[CONTRIBUTION FROX
THE
DIVISION OF PHYSIOLOGY, NATIONALIWSTITUTE OF
HEALTH]
STUDIES IN THE ACRIDINE SERIES. 111. DIALKYLAMINOALKYLAMINES DERIVED FROM 5- AXD 7-Bz-METHOXY9-CHLORO-1,2,3 ,4-TETRAHYDROACRIDINES‘ LEWIS J. SARGENT
AND
LYNDON SMALL
Received February 86, 1947
The preparation and properties of a series of 9-dialkylaminoalkylaminotetrahydroacridines were described in a recent paper from this laboratory (l),and it was shown that these substances were devoid of plasmodicidal activity. The presence of four additional hydrogen a1,oms on one of the benzenoid rings of tetrahydroacridine (I) apparently resultti in a system whose chemical demeanor is at once reminiscent of the acridines as well as of certain quinolines. The failure of the above-mentioned series of compounds to arrest-if only transiently-avian malarial infections ( P . gallinaceurn), may conceivably be attributed to the absence of those bz-substituents (uiz., chlorine and methoxyl) now known to be requisite for activity in Ihe structurally analogous schizonticide Atabrine (2), on the one hand, and the various, reputedly active, substituted 4-aminoquinolines (3) on the other. Insofar as the properties and reactivity of the meso function para t o the heterocyclic nitrogen are concerned, the little-studied tetrahydroacridines (I) appear to be more closely related to the dkyl- or aryl-quinolines (11) than they are to acridine, the system upon which Atabrine is built (1). Variously substituted 4-aminoalkylquinolines of type IIa were the subject of recent, careful studies by Steck and his colleagues (4) who, uniortunately, gave no data regarding the activity of their compounds. Holcomb and Hamilton ( 5 ) , as well as Van Arendonk and Shonle (6)) in reexamining earlier work of Russian investigators (3), turned to 4-aminoalkylquinolinesof type TIb which they reported to be slightly active. Gilman and Spatz (7)extended these ideas and introduced t4henovel “open-models" of htabrine which were, in effect, arylquinolines of type IIc. Exhaustive studies with Atabrine (2) have demonstrated that the effect of the methoxyl group upon antimalarial activity is virtually insignificant when compared witb the contribution made by the chlorine atom. “Desmethoxyatabrine” was found t o be nearly seven times as active as “deschloroatabrine” (2). On the other hand, less definite data are available relevant to the respective effects of the methoxyl group and the chlorine atom on the activity of alkyl substituted 4-aminoquinolines, though it appears that here, too, the influence of the chlorine atom is greater than that of the methoxyl group (3). In continuing our studies with the 9-dialkylaminoalkylaminotetrahydro‘This work was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the National Institute of Health. Communication X X I I I in the series “Attempts t o Find New Antimalarials.” 567
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LEWIS J. SAROEINT AND LYNDON ShfALL
acridines, it was logical to extend these investigations to include bz-methoxyl-as well as bz-chloro- substituted tetrahydroacridines in order to ascertain the influence of these substituents on plasmodicida! activity. This communication concerns itself with the 5- and 7-bz-methoxy-9-aminotetrahydroacridines. The desired 5- and 7-methoxy-l , 2,3,4-tetrahydroacridoneswere prepared by the method of Hughes and Lions (8). The latter investigators extended the Conrad and Limpach (9) synthesis of 4-hydroxyquinaldines, and prepared numerous tetrahydroacridones through condensation of the appropriate aniline with ethylcyclohexanone-2-carboxylatefollowed by cyclization of the resulting ethyl-2-arylamino-1-cyclohexene-1-carboxylates.The methoxytetrahydroacridones which we synthesized by this procedure were smoothly converted t o the corresponding 9-chloro derivatives by treatment with phosphorus oxychloride. The condensations of the methoxy-9-chlorotetrahydoacridines with the various amines (Table I) were effected as recorded previously (1). It waa
R
R
I
1. 9-Aminotetrahydroacridine 11.4-Aminoquinoline (R = Dialkylaminoalkylamine) (R = Dialkylaminoalkylamine) a) R’ = CHs b) R” = CHa c) R”’ = 3-Chlorophenyl found advantageous, however, to increase the reaction time from 24 to 60 hours (at 180”)to ensure better conversion to the desired product. Apart from the morphdino- and piperidino-substituted 7-methoxytetrahydroacridines, which were crystalline and could be sublimed unchanged in a high vacuum, the bulk of the reaction products were viscous oils. For the pharmacological tests, the latter were converted to the crystalline phosphates (solvated) since, in most cases, the hydrochlorides were not readily accessible. On the other hand, the perchlorates and picrates served best as analytical specimens, crystallizing solvent-free. The yields of the several methoxy-9-aminotetrahydroacridines dealt with in this investigation ranged from 4oy0, for the piperidino analog, to 9570, realized in the dibutylamino member of this series. Acknowledgment. The amines employed in this investigation were made available to us by Dr. R. C. Elderfield (Columbia Univ.) and Dr. Xathan Drake (Univ. of Maryland). Dr. George H. Coleman (State Univ. of Iowa) supplied the ethylcyclohexanone-2-carkoxylate. The micro-analytical data are by C. A. Kinser and Betty Mount. EXPERIMENTAL
Melting points are uncorrected. The experimental details given below are repreaentrrtive of the methods used in this investigation.
