[CONTRIBUTION FROM THE DIVI~ION OF PHYSIOLOQY, NATIONAL INSTITUTE OF HEALTH^
ATTEMPTS TO FIND NEW ANTIMALARIALS. VI. SOME HETEROCYCLIC SULFANILAMIDE DERIVATIVES’ LEWIS J. SARGENT
AND
LYNDON SMALL
Received November 16, 1946
The remarkable bacteriostatic powers of the sulfanilamide group are so well established that it was logical that this class of compounds should be considered when orientation experiments were undertaken in a search for new antimalarials. The therapeutic effect of several sulfonamide derivatives has been demonstrated in connection with simian as well as avian malaria (1, 2,3,4). In some cases a residual immunity was found to persist for periods up to three months (2))but it was questionable if any complete cure was effected. Moreover, recent studies in this laboratory ( 5 ) showed that sulfadiazine and, to a lesser extent, sulfaguanidine exhibit definite prophylactic properties in avian infections. These interesting findings justified further exploration of this field of compounds. The availability of the following heterocyclic amines: 6-methoxy-l,2,3 ,4tetrahydroquinoline,2 6-rnethoxy-8-aminoquin0line,~1,2 ,3,$-tetrahydroquinoline,2 1,2 ,3 ,4-tetrahydroisoquinoline (6), trans-decahydroquinoline (7), and 9,lO-dihydroacridine (8),prepared in connection with other work in progress in this laboratory, made it possible t o prepare a mixed series of sulfonamide derivatives with the view of studying their possible antimalarial properties. The condensation of the various heterocyclic amines with N4-acetylsulfanilyl chloride was effected in one-half minute in boiling pyridine solution, from which the crude N-acetylsulfanilamides were precipitated with hot water. In the case of dihydroacridine a longer period of heating (3 minutes) waa required to complete the reaction. Hydrolysis of the N-acetyl groups proceeded smoothly ; alcoholic alkali proved ineffective. with either aqueous or alcoholic HC1 (8-15y0) The following experimental details (condensation as well as hydrolysis) were generally adhered to in the preparation of the several compounds described below, We are indebted t o Ass%Chemist E. A. Garlock for the analytical data; m.p.’s are uncorrected. EXPERIMENTAL
N*-dcetyl-N~-(6-methoxy-l,~,S,~-tetrahydroqu~nolyl)sulfan~~am~de. An intimate mixture of 6 grams of 6-methoxy-1,2,3,4-tetrahydroquinoline and 9 grams (5% in excess of 1 mole) of N4-acetylsulfanilyl chloride was covered with 25 ml. of purified, anhydrous pyridine, and the red solution boiled for one-half minute. The reaction mixture was poured The work described in this paper was done under a transfer of funds, recommended by the Committee on Medical Research, from the Office of Scientific Research and Development t,o the National Institute of Health. 2 6-Methoxy-l,2,3,4-tetrahydroquinolinewas prepared by high-pressure reduction (copper-chromite) of 6-methoxyquinoline; for latter see Skraup, Monatsh., 6, 760 (1885). 6-Methoxy-8-aminoquinolinewas prepared by reduction (SnC12 HC1) of 6-methoxy8-nitroquinoline; for latter see Chem. Abstr., 22, 1216 (1928). 1,2,3,4-Tetrahydroquinoline was prepared by high-pressure reduction (copper-chromite) of quinoline. 179
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into 200 ml. of boiling water and the product filtered, washed with water, and dried. Recrystallization from slightly diluted ethanol (Norit) afforded 11.6 grams of stout prism clusters, m.p. 222-224'. N1-(6-Methoxy-l, d , ~,~-tetrahydroquinolyl)sulfani~amide. T o a suspension of 8.4 grams of the above material in 68 mi. of ethanol, 17 ml. of concentrated HCl was added and the mixture heated under reflux (steam-bath) for 30 minutes. The resulting solution was poured into 500 ml. of cold water containing an excess of ammonium hydroxide, and the product filtered, washed with water, and dried. After two recrystallizations from 70% ethanol, 6.8 grams of colorless prisms was obtained, m.p. 153.5-155'. N'-Acetyl-N1-(9,lO-clihydroacridyl)sulfanilamide. I n the condensation of 3.4 grams of 9, IO-dihydroacridine with 4.6 grams of N4-acetylsulfanilyl chloride in 18 ml. of anhydrous pyridine, i t was necessary to boil the solution for a t least three minutes to ensure complete reaction. N1-(9,lO-Dihydroacridy1)sulfandamide.A suspension of one gram of N4-acetyl-"(9,lO-dihydroacridy1)sulfanilamidein 8 ml. of absolute ethanol with 2 ml. of conc'd HC1 was heated on the steam-bath (reflux) for 20 minutes. The dark-colored solution was filtered from a small amount of insoluble material and the filtrate poured into cold water (50 ml.). The gum which separated solidified when triturated with a little warm 2 N HC1probably the hydrochloride. The latter was collected and converted to the free base by digesting with warm 2 N ",OH. Crystallization from 70% ethanol yielded colorless leaves contaminated with some prisms; the mixture melted over the range 155-115'. It was found that the prismatic material could readily be removed by sublimation a t 125-130°/0.5 mm.; this proved t o be 9,10-dihydroacridine, identified by its melting point (172-173') alone or mixed with a n authentic specimen. The non-volatile or desired product crystallized from 70% ethanol in glistening, hexagonal plates, m.p. 203-204.5'. SUMMARY
A series of hetgrocyclic substituted sulfanilamide derivatives has been prepared. Two members of the series, SN 190 and SN 2510, showed slight plasmodicidal activity towards P. gallinaceurn (chick infection). BETHESDA 14, MD.
REFERENCES (1) SINQH AND SINQH, J. Malaria Inst. India, 2,181 (1939). (2) COQQESHALL, Am. J. Trop. Med., 18,715 (1938). (3) DIKSHIT AND GANAPATHI, J. Malaria Inst. India, 3,525 (1940). (4) MARSHALL AND CO-WORKERS, J. Pharmacal., 76, 89 (1942). (5) COATNEY AND COOPER, U.S. Pub. Health Reports, 69, 1455 (1944). (6) CROMWELL AND CRAM, J.Am. Chem. Soc., 66,305 (1943). (7) ADKINS AND CRAMER, J.Am. Chem. SOC.,62,4349 (1930). (8) ADKINSAND COONRADT, J. Am. Chem. SOC.,63, 1563 (1941).
