effect. A large number of sulphones were then examined by these investigators, who found1 that di-sulphones in which the sulphone groups are united to two different carbon atoms, are inert; for example, ethylene-diethyl sulphone

CH2-SO-C2H¿

CH2-SO2-C2H5

They also found that sulphones derived from methane (i.e. those in which the two SO2 groups are united to a CH, group) are inert, as also are those containing methyl groups but no ethyl groups.

On the other hand, ethylidene-diethyl-sulphone

CH3-CH(SO2. C2H5)2

has a similar action to that of sulphonal, while the entrance of an ethyl group into the central methylene group also brings about the appearance of a narcotic action.

E.g. C2H5-CH(SO2. CH3)2, slight narcotic action.

logical action to, sulphonal ("reversed" sulphonal).

prolonged action than sulphonal. Tetronal, (C2H5)2C(SO2C2H5)2,

1 Zeit. physiol. Chem., 14 (1890), 52.

is very insoluble, and therefore is not so good an hypnotic, but for dogs it appears to have the most powerful action of all the sulphones.

The above examples indicate that the intensity of the hypnotic action appears to be conditioned by the number of ethyl groups in the molecule. A study of the fate of these compounds in the body has revealed the curious fact that those sulphones which are readily decomposed by ordinary chemical means are relatively stable in the organism, while those which are more resistant to ordinary chemical reagents are oxidized by the organism. For example, sulphonal, "reversed" sulphonal, trional and tetronal, though very stable to strong reagents, such as permanganate, are to a great extent decomposed in the organism, while CH2(SO2. C2H5)2, which is easily decomposed by alcoholic potash, is found unaltered in the urine.

Sulphonal and trional are of great practical importance, as they are amongst the most widely used hypnotics. Technically, sulphonal is prepared by the condensation of ethyl mercaptan and acetone in the presence of zinc chloride, and oxidation of the mercaptol thus formed with excess of permanganate.1

Trional is prepared in a similar manner, but the preparation is complicated by the necessity of introducing the extra ethyl group in place of methyl. This can be done in three different ways.2

(1) Methyl-ethyl-ketone is condensed with ethyl mercaptan by means of dry HCl, and the resultant mercaptol oxidized.

1 Baumann, Ber., 19 (1886), 2808.

2 D. R. P., 49,073, 49,366; Fromm, Annalen, 258 (1889), 148.

This method is strictly analogous to the method of preparing sulphonal.

(2) Propionic aldehyde is condensed with ethyl mercaptan, and the product oxidized as before. The oxidation product is then methylated with methyl iodide and caustic soda to form trional.

(3) By starting with ordinary aldehyde, instead of propionic aldehyde, and ethylating with ethyliodide and sodium ethylate in the last stage instead of methylating, trional can be obtained,

CHAPTER V

ANTIPYRETICS AND ANALGESICS

(DERIVATIVES OF ANILINE AND PHENYLHYDRAZINE)

THE substances to be dealt with in this chapter include some of the most important of the synthetic drugs. These substances were originally introduced on account of their power of reducing the body temperature in fever (antipyretic action), but their present importance is due, to an even greater extent, to their action on the nervous system in soothing pain (analgesic action).

The original idea of chemists was to produce a compound with properties similar to those of quinine, and this they sought to accomplish by preparing substances the composition of which was closely related to that attributed to that compound. The formula in vogue for quinine, was however incorrect, but in spite of this, several compounds were produced which had a marked antipyretic effect, but which lacked one very important attribute of quinine, namely, its specific effect against malaria. Quinine was shown to be a derivative of quinoline, and further to differ from the less active cinchonine in containing a methoxy group in the epi (1-6) position to the quinoline nitrogen, CH2O

5

N

Quinoline itself has an antipyretic action, but

cannot be used as a drug, owing to its unpleasant by-effects. Paramethoxyquinoline has a weaker antipyretic action than quinóline, but in accordance with the previously mentioned fact that tetrahydroquinoline has a stronger physiological action than quinoline, it was supposed that quinine was a derivative of. epimethoxy-tetrahydroquinoline. This supposition is now

known to be incorrect, but nevertheless when 6-methoxy

with a strong antipyretic action, though without any specific effect in malaria. It is not used as a drug, as it has harmful effects on the blood and kidneys.

Some earlier experiments had been carried out on N.-alkyl quinoline derivatives, and it was found that the introduction of an hydroxyl group caused the effect to appear more rapidly, but also to cease more quickly and suddenly. For example,

more rapid than Kairoline A or Kairoline B, which are respectively N.-ethyl-tetrahydro- and N.-methyl-tetrahydro-quino

These substances are all useless, owing to their toxic action on the red blood-corpuscles. It is now thought that the specific action of quinine is due more to the "loiponic acid" half of the molecule than to the quinoline half.

Although the artificial quinoline derivatives have proved useless in medicine, a compound produced by Knorr,1 with the

1 Annalen, 238 (1887), 137.