-ISTIRADIATION AGESTS. I11
-\larch 1970
protein binding, 34; CDjo >400 mg,'kp. A n d . ~Cl2H~1X;O&) C, H, S .
Acknowledgment.-The author.< e s p r e s their appreciation to l I r . C. I. Kennedy for micruanalpes, l l r . J. G . Schmidt for infrared spectra. 3Iew-+. D. Iinapp
251
and R. Wargel for assistance in preparing intermediates, and Dr. W. T. Comer for helpful comments and suggest,ions. The authors n-ish to thank D. L. Elliott, AT. Fuquay, R. lleyers, J. E. Salmon, J. R. Harris, R. Stratman, and P. Zwadyk for their valuable technical assistance.
Potential Antiradiation Agents. 1II.l N- Substituted ,iminoethanethiosulfuric Acids DANIEL rA.I < L \ I J I \ Y ,
l r . GRESAS,A N D D.4VID
~ I A R ~ E
P. JACOBCS
It'alfer Reed A r m y Instrfide o f ti'esenich, Diiision of Medicznal Cheniisti y, Tt'ashznglon, D.C.
20012
KeceTied September 22, 1969
A series of N-monoalk?-l-subatit~ited2-aniiiioethanethiosulfiiric acids was prepared for testing as potential antiradiation agents. The cornpoiinds were synthesized by the direct alkylation of the sodium salt of "aminoethanethiosulfuric acid with primary alkyl bromides, by the reaction of the appropriate .\-alkylaminoethyl halide hydrohalides with sodium thiosulfate. 91' by the ring opening of 1-srtbstituted aziridines with ammonium thiosulfate. Excellent radioprotective activity i>70 C;- survival) was ob t aiiied wit h those 2-aminoethanet hiosdfuric acids which were N-substituted by methyl, n-octyl, 2-octyl, n-nonyl, 2-nonyl, 3-IlOny1, a-decyl, 2-decyl, B-decyl, 3,7-bimethyloctpl, 4-phenylhutyl, a i d 5-phetiylpeiityl groups.
In a11 earlier paper2 we described the -ynthe-k and radioprotective properties of a serie- of :m~inoalkanethiosulfuric acids possessing a primary amino group. I t was shown that optimal activitjr n-a- obtained when the SHZ and SSOsH functions were .eparated by two CH, groups. The high antiradiation activity -hewn by many N-alkylaminoethanethiolgl .ugge.;ted that 2amirioethanet hiosulfuric acids which were S - w b qtituted also might be useful a< potential antiradiation drugs. In this paper we report on the antiradiation propertiec of a series of S-monoalkyl-substituted "aminoethanethiosulfuric acids, the syntheqis of many of which was described by us p r e v i ~ u s l y . ~ Chemistry The previously unreported N-alkylaminoet hnnethiorulfuric acids (Table I) were prepared by two general methods. Method A involved the direct alkylation of 2-aminoethariethiosulfuric acid a- the S a \alt with a primary alkyl bromide in EtOH-HIO The dialliylRBr
+ H2NCHrCHzSSOa- 4 RNHCH,CH!SSOTH + Br-
ated by-product was separated from the de.;ired monoalkj lated 2-ami1ioethanethio~ulfuric acid by repeated recrystallizations. ,\lethod B utilized the reaction of -odium thioalfate with an N-alkylaminoethyl halide h\-drohalide in H20 or EtOH-H20. The N-alkylaniinoethanol precursors
x-+ s o 8 * -+ -
K$H,CH?CH~X
KKHCH?CH?SNBH
+2s-
(1) P a r t 11: D. L. Klayman, 32. >I. Grenan. and D . P. Jacohur, J . J f e d . Ckem., 12, i 2 3 (1969). ' 2 ) P a r t I: D. L. Klayman, M. BI. Grenan. and D. P. Jacohus, ibid., 12, 510 (1969). ( 3 ) Annual Report, F Y 1964, \F-alter Reed Army Medical Center, Kalter Reed Army Institute of Research, Dirision of 1Iedicinal Chemistry, \\-ashington, D. C. Available through the Defense Documentarion Center. Cameron Station, Alexandria, Va. 22315. as Re1,ort .\D 601934. t4) I). L. Klayman and \Y.F. Gilmore, .I. M e f / . C h r m . . 7 , 823 (1964).
were prepared either by the direct alkylation of 2aminoethanol by the method of Wright, et u Z . , ~ or by the reaction of a carboxylic acid with 2-aminoethanol to yield an N-(2-hydroxylethyl)amide n-hich was reduced with LAH in T H F . The resultant ?J-substituted aminoethanols were converted into the amino halide form by treatment with SOClz or 487, HBr. Results and Discussion Compounds 1-18 constitute a homologou3 series of aminoethanethiosulfuric acids S-subqtituted with unbranched alkyl groups. The first five members mere the most water soluble arid the least toxic. However, any appreciable radioprotective activity was limited to those compounds substituted with N e (1) or E t (2), while slight activity was shown by the P r compound (3). Increased toxicity and absence of activity marked compounds 4-6, but activity was restored to the serie5 with the heptyl-substituted compound (7) and rose steadily, reaching a peak effect with 10. Compound 10 not only conferred a high degree of protection to the mice, but did so a t a considerably smaller dose ( 5 mg kg) than that required by most radioprotective thiosulfuric acids. I n contrast to 2-mercaptoethylamine (MEA), whose duration of maximum radioprotective activity extends to 13 miri and then diminishes rapidly thereafter,6 the duration of activity of 10 extends clohe to 1 hr. Compound 10, while effective when given parenterally and moderately protective when given subcutaneously, is ineffective x h e n given orally. Other agents in this class, which protected after parenteral injection, also failed to protect when administered by intubation. Attempts to induce absorption included acidification of the intestinal contents of the mouse and the use of ethylenediamirietetraacetic acid which promotes the absorption of a \vide variety of poorly (5) J. R. K r i g h t , E. H. Lincoln, R . T. Heinzelmann, and J. H. Hunter. J. Amer. Chsm. Sac., 73, 3536 (1950). (6) Z. 1f. Bacri, "Chemical Protection Against Ionizing Radiatiun." Charles C . Thomas. Springfield, Ill., 1965. pp 126-129.
