Myotic effects

Furthermore, in the particular type of phosphate molecule under discussion (VI) we showed that when X is fluorine, compounds of high toxicity result whereas myotic effect is absent and toxicity of a low order if X = H, Et, OH, OEt, OCH2CH2C3, OCH2CH2F, Cl, NH2, NHMe, NHPh, CH2CH2F, CN, SON, etc.1 In Chapters rv and vi, however, we consider in more detail cases where X is not fluorine, but nevertheless toxicity results. Toxicity is also of a low order in the aromatic series for example, diphenyl phosphorofluoridate is relatively non-toxic and devoid of myotic properties. We also showed that ethyl phosphoro-difluoridate, (C2H50)P0F2, had neither myotic nor toxic action.1... 

In view of the high toxicity and very pronounced myotic effect of di-isopropyl phosphorofluoridate, di ( 1 Z dichlorowo propyl) phosphorofluoridate (XVI) was of special interest. It was prepared from l 3-dichlorohydrin and phosphorus trichloride. It did not have any appreciable myotic effect and the toxicity was of alow order. Di ( 1 -ethylpropyl) phosphorofluoridate (XVII),... 

Discussion. From the investigations of the compounds described so far, it is evident that the myotic effect and toxicity of the molecule POX(0 CH-fti2 )2 depend upon the nature of X, B and B. In this particular type2 of molecule if X is fluorine, then high toxicity and myotic properties result. Myotic effect is absent and toxicity is of a low order if X = H, Et,... 

In the molecule (X = F), the pupil-constricting action and toxicity are increased by a secondary grouping (e.g. R=R = Me . R = Me, 72 = Et RR = cycZohexyl R = Me, R = CH2 CHMe2). Furthermore, it appears that for non-cyclic compounds both R and R, for the best results, must be unsubstituted hydrocarbon radicals (e.g. if R = Me and R = C02Et the compound is scarcely toxic). Similarly, if R =. S = CH2C1, both the myotic effect and toxicity are of a low order. Among unsubstituted (non-cyclic) secondary radicals, the best results seem to be obtained when one group, at least, is Me for example, if. R =. R = Et, the toxicity is considerably reduced. 

Turning again to primary phosphorofluoridates (R = H), if R is substituted, e.g. in di-(2-chloroethyl) phosphorofluoridates, the toxicity and myotic effect are greatly inferior to those shown by the unsubstituted diethyl phosphorofluoridates. Toxicity is also very low in the aromatic series for example, diphenyl phos-phorofluoridate is non-toxic and devoid of myotic properties. Similar remarks apply to certain sulphur analogues, e.g. diethyl phosphorofluoridodithiolate, POF(SEt)2 (preparation, p. 54). 

In view of the rapid toxic action and myotic effect of the dialkyl phosphorofluoridates and of the high toxicity of some of the phosphorodiamidic fluorides, we prepared2 and examined a hybrid molecule containing the essential features of each type of compound. The first to be examined was ethyl phenyl-phosphoramidofluoridate (VII). One mol. of phosphorus oxy-dichlorofluoride was added to 1 mol. of ethyl alcohol, and the resulting ethyl phosphorofluoridochloridate (which it was not necessary to isolate) was treated with aniline. 

Pour of us were exposed to a concentration of 1 part in 10 for 5min. Atightnessacrossthechestwas noticed. Some 5 min. after leaving the chamber, myosis set in, and became intense and caused severe incapacitation which lasted for 5 days. One observer suf-fered fix>m sickness and diarrhoea in addition to the myotic effect. ... 

Introduction of a 0.01% solution of aceclidine into the conjunctival sac of rabbits reduced the pupil diameter on the average by 3 mm, the maximum myotic effect appearing in 20-30 minutes and having a duration of 1.5-2 hours. A 0.1% solution caused reduction of the pupil diameter by 5 mm and maximum myosis was produced by a 5-10% solution [122]. Administration of a 2% solution of aceclidine to rabbits 60 minutes after administration of a 2% solution of atropine sulphate removed mydriasis completely, the latter reappearing after 5 hours [127]. Aceclidine did not cause local anaesthesia [127]. After administration of a solution of aceclidine hydrochloride to rabbits the compound could be detected in the animal s blood serum [127]. Administered subcutaneously to rats at a dose of 25-50 mg/kg aceclidine caused intense salivation, lacrimation (chromodacryorrhea) and diarrhoea. Toxic doses produced tremors and convulsions. The acute LDgQ in rats was 45 mg/kg on intravenous administration, 225 mg/kg on subcutaneous administration [122] and 105 mg/kg when administered intraperitoneally [127]. The acute LDgo for white mice was 36 mg/kg, i.v. 112.5 mg/kg, s.c. and 165 mg/kg when administered per os [122]. In rabbits aceclidine at doses of 1 mg/kg i.v., 10 mg/kg s.c. and 25 mg/kg per os caused intense salivation, myosis and diarrhoea. 

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