Sovember 1969 SOTES 1103

azinecarboxamide (IV). Oxidation of IV with H202 TABLE I

gave the 5-mesyl derivative V, which is then easily YIELDS,PHYSICAL, DATA
AND AXALYTICAL
converted to VIa by treatment with KH3. The 5- Yield, hlp, Recrystn
methylamino compound VIb was also prepared in this KO. % "C solventa Formula Analyses

manner. IIa 32 288* W CeH,NsOz C, H, S

IIb 16 240 31 CeH6CliY~j02 C, H, ?i, C1
IIc 28 218 11 C8HiiC1K~602 C, H, N, C1
IId 29 198 ?\I CioHijCIN602 C, H, N, C1
IIe 27 165 31 C ~ Z H I ~ C ~ Nc, ~O H,YN, c1
IIf 16 148 31 CiiHnCIN602 C, H, X, C1
IIg 24 191 11 CioHisCl~sOz C, H, s,C1
IIh 36 168 31 CloHi3ClN602 C, H, X, C1
IIi 54 176 C L L H I ~ C c, ~ NH,~ 5~ ,~c1
IT 27 22.5' 31 CiHsCIN5OpS If, IT,CI, S: 0
v 41 215' ;\I C7H,ClNjOiS C, H, N, C1, S
IV T?a X2 260' 31 C ~ H ~ C ~ N C OC,? H, N , C1
c1y~yCONHCONH,
I II -NH,R
VIb 37 24.ib ;\I CiHsC1N& C, H, ?;, C1
a W = HzO, 1 2 = M e O H . * Compoimd melts with decomposi-
tion. c C: calcd, 32.1; found, 32.6.
analytical sample was prepared by crystallizing the product from
AIeOH.
CI,fKCONHCOIH2 N-Carbamoyl-3-amino-5-methylmercapto-6-ch~oropyrazine-
carboxamide (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
RHN " NHL 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
VIa, R = H
mole) of methyl 3-amino-5-methylmercapto-6-chlorop~t~azine-
b. R = CHJ carboxylate and stirring continried an additional 2 hi. The re-
action mixture was then poured onto 15 g of ice-HpO made slightly
Pharma~ology.-~411 of these compounds were tested acidic with ilcOH. il yellon- solid precipitated from roliitioii was
for diuretic activity in both normal rats and hydrated filtered and washed with HpO to give 0.7 g of crude product.
dogs. The normal rats and hydrated dogs were given Crystallization from MeOH gave 0.3 g (27%) of product, mp
several doses according to the procedures of Cummings, 225' dec, A":, 5.77 and 5.93 p.
N-Carbamoyl-3-amino-5-mesyl-6-chloropyrazinecarboxamide
et uL.,'O and Little and Cooper,'l respectively. Com- (V):-A suspension of 1.0 g (0.004 mole) of iY-carbamoyl-3-
pounds IIa-f and VIa,b were found to be active in the am1no-5-methylmercapto-6-chloropyrazine~arboxamide (11') i n
rat. They increased the total urine volume and en- 40 ml of AcOH and 10 ml of 30% aqiieoii* H?Op T T ~ Sstirred at
hanced the excretion of N a + and C1-. However, only room temperatiire. After 110 hr an additional 3 ml of 3 0 5 H20B
one of the compounds, IIa, showed antikaliuretic was added and stirring was continued for a total of 168 hr. The
yellow solid which precipitated was removed by filtration and
activity. When coadministered with quinethazone, washed with EtOAc to give a total critde yield of 0.63 g. Re-
N-carbamoyl-3-aminopyrazinecarboxamide (114 crystallization from AIeOH yielded 0.45 g (41Yc) of prodiict:
showed a slight potentiation of the quinethazone- mp 21.5" dec;: : A: 5.80, 5.88, and 5.97 p.
induced natriuresis. All of the compounds were tested N-Carbamoyl-3,5-diamino-6-chloropyrazinecarboxamide (VIa).
in the dog and found to be inactive. I I a a t low doses -A siispension of 0.42 g (0.0014 mole) of IT-carbamoyl-3-amino-
5-mesyl-6-chloropyrazinecarboxamide (V) in 2 ml of i-PrOH was
in combination with quinethazone again showed a stirred while 0.14 g of NHI in 4 ml of i-PrOH was added and the
natriuretic effect, but it was too small to be significant. 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
Experimental Sectionlz 260" dec,: : A: 5.84 and 6.01 p.
Methyl 3-aminopyrazinecarboxylate (Ia) was prepared from Acknowledgments.--We n-ish to t'hank Drs. ,J. R.
3-aminopyrazine-2-carboxylic acid by the method of Ellingson,
Henry, and McDonald.1a Cummings and R. Z. Gussin and associates for the
Substituted methyl 3-aminopyrazinecarboxylates (Ib-i, 111) pharmacological dat'a.
were prepared following the procedure of Cragoe, et al.1
General Procedure for the Substituted N-Carbamoylpyrazine-
carboxamides (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 Potential Antiparkinsonism Agents.
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 Quinuclidinyl Benzhydryl Ethers
mole of the methyl substituted 3-aminopyrazinecarboxylate.
This was left to stir for 2 hr. The reaction mixture was then J. LARSG. SILSSOS,JORGENW.~GERMARK,
poured onto 25 g of ice-HpO made slightly acidic with AcOH. A N D RICHARDDAHLBOM
The mixture was stripped t o dryness and HzO was added to
precipitate the crude product. The solid was then dissolved in Department of Organic Chemistry, Faculty of Phawnacy,
hot 3 N HCl, filtered, and precipitated with dilute NaOH. An Box 6804, 113 86 Stockholm, Sweden
(10) J. R.Cummings. J. D. Haynes, L. M. Lipchuck, and M. A. Romberg, Receizied June 12, 1969
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 As part, of our current study of quinuclidine deriva-
points were taken on a hlel-Temp apparatus and are uncorrected. Micro- tives of potential pharmacological value,' we have
analyses were performed by Mr. L. Bf. Brancone and staff, where analyses
are indicated only by symbols of the elements, analytical results obtained (1) (a) J. L. G. Nilsson, J. Wigerrnark. R. Dahlhom, and W. XI. Benson,
for those elements were within f0.47, of the theoretical values. Acta Pharm. Suecica, 5 , 9 (1968); (b) J. L. G. Silsson, J. Wigerrnark, and
(13) R. Ellingson, R . L. Henry, a n d F . G. McDonald, J . Am. Chem. Soc.. R. Dahlbom, ibid., 5, 71 (1968); (c) R. Dahlbom and J. Dolhy, ibid.. 6,277
6 1 , 1712 (1945). (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 con-
clu.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
November 1969 XOTES 1103

