A Chemical and Pharmacological Study of Some Compounds Derived from 3,4-Xylidine
Twelve derivatives of 3,4-.uylidine, consisting of three simple related xylidines. two quinolines, a, cinnoline and six dimethylbenz [ f ] azepines, were synthesized :is potential antimetabolites of riboflavin and vitninin Biz. They xer? exmined for toxicity, pharmacological activity and screened chemotherapeutically against malaria, trypanosomiasis, yellow fever and Crorker siircornit 180 in mice. T n o of the dimethylbenz [f] azepine derivatives showed markrd activity :tgainst Crockrr sarcoma, the most active compound comparing favorably in activity with a therapeutically active antitumor drug, triethanonielamincl. TKOother closely related compounds bearing the same heterocyclic ring showed weaker :tntituinor :tctivit>but these were not well tolerated in the strain of mice used for tumor \vor!i. Thc, compounds were, on the whole, well tolerated and 110 dcnionstrahle pharinnrological effects were elicited at relatively high concentratioris. XOIIPof the‘ coinpounds tested showed activity against rsperimcmt:tl infections c-if ninlari;t. tr>.panosomiasis or yelloiv fever.
Derivatives of 3,4-xylidine were subjected t o biological testing with the hope that they might prove to be antimetabolite\ of riboflavin and vitamin BIZ. Riboflavin has been shown to play iome role in thc development of malarial and trypanosoma1 infections,' and also in certain forms of tumor g r o ~ t h . There ~ is widencLe that vitamin B12 is synthesized by spontaneous mammary tumors4 on hich the tissue is partly dependent,j and a simple xylidine derivative. i i s d a. a potential antimetabolite caused temporary regression ol the tiimor." Other related xylidine derivatives have been shoi3-n to be active against influenza virus,' and this led 11: t o include a t activity. The compounds include three simple related xylidincs, two qiiinolines, a cinnoline and six dimethyl benz [flazepine derimtives. P. F. Clark, Ann. Rev. .MicrobioZ.. 4, 349 (1950). R . G~ Yaeger and 0. 3 , Miller, E z p e r . Parasitol., 10, 227 (1960). H. C. Stoerk a n d G. A. Emerson, Proc. SOC.E x p . B i d . N. Y., 70, 703 (19.19). D. W. Woolley, PTOC. Nat. Acad. S c i . C'. S. A . , 39,G (1953). D. W. Woolley, "Antimetabolites a n d Cancer," American Asstic. Sor Adranrrnient of Rrience, Washington, D. C . , 1955, p. 163. (6) n.W. Woolleyand G. Schaffner, Conce,. Res., 1 4 , 8 0 2 (1954). ( 7 ) R. J. Clark, A. Isasca, and .I. W d k e r , Brit. J . Pharniacol., 13, 924 (1958J. (1)
12) (:3) (4) (5)
November, 1962
3,4-XYLIDINE DERIVATIVES
1235
1. N-3,4-Dimethylphenylsuccinamicacid8 2. 2-8-Carboxypropionyl - 4,5 - dimethylacetanilides 3. 2-p-Carl~oxypropiony1-4,5-dimethylaniline hydrochloride hydrates CH3& 4. Sodium 2,6,7-trimethyl-4-hydroxyquinoline- CH3 3-acetate dihydrate H O 5. 6,7-Dinnethyl-2-hydroxyquinoline- 4 - carboxI ylic acitl acetates 6. 6,7-Diniethyl- 4 - hydroxycinnoline - 3 - acetic acid c CH3l3-J" I . 2,3,4,5-'I'etrahydro-7,8-dimethyl-2,5,CH3 dioxobenz[f] azepines H O 8. 4-( p-Dimethylaminophenylamino)-2,5,I1 dihydrc1-6,7-dimethyl-2,5-dioxobenz [f] 11, R=NH(=JN(cH~)~ azepines 9. 4-( Piperidinomethyl)-2,5-dihydro-7,8II, R = C H ~ N ~ dimeth,yl-2,5-dioxobenz[f] azepine A 10. 4-( Met hyl-l-piperazinomethyl)-2,5,11, R=CHzNUNCH3 dihydro-7,8-dimethyl-2,5-dioxobenz [f] azepine 11. 4-Hydroxy-2,5-dihydro-7,8-dimethyl-2,5-dioxobenz [f] azepine* 1%. 3-(Pip~ridinomethyl)-4-hydroxy-2,5-dihydro-7,8-dimethyl-2,5-dioxobenz [f ] azepine
