed and a coiiiit was made of the iiiimber of ~ w r m sremaining in the intestine. The iuimediThe compounds cated mire had 35-40 worms; the table rerords tlie permitage rediictioii carised hy the actioii of the test compoiiiid. were tested 011 sheep which had beeii experimetitally infected with six species of gastroiiitestiiial tieniatodes: Haemonchus contortus, Cooperia cwticei, Trichosirong!jlas colitbri:fo~rriis,?'richostrong?jlii,s axei, Osterlayki circiiiiicincla, aird A\-emalodirzts spathiyer. The compoiinds were admiiiibtered iti twc equal doses 011 coiiseciitive days, atid the mimlier of eggs per gram of feces was determined during a 7-day period. The table lists the perceiitage rediictioii in the egg cowit a t the end of t,his period. So particiilar species specificity in anthelmititic actioii was observed with this serie? of compoiuids. A dose of 10 mg 'kg was administered orally t o each of three mice, followed by the admiiiiatratioii of an infection of 100,000 emhrj-onated A. m u m egg?. A secoiid dose of 10 mg/kg was administered 4 hr later. -4fter 8 days the mire were sacrificed aiid the extent' of Iiiug lesioiis was deterniiiied by gross examination of the liiiigs for the niimber atid size of hemorrhagic areas diie to the migratioii of the .hearis larvae. The table lkta the perceiitage reduction iii lung lehioiis of the treated animals as compared with the iiiimedicatecl coiitrols. e The lest compoiirids were adniiiiistered at, a level of 100,000 embryonated A. mum eggs was of 0.0ly; iii feed for a period of IO days to two pigs in concrete-floored pens. -411i~ifect~ioii administered 3 days after the start of the iiicliisioii of the test compouiid in the feed. The animals were sacrificed after 10 days. The pereelitage rediictioii in liver lesiviis due to migrating Ascaris larvae in treated animals as compared with controls was determined by countiiig the small white scars ("milk spot.'!) found on the surface of the liver. The number of lesions was 500 or greater in unmedicated controls 137 animals); beyond SO0 the lesions teiided to coalesce and could not be counted separately. The procedure used to det'ermirie the number of larvae in the liiiigs of the pigs was based on the method described for mice by 1). K. Hass (Ph.D. The&, Griiversity of J$7isconsi~i,1962). In 5i control animals, the number of larvae found after sacrifice varied from a low of 10,000 to a high of 49,000, for ati average valiie of 25,000.
Experimental Section1 l-(5-Azetidino-2,4-pentadienylidene)azetidinium Perchlorate (1).2-A solution of azetidine3 (7.0 g, 0.122 mole) in N e O H ( 5 2 ml) was added to 1-(2,4-dinitrophenyl)pyridiriiiim chloride (17.3 g, 0.061 mole) in MeOH (75 ml) a t room temperature. The temperatiire rose spontaneoiisly t o 50", and the siispension was allowed to htarid overnight. The precipitated 2,4-dinitroaniline was filtered, atid tlie filtrate was evaporated t o dryiiess and extracted with 1120 1430 nil), giving a fiiriher precipitate of 2,4dinitroaiiilirie (iota1 10.8 g, tlieory 11.2 g ) . IIC10, was added to the aqueoiis extract at, 0" to give the produc*t,nip 184-185' (from EtOH), yield 13.9 g (Kay;). The other compounds (excluding 27) listed in Table I were prepared in the same way, except that in a few cases, brief periods of reflux were required before the theoretical quantit,y of 2,4dinitroaiiiline was formed. Pamoate salts were prepared by adding sodium pamoate to the aqueous solutions of the chloride salts. [5-(Dibenzylamino)-2,4-pentadienylidene] dibenzylammonium Chloride (27).-A solution of dihenzglamine (8.0 g, 0.04 mole) and gli~t.acoti:tldeliy~le diaiiil hydrochloride (5.7 g, 0.02 mole) i n EtOlT 120 1111) WMS t~dlrisedfat, I5 i r i i t i atid nllowed i o statid ovei'night. l'lir h l J ~ l l ~ i O w:ttl r v : q ) ~ ) t ~ : ~ ~ tlrytiesh ed r t t ~ d~ I i ere\itlue .~
~
(1) RIeltirig puiiitx \ \ e r ~IaLrii on 3 'I'll~jmua-IIut~vpr nlelting jiuirit :ll>pardtu.; ark1 a r e correct rd. (2) 1;. I X r r , J. Kotschy, and €1. Kausen, Ber. Bunnenges. P h y c . Cliem., 69, 11 (1965). T h e U Y spectrum of tlie perchlorate salt is given, but t h e
compound is not otherwise described. '3) D. H. Kadsworth, J . Org. Chem.. 32, 1184 (1967).
was crystallized from MeOH-EtOile-Et20 to give the product in a hydrated form, yield 3.0 g (297,). 1-(Piperidinomethy1ene)piperidinium Perchlorate (29).--8 mixtiire of piperidine (4.26 g, 0.05 mole), piperidine perchlorate (9.28 g, 0.0.5 mole), aiid triethyl orthoforniatr (7.41 g, 0.05 mole) iii EtO1-I (10 ml) was refliixed for 4 hr and allowed t o stand overnight. The product separated on addition of ether giving 11.2 g (8OC,i,, m p 2111-21'i0). The analyt.ica1 sample melted at 233~t:~llimlioii (Et 011). ~ I n a lICiITT~iCIN~O~) . C, H,
-
3-Methyl-1 134 3-methylpiperidino)allylidene] piperidinium Chloride (30).-The general method of 1Ialliotra atid JVhitiiigl was emploj-ed for the allylidetie derivatives. -4 sollition of propiolaldehyde (5.3 g, 0.1 mole) i i i .\IeOII (15 ml) was added dropwise to a solritioii of 3-niethylpiperidiiie (10.9 g, 0.11 mole) i n LIeOH (25 ml) at, 0' and the solutioii was allowed to stand a t 0" for 18 hr. Fractionation yielded 3-(3-methylpiperidiiio)propenal, bp 125-130" (0.1 mm), yield 10.5 g (68.5(,&). A solution of this compound (6.1 g, 0.04 mole) and %methylpiperidine perchlorate (8.76 g, 0.044 mole) in EtOH (33 ml) was refliised for 2 hr. I t was passed throriyh a roliimn of Amberlite IRA-4OO i t 1 the chltr1,idef~)i.rn ared i t 1 lleO11 (200 1111) and the clliiaie was evapul~uierl. ( ' 1 llizai,ioti o f the residite from .4r.\Ie-Et2C) yielded 4.U g ) l l f ~ ~ l ~ ~ m~ p~ ll ol 4i ~l ~ l to ~ .~o. . ! M L ~ (CiiHriCllj~.2HH,O) . (>,13, X. 1-(3-Piperidinoallylidenejpiperidinium Perchlorate (31 ).---i wliitioii of propiolaldehyde ( 3 . 5 g, 0.1 mole) iti 1IeOIl (15 ml) was added dropwiae to piperidine (9.5 g, 0.11 mole) ill 11eOII _____
(4) S. S. Malliotra and hf. C. Whiting, J . Chem. Soc., 3812 (1Y60).
