COMMUNICATIONS T O T H E EDITOR A NEW CLASS OF POTENT CENTRAL NERVOUS SYSTEM DEPRESSANTS
chloroethyl isocyanate7and a-naphthylamine or by treating 1-( 1-naphthyl) -3-(2-hydroxyethyl) -urea with thionyl chloride in refluxing chloroform. Sir: Acidic degradation of I with boiling 3N hydrochloric Slthough the first 2-amino-2-oxazolines (pseudo- acid leads to V. ureas) were synthesized over fifty years ago, The iodo analog, 1-(l-naphthyl)-3-(2-iodoethyl)compounds containing that grouping have until grea (VI), m.p. 176.0-178.O0; , : :A: 3.09, 6.17, 6.39, now received only cursory pharmacological exami- 6.60, 6.68; (Anal. Calcd. for C ~ ~ H I ~ X Z C, O I 45.9; : n a t i ~ n . We ~ now wish to report the synthesis, in HI 3.85; N, 8.24. Found: C, 45.9; 13, 3.9-1-; the course of a systematic search for new psycho- N, 8.25) was prepared by refluxing I1 with exceqs therapeutic agents, of the previously unknown sodium iodide in acetone s o l ~ t i o n . ~ 2-(l-naphthylamino)-2-oxazoline (I). This comFollowing oral or parenteral administration OF the pound represents a new structural type of central oxazoline I to cats, dogs and monkeys, markctl nervous system depressant, which displays a unique quieting was observed accompanied by mtisclc. pharmacological profile. relaxation and increased ease of handling. In Treatment of a-naphthyl isocyanate with p- potentiation of hydroxydione (21-hydroxypregbr~moethylamine~ in benzene solution led to 1- nanedione sodium succinate) anesthesia, I proved ( 1-naphthyl) -3-(2-bromoethyl) -urea (11), m.p . somewhat more potent than either reserpine or 146.8-147.2’; . : : A: 3.10, 6.19, 6.41, 6.60, 6.70; chlorpromazine, while all three drugs depressed thc> (-4nal. Calcd. for C I ~ H I ~ N Z OC, B ~53.3; : HI 4.47; spontaneous motility of mice to a similar degree. N, 9.56; Br, 27.3. Found: C, 53.1; HI 4.37; Spinal cord depressant activity could be demonN, 9.76; Br, 27.1). Alternatively, I1 could be strated with lower doses of I than wcre recluiretl synthesized by treating P-bromopropionyl chloride5 with the distant structural relative, 2--a1nitio-~?with sodium azide under thermal-rearrangement chlorobenzoxazole.10 Metrazole convulsions werc conditions to afford the previously unknown P- facilitated by pretreatment with I, as is thc C ~ W bromoethyl isocyanate, which was not isolated but with reserpine.l’ allowed to react directly with a-naphthylamine ( 7 ) H . Wenker, THISJOURNAL, 68, 21308 (1936); W Siefken. i i i r r t , affording the desired compound. The urea I1 562, 7 5 (1949). (8) R.W. Charlton and A. R. D a y , J. Org. Chem., 1, 552 (193(?). readily underwent intramolecular cyclization in (9) I n animals the 8-bromoethyl urea I1 displays n spectrum of boiling waterE to give a solution of Z-(l-naphthyl- pharmacological actions similar to I, although much higher doses arc amino)-2-oxazoline hydrobromide, from which required. Since it can be demonstrated t h a t any efficient solvdytic dilute ammonium hydroxide precipitated the free medium (e.&, methanol, dimethylformamide) will effect t i l L ’ i l i w base I, m.p. 123.4-124.6; E:. 