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).
I IO4
I
I
:!(I
I t I \ cl\rld(>tlt troiii l':ible 11 th:it 1 3 have p I ' ~ ) ! l ~ ) \ i t i c d ceritr:rl and peripheral tirlticholiIiergic activity. I f t h c ratio between the mpdriat,ic and tremorolytic dobes i s titken a h 2% measure of t hc>\electivit,y of the compoundi for the C S S , it can be concluded that they are some\\ hat more iclectivc than atropine in this reipect The drop i i i mydriatic potency and loss of tremorolyt,ic effect of 4 arid 5 15 tiote\\-orthy, but the experimental cvidence :ivailnblc I < too \cant\- to permit any conclu.ioii> t o be drav t i :is to the cauie of this.. C'ompoundi 1 3 :ilzo dizplay *trong anticholiriergtc ,ictivity when irstcd on t h c isolated guinea pig ileum. 1 7 ) [a)> l\irdling, 4 c t r ~ ~ h r ~ r w i i I~o +o zl i o l , 8 , 11: 1 1 9 5 2 ) 1131 3 \\led liny i h z d 9, 75 (19511
XOTES
November 1969 Experimental Section AIclting points were determined wit,h an electrically heated ineta1 block, using calibrat,ed Anschuta t,hermometers. Microanalyses were performed by Dr. A. Bernhardt, Mulheim, West Germany. I r spectra were determined on a Perkin-Elmer spectrophotometer Model 337 in KBr. 2-Methylbenzhydr01,~2-ahlorobenzhydr01,~ 4-chlorobenxhydr01,g and 2,2'-dimet,hvlbenxhydro11a were prepared as described in the literature. Preparation of quinuclidiilyl ethers was accomplished as illustrated for 3-quinuclidinyl benzhydryl ether (1). Benzhydrol (7.4 g, 0.04 mole) and 3-quinuclidinol (5.6 g, 0.044 mole) iyere thororighly mixed arid heated to 70' to form a homogenoiib melt. p-Toluenesiilfonic acid (8.75 g, 0.046 mole) was added and the flask was evaciiated. This caused H20to evaporate from the mixtiire, and the melt solidified. The temperature was then raised to 140' when the solid melted, and the evacuat>edflask was kept at, this temperature for 3 hr. After cooling, the solid material was dissolved in 5 S NaOH mid extracted with EttO. The extract was washed with H,O and dried (NaZS04) and the hydrochloride precipitated wit,h dry HC1. Recrystallization from EtOH-Et20 afforded 8.3 g (69Tc) of 1, mp 194-1955'. The X e I derivative (6)was obtained when a solution of the base 1 and 1 eqiiiv of M e 1 in dry MezCO was allowed to st,and at room temperature for 24 hr. The quakrnary salt precipitated in an analytically piire stat,e, mp 193-194'. Recrystallizat,ion from EtOH-Et,O did not raise the melting point.
1103
tion of the Scherrer method to the synthesis of meso3 ,+his (4-aminophenyl) hexane (I I) from n?eso-hexestrol (1) require(] forcing wnditions in order to ensure hi+ arylation of (I). The meso-hexestrol (I) was condensed with 2 moles of 4-chloro-2-phenylq~inazoline~ in DMSO using KO-t-Ru as the condensing agent. The X,4hiii [4-(2-phenyl-4-quinazolinyloxyphcnyl) ]hexane (VI thus formed, was heated at 3x0" to yield 3,4-bir[3-(4oxo-2-phenyl-3 (4H)-quinazolinylphenyl) ]hexane (VI). This material was hydrolyzed in ethanolic SaOH to give 11.; Amines I1 and J711gave the respective methane and butanesulfonamides 111, IT, VIII, arid IX. SaBH4 reduction of 3-methanesulfonamidoestra-l.~3,.i(lO)-trien-l'l-one (VIII) gave the estradiol analog. 3met hanesulfonamidoe5t ra- 1,X,5 (10)-trien- 176-01 (X).
H
CH,
Acknowledgments.-The authors are indebted to Xstra Pharmaceutical Products, Worcester, Mass., and AB Astra, Sodertalje, Sweden, for carrying out t'he pharmacological tests.
I.X=OH
11, X = NH2 111, X = CH3S02NH IV, X = n-C,H,SO,NH
(8) J. H . Lamneck. Jr.. and P. H. \Vise, N a t l . Advisory Comm. Aeron., Tech. S o t e 2330, 15 (1950); Chem. Ahstr., 46, 6609k (1951). (Y) A . E . Chichibahin and A. A. Shesler, J . Russ. Phys. Chem. Soc.. 66, 149 (192,;): Chem. Abstr.. 19, 3269 (1925). (10) Ll. R . Boyd and H . H. Hatt, J . Chem. SOC.,898 (1927).
Alkylsulfonamido Estrogens nOL6L\S J O i l I"
L.
~ ~ I h O L I S I , K1,) U k N E G. GILLO, ?\IIhII LLI, G O K D O It.~ MCKIKNFY, \>I) A A L ~ R S E N
Jleud Johnson Research Cider, Mead Johnson ELanszille, Indzana 47721
R-
0
Cornpanu,
R c c e i d March 17, 1969
Recent papers from these laboratories have described the novel bioisosteric relationship between the methanesulfonamido group and the phenolic hydroxyl group in a phenethanolamine series.' As a logical extension of this work, we have attempted to determine whether this bioisosteric relationship could be projected to other compounds of biological interest possessing a phenolic hydroxyl group. The application of this bioisosteric relationship to steroidal and nonsteroidal estrogens was of special interest because of the potential usefulness of these compounds as antiuterotropic and/or antifertility agents.? The amines and diamines used as starting materials were prepared according to the general method of Scherrer for conversion of phenols to a n i l i n e ~ .Applica~ (1) (a) .I. h. Larsen and P.>I. Lish, .Vature. 103, 1283 (1964): (h) R . H . Uloth. J. R . Klrk, K.-1 Gould, and .i. A. Larsen, J . .Wed. Chem.. 9 , 88 (1966); (0) A . A. Larsen. N'. A. Gould. H . R . Roth, W.T. Comer, R . H . Uloth, K . W.Dungan, and P XI. Lish. T h t d . , 10, 462 (1907). (2) C. W. Emmons, J . R e p r o d . Fertilzty, 9 , 227 (1965); (h) D. J Collins and J. J. Hobhs. Aust. J . Chem., 110, 1413 (1967). (3) R . A . Scherrer, Abstracts of Papers, 145th National Meeting of the American Chemical Society, New York, E.Y . , Sept 1963, p 334.
VI
VII, R = NH2 VIII, R = CH3S02NH IX, R = C4H9SO2NH
"U
CA I T
X
These alkylsulfonamido analogs were tested in our laboratories for one or more of the following three types of biological activity, uterotropic,6 antiuter~tropic,~ and (4) A l . hI. Endicott, E . Wick. AI. L. Mercury, and h l . L. Sherrill, J . A m . Chem. S o c . , 68, 1299 (1946). ( 5 ) B . R . Raker, ihid., 66, 1672 (1943); (h) G. Fodor and J. Wein. J . Chem. Soc.. 684 (1948). report mp 80° for the racemic diamine. (6) B. L. Ruhin. A. S. Dorfman, L. Black, and R . I . Dorfman, Endocrinology. 49, 429 (1951). ( 7 ) R . I . Dorfman and F. A. Kinel, Steroids, 1, 185 (1903).
