[CONTEIBUTIONFROM THB DIVISIONOF PHYSIOLOGY, NATIONALINSTITUTE OF HBALTE]
ATTEMPTS TO FIND NEW ANTIMALARIALS. XXII. BIGUANIDE DERIVATIVES O F PHENANTHRENE' EVERETTE L. MAY Received December 19, 10.48
In a foregoing communication (I), l-isopropyl-5-(9-phenanthryl)biguanide (I), a phenanthrene analog of Paludrine (2), was reported to be ineffective against gallinaceum malaria in chicks. Since Paludrine contains chlorine, and aa nuclear chlorine generally enhances antimalarial activity (3), a logical step appeared to be the synthesis of a representative of I containing this element.
CI*Hg-9-NHC(:NH)NHC(:NH)NH-i-CaH, (I) c14H8{:HC( :NH)NHC( :NH)NH-i-CaH, (11) Ci*He-3-NHC(:NH)NHC( :NH)NH-i-CaH, (111) C14He-9-NHC(:NH)NHCN (IV) Me2NH'HC' > C&e-9-NHC( :NH)NHC ( :WH)NMeZ (V) N~ v C14Hg-9-N: C(SCHa)NH2 (VI) NHzC( :NH)NMel Accordingly, I1 was synthesized in a manner described previously (1) from 1-cyano-3-isopropylguanidine and 3-chloro-6-phenanthrylaminehydrochloride. The latter was obtained by a Beckmann rearrangement of the oxime of 3-chloro6-acetylphenanthrene. For biological comparison, the chlorine-free analog (111) of I1 was likewise prepared from 3-phenanthrylamine hydrochloride. Also included in this paper is 1,l-dimethyl-5-(9-phenanthryl)biguanide(V). Attempts t o obtain V by the reaction of 2-methyl-l-(9-phenanthryl)-2-thiopseudourea (VI) with dimethylguanidine failed. Furthermore, previous efforts (1) to condense l-cyano-3-(9-phenanthryl)guanidine(IV) with aliphatic amine hydrochlorides to give corresponding biguanides were unsuccessful. It has now ' been found that by fusing a mixture of IV and dimethylamine hydrochloride, V is formed in a yield of about 50%. Similarly, I could be prepared from IV and isopropylamine hydrochloride. All of the compounds tested (11, 111, and V) were inactive. E XPERIMENTAL2*3
9-Phelaunthrylthiourea. A mixture of 1.9 g. of 9-phenanthrylisothiocyanate (1), 20 cc. of ethanol, and 8 cc. of lO-lS% alcoholic ammonia was shaken in a stoppered flask at 40"for 15-20 minutes. On cooling 1.9 g. of the thiourea was obtained, m.p. 201-203'. It crystallized from ethanol in thin rectangles of m.p. 203-204" (decomp.).
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1 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 to the National Institute of Health. 2 All melting points are uncorrected. VThe microanalyses were carried out by C. A. Kinser and Betty Mount of this Laboratory. 443
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Anal. Calc'd for ClsH12N2S:C, 71.42; H, 4.79. Found: C, 71.37; H, 4.75. R-Methyl-1-(9-phenanthryl)-R-thiopseudourea (VI). By refluxing together for ten minutes, 0.5 g. of 9-phenanthrylthiourea, 0.3 g. of methyl iodide, and 5 cc. of absolute ethanol, cooling, making slightly ammoniacal, and diluting with water, V I was obtained in a 0.5-g. yield. It crystallized from aqueous ethanol (Korit) in hexagons of m.p. 159-160'. Anal. Calc'd for C16H14N2S:C, 72.15; H, 5.30. Found: C, 72.11; H, 5.26. Attempts to condense this compound with 1,l-dimethylguanidine to obtain the corresponding biguanide, were unsuccessful. It could, however, be desulfurized (15% alcoholic NH, at 100" in a sealed tube) to 9-phenanthrylguanidine, m.p. (hydrochloride) 256-258" (1). S-Chloro-6-phenanthrylamine.A mixture of 4.2 g. of 3-chloro-6-acetylphenanthrene (3), 3.6 g. of hydroxylamine hydrochloride, 8 cc. of pyridine, and 25 cc. of absolute ethanol was refluxed for one-half hour and diluted with 5-10 cc. of water; yield of oxime 4.3 g., m.p. 