At the same time that this general agreement to consider these bases as the starting point in the endeavor to effect the synthesis of the natural alkaloids had been arrived at by chemists, it was thought well to look into the question whether these bases and their immediate derivatives had any therapeutic value of their own.
Piperidine, the decomposition product of piperine, which we have shown may be considered to be hexahydropyridine, was examined by Dr. Kronecker, of Berlin, at the request of Prof. Hofmann, and was found to have an action upon animals in many respects resembling that of conine. Prof. Filehne, of Erlangen, who has studied a large number of these pyridine and quinoline derivatives, found, moreover, that the hydrochlorate of ethyl-piperidine had a physiological action quite analogous to that of conine.
The physiological action of quinoline itself has been studied quite extensively by Donath and others, and it was found that several of its salts were quite valuable febrifuges, acting very like quinine, and capable in cases of being used as a substitute for it. In general, the hydrogen addition products were found to be more active than the simple base, an observation entirely in accord with the theory formed by Wischnegradsky, and by Konigs, as the result of the study of the decomposition products of the alkaloids, viz., the alkaloids are in general hydrogen addition products of pyridine and quinoline, or of the two bases combined. Thus Prof. Filehne found that hydrochlorate of tetrahydroquinoline was much more energetic in its action than quinoline, but could not be used on account of a too powerful local effect. The hydrochlorate of dimethyl-tetrahydroquinoline, which was distinguished by its strong bitter taste, much resembling that of quinine, had an effect like that of curare poison. The most decided febrifuge action, however was found by Prof. Filehne to reside in the hydrochlorate of oxyhydro-methyl-quinoline, introduced to public notice by Prof. O. Fischer under the name of "Kairin," and in the acid sulphate of tetrahydro-methylquinoline, introduced under the name of "Kairolin." These compounds had a very surprising febrifuge action, without any unpleasant after effects or local disturbances.
The most active workers in the field of synthetic formation of the alkaloids have been Wischnegradsky, of St. Petersburg--who, unfortunately for science, died at an untimely age in 1880--Königs and Fischer, of Munich, and Ladenburg, of Kiel. The study of the decomposition products of the cinchona alkaloids especially points quite distinctly to the probable existence in quinine of a hydrogen addition product of pyridine, in combination with a methyl-quinoline group. The many experiments that are now being made to test this and other questions that suggest themselves, will not long leave us in the dark. Whether a practical commercial synthesis of quinine will follow is another matter, but it is within the bounds of possibility, or perhaps even of probability.
It must not be supposed that no syntheses of alkaloids have been effected as yet. By heating butyl-aldehyde with alcoholic ammonia is formed paraconine, an alkaloid isomeric with the natural conine, but differing in physiological action. By the action of sodium upon pyridine is produced a compound C10H8N2, known as dipyridyl, and this, under the influence of nascent hydrogen, takes up six atoms and becomes isonicotine C10H14N2, a physiologically active alkaloid, isomeric with the true nicotine. The formation of a series of alkaloids under the name of codeines, by the substitution of other organic radicals instead of methyl in the codeine reaction, has already been alluded to. Atropine can be formed by uniting tropine and tropic acid, the two decomposition products already noted. The latter of these products is already shown to be capable of synthetical formation, and the other will no doubt be formed in the same way. The artificial atropine is identical with the natural alkaloid. Ladenburg has also formed a series of artificial alkaloids, called tropeines, by uniting the base tropine with different organic acids, as in the case of the compound of mandelic acid and tropine, known as homatropine, an alkaloid of action similar to atropine, but possessing some decided advantages in its use. Piperine has also been made by the uniting of piperidine and piperic acid, and, as piperidine has already been formed from pyridine, we have here a true synthesis also. Both theobromine and caffeine, its methyl derivative, have been made from xanthine, which itself can be formed from guanine, a constituent of guano.
We may conclude from this reference to what has been done in the last few years, that the reproach mentioned in first speaking of the alkaloids as a class, that almost nothing was known of their constitution, will not long remain, and that as their molecular structure is laid bare in these studies now being made, keen-sighted chemists will effect their artificial formation. When these most valuable compounds can be made by exact methods, in a state of entire purity, and at a cost much below that paid for the present extraction of them from relatively rare plants, organic chemistry will have placed all of us under obligations as great as those owing any branch of science, no matter how practical we call it.--Amer. Jour. of Pharmacy.