3.36, 3.55, 5.98, cyclization of the urea I1 t o t h e oxazoline I a t room temperature. i t 6.08, 6.38, 6.64; (Anal. Calcd. for C I ~ H ] Z ~ \ ; ~tseems O : highly probable t h a t a similar in vi110conversion is involved i t 1 h e pharmacodynamics of 11. Further investigation of this n o d C, 73.6; H, 5.70; N, 13.2. Found: C, 73.5; metabolic transformation is contemplated. Neither the iodo nor HI 5.60; N, 13.1). chloro analog is as active as I1 when evaluated by the technique Treatment of I with anhydrous hydrochloric anesthesia potentiation in rats. T h e whole picture of ;)I B i U O tttinformation t o a n active species by intramolecular alkylation, as well : I acid in methylene chloride solution afforded the varying potency among halogen analogs is reminiscent of the 8-halo corresponding hydrochloride salt, m.p. 150.2- ethylamine adrenergic blocking agents (G. E. Ullyot and J. I.‘ k’erwirl 150.5O; . : : A: 3.25, 3.53, 6.00, 6.18, 6.2S, 6.33, “Medicinal Chemistry,” John Wiley and Sons, Inc., New York. S .1- , (3.41, which reverted in boiling 2-propanol to 1-(1- Vol. 11. 1956. p , 234). (101 I\’. H . Funderburk and R. T. Woodcock. Fed PYoc , 1 4 , 311 naphthyl)-3-(2-chloroethyl) -urea (IV), m.p. 145.6- (1955); K. Kamijo and G. B. Koelle, i b d , 14, 3Sii (1%:); I ) . 1’ 146.4; , ::A: 3.07, 6.14, 6.40, 6.65; (Anal. Calcd. Marsh, ibid.,14, 366 (1955). ( I 1) T h e detailed pharmacology of I will be published elsewhere for CI3Hl3iV20C1: C, 62.8; H, 5.27; N, 11.3. BARRY If.BLOOM Found: C, 63.1; HI 5.26; N, 11.1). The synLABORATORIES JOSEPH F. GARDOCK1 thesis of I V could also be accomplished from p- RESEARCH CHAS.PFIZIIRA N D Co., INC. DUNCAN E. IlmCimox (1) R . H. Wiley and L. L. Bennett, Jr., Chem. Reus., 44, 404 (1949); J. W. Cornforth. “Heterocyclic Chemistry,” 1‘01. 5, John Wiley and 1957, Vol. 11, pp. 384-388,390. Sons, Inc., New York, N. Y., (2) For more recent chemical studies. see A. F. McKay and coworkers, THISJOURNAL,78, 486, 1618, 6144 (1956); C a n . .I. Chena., 35, 8 (1957), and earlier papers. (3) C. J. Rose, H. A. Shonle and K. R. Chen, Phurmacrulicnl Archiues, 11, 81 (1940); R. Gebauer, German Patent 694,133 (July 26, 1940); C . A . , 38,5259 (1941). (4) hl. Engelmann, U. S. Patent 2,027,031 (Jan. 7, 1936); C . A . , 30, 1519 (1936). (5) C. S . Hamilton and C. L. Simpson, THISJ O U R N A L , 51, 3158 (19’29); R. Dahlbom, Acta Chem. Scand., 7, 873 (1953). (6) In accord with earlier observations in t h e 8-haloalkylurea series,
RROOKLPX.NEWYORK GERALD n.~ , A I : I I A C l I RECEIVED JUNE 17, 1957
BIS-( CY CLOPENTAD1ENYL)-TITANIUMDICHLORIDE -ALKYLALUMINUM COMPLEXhS AS CATALYSTS FOR THE POLYMERIZATION OF ETHYLENE Sir :
The recent publications of Katta and coworkers’,? on the use of bis-(cyclopentadien4.1)-,
(1) G . N a t t a . P . Pino, G. Mazzanti, U. Giannini, E, I l a n t i c a nnd alkali-catalyzed cyclization of I1 proceeded via alkylation on nitrogen 31. Peraldo, C h i m e . rizd. ( M i l a n ) , 39, 19 (1957); C . A . , 51, 7010 t o produce l-(l-naphthyl)-2-imidazolidone(III), m.p. 180.4-181.6°, (1957). XKBr ms.. 3.17, 3 . 3 2 , 3.57, 5 . 9 7 , 6.31, 6 . 7 2 (Anal. Calcd. for CIIHIZNZO: (2) G . N a t t a , P. Pino, C . hlazzilnti a n d U. Giannini, ‘l‘rlrs TOIIIWAI.. C , 7 3 . 6 ; H.5 . 7 0 ; N , 13.2. Found: C 74.2; H , 5 . 6 1 ; N, 13.3). 79, 2975 (1957).