Experimental Section tion of the Scherrer method to the synthesis of meso-

AIclting points were determined wit,h an electrically heated 3 ,+his (4-aminophenyl) hexane (I I) from n?eso-hexestrol
ineta1 block, using calibrat,ed Anschuta t,hermometers. Micro- (1) require(] forcing wnditions in order to ensure hi+
analyses were performed by Dr. A. Bernhardt, Mulheim, West arylation of (I). The meso-hexestrol (I) was condensed
Germany. I r spectra were determined on a Perkin-Elmer with 2 moles of 4-chloro-2-phenylq~inazoline~ in DMSO
spectrophotometer Model 337 in KBr.
2-Methylbenzhydr01,~2-ahlorobenzhydr01,~ 4-chlorobenxhy- using KO-t-Ru as the condensing agent. The X,4-
dr01,g and 2,2'-dimet,hvlbenxhydro11a were prepared as described hiii [4-(2-phenyl-4-quinazolinyloxyphcnyl) ]hexane (VI
in the literature. thus formed, was heated at 3x0" to yield 3,4-bir[3-(4-
Preparation of quinuclidiilyl ethers was accomplished as oxo-2-phenyl-3 (4H)-quinazolinylphenyl) ]hexane (VI).
illustrated for 3-quinuclidinyl benzhydryl ether (1). Benzhydrol
(7.4 g, 0.04 mole) and 3-quinuclidinol (5.6 g, 0.044 mole) iyere This material was hydrolyzed in ethanolic SaOH to
thororighly mixed arid heated to 70' to form a homogenoiib give 11.; Amines I1 and J711gave the respective meth-
melt. p-Toluenesiilfonic acid (8.75 g, 0.046 mole) was added and ane and butanesulfonamides 111, IT, VIII, arid IX.
the flask was evaciiated. This caused H20to evaporate from the SaBH4 reduction of 3-methanesulfonamidoestra-l.~3,.i-
mixtiire, and the melt solidified. The temperature was then (lO)-trien-l'l-one (VIII) gave the estradiol analog. 3-
raised to 140' when the solid melted, and the evacuat>edflask
was kept at, this temperature for 3 hr. After cooling, the solid met hanesulfonamidoe5t ra- 1,X,5 (10)-trien- 176-01 (X).
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'. CH, H
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.
Acknowledgments.-The authors are indebted to I.X=OH
Xstra Pharmaceutical Products, Worcester, Mass., and 11, X = NH2
AB Astra, Sodertalje, Sweden, for carrying out t'he
111, X = CH3S02NH
pharmacological tests.
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 ~ ~ I h O L I S I , K1,) U k N E G. GILLO,
J O i l I" L. ?\IIhII LLI, G O K D O It.~ MCKIKNFY,
\>I) A A L ~ R S E N
0
Jleud Johnson Research Cider, Mead Johnson R- Cornpanu,
ELanszille, Indzana 47721
R c c e i d March 17, 1969

Recent papers from these laboratories have described

the novel bioisosteric relationship between the methane- VI
sulfonamido 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 "U CA I T
relationship to steroidal and nonsteroidal estrogens was VII, R = NH2
of special interest because of the potential usefulness VIII, R = CH3S02NH X
of these compounds as antiuterotropic and/or anti- IX, R = C4H9SO2NH
fertility agents.?
The amines and diamines used as starting materials
These alkylsulfonamido analogs were tested in our
were prepared according to the general method of
laboratories for one or more of the following three types
Scherrer for conversion of phenols to a n i l i n e ~ .Applica-
~
of biological activity, uterotropic,6 antiuter~tropic,~
and
(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 (4) A l . hI. Endicott, E . Wick. AI. L. Mercury, and h l . L. Sherrill, J . A m .
(1966); (0) A . A. Larsen. N'. A. Gould. H . R . Roth, W.T. Comer, R . H . Chem. S o c . , 68, 1299 (1946).
Uloth, K . W.Dungan, and P XI. Lish. T h t d . , 10, 462 (1907). ( 5 ) B . R . Raker, ihid., 66, 1672 (1943); (h) G. Fodor and J. Wein.
(2) C. W. Emmons, J . R e p r o d . Fertilzty, 9 , 227 (1965); (h) D. J Collins J . Chem. Soc.. 684 (1948). report mp 80° for the racemic diamine.
and J. J. Hobhs. Aust. J . Chem., 110, 1413 (1967). (6) B. L. Ruhin. A. S. Dorfman, L. Black, and R . I . Dorfman, Endo-
(3) R . A . Scherrer, Abstracts of Papers, 145th National Meeting of the crinology. 49, 429 (1951).
American Chemical Society, New York, E.Y . , Sept 1963, p 334. ( 7 ) R . I . Dorfman and F. A. Kinel, Steroids, 1, 185 (1903).