[CONTaIBUTION FBOM TEE
DIVISION OF PHYSIOLOGY, NATIONAL INSTITUTE OF HEALTH]
ATTEMPTS TO FIND NEW ANTIMALARIALS. XVIII.1*2AMINO ALCOHOLS OF THE TYPE-CHOHCH2NR2 DERIVED FROM 3-BROMO-10-ACETYLPHENANTHRENE EVERETTE L. MAY
AND
ERICH MOSETTIG
Received July 23, 1946
In previous papers (1,2,3) of this series we described the synthesis of nuclearchlorinated phenanthryl alkamines of the formulas I, 11,and 111,and compared their plasmodicidal effectiveness with that of the corresponding “des-chloro” compounds.
Y
I y
I1
I11
-CHOHCHzNRa
Mauss (4) reports that the bromine-analog (IV) of Atabrine is only half as active (Plasmodium cathemerium, canary) as Atabrine itself. On the other hand, Schultz, Goldberg, Ordas, and Carsch (5,6) demonstrated that there is no significant difference in therapeutic action (P. gallinaceurn) between analogous members of the 9-bromophenanthryl-3-alkamine series (Va) and the 9-chlorophenanthryl-3-alkamine series (Vb) . CHOHCH2N&
A
IV Va,
Vb,
X = Br X = C1
1 f i e 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. a Studies in the Phenanthrene Series XXXIV.
627
628
EVERETTE L. MAY AND EXCH MOSETTIG
Thus it appeared to be of interest to replace the chlorine in I, 11, or I11 by bromine, in order to study the effect of this chemical change upon therapeutic effectiveness. Of types I, 11,and I11 the bromine analog of I11 appeared most readily available, and a convenient starting material for its preparation, namely 3-bromo-10phenanthrenecarboxylic acid has been described (7). This acid was converted by the Arndt-Eistert reaction via the diazo ketone to 3-bromo-10-u-bromoacetylphenanthrene. We prepared four amino alcohols (dibutylamino to diheptylamino derivative) by exchanging the u-bromine atom with the appropriate amine, and reducing the resulting amino ketones with aluminum isopropoxide. In comparing the biological data (8, 9) of the nuclear-brominated alkamine$ and their “chloro analogs” (3), one finds no significant difference between the two series. The tolerated doses lie in the same range. The therapeutic effectiveness of the members of the bromo series is approximately of the same order (or slightly higher) than that of the corresponding “chloro analogs”. None of TABLE I AMINO ALCOHOLS SOLVENT
l
Y.P.,
“c
IAbsolute
226-228.5
Zo:ute EtOH-MenCO1214-215
Absolute I1952Kl EtOH-Me&O
i
1I
H% -
APPEAPANCE
I
Clusters of
CuHnBrClNO 62.00
6.72
62.12 6.48
8Et0ds
CnHrsBrClNO 63.35
7.16
63.06 7.05
Prisms
CiaHaBrCWO 64.55
7.54
64.25 7.23
CpHtrBrClNO 65.63
7.64 65.91 7.66
EtOH-M&O
-
the four amino alcohols described herein, shows any activity against sporozoiteinduced gallinaceurn malaria (9). Acknowledgments. We wish to thank Mr. Edward A. Garlock, Jr. for carrying out the microanalyses. We are indebted to Mr. H. George Latham, Jr. for valuable assistance. EXPERIMENTAL4
3-Bromo-10-phenanthrenecarboxylic acid was prepared as described by Pschorr and Schiitz (7). These authors reported the m.p. 187”for the intermediate a-(p-bromophenyl)o-nitrocinnamic acid. We observed the m.p. 169-170”. Occasionally, when the temperature rise was gradual, i t would sinter a t 175”and melt a t 191-192.5 ’, suggesting dimorphism. 9-Bromo-IO-phenanthroylchloride. A mixture of 5 g. of the acid and 20 cc. of freshlydistilled thionyl chloride was refluxed for one to two hours. Excess reagent was evaporated in vacuo and the residue recrystallized from benzene-ligroin (30-60”); yield 4.6 g. (87%), 8 The Survey Number, designated SN, identifies a drug in the files of the Survey of Antimalarial Drugs. Activities of drugs so listed will be published in a forthcoming monograph. The SN of the drugs which were submitted t o biological test, are given in the Experimental (Table I). 4 All melting points given, are uncorrected.
ATTEMPTS TO FIND ANTIMALARIALS.
