3,004,026 United States Patent Office Patented Oct. 10, 1961 1. 3,004,026 septic. Thus, it has been recommended that a salt ex-. HEXAMETHYLENETETRAMINE HIPPURATE hibiting an acid reaction, such as ammonium chloride, Alexander Galat, 126 Buckingham Road, Yonkers, NY. ammonium nitrate, sodium acid phosphate or the like, No Drawing. Filed Aug. 28, 1959, Ser. No. 836,618 be administered together with Methenamine. However, 1. Claim. C. 260-248.5) 5 impractically and/or dangerously high dosages of such salts must be given in order to make the urine acidic and This invention relates to a new and useful organic com even so acidification of the urine does not occur with all pound. More particularly, this invention relates to a new patients. . . - ...... organic compound useful as a urinary tract antiseptic. In Another approach that has been employed in an at an even more specific aspect thereof, this invention relates O tempt to solve the difficulty involves administering to hexamethylenetetramine hippurate. Methenamine in the form of a salt with an organic acid. The principal object of this invention is to provide It is postulated that decomposition of such a salt in the hexamethylenetetramine hippurate, a new organic com urine will result in the production of the acid medium re pound of high utility. quired for manifestation of the antiseptic action of Corollary objects of this invention will become appar 15 Methenamine. ent as the description thereof proceeds. Salts of Methenamine with such acids as anhydro For the better understanding of this invention, the methylenecitric, acetylsalicylic, borocitric, citrosulfuric, following example is a complete description of a pre mandelic, phenoxyacetic, salicyclic, sulfosalicylic, salicyl ferred procedure for the preparation of the new and use oxyacetic, sulfoxylic, and the like have been prepared ful compound of this invention. 20 and tested as urinary antiseptics with invariably unsuc Example cessful results. It will be noted that all of these acids are, from the standpoint of the human body, foreign sub One hundred and seventy nine grams (one mole) hip stances exhibiting, to a greater or lesser degree, toxic puric acid (benzoyl glycine) and 140 g. (one mole) hexa physiological effects. The human body attempts to eli methylenetetramine were heated under reflux in 500 ml. 25 minate these substances by various metabolic and other methanol. The small amount of water necessary to give reactions, one of which involves neutralization of these a clear, homogeneous solution was added to the resulting foreign acids. To accomplish this reaction an abnor reaction mixture which was then evaporated to dryness. mally large amount of alkali is excreted into the urine, The residue soon crystallized, a procedure that could be this amount being so great that the urine exhibits an even greatly accelerated by seeding with crystals of hexameth 30 higher pH than prior to the administration of the salt. ylenetetramine hippurate from a previous preparation. As a result, Methenamine therapy through use of such The resulting solid product was broken up and pulverized. salts is erratic, unreliable and, more frequently than not, Hexamethylenetetramine hippurate is stable on exposure completely ineffective. to air and is soluble in water and alcohol. It melts at Hippuric acid, while present in greatest concentrations 105-10 C. in the urine of herbivorous animals, is also a normal but Hexamethylenetetramine is a well known chemical comparatively minor component of human urine. When compound that appears on the market under such trade administered to humans even in extremely large amounts names as Aminoform, Formin, Hexamine, Methenamine, (e.g., 15 g. daily) hippuric acid is completely devoid of Urotropine, et cetera. For convenience this compound toxicity and does not result in any unusual physiological will be designated Methenamine throughout the remainder 40 action such as renal adjustment to the acid load with in of this specification while the new compound of this in creased excretion of ammonia. vention will be correspondingly designated Methenamine As a result of the above favorable properties of hip hippurate hereinafter. Methenamine is a monacid base puric acid, oral administration thereof produces and and accordingly unites with an equimolecular quantity of maintains an acid reaction in the urine. This is demon the monobasic hippuric acid to form the new compound 45 strated by the data of the following table showing typical of this invention. results obtained by oral administration of hippuric acid Methenamine is a well known, safe and effective uri to a human subject: nary antiseptic. (See, for example, The Dispensatory of the United States of America, 25th edition, page 844.) Daily Dose The antiseptic properties of Methenamine are due to the 50 Hippuric pH of Urine formaldehyde formed as a result of the hydrolysis of Acid, Grams

Methenamine in acid medium, specifically at a pH below 6.0. At a pH of 6.0 or above, and particularly in an O 6 alkaline medium, Methenamine is completely devoid of 16 antiseptic action. 8 8 While normal urine is usually very slightly acidic, urine 12 generally exhibits an alkaline reaction when an infection 2 2 of the urinary tract exists. This is due primarily to bac O terial decomposition of urea and other nitrogenous elimi O 0. nation products with the production of ammonia. Obvi 0 ously then, more frequently than not pathogenic condi O tions which require the beneficial antiseptic action of Methenamine for their amelioration produce an environ It will be noted that prior to the start of the experiment, ment in which Methenamine is incapable of exhibiting an the subject had urine exhibiting a typical very slightly antiseptic action. Also, it is to be noted that the hy drolysis of Methenamine produces ammonia and accord 65 acid reaction. Soon after the initiation of the oral ad ingly, aside from any other considerations, hydrolysis of ministration of hippuric acid (in divided doses) at a rate Methenamine tends to produce an environment that re of 8 to 16 grams per day the urine became distinctly acid tards and finally prevents further hydrolysis of Methen (pH 5.2-5.3) and remained so throughout the period of 81, administration of the hippuric acid. Soon after termina 70 tion of oral administration of hippuric acid the reaction Many attempts have been made to eliminate the above of the urine returned to the original just barely acidic described limitation of Methenamine as a urinary anti condition. 3,004,026 3 4 The Methenamine hippurate of this invention acts simi I claim: larly with respect to its effect on urine pH and because of Hexamethylenetetramine hippurate. the acid environment resulting, the Methenamine portion of the compound exhibits its beneficial antiseptic action. References Cited in the file of this patent Thus, administration of Methenamine hippurate at a rate of 5 g. per day is well tolerated and no toxic effects are 5 UNITED STATES PATENTS observed. The pH of the urine is brought to below 6.0 2,449,040 Schideler et al. ------Sept. 7, 1948 and the Methenamine portion of the compound produces 2,764,581 Scholz et al. ------Sept. 25, 1956 a strongly bactericidal effect. OTHER REFERENCES Be it remembered, that while this invention has been O described in connection with specific details and specific Sidgwick: Organic Chemistry of Nitrogen, page 42, embodiments thereof, these details and embodiments are Oxford University Press, 1937. illustrative only and are not to be considered limitations Chemical Abstracts, vol. 49, col. 16,002 (1955). on the spirit and scope of said invention except insofar Smolin et al.:"s-Triazines and Derivatives," page 551, as these may be incorporated in the appended claim. 15 Interscience Publishers Inc., February 1959.