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suspended by loops of sheet zinc or tin, so that i t is easy t o lift a n y one of t h e m for t h e purpose of p u t t i n g a beaker in place or removing it or f o r washing d o w n particles f r o m t h e sides. The flasks a r e a b o u t 2 ‘/8 in. in diameter, so as t o rest properly in t h e m o u t h of a n e x t r a tall beaker 2 in. diameter, 6 in. tall, and of a b o u t 3 7 5 cc. capacity. The addition of a few drops of a m y l alcohol t o prev e n t foaming also p r e v e n t s material from creeping up the sides of t h e beakers. T h e following are some of the duplicate determinations m a d e with t h i s a p p a r a t u s .
141
CRUDET
F CCIITBNT ~ ~
L
~
~
LL
FEEDSTUFF Per cent Per cent Cottonseed Meal.. 15.28 15.23 Cottonseed Meal.. 12 .OO 11.95 10.35 Cottonseed Meal.. 10.45 27.25 Cottonseed Feed.. 26.70 Brewer’s Dried Grains.. 14.43 14.73 Brewer’s Dried Grains.. 14.13 13.68 Distiller’s Dried Grains. 11.20 11.15 Distiller’s Dried Grains. 12.85 12.98 Alfalfa Meal.. 31.10 31.80 Wheat Bran and C o b . . 17.95 18.00 Wheat Bran.. 10.75 10.53 Wheat Shorts.. 9.28 9.20 Mixed Feed Wheat and Corn). ....... 11.98 11.76 Mixed Feed ICorn, Oats, and Alfalfa), 16.78 16.93 Rye Feed. 4.60 4.45 Hominy Meal.. 3.95 4.13 Chick F o o d . . : 2.88 2.93 KENTUCKY AGRICULTURAL EXPERIMENT STATION LEXINGTON, KENTUCKY
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ADDRESSES AND CONTRIBUTED ARTICLES A REVIEW OF THE AMERICAN PATENT LITERATURE ON ARSPHENAMINE (SALVARSAN) AND OTHER ARSENICALS B y H. F . LEWIS Received November 22, 1918
At the present time there is much interest in the United States patents on the aromatic arsenic compounds due to the manufacture of these preparations in America. It has recently been necessary in connection with the work of the Color Laboratory to study the United States patent literature in this field and in order to prevent a duplication of work, the results of the investigation are herewith presented. For some time the value of inorganic arsenic salts had been known in the treatment of trypanosomiasis. Much of the early work was conducted by the Liverpool School of Tropical Medicine, but the inorganic salts they employed had the disadvantage of being toxic in dosage sufficient to have great effect on the trypanosomes. In the year 1902, the Vereinigten Chemischen Werken, A-G, Charlottenburg, introduced the sodium salt of p-aminophenylarsenic acid as an almost non-toxic arsenical, under the name atoxyl.1 This compound permits 40 to 50 times as much arsenic to be administered as in the case of sodium arsenite. In the same year, Ehrlich and Shiga2 started their researches on the subject of chemico-therapeutics, the treatment of parasitic diseases through the injection of chemicals. They studied the effect of atoxyl on trypanosomes, but the strain they used, which happened to be the only one a t hand, lately was found to be the only one nonreactive with arsenicals, and thus they observed no influence. A different result was obtained in 1905 in the Liverpool Tropical Institute by Thomas and They used a strain of trypanosome, which was extremely sensitive to arsenic compounds and so they were able to ascertain a favorable action on trypanosomiasis. When Ehrlich4returned to the study of atoxyl in 1905,he made the discovery that this compound is the sodium salt of p-aminophenylarsenic acid and not m-arsenic acid anilid, as had been stated.6 This discovery opened the way to many new syntheses of compounds possessing greater therapeutic value than the parent atoxyl. Atoxyl was first used as a cure for sleeping sickness and this led to its use in diseases caused bv the Sbidlaceae and esveciallv in the cure of syphilis. I n this case, greater doses were necessary and disagreeable after-effects were obtained, blindness being Pharm. Ztg., 47 (1902), 170 and 211; Chem. Zenlr., 1 (1902), 775. B e d . klin. Wochschr., 4 1 (1904), 329 and 362. 3 Liverpool School of Tropical Research, “The Trypanosomes, Trypanosomiasis, and Sleeping Sickness,” Memoir, 16, 50. 4 Ehrlich and Bertheim, B e y . , 40 (1907), 3292. 5 Chem. Ztg., 1, 947; Pharm. Ztg., 47 (1902). 2104. 1
1
caused in many cases. The advent of many new remedies, in addition to the disagreeable after-effects, caused a great diminution in the use of atoxyl. Strange to relate, atoxyl has no action on the trypanosomes in vitro. The fact that this compound has such a marked action on trypanosomes in the human body points to a change taking place in the structure of atoxyl after it enters the body, This Ehrlich and others’ to be due to the reductionof
atoxY1 to P-aminoPhenYlarsenious oxide,
6
, a ComPoUd in
AS = 0 which arsenic is trivalent, that is, unsaturated. On the basis of the Ehrlich theory of immunity, the unsaturated arsenic will unite with the trypanosome, forming an arsenoceptor. Owing to the harmful after-effects of too great a dose of atoxyl, the efforts of investigators were directed toward obtaining compounds of arsenic that would be of value therapeutically and which would a t the same time be without the harmful aftereffects. Such known aryl arsenic compounds as atoxyl, arsenobenzene,2 oxyphenylarsenic acid, and phenylglycinarsenic acid* were used as starting materials in these syntheses. The first American patent on the general subject was applied for by Ehrlich and Bertheim,4 who stated that when p-aminophenylarsenic acid is boiled with acids, acyl derivatives may be obtained. These are of the type of C ~ H ~ ( N H C O C H ~ ) A S O ~ H ~ ( I :4). This patent was assigned to Farbwerke vorm Meister Lucius and Bruening, as are all of Ehrlich’s patents. A. Michaelis and C. Schultesin 1881 and 1882 showed that by reducing either phenylarsenic acid or phenylarsenious oxide with the proper agents, such as phosphorous acid, the arsenobenzene, As = As,
A A
[v1 v) , could be produced.