STUDIES I N 1'BE ACRIDISE SERIES.
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I
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LEWIS J. SAHGEKT AND LYNDON SMALL
7-Methoxy-9-chloro-l ,2,9,4-tetrahydroacridine. Ethyl cyclohexanone-2-carboxylate (61 g.) and p-anisidine (44 9.) condensed rapidly without catalyst, and the water formed was removed at 100" under diminished pressure. The powdered material was cyclized in 500 ml. of heavy liquid petrolatum a t 285", yield 68 g. (83% over-allj. The crude acridone was added slowly t o 200 ml. of phosphorus oxychloride at loOD, and refluxed for 30 min. This was decomposed with ice, and stirred into solution at room temp. The hydrochloride crystallized rapidly, and was washed with cold 3 X HCl. It w a dissolved in one liter of hot water, decolorized, and precipitated crystalline while still warm, with 3 N ammonia; recrystallized from 250 ml. of alcohol, hard white crystals, m.p. 123-123.5",photosensitive; yield 62 g. (85%). Anal. Calc'd for Cl4Hl4C1NO:C, 67.9;H, 5.70. Found: C, 68.2; H, 5.58. 6-Methoxy-9-chloro-1 , d , S , 4-tetrahydroacridine. Three-tenths mole (51 g.) of ethyl cyclohexanone-2-carboxylate and 0.3 mole (37 9 . ) of o-anisidine were condensed (5 drops of 6N HCl necessary) and the product cyclized as above, yield 38 g. (55%); from 500 ml. of alcohol, 22.5 g. (33%). This was added cold t o 60 ml. of POCla, refluxed for 30 min., and poured on ice; the crystals slowly dissolved, and the base waa precipitated with ammonia, 22.5 g. It was recrystallized twice from 40 ml. of methanol, removing a little inorganic material; 19.6 g. (81%), yellow needles, m.p. 128-128.5'. Anal. Calc'd for C I ~ H ~ ~ C I K C,O67.9; : €1, 5.70. Found: C,67.9;€1, 5.88. 7-Methoxy-9(~-di-n-but~laminopropylamino)-I,.t ,9,.$-tetrahydroacridinephosphate. Condensation of 6 g. of 7-methoxy-9-chloro-l,2,3,4-tetrahydroacridine with 9 g. (2 moles) of 3-di-n-butylaminopropylamine and a little copper-bronze powder was effected in a sealed tube heated at 180" for 60 hrs. The light brown, partially crystalline reaction product was worked up in the manner set, forth in an earlier paper (l),and yielded 9.6 g. (95%) of a dark yellow syrup which was converted to the crystalline phosphate by treating, a t On, with 25% to Congo acidity. Recrystallization of the crude, solvated salt (12 6.) alcoholic from methanol (Norit), gave 7 g. of colorless, needle-rosettes, m.p. 222-224" d . As a rule, the perchlorates of the various reaction products were prepared with 25% alcoholic HClO,; alcoholic picric acid (5%) served in the preparation of the picrates. SUMMARY
Seven ?-methoxy-, and three 5-methoxy-9-dialkylaminoalkylaminottrahydroacridines, as well as the intermediate 7- and 5-methoxytetrahydroacridones have been prepared. Antimalarial activity towards P . gullinaceurn (chick infection) was absent in both series of drugs. BETHESDA14, MD.
REFERENCES (1) SARGENTAND SMALL,J . Org. Chem., 11, 359 (1946).
(2) MIETZSCH AND MAUSS,German Patent 553,072,Chem. Abstr., 26,4683 (1932);CHERNTSOV AND DROSDOV, J . Gen. Chem., (U.S.S.R.), 9, 1435 (1939); Chem. Abstr., 34, 1667 AND TRAVIN, J . Gen. Chem., (U.S.S.R.),11,243 (1941);Chem. (1940);MAGIDSON This Laboratory, unpublished results. Abstr., 36,7965 (1941); COATNEY, (3) ANDERSAG,BREITNER,A N D JUNG,C . S. Patent 2,233,970;Chem. Abstr., 36, 3771 (1941); MAGIDSON AND RVBTSOV, J . Gen. Chem., (U.S.S.R.),7,1896 (1937);Chem. Abstr., 32, 564 (1938); HAL'PERIX, illed. Parasitol. Parasitic Diseases, (CJ.S.8.R.), 9. No. 1-2, 44 (1940);Chem. Abstr., 36, 1674 (1912). (4) STECK,et al., J . Am. Chem. Soc., 68, 129, 132, 380, 1241 (1946). (5) HOLCOMB AXD HAMILTON, J . A m . Chem. Soc., 64, 1309 (1942). (6) VANARENDOXK AXD SHONLE, J . Am. Chem. Soc., 66, 1284 (1944). (7) GILMANAXD SPATZ,J. Am. Chem. Soc., 66,621 (1944). (8) HUGHES AND LIONS,J. Proc. Roy. Soc. N . S . W Q Z ~ 71, S , 458 (1937-8). (9) CONRAD AND LIMPACH, Ber., 20,944, 948 (1887);LIMPACH, Ber., 64, 969 (1931).
