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United States Patent (19) 11 Patent Number: 4,663,322 Beyer, Jr

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United States Patent (19) 11 Patent Number: 4,663,322 Beyer, Jr United States Patent (19) 11 Patent Number: 4,663,322 Beyer, Jr. 45 Date of Patent: May 5, 1987 54 ANTIHYPERTENSIVE HYPERURETIC AND Sweet, C., et al., Clin. Sci, Mol. Med., 48: 147-151, 1975. SAILURETICAGENT COMBINATIONS Amery, A., et al., New Eng, J. Med., 295: 1198-1199, 76 Inventor: Karl H. Beyer, Jr., P.O. Box 387, 1976. Penllyn, Pa. 19422 Morrison, R., et al., Organic Chemistry, 3rd Ed., Allyn and Bacon, Boston, 1973, p. 817. (21) Appl. No.: 792,236 Chemical Abstracts, 82:80803v (1975) Mendelzon, J., et 22 Filed: Oct. 29, 1985 al., Rev. Argent. Cardiol., 1974, 42(4), 278, 280, 282,284, 289-90). Chemical Abstracts, 88:45134e (1978) Schena, F., et al., Related U.S. Application Data Clin. Ter, 1977, 82(5), 489-94). 63 Continuation of Ser. No. 336,736, Jan. 4, 1982, aban Chemical Abstracts, 85:177484s (1976). Kubo, K., et al., doned. Japan, Kokai 76 52,185, 5/8/76). 51 Int. Cl..................... A61K 31/54; A61K 31/495 Benos, D., et al., J. Gen. Physiol, 68(1): 43-63 (1976). 52 U.S. C. ..................................... 514/222; 514/255 Primary Examiner-Richard A. Schwartz 58 Field of Search ................................ 514/255, 222 Attorney, Agent, or Firm-Oblon, Fisher, Spivak, (56) References Cited McClelland & Maier U.S. PATENT DOCUMENTS 57 ABSTRACT 3,313,813 4/1967 Cragoe ................................ 544/.407 Hyperuretic agents of the formula: 3,345,372 10/1967 Hanifin et al................... 544/407 X OTHER PUBLICATIONS R? N Rl (I.) Physicians' Desk Reference, 40th Ed., 1986, pp. 199-1200. y Beyer, K., et al., Pharmacol. Rey, 34: 287-313, 1983. 3 N I R Saito, I, et al., Cardiovasc. Res., 10:149-152, 1976. R N C Beyer, K., Clin. Therap, 1: 425-443, 1978. Zanchetti, A., et al., Am. J. Cardiol, 37: 675-691, 1976. Singh, B., et al., Brit. Med. J., 1: 143-146, 1967. wherein Gombos, E., et al., New Eng. J. Med., 275: 1215-1220, Y is O or NH; 1966. R is OH; NHCONR4R5; or N-C(NR4R5); Kampffmeyer, H., et al., Clin. Pharmacol. Therap, 9: R1 and R2 are hydrogen, amino, or mono- or disubsti 350-354, 1968. tuted amino, provided that Rand R2 may not both be McCaa, R., et al., Adv. Exp. Med. Biol, 130: 227-255, amino or substituted amino; and 1980. R3 is hydrogen or halo; Weber, M., et al., Arch. Int. Med., 137:284-289, 1977. in combination with saluretic agents such as hydrochlo Vaughan, E., et al., Circ. Res., 42: 376-381, 1978. rothiazide; are useful for treating hypertension. Esler, M., et al., Am. J. Cardiol, 36: 708-715, 1975. Morganti, A., et al., Am. J. Cardiol, 43: 600-604, 1979. 16 Claims, No Drawings 4,663,322 1 2 actively secreting and reabsorbing urea in addition to ANTIHYPERTENSIVE HYPERURETIC AND being filtered at the glomeruli and undergoing passive SAILURETICAGENT COMBINATIONS back diffusion. Moreover, it has been discovered that the pyrazinoic This application is a continuation of application Ser. 5 acid derivatives utilized in the present invention are No. 336,736 filed Jan. 4, 1982, now abandoned. capable of inhibiting the active renal tubular reabsorp tion of urea, predominantly; whereas other pyrazinoic BACKGROUND OF THE INVENTION 1. Field of acid derivatives such as the fluoro analog of amiloride the Invention inhibit preponderantly active tubular secretion of urea The present invention is concerned with the combi- 10 without significantly inhibiting active reabsorption of nation of certain pyrazinoic acid derivatives useful as urea. In so doing they lower urea blood levels and in hyperuretic agents and various sailuretic agents; and crease the osmotic concentration of urine as indications with pharmaceutical compositions and methods of of their capability of influencing osmotically modulated treating hypertension in which the active ingredient functions of cells and cell membranes. These may thus employed is a combination of one of said pyrazinoic 15 be called osmoregulatory agents to identify their role in acid derivatives and a saluretic agent. therapy. Combined with various saluretic agents, their In mammals, including man, urea is the principal end usefulness is considered to extend from the management product of nitrogen metabolism. Urea is synthesized in of mild hypertension and pulmonary edema to the neu the body through the intermediation of the ornithine rological symptomatology of malignant or severe hy urea cycle as from the more toxic ammonia and carbon 20 pertension. dioxide. Some twenty-five grams of urea are synthe 2. Brief Description of the Prior Art sized in the human body per day and excreted primarily Cragoe U.S. Pat. No. 3,313,813 describes 3-amino by way of the kidneys. 5,6-disubstituted-pyrazinoyl guanidines and their use as Urea and sodium (chloride) constitute the principal diuretic, natriuretic agents which selectively enhance osmotically active constituents of the body. Whereas 25 the excretion of sodium ions without causing an in this osmotic role is similar for the two, urea and salt, crease in excretion of potassium ions. they differ in important respects. Sodium chloride must Benos et al. in J. Gen. Physiol. 