XvlII
629
m.p. 158-159.5". Recrystallized again from benzene, followed by sublimation in high vacuum, the material melted at 160-161"; large needles. Anal. Calc'd for C15HsBrClO: C , 56.37; H, 2.52. Found: C, 56.23; H , 2.77. When a mixture of benzene and thionyl chloride was used in this preparation, there was only partial conversion (about 40%) to the acid chloride. The remainder of the material was recovered as a difficulty soluble solid (probably anhydride) of m.p. 279-283". It was insoluble in alkali but could be hydrolyzed to 3-bromo-IO-phenanthrenecarboxylic acid with refluxing sodium hydroxide-dioxane solution. 1-Bromo-1O-w-bromoacetylphenanthrene.To a stirred mixture of 300 cc. of an ether solution of diazomethane (from30 g. of nitrosomethylurea) and 130 cc. of dry benzene was added 16 g. of 3-bromo-10-phenanthroyl chloride during one hour (temperature 0" to 5"). The resulting suspension was stirred an additional 1.5 hours a t 0" to 5" and for ten hours a t room temperature. After thorough cooling in ice, the diazo ketone (12, g. of m.p. 150" with gas evolution) was collected, stirred in suspension with 120 cc. of dioxane, and a solution of 8 cc. of 40% HBr in 8 cc. of dioxane added during twenty minutes (temperature 20-25"). Five grams of sodium carbonate in 10 cc. of water was added and the dioxane evaporated in vacuo a t a bath temperature below 50". The residue was partitioned between warm benzene and water, the benzene layer dried over sodium sulfate and concentrated to 25-30 cc. On dilution with ligroin (30-60"), the bromo ketone separated in a yield of 12.5 g. (66% based on acid chloride), m.p. 121-124.5'. It crystallized from ethyl acetate in large, pale yellow needles of m.p. 129-130". Anal. Calc'd for ClsHleBroO: C, 50.83; H, 2.67; Br, 42.28. Found: C, 51.87; H, 2.90. Another recrystallization did not change the m.p. Found: C, 51.63; H, 2.82; Br, 43.05. In later runs another crystalline modification (m.p. about 110") of the bromo ketone wa8 isolated. 3-Bromo-10-acetylphenanthrene. A mixture of 0.5 g. of the crude bromo ketone above (either modification), 0.3 g. of palladium-charcoal (5% Pd), and 25 cc. of absolute ethanol absorbed one mole of hydrogen in forty-five minutes. After warming on the steam-bath, catalyst was removed and the filtrate concentrated to about 10 cc. On cooling, 3-bromo-10acetylphenanthrene separated in a yield of 0.3 g., m.p. 142.5-144". One recrystallization from absolute ethanol followed by sublimation in a high vacuum gave needles of m.p. 144.5-145.5". Anal. Calc'd for ClsHllBrO: C, 64.22; H, 3.71. Found: C, 64.40; H, 3.61. Amino alcohols. A mixture of 5 g. of 3-bromo-1O-~-bromoacetylphenanthrene, two equivalents of secondary amine, 22 cc. of dry ether, and 3 cc. of acetone was shaken for two to six hours, cooled in the ice-box and secondary amine hydrobromide filtered off. The filtrate was evaporated to dryness in vacuo and the residue reduced with 20-30 cc. of 3 N aluminum isopropoxide (IO) (1.5-2 hours). The residue from evaporation of the isopropanol in vacuo, was partitioned between ether and an excess of 10% sodium hydroxide. The ether layer was washed twice with water, dried over sodium sulfate and acidified with 5-6 cc. of 20% alcoholic HCl to give the crystalline amino alcohol hydrochlorides in 6348% yields (based on bromo ketone). SUMMARY
Four amino alcohols derived from 3-bromophenanthrene, and carrying the alkamine side chain in position 10 have been prepared. The evaluation of these compounds as antimalarials is discussed. BETRESDA 14, MD.
630
EVBJBETTE L.
MAY
AND ERICH MOSE'Fl'IG
REFERENCES (1) MAYAND MOSETTIG, J . Org. Chem., 11,429 (1946). (2) MAYAND MOSETTIG, J . Org. Chem., 11,435 (1946). J.Org. Chem., 11,441 (1946). (3) MAYAND MOSETTIG, (4) MAUSS,Medizin und Chemie, 4,60 (1942). GOLDBERG, ORDAS,AND CARSCH, J. Org. Chem., 11,307 (1946). (5) SCHULTZ, (6) SCHULTZ, GOLDBERG, OBDAS,AND CARSCH,J . Org. Chem., 11,320 (1946). (7) PSCHORR AND SCHUTZ, Ber., 39, 3118 (1906). (8) EDDY,Unpublished results. (9) COATNEY AND COOPER, Unpublished results. (10) MAYAND MOSETTIG, J . Org. Chem., 11, 1 (1946).
