458 Journal of illedicinal Chemistry, 1971, Vol. 14, S o . b
The anticancer activity in five oxazoles, 1-, 2-, 3-, 5-, and 8-0 was screened by the method of Apple and Greenbergs using sarcoma 5180 in white albino mice weighing 20-25 g. The animals were injected ip with 2 X 106 cells of exponentially growing ascites cancers. After 24 hr they were injected ip with 666 mg/kg of oxazole in suspension. Normal saline was used in control animals. Ten mice were used for each test. After 7 days, the animals were sacrificed by cervical dislocation, the body was slit open, and tumor cells were washed into a 50-nil cylinder with a spray jet of isotonic saline. Subsequently, dilutions were made to 104-105 cells/ml for counting. The number of tumor cells were counted using a Coult,er Counter (a particle impedance transducer, Coulter Electronics, U.S.S.) The cell count of the treated animals ( T ) is compared with that of the control ariimals ( C ) . The effect of the drug, in preventing cancer cell growth is calcd and expressed as per cent inhibition. The data are given in Table 111. S,S'-Dialkyl or -diary1 dithiooxaldiimidates xere prepd as previously described.* S,S'-Di-p-methoxybenzyl dithiooxaldiimidate was prepd from p-methoxybenzyl mercaptan and ( C S ) , i n 55% yield, mp 169-1i0". A n a l . (ClsH2,N,0$3r), C, €1, N, S. Oxazoles were prepd by modifications of t'he previously described procedure.* The prepn of 5-beiiayliiide~iamino-4-pmethoxybenzylmercapto-2-phenyloxazole (4-0) illtistrates t,he procediire. 8,s'-Di-p-methoxyberiayl dithiooxaldiiniidate ( i . 2 g, 0.02 mole) and 5.3 g (0.05 mole) of PhCHO were heated a t 100" for 1.5 hr and 50 ml of abs EtOH was added to the reaction mixt'. On cooling yellowish orange cryst sepd, mp 105-108°. Crystn from EtOH afforded 5.2 g (65%) of the oxaaole, mp 110-111". Hydrolysis of Oxazoles to Nitriles and Amides.-The oxazolea were subjected to mild hydrolysis to give the corresponding nitrile. The procedure is illustrated by the p r e p of a-benzoylamino-a-beiizylmercaptoacetoiiitrile (3-N). To 3 . i g (0.01 mole) of 5-t1enay11nercapto-2-phenyloxaaole (3-0) in 150 ml of ILZenCO was added 100 ml of 5% HCI. The mixt was allowed to stand for 5 niiri at 25" and was neutralized with NalCOa, dild to 400 ml with H20, satd with NaC1, and extd with EtzO. The Et& exi was dried (XazSOd) and evapd to a residue which when d from PhH gave 1.2 g (45Yc) of the nitrile 3-N, rnp 100105": further crystn from EtOH gave t,he a n d . sample, mp 105106'. The hydrolysis of oxazoles to amides i3 illustrated by the prepn of a-benzoylaniino-a-benzylmercaptoacetamide(3-A). To a clear aolri of 3 g (0.008 mole) of 5-berizylideneamino-4be1izylniercapto-2-phe11yloxazole (3-0) in 50 ml of Me*CO was added 50 ml of 5'31 HCI. The reactioii mixt was heated under reflux for 2 hr, cooled, and neutralized with NaHC03. Removal of 3ZesCO under reduced pressure afforded the crude amide, mp 144-151'. Crystn from abs EtOH yielded 1.4 g ( 5 8 5 ; ) of amide 3-A, mp 154.5-155'.
Acknowledgments.-We are indebted to l l r . Richard Simmons for technical assistance. (6) AI, ;IppIe and I). XI, Greenberg. Cancer Chemoliier. R e p . , 61, 456 (1967).
Mannich Derivatives of Medicinals. 2. Derivatives of Some Carbonic Anhydrase Inhibitors GI:OI:GI.:
h1. s I l ~ ~ G l < l\iv,I L L I A M C. B A K R I K G I ~ R , A N D J a h i m E. KRUI~GICR
Pharmacc,iitical Product and Process Deaelopment Section, I,cdrrlc Laboratories Division, .4merican Cyanamid Company, Pcarl River, lYew York 10,963 1 2 e c c i k l M a y 23, 1 x 0
.4n earliei, report described the preparation of a series of nuclear-substituted Nannich bases of the phenolic sulfonamide 1. This paper describes the results of an .J.
111 G . A I . Sieper, \ \ . C . Barringer, E'. AI. Callalian, K . Gruenfeld, and F. IVeidenIieimer, J . I'horm. Sei., 60, 86!J (1961).
NOTES
investigation of Mannich-type derivatives of the carbonic anhydrase inhibitor sulfonamides 2a (acetazolamide) and 3a (methazolamide).3 T h p present oh-
1
N--N RCONH~~)--SO,NHR 2a,R =CH3; R'
=H
3
b, R = CHJ;R = CH2N
c, R = C2HS;R = CH2N
d, R = n-CCiHi; R' = CH,N
3
f , R = CHB; R' = CHZN(C2H5)2 g, R=CH3; R'=
CH,NHCH,COOH
h, R = CH,; R = CH2-Nn0
W
i , R = CH3;R' = CH2NnNCH, W
jective was to obtain derivatives having increased solubility which would also rapidly regenerate the parent compounds under physiological conditions. It was expected that for these materials, derivatization would occur at the amide or sulfonamide group, giving a hydrolytically labile >SCH2Y< linl
