The effectiveness of Parpanit in the treatment of organophosphorus poisoning was examined and compared with that of atropine sulfate. The potency of Parpanit was assessed in the mouse, rat, hamster, guinea pig, and rabbit against sarin, tabun, soman, CMPF, and DSDP in treatments in which the oximes P2S and TMB4 were used both singly and together. The effectiveness of the treatments utilizing both cholinolytics varied with the species used for assay, with the oxime used in combination, and with the nature and level of challenge of the organophosphorus inhibitors. The mean activity of Parpanit relative to atropine taken from a total of 102 trials indicated it to be 4.2 times as effective, with the potency ratio varying from 0.17 to 100 depending on the specific test. The acute oral toxicity of Parpanit in weanling rats was 2.9 g/kg (2.4–3.4). In a chronic toxicity study where daily oral doses as high as 1/5 LD50 were applied for 30 days, no evidence of accumulative effects could be found nor was there any evidence that the protective capacity of Parpanit against sarin was affected by the extended application of the drug.

Interaction of potassium 1-phenylcyclopentanecarbosylate and 2-diethylaminoethyl chloride in a b s o l~~t e ethanol proveti the most satisfactory of four nietllods esami~ied for the preparation of 2-diethylaminoethyl 1-phenylcyclopentanecarbosylate hydrochloride (Parpanit). This procedure was used to obtain 2-(ethyl-2'-tluoroethyla11~i11o)ethyl ( I ) , 2-(ethylisopropyla~~~i~io)-ethyl (II), 3-diisopropylaminoetli~~l (III), 2-pyrrolidinoethyl (IV), and 2-pipericlinoeth).1 (V) 1-phenylcyclopentanecarbox~~1nte hyclrochloridcs. 2-Dicthylaminoethyl 1-(p-nitrophenyl)-cyc!opentanecarbos).late hydrochloride (111) was also preparcd in this way but was obtained Inore coliveniently by direct nitration of 2-diethyla1ninoeth).I l-pl~enylcyclopentanccarboxy-late. The preparation of intermediates required in thesc syntheses is described.P r e l i~n i n a r~ results are glven on the potency of these compounds as substitutes for atropine sulphate in the llsual osime and atropine sulphate treatment of mice which have bcen poisoned with Sarin.I n connection with extension of our studies on the usefulness of substitutes for atropine in the treatment of Sari11 poisoning (1,2) it became necessary to prepare certain analogues of 2-dietliylaminoetl1>~l 1-phenylcyclopentanecarboxylate hydrochloride, which is ltnown co~nmercially as Parpanit, Panparnit, Caranliphe11 hydrochloride, or Pentaphen. i\/Iany compounds of this type have been synthesized previously and the method nzost frequeiltly employed has been interaction of the acid chloride with the requisite aminoalcohol in a n aromatic solvent (3-8) (method 1). Other procedures which have bee11 utilized less frequelltly include transesterification of ethyl 1-phenylc~~clope~~tai~ecarbosylate with an an~inoalcohol and sodium in xylene (8-11) (method 2 ) ; interaction of an alltali ~n e t a l salt of the acid and an aminoalltyl halide in a hyclrocarbon s o l v e~~t (5,7, 12-14) (method 3); treatment of the acid chloride with an a~~~i n o a l c o h o l hydrochloride in a llydrocarbo~i solveilt ( 5 ) (method 4 ) ; and heating the acid with an aminoalltyl chloride hydrochloride in an alcohol (5) (method 5). J/Iethod 2 was considered unsuitable for preparation of the co~llpounds required because it sometimes furnishes very poor yields (11). I t was not clear, however, which of the other four procedures referred to above ivoulcl be most satisfactory. Accordingly, the merits of methods 1, 3, 4, and 5 were briefly exa~ni~zecl with respect to yield and ma~lipulative c o~~v e~~i e n c e for preparation of 2-dietl~ylarninoetl~~~l 1-phenylcyclopenti~~~ecarboxylate hg~drochloride (3).Interaction of equi~nolar quantities of 1-phenylcyclopentanecarboxylic acid chloride and 2-dietllylami11oetl1a1~0l in anhydrous benzene under reflux for 2 hours furnished the ester hydrochloride in 65y0 yield. Prolonging the period of reflus did not improve the yield (method 1).When potassium I-pl1e1~ylcyclopentnnecarboxy1ate was heated under reflux in absolute ethanol for 18 hours with a 20 mole% excess of 2-diet...

