Compounds V and VI1 were similarly injected daily in doses of 1.4 pmoles, L e . , a t 200 times the thyroxine level. The results of the ass:iy, listed in Table 11, fail to shoq- any thpromimetic or :uitithyroid rfl'cv;t. of conipoiiiids IT xiid T'II. Conipi~iiiid TI was foiind iiiactivr a i 1000 t i m e s the thgroxilir dorr iii a previous experiment.
Many biguanides display the ability to lower the blood-sugar levels of animals.' In this communication we describc the syntheqis of two phosphinylguanidines of t,ypr 1. Thcse compounds rrprrsent examples of a
(rIT i( r
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The compoiind was converted to the picrate, yellow needles, mp 207-208" (from ethanol). Anal. Calcd for CllHI9X8O8P:C, 31.28; If, 4.50; N, 26.54; l', 7.35. Foiiiicl: C, 31.43: 11, 4.55: N, Z . ! I ! ) ; l', 7.21. 2- jBis(dimethylamino)phosphinyl]-1,1,3,3-tetramethyIguanidine.-With stirring, 12.0 g (0.1 mole) of l,l,:~,3-tetraniet,hylguaiiidiiie and 8.5 g (0.05 Inole) of N,N'-bisdiniethylpliosphorodiamidic chloride were mixed. After the exothermic reaction subsided, the mixture was heated on a steam bath for 30 min iinder nitrogen. The mixture was taken up in ether and filtered, and the filtrate was concentrated under reduced pressure to n liclriid containiiig some solid. After filtration, t,he material was distilled t o give -5.8g of colorless liquid, bp 130-135' (0.6 mm). 1:edistillatioli gave 3.9 g (3lCG)of colorless liqiiid: hp 12:;-12G0 (0.3 mm); infrared (CIlC13), strong bands a t 8.6 (1'=0) n i i t l 1 0 . l p (PN).5 Anal. Calcd for CpHJTjOP: C, 43.37; H,9.63; N, 28.11; P, 12.44. Found: C, 42.98; H,9.7'5; N, 27.21; P, 12.48. The compound was converted to the picrate, yellow prisms, mp 168-16s" (from ethanol). Anal. Calcd for CI5H2,N8O8P:C, 37.66; H, 5.65; N, 23.4;3: P, 6.49. Foiind: C, 38.00; IT, 5.61; S, 23.37: P, 6.73.
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Salts of a-Amino-p-toluenesulfonamide
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novel system in which one of the carbon atoms of a higuanide skeleton has been replaced with a P=O unit. The reactions of commercially available K,X'-bisdimethylphosphorodiamidic chloride (2) with guanidine2 and 1,1,3,3-tetramethylguanidinegave 2- [bis(dimethylamino)phosphiriyl]guanidine (1, R = H) and 2-[bis(dimethylamino)phosphinyl]-l,l,3,3-tetramethylguanidine (1, R = CH,), respectively. The phosphiny lguanidines 1 were administered as suspensions in 0.5% sodium carboxymethylcellulose solution orally a t 230 mg/kg to normal chicks and intraperitoneally at 200 mg/kg to normal rats. Blood glucose levels, estimated as "reducing sugar'' content by the method of Hoffman as modified for the Technicon hutoA n a l y ~ e rwere , ~ riot depressed significantly below controls when determined at 2 hr after dosing for chicks arid 3 hr after dosing for rats. Experimental Section4
2-[Bis(dimethylaminojphosphinyl]guanidine.-To 5.5 g (0.094 mole) of giianidinez was added dropwise with stirring and icebath cooling diiring 1.5 min 8.2 g (0.048 mole) of ru',N'-bisdimethylphosphorodiamidic rhloride. The mixture was allowed to stand for 16 hr at room temperatiire, taken up in hot acetonitrile, arid filtered. Upon cooling, a solid, 1.6 g, mp 170-180", separated from the filtrate and was collected. Recrystallization from acetonitrile gave 1.0 g illc:) of colorless needles: mp 179-182" clec; infrared (KBr disk), Ytrong bands at 2.9 ( S H ) , 8.8 (P=O), niid 10.1 p (PX j.5 Anal. Calcd for C3HlaN50P: C, 31.09; H, 8.29; N, 36.27. Foririd: C, 30.3.5; H, 8.07: S , 36.43. (1) Salts of ptienetliylbiguanide, 1,l-dimethylbiguanide, and n-butylhiguanide are utilized in t h e clinical control of diabetes: L . J. P. Duncan and B. F, Clarke, A n n . Rec. Pharmacol., 6 , 151 (1965). ( 2 ) \V. Marckwald and F. Struwe, Ber., 55, 458 (1922). (3) I T - , S. Hoffman, J . B i d . Chem., 120, 51 (1937). T h e animal testing was carried out by Drs. C . Roshart, S.Gordon, and E. T O C Wof these laboratories. (4) Melting points were determined in a Hershberg apparatus and are unrorrected. llicroanalyses were performed by Mr. L. RI. Rrancone and staff. (A) N . 13. Coltliup, L. H. Daly, a n d S. E. Wiherly, "Introduction t o Infrarecl anll Ramnn ~ p ~ r t r ~ i ~ ~.\radernic ~ i i ~ y ,Press " Tnc., N e w York, N . Y., 1964, 1 ) 4~1.5,
a-Arnino-p-t,oluenesulfonamidel has been in the armamentarium of the physician as a broad-spectrum antibacterial agent for almost a quarter century. It was synthesized and described by Klarer2g3and its outstanding therapeutic properties were first reported by Domagk4 and summarized by N ~ r t h e y . ~ Recently, it was found that this sulfonamide hydrochloride was a useful topical agent in burn wound sepsome patients, particularly those who s i ~ . ~ , Homever, 7 mere treated with large quantities of this drug, developed metabolic acidosis. I n order to overcome this side effect' we have prepared a series of new organic salts (Table I). The chemical isolation of the acetate, the salt of choice, now undergoing clinical trials, has not been report'ed in the literature, and it was only alluded to as a potent'ially useful compound.*r9 Its use for the treatment of burns, in a hydrophillic ointment' base, has successfully overcome the problem of met'abolic acidoSlS.
Skulan and Hoppe'O infused 0.5 14 aqueous solutions of the hydrochloride and acetate salts in t'he marginal ear veins of unanesthet'ized nonfasted male rabbits. The hydrochloride produced a marked progressive fall in blood p H and plasma total COz concentration, (1) Also known a s a-aminomethylbenzenesulfonamide, homosulfanilamide, SulfamylonE, marfanil, mafenide, etc. (2) J. Klarer, Klin. Vochschr., 20, 1250 (1941). (3) J. Klarer, U. 9. P a t e n t 2,288,531 (1942). (4) G. Domagk, Klin. Wochschr., 21, 448 (1942). (5) E. H. Northey, "The Sulfonamides a n d Allied Compounds," Reinhold Publishing Corp., New York, N. Y., 1948, p 252. (6) R. €3. Lindberg, R . E. Brame, J. A . Moncrief, and A . D. Mason, Federation Proc., 23, 1725 (1964). (7) R. B. Lindberg, J. 4 . Moncrief, \V. E. Switzer. S. E. Order, and IT-. hliller, J. Trauma, 6, 601 (1965). (8) J. -4.Mendelson a n d F. B. Brinkley, U. S.Patent 3,230.140 (1966). (9) J. A. Moncrief, R . B. Lindberg, TV. E. Switeer, and A. Prrlitt, .Ir%, d r c h . SurQ., 92, 558 (1966). (IO) T. W ,Skiilnn n.nd .I. 0 , JToppe, Life S r i . , in press.
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