which is reduced to the corresponding amine (V.) by means of ammonium sulphide. This amine is then converted, by formic acid, into its formyl derivative (VI.), which loses H2O and yields theophylline (VII.) when heated with alkali. 8-Amino-theophylline is obtained by the action of ammonia on 8-chloro-theophylline,1 and has strong diuretic action. 8-Amino-paraxanthine and its alkyl derivatives have been obtained in a similar manner.2 3-Mono-methyl-xanthine has an appreciable diuretic action, but in 7-mono-methyl-xanthine it is vanishingly small. The diuretic action of xanthine itself is extremely small, and that of iso-caffeine (1-7-9 trimethyl-xanthine) is also very weak. Uric Acid Solvents, etc.--The various compounds that have been advocated as remedies for gout may be divided into two classes those which are designed to diminish the formation of uric acid in the body, and those which are intended to act as solvents for the uric acid after it has been formed. Of the latter class it may be said that many substances have been obtained, such as piperazine and urotropine, which are capable of dissolving uric acid in vitro, but are probably quite incapable of dissolving it in the highest possible concentrations that can be present in the body. Naturally many compounds have been prepared which are intended to combine both functions. For example, quinic acid, CH7(OH). COOH, which exists in cinchona bark and coffee beans, is said to diminish the formation of uric acid, and its lithium and piperazine salts have been introduced under the names of Urosin and Sidonal respectively. In these cases the lithium or piperazine is intended to act as a uric acid solvent. It has also been noticed that the presence of organic acids 1 D. R. P., 156,900. in the organism generally decreases the amount of uric acid formed, and that this effect is greater in proportion to the number of carbon atoms present in the acid. For this reason the use of diphenyl tartrate has been suggested, (-CH(OH)-COOCH)2, and salicylic acid has also been used, especially in the form of a condensation product of saligenin and tannic acid. A salicylate of urea has been recommended under the name of Ursal. Other compounds used for this purpose are hippuric acid, methylene-hippuric acid— CH–CO_N and its meta-nitro compound.1 CH2-CO CH-O Drugs of the second class, namely those the function of which is to prevent the deposition of uric acid rather than to prevent its formation, are more numerous. The alkaline carbonates have been widely used for this purpose, and especially lithium carbonate, as it has been found that the lithium salt is by far the most soluble of all the inorganic salts of uric acid. The alkaline tartrates, citrates, etc., are also used as well as the carbonates. The bad effects of lithium on the nervous system have led to the introduction of various organic bases which form even more soluble salts with uric acid. The employment of lithium and these bases as uric acid solvents is fallacious, because there is always sufficient sodium present in the body to form the sparingly soluble sodium urate, and a double decomposition between salts takes place with the formation of the least soluble. If we designate sodium urate for the sake of simplicity as NaU, then an equation such as LiU + NaCl NaU+ LiCl, will run from left to right under the conditions present in the organism. Nevertheless, some benefit may often be derived from these remedies, although it is not due to their solvent action on the uric acid. Of the various organic bases that have been used as substitutes for lithium, piperazine is the most important. It was obtained by Hofmann by the action of ammonia on ethylene dichloride or dibromide.2 1 D. R. P., 148,669. 2 Hofmann, Proc. Roy. Soc., 10 (1860), 231; Ber., 23 (1890), 3297. It is most readily purified by treating the reaction mixture with nitrous acid, whereby nitroso-piperazine— is obtained, from which piperazine can be regenerated by the action of hydrochloric acid or reducing agents.1 Many different modifications of this synthesis have been devised, but only one of them calls for mention. By the action of aniline on ethylene dibromide, diethylenediphenyldiamine is obtained, which yields a nitroso compound on treatment with nitrous acid. It has been shown that this on treatment with alkalies yields piperazine and nitrosophenol. Aniline with ethylene dibromide gives— 2 Ibid., 60,547, 63,618, 66,461, 65,347, 70,055, 71,576, 83,524, 70,056, 73,125, 67,811, 73,354, 74,628, 98,031, 100,232. See Friedländer, Fortschr., III. 948, IV. 1201. 3 Hofmann, Proc. Roy. Soc., 9 (1858), 277. ⚫ Bischler, Ber., 24 (1891), 717; and D. R. P., 60,547, etc. is known as Lysetol, and has the advantage of being non-poisonous and non-hygroscopic. Dihydroxypiperazine has also been investigated, and it resembles piperazine in its properties of a uric acid solvent. It is obtained by polymerizing aminoacetaldehyde with cold hydrobromic acid.1 prepared 2 and introduced under the name of Lysidin. It is said to be eight times as strong as piperazine in its solvent action on uric acid in vitro. Similar propenyl and butenyl derivatives have been prepared.* Urotropin (hexamethylenetetramine), cf. Chapter XI., has been recommended as a uric acid solvent, its salt with quinic acid being known as Quinotropin, and its salicyl derivatives as Saliformin. Helmitol, or New-urotropin, is the anhydromethylene-citrate of hexamethylene-tetramine. The acid, is obtained by heating citric CH CO-O CH2-COOH CH2-COOH acid with paraformaldehyde, or in better yield by the action of chlor-methyl alcohol, Cl. CH2-OH, on citric acid at 130°-140°C.5 The sodium salt of the acid has also been used by itself as a uric acid solvent, under the name of Citarin. According to Tunnicliffe and Rosenheim, the solubility of uric acid in blood serum is raised by the presence of piperidine, and they suggested the use of piperidine tartrate. 1 E. Fischer, Ber., 27 (1894), 169. 2 Ladenburg, Ber., 27 (1894), 2952. + Klingenstein, Ber., 28 (1895), 1173, 3068. 3 Deut. med. W., 1 (1894). 5 D. R. P., 129,255, 150,949. Lancet (1898), 189. CHAPTER XVI PURGATIVES AND OTHER SUBSTANCES ACTING ON THE GASTROINTESTINAL TRACT Anthraquinone Derivatives. Many aperient drugs, such as cascara, rheum (rhubarb), senna, and aloe, contain hydroxyl derivatives of methyl-anthraquinone. The position of the methyl group in these substances is not quite certain, but it is probable that most of them are derivatives of a-methylanthraquinone, CH3 CO CO These substances are very valuable as purgatives, owing to the fact that they have but little effect on the stomach and do not cause inflammation of the intestine. On the other hand, some of the drug is absorbed from the intestine into the system, and is liable to have an undesirable action on the kidneys. This effect is usually very slight, however. Chrysophanic acid, dihydroxy-methyl-anthraquinone is one of the milder of the natural purgatives of this group, and is present in rhubarb and many other purgative drugs, usually as a glucoside, chrysophan. The number and position of the hydroxyl groups has a powerful influence on the physiological action of the substance. For example, 1 Jowett and Potter, J. C. S., 85 (1903), 1327. |