68(1): 43-63 (1976) be obtained from some exogenous source, and the distri describe the effect of amiloride and some of its analogs bution of sodium is essentially limited to extracellular on cation transport in isolated frog skin and thin lipid fluid, including plasma water. Urea is synthetized by the 30 membranes. body in large amounts, and its distribution is both intra However, none of the above references in any way cellular and extracellular-being equivalent to total suggests the use of the particular pyrazinoic body water. (Potassium serves the intracellular osmotic acid derivative hyperuretic agents utilized in the pres role assumed by sodium extracellularly.) ent invention for treating hypertension, eclampsia, ure When excess sodium is consumed, or retained by less 35 mia, and the like, since these references fail to suggest than adequate renal function, iso-osmotic pressure is the hyperuretic activity of said pyrazinoic acid deriva sustained by thirst-stimulated increased fluid consump tion and by fluid retention which may lead to increased tives, and since said derivatives do not have sufficient blood pressure and/or edema. saluretic and antikaluretic activity to be useful in accor In the presence of impaired renal function sufficient 40 dance with the requirements described in said refer to reduce urea excretion, its accumulation may be eCeS, enough to cause increased intracellular as well as extra DETAILED DESCRIPTION OF THE cellular fluid accumulation, if iso-osmotic relationships INVENTION AND PREFERRED are sustained by fluid accumulation. In severe circum EMBODIMENTS stance, uremia may result. It is this intracellular/ex- 45 tracellular accumulation of fluid that is most likely to In accordance with the present invention there is account for the symptomatology as well as the signs of provided a pharmaceutical composition for treating uremia. At sub-uremic elevations of urea and body hypertension and edema comprising a pharmaceutically water levels the symptomatology may well be confused acceptable carrier and a therapeutically effective with salt retention, in which case therapy based on 50 amount of the combination of saluresis or hyperuresis may be used interchangea (a) a compound of the formula: bly-to some extent. (I.) The present state of clinical knowledge recognizes R2 N R that urea is filtered with plasma water at the glomeruli of the kidney and that a portion of that filtered urea 55 y undergoes passive back diffusion in the course of urine 3 N I R formation by the nephron. The passive back diffusion of R N C urea can be reduced by increasing the transit rate, i.e., increasing the urine flow. wherein Increased transit rate can be induced (1) by expand- 60 Y is O or NH, ing body fluid volume, which is self-defeating from a R is OH; NHCONR4R5; or N=C(NR4R5); where therapeutic standpoint; (2) with the aid of an osmotic R* and R5 are each independently selected from the diuretic, e.g., mannitol, which is impractical because of group consisting of hydrogen; C1-10 alkyl, straight or the need to administer large amounts parenterally, or (3) branched chain; aryl C1-4 alkyl; mono- or disubstituted temporarily, by the use of potent saluretic agents at 65 aryl C1-4 alkyl where the substituents are fluoro, chloro, dosages sufficient to alter electrolyte balance. bromo, iodo, or C1-10 alkyl, straight or branched chain; In accordance with the present invention, it has been R and R2 are each independently selected from the discovered that the mammalian kidney is capable of group consisting of hydrogen, amino, and mono- or 4,663,322 3 4. disubstituted amino where the substituents are C-10 consisting of sweetening agents, flavoring agents, color alkyl, straight or branched chain, or C3-8 cycloalkyl; ing agents and preserving agents in order to provide a provided that R1 and R2 may not both be amino or pharmaceutically elegant and palatable preparation. substituted amino; and Tablets contain the active ingredient in admixture with Riis hydrogen; fluoro; chloro; bromo; or iodo; and a non-toxic pharmaceutically acceptable excipients pharmaceutically acceptable salt thereof; and which are suitable for manufacture of tablets. These (b) a saluretic agent selected from the group consist excipients may be, for example, inert diluents, such as ing essentially of ethacrynic acid; furosemide; bumeta calcium carbonate, sodium carbonate, lactose, calcium nide; muzolimine; benzothiadiazines including chloro phosphate or sodium phosphate; granulating and disin thiazide and hydrochlorothiazide; chlorothalidone; 10 tegrating agents, for example maize starch, or alginic quinethazone; metholazone; indacrinone; acetazolam acid; binding agents, for example starch, gelatin or aca ide; ethoxyzolamide; and methazolamide. cia, and lubricating agents, for example magnesium Preferred combinations of the present invention are Stearate, stearic acid or talc.
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