Sovember 1969
1103
SOTES
azinecarboxamide (IV). Oxidation of IV with H202 gave the 5-mesyl derivative V, which is then easily converted to VIa by treatment with KH3. The 5methylamino compound VIb was also prepared in this manner.
IV
-
c1y~yCONHCONH, I
NH,R
II
CI,fKCONHCOIH2
RHN
"
NHL
VIa, R = H b. R = CHJ
Pharma~ology.-~411 of these compounds were tested for diuretic activity in both normal rats and hydrated
dogs. The normal rats and hydrated dogs were given several doses according to the procedures of Cummings, et uL.,'O and Little and Cooper,'l respectively. Compounds IIa-f and VIa,b were found to be active in the rat. They increased the total urine volume and enhanced the excretion of N a + and C1-. However, only one of the compounds, IIa, showed antikaliuretic activity. When coadministered with quinethazone, N-carbamoyl-3-aminopyrazinecarboxamide (114 showed a slight potentiation of the quinethazoneinduced natriuresis. All of the compounds were tested in the dog and found to be inactive. I I a a t low doses in combination with quinethazone again showed a natriuretic effect, but it was too small to be significant. Experimental Sectionlz
TABLE I YIELDS,PHYSICAL, AND AXALYTICAL DATA Yield,
KO.
%
hlp, Recrystn "C solventa
Formula
Analyses
288* W CeH,NsOz C, H, S 240 31 CeH6CliY~j02 C, H, ?i, C1 218 11 C8HiiC1K~602 C, H, N, C1 198 ?\I CioHijCIN602 C, H, N, C1 165 31 C ~ Z H I ~ C ~ Nc, ~O H,YN, c1 148 31 CiiHnCIN602 C, H, X, C1 11 CioHisCl~sOz C, H, s,C1 191 168 31 CloHi3ClN602 C, H, X, C1 C L L H I ~ C c, ~ NH,~ 5~ ,~c1 176 22.5' 31 CiHsCIN5OpS If, IT,CI, S: 0 ;\I C7H,ClNjOiS C, H, N, C1, S v 215' T?a 260' 31 C ~ H ~ C ~ N C OC,? H, N , C1 VIb 24.ib ;\I CiHsC1N& C, H, ?;, C1 a W = HzO, 1 2 = M e O H . * Compoimd melts with decomposition. c C: calcd, 32.1; found, 32.6.
IIa IIb IIc IId IIe IIf IIg IIh IIi IT
32 16 28 29 27 16 24 36 54 27 41 X2 37
analytical sample was prepared by crystallizing the product from AIeOH. N-Carbamoyl-3-amino-5-methylmercapto-6-ch~oropyrazinecarboxamide (IV).-To 15 ml of dry D N F was added 0.3 g (0,005 mole) of iirea. To the stirred solritioii cooled t o - 15' was added 0.25 g (0.005 mole) of KaH (50qG in oil). Thiq ~ v a aleft. to stir for 1 hr. To the cooled mixtiire was added 1.0 g (0.004 mole) of methyl 3-amino-5-methylmercapto-6-chlorop~t~azinecarboxylate and stirring continried an additional 2 hi. The reaction mixture was then poured onto 15 g of ice-HpO made slightly acidic with ilcOH. il yellon- solid precipitated from roliitioii was filtered and washed with HpO to give 0.7 g of crude product. Crystallization from MeOH gave 0.3 g (27%) of product, mp 225' dec, A":, 5.77 and 5.93 p. N-Carbamoyl-3-amino-5-mesyl-6-chloropyrazinecarboxamide (V):-A suspension of 1.0 g (0.004 mole) of iY-carbamoyl-3am1no-5-methylmercapto-6-chloropyrazine~arboxamide (11') i n 40 ml of AcOH and 10 ml of 30% aqiieoii* H?Op T T ~ Sstirred at room temperatiire. After 110 hr an additional 3 ml of 3 0 5 H20B was added and stirring was continued for a total of 168 hr. The yellow solid which precipitated was removed by filtration and washed with EtOAc to give a total critde yield of 0.63 g. Recrystallization from AIeOH yielded 0.45 g (41Yc) of prodiict: 5.80, 5.88, and 5.97 p. mp 21.5" dec;: : A: N-Carbamoyl-3,5-diamino-6-chloropyrazinecarboxamide (VIa). -A siispension of 0.42 g (0.0014 mole) of IT-carbamoyl-3-amino5-mesyl-6-chloropyrazinecarboxamide (V) in 2 ml of i-PrOH was stirred while 0.14 g of NHI in 4 ml of i-PrOH was added and the mixtiire was refluxed for 1 hr. The soliition ITas cooled in an ice bath and the yellow product that separated was removed by filtrat,ion. Crystallization from 3IeOH yielded 0.27 g ( 8 2 5 ) , mp 260" dec,: : A: 5.84 and 6.01 p.
Methyl 3-aminopyrazinecarboxylate (Ia) was prepared from 3-aminopyrazine-2-carboxylic acid by the method of Ellingson, Henry, and McDonald.1a Substituted methyl 3-aminopyrazinecarboxylates (Ib-i, 111) were prepared following the procedure of Cragoe, et al.1 General Procedure for the Substituted N-Carbamoylpyrazinecarboxamides (IIa-i).-To 15 ml of dry D M F was added 0.9 g (0.015 mole) of urea. To the stirred solution cooled to -15' was added 0.7 g (0.015 mole) of iYaH (50y0 in oil). The mixture was left to stir for 1 hr. To the cooled mixture was then added 0.004 mole of the methyl substituted 3-aminopyrazinecarboxylate. This was left to stir for 2 hr. The reaction mixture was then poured onto 25 g of ice-HpO made slightly acidic with AcOH. The mixture was stripped t o dryness and HzO was added to precipitate the crude product. The solid was then dissolved in hot 3 N HCl, filtered, and precipitated with dilute NaOH. An
Acknowledgments.--We n-ish to t'hank Drs. ,J. R. Cummings and R. Z. Gussin and associates for the pharmacological dat'a.
(10) J. R.Cummings. J. D. Haynes, L. M. Lipchuck, and M. A. Romberg, J . Pharmacol. E z p . Ther., 128, 414 (1960). (11) J. M. Little and C. Cooper, Jr., Fed. Proc., 9,296 (1950). (12) Yields, physical data, and analyses are listed in Table I. Melting points were taken on a hlel-Temp apparatus and are uncorrected. Microanalyses were performed by Mr. L. Bf. Brancone and staff, where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within f0.47, of the theoretical values. (13) R. Ellingson, R . L. Henry, a n d F . G. McDonald, J . Am. Chem. Soc.. 6 1 , 1712 (1945).
Receizied June 12, 1969
Potential Antiparkinsonism Agents. Quinuclidinyl Benzhydryl Ethers J. LARSG. SILSSOS, JORGEN W.~GERMARK, A N D RICHARD DAHLBOM Department of Organic Chemistry, Faculty of Phawnacy, Box 6804, 113 86 Stockholm, Sweden
As part, of our current study of quinuclidine derivatives of potential pharmacological value,' we have (1) (a) J. L. G. Nilsson, J. Wigerrnark. R. Dahlhom, and W. XI. Benson, Acta Pharm. Suecica, 5 , 9 (1968); (b) J. L. G. Silsson, J. Wigerrnark, and R. Dahlbom, ibid., 5, 71 (1968); (c) R. Dahlbom and J. Dolhy, ibid.. 6,277 (1969).
