Eound, '
:irrylaiiiides (n = 1-6) as antitumor agents has becii calaimed by several laboratories,6 arid the results of the a11titumor screening of a large number of aziridirie rampounds have been tabulated.' The results obtained for some of the compounds reported in this paper are giveti in Table I along with data for "HS?" obtained in a similar test system. Compound 12 ( n = S) demonstrated interesting activity in this screen, its favorable therapeutic index being coupled with a low degree of 1 ~ 0 1 inarrow 1~ depression. Experimental Section T h e follovkig are geileral pro~edures~ " I I I , t h e prrpnr:it ioii 01 c.ompounds reported in Tables I1 arid 111. N,N'-Decamethylenebisacrylamide (9).-AcryIyl c.liloi,ide (11.8 ml, 13.5 g, 0.15 mole), dissolved iii l j 0 nil of benzeiie, atid K2COJ (27.6 g, 0.20 mole) were stirred at 0' under Sy. To t h i h mlutioii \yay added 6.5 g (0.039 mole) of 1,10-decamethyleiiediamitie dissolved in 250 ml of benzene. -4fter additiiiti \v:w complete (0.5 hr), t,he reaction was stirred at 0' for 2 hr. \Vnter wis t,heii itdded and t,he resiiltirig precipitate collected t ~ yfili r:it ioii. The resiche was then t,riturated with 0.1 dV IiC1 and ( I . I .\ NaOIT, washed with water, filtered agaiii, arid dried in z'uciio. This gave 8.2 g (70.7%) of white, solid acrylamide. Crystallization from methanol a t -80' gave an ailalytical sample, nip 1 1X-122". F€eat,ingof these comporinds led t,o polymerizntioti: X;:O' 5.98 and 6.04 (C=O), 6.17 (C=C), 3.08 p ( S H ) . N,N'-Decamethylenebis( 8-aziridinylpropionamide) ( 13).-~-.4 mixture if 2.00 g (0.0071'2 mole) of bisacrylamide 9, 30 nil oi rnethitriol, atid 3.66 ml (3.05 g, 0.0712 mole) of aziridine tis -tiired itt room temperature for X days under tniide did not dissolve at first, but after 4 d was clear. The solvent was removed in ZUCILO and the residrie wiia dried a t 1 mm for 12 hr to yield 1.04 g (61.5:-i) of whit'e, hpoiigy solid: A"':, 6.1 (C=O), 3.04 p (NIT). -411analytical i;tmple, mp 194", of the bis-mustard hydrochloride W R S preparrd Iiy reaction with gaseous HC1 in ethanol.
- .
11
s
7 , .-I2
12.11
7 !I"
II 7
s ,"li
I I I1
s . .-I: I
IO li
Scptcmhcr 19Di for the synthesis of 3-halogenated thyronines, particularly the unl;nowii 3-chlorothyronine, the chlorinated clerivates of whirh \\-auld lie of pharmac.ologic.al interest if they were to lead to an iodine-free thyroxine antagonist. Of the methods available for the synthesis of 3iodothyronine,* that of Roche and collaborators,2d wherein the diphenyl ether linkage of the thyronine analog is formed by I: condensation in aqueous solution, WLS considered to have the potentid of producing reasonable quantities of 3-halogenated thyronincs with t hc minimum possibility of c,oiitamiiiatioii by X,.it1ih:ilogeiiated products. Indeed, by this mcthod 3iodothyronine could readily be syiithesized using, i i i the present iiistance, hippuric rather than aceturiv acid in the Erlenmeyer azlactone ~ y n t h e s i s . ~ However. synthesis of the desired chlorothyronine was not achieved in this manner. Treatment of the diazotized amine with the strongly acid solutions of cuprous chloride usually employed in the Sandmeyer react ion caused considerable dechlorination. And, in contrast to the analogous iodine compound, the solubility characteristics of the chloro compound did not differ sufiriently from those of the unchlorinated compound to permit purification by c~rystnllizntionas :L matter of prac6c.d synthesis. The lability of the iodine atom in 3-iodothyronine has been studied in depth by Jorgensen and Reid.J I t now appears that the chlorine atom in nionochlorothyronine is unstable under the conditions of the Sandmeyer reaction which readily permit synthesis of the dichloro derivative.j The reaction was not investigated further since it was found possible to adapt the iodonium salt reaction, successfully used in the case of 3,S-dihalogenated thyronines,6 to the synthesis of 3-chloro- as well as 3-iodothyronine. Optically active conipounds could be expected by this route. Although no reaction took place under conditions which led to good yields of dihalogenated derivatives, in methanol either a t boiling temperature6brdor at room good yields of monohalogenated thyronines were obtained in dimcthylformamide at slightly elevated temperature, "
I,
951
KOTES
I? = CHO
11. 111; I \', I.,
1-1, 1.11,
( 2 ) ( a ) J . Roclie, R . llicliel, and JV. \Yolf, C o m p t . Rend., 239, 597 (1954): (b) Bull. SOC.Cltim. Frrincr, 464 (1957); ( e ) G. L. Gemmill, .J. J. .indeIson. and h. Burger, J . A m . Chem. SOC., 78, 2434 (1956): ( d ) J. Roclie, R. hlichel, (e) J. S. Varcoe ,J, Nunez, and C. Jacquemin, C o m p t . Rend., 246, 77 ( 1 9 5 i ) ; and \T. K. Warburton, J . Chem. Soc., 2711 (1960). (3) Subsequent t o the work on t h e iodo compound, exploitation of this route was reported in the patent literature: R. I. lIeltzer, L-,8. Patent 2,954,399 (1960). ( 4 ) E,C. .Torgemen and .J. A . \T. Reid, J . O r g . Chrm., 29, 3396 (1964). ( , 5 ) IV. I
