Comparative Pharmacology of Some Thiomorpholine Derivatives

Abstract

Gardner and Haenni 1 described a series of compounds containing the morpholine rings, which they claimed exhibited some local anesthetic activity. The general structure of their compounds is expressed by the formula,

Burrows, 2 under the direction of Professor E. Emmet Reid in the Laboratory for Organic Chemistry, Johns Hopkins University, prepared 2 series of analogous compounds, which the writer had the privilege of investigating pharmacologically. One series was composed of thiomorpholines. The first of these, labelled No. 0, is thiomorpholine ethanol and has the following structure,

In addition, 7 esters were prepared from this alcohol, namely, the acetate, propionate, butyrate, valerate, caproate, heptoate and ben-zoate. In this paper these are labelled Nos. 1 to 7, respectively. A second series of compounds, analogous to the thiomorpholines and containing 2 oxygen atoms attached to the sulphur, was also prepared. These may be termed sulphoxy-thiomorpholines, the first member of the series, sulphoxy-thiomorpholine ethanol, being labelled No. Ox; and the 7 other members, esters similar to those of the thiomorpholines, being labelled lx to 7x, respectively. The structure of the first member of this series is as follows:

The action of aqueous solutions of these 2 series of compounds was studied on living seedlings of Lupinus albus, on tadpoles of Rana pipiens, on goldfish, Carassius auratus, and on cats under ether anesthesia.

Effect on Plants. Seedlings of Lupinus albus were grown in plant-physiological solutions containing the drugs in concentrations of 1:500. The effect is shown in Table I. Both series of compounds inhibited the growth of the plants, the least toxic being Nos. O and Ox. The sulphoxy-thiomorpholines were in every case more toxic than the plain thiomorpholine compounds.

Effect on Tadpoles. Tadpoles of Rana pipiens, 4 weeks old, were placed in solutions of the drugs, 1:1,000 and 1:500. The results obtained in the weaker solution were as follows:

The toxicity increased progressively from compound 0 to ester 6. Compound 7, or the benzoic acid ester, however, was less toxic than some other aliphatic esters.

Toxicity for Goldfish. Small goldfish, 2 in. long, were placed in solutions of 1:250 of both series of compounds. Time of onset of muscular incoordination, indicated by floating on the side, and the time required to effect respiratory paralysis were both noted. The results are exhibited in Table II. Here again the esters were progressively more toxic than the mother substance, or thiomorpholine ethanol. The sulphoxy compounds were all more toxic than the plain thiomorpholine compounds.

Summary. 1. The pharmacology of thiomorpholine ethanol and 7 esters thereof was compared with that of sulphoxy-thiomorpholine ethanol and 7 esters thereof in respect to local anesthetic effect, toxicity and action on blood pressure and respiration. 2. Only the benzoic ester of thiomorpholine-ethanol showed any appreciable local anesthetic effect, and none of the sulphoxy-thiomorpholine compounds revealed any definite local anesthetic action. 3. The toxicity of both series of compounds is not very great but the sulphoxy-thiomorpholine derivatives are in general more toxic than the thiomorpholine derivatives.