Three aspects of the reported oral toxicity of Clostridium botulinum toxin, Type A, were investigated. No demonstrable migration of the crystalline toxin from the lumen of the intestine into the blood stream of the dog could be found. Evidence indicating that the crystalline toxin was inactivated by pepsin and chymotrypsin was obtained, but the toxin was found to be resistant to the action of trypsin. Comparison of the oral toxicity and the intraperitoneal toxicity of the crystalline toxin revealed that the product was not orally toxic. A spray-dried crude preparation of the toxin demonstrated a low oral toxicity.

In preceding papers of this series (1, 2) the preparation of several analogues of 5'-diethylaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride (Parpanit) and certain of their quaternary salts was described. These coinpounds were required for evaluation of their efficacy as substitutes for, or adjuncts to, atropine in the treatment of sari11 poisoning (3-5). T h e preparation of fifteen additional analogues of Parpailit and four N-methyl-4'-piperidyl 1-arylcycloall~anecarboxylate hydrochlorides required for extensioil of these studies is reported herein. The compounds prepared and their properties are listed in Tables I to VI, and representative preparations are described in the Experimental section.The majority of the Parpanit analogues (Table IV) was prepared by the interaction of potassiuin 1-phenylcyclopentanecarboxylate \\-it11 the appropriate diall;ylai~~inoalkyl chloride, followed by treatment with dry hydrogen chloride netho hod F) in ethanol ( 1 , 6 , 7 ) .This was the most useful synthetic method when the requisite internlediate dialliylaminoalliyl chloride hydrochloride could be readily prepared, or ~vhen prepared, could be brought into reaction. 3'-Diethylaminopropyl 1-phenylcyclopentanecarboxylate hydrochloride, for example, was obtained in 62y0 yield from 3-diethylaminopropyl chloride and potassium 1-phenylcyclopentanecarboxylate, whereas the interaction of 3'-cl~loropropyl 1-phenylcyclopentanecarboxylate with diethylamine according to the general method of Weston (8) furnished only a 30% yield (nlethod 13).The potassiuin salt method proved impractical for the synthesis of 3'-quinuclidinyI 1-phenylcyclopentanecarboxylate hydrochloride. 3-Quinuclidinyl chloride hydrochloride is readily prepared by the action of thionyl chloride upon 3-quinuclidinol (9). 3-Quinuclidinyl chloride (lo), however, could not be induced to react with potassium 1-phenj lcyclopentanecarboxylate, presuinably because the rigidity of the ring system prevents the SKI reaction by inhibiting carbonium ion formation and also shields the 3-position fro111 SN2 attack. This compound was therefore prepared by interaction of l-phenylcyclopentanecarbonyl chloride and 3-quinuclidinol in anhydrous benzene (cf. refs. 1, 8 , 11-13; method I<), or by transesterification of methyl 1-phenylcyclopentanecarboxylate with 3-quinuclidinol in toluene using a catalytic amount of sodium, followed by treatment with dry hydrogen chloride (cf. refs. 13, 14, 16; method J ) . Transesterification of 3-quinuclidinol with ethyl 1-phenylcyclopentanecarboxylate (17) was unsuccessf~~l. 2'-t-ButylmethyIaminoethyl 1-phenylcyclopentanecarboxylate hydrochloride was prepared by the interaction of 2'-t-butylaminoethyl 1-phenylcyclopentanecarboxylate with ethyl iodide in benzene, folIo\ved by ion exchange (method G).T h e N-methyl-4-piperidyl hydrochloride esters of 1-phei~ylc~~clopentanecarboxylic, 1-phenylcyclobutanecarboxylic, 1-p-n~ethylphen~~lcyclobutanecarboxylic, and l-p-methoxyphen~~lcyclobutanecarboxylic acids were prepared by treatment of the appropriate...

Three aspects of the reported oral toxicity of Clostridium botulinum toxin, Type A, were investigated. No demonstrable migration of the crystalline toxin from the lumen of the intestine into the blood stream of the dog could be found. Evidence indicating that the crystalline toxin was inactivated by pepsin and chymotrypsin was obtained, but the toxin was found to be resistant to the action of trypsin. Comparison of the oral toxicity and the intraperitoneal toxicity of the crystalline toxin revealed that the product was not orally toxic. A spray-dried crude preparation of the toxin demonstrated a low oral toxicity.