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Experimental 2,4,6-Trinnethyl-4-hydroxyquinoline-3-acetic Acid (Compound 4j.-N-Acetyl(13.2 9.) was heated ovenight on a 2-~-carboxypropionyl-4,5-dimethylaniline water-bath with 2 N NaOH (55ml.). Charcoal was added, and after filtering the solution was left to cool when a sodium salt (8.6 g.) separated, m.p. 360" dec. (sublim.) (fromwater). Anal. Calcd. for C14H14NKaOa.2H20: C, 55.5; H, 6.0; N, 4.6; Na, 7.6. Found: C, 55.7; H, 6.1; N, 4.75; S a , 7.25. The ultraviolet spectrum showed maxima a t 220, 245 and 320.5 mp with log B 1.99, 2.15 and 1.38, respectively. Neutralization of a dilute solution of the salt gave the free acid, no m.p. below 420" (from dimethylformamide). Anal. Calcd. for Ci4Hi~N03: C, 68.5; H, 6.2; 0, 19.6; N, 5.7; acetyl, none. Found: C, 88.6; H,6.2; O,20.0; N, 5.9; acetyl, nil. This compound gave a red ferric chloride color and formed an unstable hydrochloride from strong acid solution. Because of these facts the 4-quinolone structure was preferred to the alternative 2-quinolone, also feasible.@l10 6,7-Dimethyl-4-hydroxycinnoline-3-acetic Acid (Compound 6).ii-2-j3-Carboxypropionyl-3,4-dimethylaniline(5.9g.) was stirred with 2 N HC1 (67 ml.) a t 5". Sodium nitrite solution (lo'%, 20 ml.) was added dropwise and the reA. H. Reos, J. Chem. Soc.. 3111 (1969). R. Camps, Ber., 32,3228 (1899). (IO) E. Wohnlich, Arch. Pharm., 261, 62G (1013). (11) K. Ychofield and J. C. E. Simpson, .I. Chem. Soc., 820 (1943).
(8) (Q)
sulting solution n-as n.armcd Thr precipitate which appeared was collc~tcil (4.8 g.) and recrystallized from acetic acid, m.p. 310" dec. Anal. Calcd. for CI2H1?X2Oa: C, 62.05; H, 5.2; K , 12.05; O! 20.6. Found: C, 62.4; H, 5.25; N, 71.5: 0, 21.2. 4-N-Substituted Aminomethyl Derivatives of 2,5-Dihydro-7,8-dimethyl-2,5dioxobenz[f]azepine.-To thc dioiic (1 g.j in propanol was added the base (1 nil.? and 40% formaldehyde solution (0.8 nil.'!. Thr mixture \vas heated unt,il thtt dione had dissolved, filtered and left to cwol when the Mannich base separatetl. These bases were considered to l)e t>he4-substit ut& derivatives as their infrared spectra retained the peaks at 3.1 li (ni) and 3.3 p (rr-j present in the starting dionv. By this method were obt,aiiicd iil tlie Morpholinomethyl derivative which originally was prepared t o charact,erizr t,lie dione and has not been tested. I t had m.p. 245" (from propanol'). Anal. Calcd. for C!;H,,N?O~: (', t!7.5: H: 7.1; S , 8.7. I.'ound: C. (\7.0: H, 6.7; S,9.3. The base picrate had m.p. 200" (from propaiiol). Ana!. Calcd. for C?3H23X;jChU:T,13.2. Found: X, 13.0. (ii) Piperidinomethyl derivative ompound S ) , m.p. 210" (froin l)ropaiiol :. A nul. Calcd. for C18H??S205: 7 2 . 4 5 H. 7.4: S , 11.3. €ourid: C:. 7 2 . 7 ; € I , i . 6 : S,9.4. The picrate h:id 111.p.2;30" (froin tliosaiiv . I n o / . Calcd. for C24H2jSgOlo: S . t3.:3. I~ouiiil:S . 1:5.35, ..., iiii: N'-Methylpiperazinomethyl derivative (Compound 10 r i i . p 208" 'i'roiii p-opaiiol', : l n < t / . ('ded. for C ' I R H ~ . I S :