211-213.5". It was dissolved (warming) in 8 cc. of acetic anhydride and 16 cc. of acetic acid, and hydrogen chloride passed into the solution for three hours. Upon standing overnight, the yield of 3-chloro-6-acetylaminophenanthrene,m.p. 234-237", was 4.2 g. A mixture of this, 32 cc. of acetic acid, and 32 cc. of 25% HC1 was refluxed for 1.5 hours to give 3.5 g. of 3-chloro-6-phenanthrylaminehydrochloride (m.p. 2&264", decomp.). The free base, prepared with dilute NH40H, melted a t 156-157" after a recrystallization from ethanol followed by a high vacuum sublimation; thick plates. Anal. Calc'd for Ct4HloClN:C, 73.84; H , 4.43. Found : C, 73.74; H, 4.39. l-(d-Chloro-6-phenanthryl)-5-isopropylbiguanide hydrochloride (11). 1-Cyano-3-bopropyl-2-methyl-2-thiopseudourea(2.0 g.) was desulfurized with 20 cc. of 10-15% alcoholic NH3 (7.5 hours in a sealed tube at 100") to give 1.6 g. of oily 1-isopropyl-3-cyanoguanidine (1). A mixture of the latter, 2.4 g. of 3-chloro-6-phenanthrylaminehydrochloride, and 20 cc. of 95% ethanol was refluxed for 3.5 hours and diluted with 30 cc. of acetone. After thorough cooling in ice, 2.3 g. of 11, m.p. 250-253" was obtained; fine, long needles from 95% ethanol, m.p. 251-252" (decomp.) . Anal. Calc'd for Cl&lClzNs: C, 58.47; H, 5.42. Found: C, 58.62; H, 5.45. The picrate crystallized from 95% ethanol in orange prisms of m.p. 197-198" (sinters from 194"). Anal. Calc'd for C26H&lNsO,: C, 51.51; H, 3.98. Found: C, 51.74; H, 4.21. i-Isopropyl-6-(3-phenanthryl)biguanide hydrochloride (111). The 1-isopropyl-3-cyanoguanidine resulting from the desulfurization of 2.0 g. of the corresponding S-methyl compound (see previous experiment), 2.4 g. of 3-phenanthrylamine hydrochloride (4),and 18 CC. of 95% ethanol were refluxed together for 2.5 hours. The mixture was cooled in ice to give 2.1 g. of I11 of m.p. 256-259"; oblong plates from 95% ethanol, m.p. 257-258'. Anal. Calc'd for CIgH&lN&: C, 64.12; H, 6.23. Found : C, 64.56; H, 6.45. The picrate gave orange prisms from 95% ethanol, m.p. 214.5-216'. Anal. Calc'd for C26H24Ng07.: C, 54.75; H, 4.41. Found: C, 54.94; H, 4.58. 1 , I-Dimethyl-6-(9-phenanthryl)biguanide(V). An intimate mixture of 0.4 g. of IV (1) and 0.2 g. of dimethylamine hydrochloride was heated at 130-140" for one hour. Upon cooling, the melt solidified and was digested with boiling absolute ethanol. After filtering from insoluble material, diluting to turbidity with ether, and filtering again, 0.3 g. of prisms contaminated with a, little dimethylamine hydrochloride separated. This was treated with dilute NH4OH and the liberated base dried in ether and recrystallized from aqueous methanol; thin prisms of m.p. 133-135".
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Anal. Calc’d for ClsHl~Ns:C, 70.79;H, 6.27. Found: C,70.93;H, 6.03. In a similar manner IV and isopropylamine hydrochloride gave the hydrochloride of I identical with that previously described (1). SUMMARY
1-(3-Chloro-6-phenanthryl)-5-isopropylbiguanide, its chlorine-free analog and
1 ,l-dimethyl-5-(9-phenanthryl)biguanide have been synthesized as potential an intermediate, was prepared antimalarials. 3-Chloro-6-phenanthrylamine, by the Beckmann rearrangement of the oxime of 3-chloro-6-acetylphenanthrene. BETEESDA14, MD. REFERENCES
(1) MAY, J . Org. Chem., 12, 437 (1947). (2) CURD,DAVEY,AND ROSE,Ann. TTOP.Med., 39,208 (1945). CURD AND ROSE, J . Chem. Soc., 729 (1946). (3) MAYAND MOSETTIO,J . Org. Chm., 11,429 (1946). (4)MOSETTIGAND KRUEGER,J . OTg. Chem., 3,317 (1938).
