KOTES
July 1967
731
with the synthesis of bis-3,6-(p-boronobenzylaniino)- 3100 cm-l in the infrared spectra. The presence of the acridine moiety was confirmed in part by the ulacrid in^,^ but this compound proved to be highly toxic traviolet spectrum which proved to be identical with at doses necessary to attain sufficient boron levels in that of 9-anilinoacridine1* 2450, 26650, 3415, tissuei.8 On this basis the synthesis of an acridine 36530 A). c*ontaininga cwborane moiety was undertaken in order In view of the observations of Creech, et aZ.,'j that to achieve a high percentage of boron in such a molecule. "one-armed" nitrogen mustards of the quinacrine Chemistry.-Preparations of a carboranylacridine by type exhibit high antitumor activity, attempts alkylation of the ring nitrogen of acridine, 9-aminowere made to synthesize X,r\'-(2-chloroethyl-p-cal.boacridine, 3,G-diaminoacridine (proflavine), and 9ranylpheny1)-9-aminoacridine (VIII) by Scheme I. acetaniidoacridine with substituted derivatives of carhorane [(B10H10C2H)CH2CH2X, X = Br, I, and SCHEME I CH3C6H5S03]and with analogous acetylenic derivatives, which could be converted to the carboranes I-\ follo\ving alkylation, were singularly unsuccessful. This failure can he largely attributed to steric factors at the 10 position (ring nitrogen) of the acridine molecule.E While pyridine condenses readily with bromoethyl- and toaylethylcarborane to give the correspondVI1 ing salts, 2,G-lutidine (2,G-diniethylpyridine), having I-\ a steric urrangenient about the ring nitrogen comparable to the wridines, failed to react even a t temperatures up to lbOO. VI11
Ia, X = Br b, X = CHJC,H5SOJ
IIa, X = B r b, CHIC6H,SOJ
x=
Similarly, acylation of acridines such as 9-aminoacridine, 9-acetamidoacridine, and 9-carbobenzyloxyamidoacridine (111) with carhoranyl acid chlorides of the type (HloHl0C2R)COCl[R = C6H5 (IVa) arid CH,CH=CH (IVb)] and with the acetylenic acid chlorides, C6HjC=CCOC1 (Tn) and CH&H2C=CCH2COC1 (T%) have proved unsuccessful to date. A n alternative method, which has been widely used in the synthesis of antimalarials of the quinacrine type"' has resulted in the synthesis of 9-(p-carboranyl)anilinoacridirie (TI). Condensation of 9-chloroacridine with p-nniiriopheiiylcarborane" was effected in refluuing toluene, yielding the hydrochloride of VI. l:ollowing neutralization with ammonium hydroxide T I was isolated and its carborane structure was confirmed in part by the characteristic B-H absorption band :it 2BCO cm-' and the carboranyl C-H band at ~
c1
( 7 ) 41. 8. Konecky and H . R. Snyder, private communication. ( 8 ) .I. H . Soloway. Propr. Boron Chem., 1, 203 (1964).
( 9 ) R. .\I Acheson, "The Chemistry of Heterocyclic Compounds," Vol. 9, Interscience Publishers Inc., New York, N. Y., 1956, p 234. (10) (a) D. AI. Hall and E. E. Turner, J . Chem. Soc., 694 (1945); (b) F. Y. \\.iselosle, "1 Survey of .intimalarial Drugs." J. W. Edwards, Ann .\rbor, Midi., 18-16. (11) AI. F,Hawthorne, 1'. .i. \Vegner, and T . E. Berry, J. Am. Chem. Soc., 37, Aid6 (1H65), a s well ab ref 311.
Compound 1'11 was synthesized and characterized by infrared and elemental analysis, but all attempts t o prepare the "one-armed" nitrogen mustard (VIII) have been unsuccessful to date. Although the structure of t'he isolat'ed product has not' been completely elucidated, the infrared spectra exhibit a split B-H band at 2500 and 2600 em-l which is characteristic of degradation of the carborane nioiety.I3 A possible alternate approach to enhanced biological activity would be the synthesis of the niethanesulfonyl derivative (mesylat'e) of VII, and efforts in this direction are currently under may in our laboratory. Biological Results.-The single-dose LDjo's of VI and VI1 were determined by suspending their hydrochlorides in saline cont'aining a few drops of a wetting agent (Tween 40). These suspensions were adniinist,ered to 6-week-old male CD1 Swiss Albino mice by intraperitoneal injection. The LD50 det'erniined in this manner using regression analysis mas 200 nig/kg and 180 mg/kg, respectively. These values are comparable to many suhstitated acridines14 (i.e., quinacrine, L D ~ o= 280 mg/kg). Thus, on the basis of boron concentration administered, use of these compounds for neutron-capture therapy would appear to be distinctly possible. The compounds were evaluated for tumor localization by three daily intraperitoneal injections of 18 pg of boron/g into C3H mice bearing subcutaneously transplanted ependyniomas.'j The animals were sacrificed 2 days following the last injection and tissues mere analyzed for boron content.16 The results are summarized in Table I. Both conipounds exhibited ele(12) 9-Anilinoacridine was prepared in this laboratory according to t h e procedure in ref 10; m p 2 3 0 ° , iit.9 mp 23OC. (13) (a) L. I. Zakharkin and 1'. X. Kalinin. Ira. Akad. Sauk S S S R . Ser. Khim., 9, 579 (1965); Dokl. S k a d . S a u k S S S R . , 163, 110 (1965); Tetrahedron Letters, 407 (1965); (b) A l . F. Hawthorne, P. A. Ivegner. and R. C. Stafford, Inorg. Chem., 4 , 1675 (1965). (14) S. D. Rubbo, Brit. J . Ezptl. Pathol., 23, 1 ( 1 9 4 i ) . (15) D. d. Matteson, A . H . Soloway, D. \V. Tomiinson, J. D. Campbell. and G. A. Nixon, J . .Wed. Chem., 7, 640 (1964). (16) A. H. Soloway and J. R. ,\lesser, BnaE. Chem.. 96, 433 (1964).
