November 1969 XOTES 1103

Experimental Section

AIclting points were determined wit,h an electrically heated ineta1 block, using calibrat,ed Anschuta t,hermometers. Micro- analyses 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-chlorobenxhy- dr01,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 H20 to evaporate from the mixtiire, and the melt solidified. The temperature was then raised to 140' when the solid melted, and the evacuat>ed flask 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.

Acknowledgments.-The authors are indebted to Xstra Pharmaceutical Products, Worcester, Mass., and AB Astra, Sodertalje, Sweden, for carrying out t'he pharmacological tests.

(8) J. H . Lamneck. Jr.. and P. H. \Vise, Nat l . Advisory Comm. Aeron. ,

(Y) A . E. Chichibahin and A. A. Shesler, J . Russ. Phys. Chem. Soc.. 66,

(10) Ll. R. Boyd and H . H. Hatt, J . Chem. SOC., 898 (1927).

Tech. S o t e 2330, 15 (1950); Chem. Ahstr., 46, 6609k (1951).

149 (192,;): Chem. Abstr.. 19, 3269 (1925).

Alkylsulfonamido Estrogens

n O L 6 L \ S ~ ~ I h O L I S I , K , 1 )UkNE 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

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- 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 relationship to steroidal and nonsteroidal estrogens was of special interest because of the potential usefulness of these compounds as antiuterotropic and/or anti- fertility 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. Thtd . , 10, 462 (1907).

(2) C. W. Emmons, J . R e p r o d . Fer t i l z ty , 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.

tion of the Scherrer method to the synthesis of meso- 3 ,+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,4- hiii [4-(2-phenyl-4-quinazolinyloxyphcnyl) ]hexane (VI thus formed, was heated at 3x0" to yield 3,4-bir[3-(4- oxo-2-phenyl-3 (4H)-quinazolinylphenyl) ]hexane (VI). This material was hydrolyzed in ethanolic SaOH to give 11.; Amines I1 and J711 gave the respective meth- ane 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. 3- met hanesulfonamidoe5t ra- 1,X ,5 (10) -trien- 176-01 (X) .

CH, H

I .X=OH 11, X = NH2

111, X = CH3S02NH IV, X = n-C,H,SO,NH

0

" VII, R = NH2

VIII, R = CH3S02NH IX, R = C4H9SO2NH

VI

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 ant iuter~tropic ,~ and

(4) A l . hI. Endicott, E . Wick. AI. L. Mercury, and h l . L. Sherrill, J . A m .

( 5 ) B. R. Raker, ih id . , 66, 1672 (1943); (h) G. Fodor and J. Wein.

(6) B. L. Ruhin. A. S. Dorfman, L. Black, and R. I . Dorfman, Endo-

(7 ) R . I . Dorfman and F. A. Kinel, Steroids, 1, 185 (1903).

Chem. Soc. , 68, 1299 (1946).

J . Chem. Soc.. 684 (1948). report mp 80° for the racemic diamine.

crinology. 49, 429 (1951).