Experimental Section
5-Nitro-3-dialkylaminomethylindoles.----'~l1~~so ~ O ~ I I ~ C J Iwr(1 I I I ~ r re pared from 5-nitroindole by the general procedure of Cavallirii arid Ilavenna,7 who prepared 5-nitrogramine. The amines were separated from accompanying polymeric material either by estraction into hot 6 S HCI, followed by precipit,ation with a r n moiiia, or by recrystallization from toluene or ethanol. 5-Amino-3-dialkylaminomethylindoles.---Theoorrespondiiig nmiiiograniines were prepared by low-pressure hydrogenation of t lie iiitro compounds over platiiiuni oxide in ethaiiol. The amiiio c~ornpounduwere somewhat unstable arid difirnll t o obtain pure. For thib reason not all of t h e nitrogrumines were suc.cw.ii'ully 1'~JllVCrtedto their amino analogs:. The 5-amiiio c,ompoundi;:w w c rwryslallized from benzene and c lohesane misturer. So tendency towards hydrogenolyais of the dialkylamino moiety TWC observed as evidenced by the eoii,~umptioii( i f onlj- 3 ecluiv. of hydrogen iri each case. 3Ielting points, yields, arid analytical data for all the new conipourids prepared are presented in Tables I :ind 11.
~
Acknowledgment. --Wo n.i.4i t o thank Dr. Samuel Ycrgusoii and his staff for the inousc behavioral data atid toxicities. Experimental Sections
Substitution i n the Hydantoin Ring. Bicyclo[S. 3.0loctane Derivatives
111.
7,7a-Dihydro-7a-methyl-l H-pyrroio [ 1,2-c]imidazole-l,3,5(2H,GH)-trione (IIa).---Three grams (0.02 mole) of I a l was dissolved in 50 ml. of hot 1,1,2,2-tetrachloroethane,and 1.5 g. (0.01 mole) of €',Os was added quickly. The mixture was refluxed 2 hr. and then filtered from the charred residue. TTpoii cvoliiig the filtrate, I l a precipitated in 85ionand nuclear degeneration of mouse Sarcoma 180 cells, but not normal embryo skin fibroblasts, over a concentration range of to lop4 When administered intraperitoneally to rats and mice at a single dose of 500 mg./kg., or at lower dosages over prolonged periods, 6-hydroxylaminopurine proved to be toxic (LDjofor a single dose, 470 mg./kg.).4 (1) This investigation was supported by funds from the National Cancer Institute, National Institutes of Health, Public Health Service (Grant C.1 03190-09) and T h e Atomic Energy Commission (Contract No. AT[30-11, 910) and aided by the G r a n t T-128F from the American Cancer Soriety and the First National City Bank Grant for Research from the American Cancer Society. Presented in p a r t a t the 150th National Meeting of the American Chemical Society, Atlantic City, N. J., Sept. 1965; Abstracts, p. 5P. A. B. is the recipient of a Public Health Service Research Career Award (3-K6-CA-22.533-0161) from the National Institutes of Health. (2) A. Giner-Sorolla and A. Bendich, J . A m . Chem. Soc., 80, 3932 (1958). (3) J. J. Biesele, unpublished results. (4) A. Giner-Sorolia, Ph.D. Thesis, Cornell Ziniversity, 1958; Dissertation Abstr., 20, 1148 (1959).
143
TABLE I EFFECT OF SOVEHYDROXYL ~ I I S O P L R I R E DERIV iTIVES OK ;\IOUSE TCMORS A N D LEI IiEMIAa Dose, mg / k g . / d w
Result
G-Hgdroxrlaminopurine Sarcoma 180 125 125 Mouse carcinoma E0771 Mouse carcinoma E0771 250 Rlouse carcinoma C1021 125 Ridgaay osteogenic sarcoma 125 Ridgwag ohteogenic sarcoma 250 Nouse leukemia P815 250 Mouse leukemia P815 reiistant t o 150 6-mercaptopurine Mouse leukemia P815 resistant to 40 6-mercaptopurine S-p-n-Ribofuranosy1-6-hydrosglnminopurine ( 11) 62, ,5 Sarcoma 180 A h u s e carcinoma E0771 125 Ridgway osteogenic snrcoma 125 1Zouse leukemia B8'2 125 Mouse leukemia B82 62. ;i Mouse leukemia P815 150 RIouse leukemia P815 resistant to 135 6-mercaptopurine RIouse leukemia P815 resistant, t o 90 &thioguanine Mouse leukemia P388 resistant to 90 6-thioguanine a The agents were administered intraperitoneally in physiological saline containing 0.5% carboxymethylcellulose for 2 weeks. -, no effect; &, slight inhibition; +, moderate complete inhibition. Data courtesy of Dr. inhibition; K. Sugiura and C. C. Stock of the Division of Experimental Cheniotherap y .
+++ + + +
++ +,
The synthesis of 9-p-~-ribofuranosyl-6-hydroxylaminopurine (11) was achieved in 90% yield by treatment of 9-p-~-ribofuranosyl-6-chloropurine (I) with an excess of hydroxylamine in ethanol. Compound I1 n7as catalytically hydrogenated to adenosine (111) in 93% yield (Scheme I). Attempts to prepare I1 from either SCHEME I
C'
bH
I
NHOH
OH
bH bH
dH b H
II
m
6-mercapto- or 6-methylmereaptopurine riboside upon interaction with hydroxylamine were unsuccessful; hypoxanthine or inosine were the reaction products.