2.i2
XSTIRADIATIOSAGEKTY. I11
March 1970
I1 RADI~ T I O S B Y N-SLHSTITUT~D ACIDS,RNHCH?CH?SSO3H
TmLE
P I w i ~ u x I o xOF ~ I I CAGIISST L X
OR
~ I ~ Y O IXt'THIOSULFURIC ~ T H
R
LDd, Inp kg'
y
Drug dose,
mdkP
Time interval, minb
Radiation dose, RC
c/c s u n I \ a1 i30-daj )
800 70 -1000 .It) Et .30 92.5 n-Pi 1000 7 n-Bii :o 1000 0 n-Pentyl 1.i 1000 0 I *I n-H exj 1 :30 1000 75 30 n-Hept! 1 1000 1.i :30 hO n-Octyl ;3 0 1000 1.5 40 h7 n-Nong 1 :30 97.5 I 13 90 n-Decyl 1000 1.i ) 0 n-Uiidecyl Y 1 :20 1000 0 10 n-lhdecyl 1000 I :30 40 n-Tridecyl 1.i :30 1000 I 20 10 n-Tetiadecyl 30 :30 1000 40 7 n-Peiitadecj-1 :;o 82.i 40 0 1.50 n-Hexadecyl 100 :30 800 200 0 n-Heptadecyl 2.30 :io 800 0 400 n-Octadec) 1 :io 2.50 800 L-Pr 270 0 1.iO 1 .i 1000 0 Cyclopiopylmethyl 300 X2.i 200 1 .i 10 f-Bi1 2.iO 1000 200 1.i 0 47.5 2,2-Dimethj lpiop) 1 1000 100 1.i 0 Cyclobiit ylniet hy1 180 1.5 1000 7.i 0 2-Heptyl 17.5 .i0 1.i 1000 0 7 .i Cycloheptyl 1000 30 i.) 100 2-Octyl 158 1000 7 .i 30 40 .s-Octyl l2.i --i.) 1 .i 800 33 1.20 4Octyl 100 1.i 800 33 1,iO Cyclooctyl 120 1.i 1000 33 2-Ethj 1-1-hexyl 180 1.i 40 1000 47 I.ononyl 140 2 2 . .i 82.5 2-No11yl .30 94 .iO 1;1 K2,i 80 :3-h'ony1 12.5 1.i 7 .i 800 20 4-KO IiyI 200 20 :30 1000 13 3,,i,,~TriniethylhevSl 100 2 .i 1.i ;30 1000 94 2-Decyl 2 .i 1.i 800 100 80 3-Decyl ;30 :30 1000 87 3,7-Dimethyloctyl 12.i 10 :30 .i3 825 20 2-Undecyl 1.50 :30 1000 0 2.3) Benzyl 100 1.5 0 1000 4 Methoxybeiihyl 180 .i0 1.i 0 800 1.io Phenethyl .5 0 1.5 40 1000 12.5 3-Phenylpropyl .i0 1.5 82.5 7 1.50 3-(m-~lethoxy)pheuylpiopyl .0i :30 1000 13 123 2-Pheiiylbutyl :30 82.5 120 94 800 4-Phenylbutyl 823 70 1.5 83 130 3-Phenylpentyl 2 .i 30 1000 27 38 6-Phenylhexyl 1 :30 0 1000 140 3,3,3-Tripheiiylpropyl 7.5 30 0 1000 11-Phenylundecyl 2 -5 2.5 :30 823 0 30 9-Acrldyl ;i0 :30 1000 0 2 Phenoxyethyl 17.5 1-5 7 50 1000 2-Pheiioxypropyl 1.50 6oCo */-irradiation a t 925-1000 It (dose rate 50-100 a Intraperitoneal administration. b Administ,ratioii prior to irradiation. Synthesis of this compound reported previorisly; R!miii); all other doses were delivered by a 300-kvp X-ray (dose rate 45 Rjmin). e Also prepared by the ring-opening of aziridines with ammonium thiosulfate; c j . D. L. Klayman, W. F. Gilmore, and T. 11. cf. ref 4. Sweeney, Chem. Ind. (London), 1632 (1965). _\le
3.50 .52.i 3.50 :300 200 8 .i 12.5 l2.i
300 :200 22.i 200 .i0
1.i 30 1.5 1.i
--
--
.411 compounds were administered by the intraperitoneal route unless noted otherwise. The principles of laboratory care aspromulgated by the National Society for Medical Research were observed. Chemistry.9 A\r-AlkylaminoethanethiosulfuricAcids, Method (9) hlelting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. Microanalyses were performed b y l l r . Joseph F. .Ilicino, hletuchen, N. J. 08840, and Schwarzkopf Jlicroanaly-
A.-The procedure4 for the direct alkylation of sodium %-aminoethyl thiosulfate was improved by increasing the quantity of the latter compound relative to the primary alkyl bromide. In general, using a 2 : 1 ratio of amine to alkyl halide was fouiid to appreciably diminish the yield of the dialkylated by-product. 6-Phenylhexyl Bromide.-To a sollition of 12.2 g (0.05 mol) of tical Laboratory, Woodside, N. Y . 1 1 3 i i . Infrared spectra were determined a s K B r pellets on a Reckman IR-5 spectrophotometer.