Ehrlich and Bertheims formed
homologues of arsenobenzene by reducing p-arylglycinarsenic acid and obtained arsenoarylglycine, of the type (COOH-CHzNH(4)-Aryl(1)0As = )2. These compounds are used for the same purpose as atoxyl. They are insoluble in water but readily soluble in alkalies. In the Nobel lecture, delivered in Stockholm, December 11, Roehl, 1 Ehrlich, Ber., 4 1 (1909); Milnch. med. Wochschr, 1909, No. 5. B e d . Win. Wochschu., 46, N o . 11; Z . Immunitdts, 11 A b t . Ref., 1909, 496. Michaelis, A n n . , 310 (1902), 275. 8 Ehrlich, Ber., 4 1 (1909), 29. 4 U. S. P. 907,016. Applied for, Oct. 3, 1907. Granted, Dec. 15, 1908. 5 6
1908.
Ber., 14 (1881), 912, and 16 (1882), 1952. U. S. P. 888,321. Applied for, Nov. 13, 1907.
Granted, May 19,
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1907,Ehrlich’ stated that up tothat time, arsenophenylglycine had proven in animal experiments to be an ideal therapeutic agent. By aid of these substances, it has been possible to completely cure every kind of trypanosome infectioxi in any animal, and that by means of a single injection. He terms such a result
S-The process of manufacturing which consists in treating nitro-p-oxyphenylarsenicacid with a hydrosulfite. Owing to the insolubility of the dioxydiaminoarsenobenzene in water, it was found necessary to obtain it in such a form as would be water-soluble and still possess all of the therapeutic “therapia sterilisans magna.” properties. This was done’ by treating a methyl alcohol soluWhen hydroxylarylarsenic acids are reduced with sulfurous tion of the substance with hydrochloric acid and precipitating acid, they give the oxides of the formula OH-Aryl-As = 0. the dihydrochloride by pouring into ether. These oxides are soluble in water and form soluble alkali salts.* The dihydrochlorides of the above compound, the dioxydiFurther reduction of the oxide with a neutral solution of hydro- aminoarylarseno compounds, are very easily oxidized to the sulfite forms a hydroxyarsenobenzene or arsenophenol. This is p-amino-oxyphenylarseniousoxides, which are very much more insoluble in water but forms a soluble sodium salt.8 toxic. In order to avoid this, a glass ampule has been patented2 In 1909, there were two patent grants made for mercury salts by Ehrlich and Bertheim. This holds the preparation in a n of p-aminophenylarsenic acid. One4 was for the salt formed by atmosphere of a non-oxidizing gas such as carbon dioxide, nitrothe reaction between an aqueous solution of the sodium salt of gen, or hydrogen. the acid and a solution of mercuric salt, and this new compound The last of the basic salvarsan patents is based upon its precipitates from the reacting solution. The other salt6 is a application in an alkaline solution.* These solutions are made by dissolving the dihydrochloride in caustic alkali of a preferred / OH strength of 15 per cent. basic salt of the constitution NH2O A s = 0, which is The compound, 3-nitro-4-oxyphenylarsenicacid, which on reduction gives the 3,3’-diamino-4,4’-dioxyarsenobenzene, is a \ OHg obtained by adding a calculated amount of mercury salt to an derivative of p-oxyphenylarsenic acid, that may be synthesized in one of several ways. alkaline solution of the monosodium salt of the acid. I-When aniline is heated with arsenic acid, p-aminophenylLudwig Bendae patented the homologues of p-aminophenyl arsenic acid is formed. The sodium salt of this acid is diazotized, arsenic acid. By treating p-aminophenylarsenic acid with cyanic acid or its giving the oxy-compound, p-oxyphenylarsenic acid.4 By diesters, carbaminoarsenilic acid or its homologues are formed.’ azotizing in acid solution, the free phenylarsenic acid is obtained These compounds are soluble in hot water and alkali, but insol- and this may be removed by extracting with suitable solvents.b 2-The arsenation of phenol is carried out by the reaction uble in cold water. They have the following constitution, between molecular amounts of phenol and arsenic acid a t the NHCONHR(4) temperature of 150”.6 Aryl 3-Finally oxyphenylarsenic acid may be formed by the
