[CONTRIBUTION FROM THE DIVIsION OF PHYSIOLOGY, NATIONAL INSTITUTE OF HEALTH]
ATTEMPTS TO FIND NEW ANTIMALARIALS. 11.l~ * AMINO ALCOHOLS DERIVED FROM PHENANTHRENE EVERETTE L. MAY
AND
ERICH MOSETTIG
Received December I d , 19.&
In the foregoing paper (1) we described a series of amino alcohols carrying the ethanolamine side chain in position 9 of tetrahydrophenanthrene. This communication deak with amino alcohols in which the side chain is attached to the 9-position of phenanthrene itself (I).
I The two series, thus, are structurally closely related, the difference consisting only in the degree of saturation of one of the terminal benzene rings of the phenanthrene nucleus. The amino alcohols were synthesized as described previously, namely, via the w-bromomethyl ketones and amino ketones. The catalytic reduction of the amino ketones to the amino alcohols proved to be rather unsatisfactory. In the fist place the hydrogen absorption took place considerably more slowly than was the case when the side chain was attached to the 2- or 3-position of the phenanthrene nucleus, or to the 9-position of tetrahydrophenanthrene. Secondly the tendency to absorb more than one molecular equivalent of hydrogen was quite pronounced. This surplus of hydrogen could not be accounted for by reductive fission. The desired amino alcohols, however, were obtained in good yields when aluminum isopropoxide in isopropanol was employed as the reducing agent. When 9-(2-trans-decahydroquinolino-loxoethy1)phenanthrene was reduced in this manner the two expected diastereomeric forms were obtained in the approximate ratio of 7:s. The tolerated doses (chicks) of these compounds are approximately the same as those of their analogs in the “tetrahydro series”. Also in this series one observes a definite decrease in toxicity with the increase in size of the dialkylamino group (Dr. Nathan €3. Eddy) (2). In regard to effectiveness against Plasmodium gallinaceum it appears that, as a whole, the drugs of this series are somewhat superior to their “tetrahydro analogs” (Dr. G. Robert Coatney and Dr. W. Clark Cooper) (3). None of the drugs showed any activity towards 1 The work described in this paper was done in part under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the National Institute of Health. * Studies in the Phenanthrene Series XXVII.
10
11
AMINO ALCOHOLS FROM PHENANTHRENE
sporozoite-induced gallinaceum malaria (3). SN 8867 (also recorded as NIH 1111) was investigated clinically, and shown to have antimalarial activity TABLE I* ANTIMALARIAL ACTIVITYOF AMINOALCOHOLS SN
I
CirEIr9-CHOHCHr
I
Q
1776 1777 1778 1779 5242 5480 6827 6828 8867 (NIH 1111) 5970
(against P. vivaz) greater than that of quinine.’ The phenanthrene alkamines are more effective inhibitors of plasma cholinesterase than their “tetahydro analogs”, but show the same general relationship between size of the dialkylamino group and inhibitory effect (Dr. Charles I. Wright) (4). ACKNOWLEDGMENT
We wish to thank G. D. Searle and Company for the supply of large amounts of 9-acetylphenanthrene, Dr. R. C. Elderfield, Columbia University, for supplying us with dihexyl-, diheptyl- and dinonyl-amine, and Mr. Edward A. Garlock, Jr., of this Laboratory for carrying out the microanalyses. EXPERIMENTAL^ 9-Acetylphenanthrene was prepared by the method of Bachmann and Boatner (5). Sa-Bromoacetylphenanthrene (6) was prepared by adding one molecular equivalent of bromine dropwise t o an ice-cooled stirred suspension of 9-acetylphenanthrene (1 g. in 5 cc. of ether). The bromo ketone was filtered off and washed with ether. The yield of product melting at 94-95’ was quantitative. 9-(I-Dipropylnmino-l-hydroxyethyl)phenanthrene hydrochloride. A mixture of 5 g. of 9*-bromoacetylphenanthrene, 3.5 g. of dipropylamine, and 30 cc. of dry ether was shaken mechanically overnight, cooled in the ice-box for one hour and the dipropylamine hydro$ I n Table I are listed the compounds which were submitted for biological investigations. I n the first column are given the identification numbers assigned t o the drugs by the Malaria Survey Office of the National Research Council. The third column shows the approximate “Quinine equivalents” expressing the effectiveness of the drugs towards Plasmodium gallinaceum,compared with that of quinine. All compounds listed in the Table were administered as hydrochlorides, except SN 1777 which was administered as base. The synthesis of S N 1776 and SX 1777 has been described previously by Mosettig and van de Kamp (6). 4 The clinical study with this drug will be published by the several groups t o whom this compound was assigned by the Board of Coordination of Malaria Studies. 6.411 melting points are uncorrected.
12
EVERETTE L. MAY .4ND ERICH MOSETTIG
bromide filtered off. The ether filtrate was made slightly acidic with 1570 alcoholic hydrogen chloride, whence the amino ketone hydrochloride (4.4 g.) separated as an oil which soon crystallized. After one recrystallization from a methanol-ether mixture (Norit must be used to ensure success of the subsequent reduction) a yield of 3.1 g. was obtained. The melting point was 163-167". When shaken under hydrogen with 0.14 g. of platinum oxide catalyst in 50 cc. of 80% aqueous methanol i t absorbed 1.15 molecular equivalents of hydrogen in twenty hours. At this point hydrogenation had practically stopped. The syrup left after filtration and evaporation of solvent was dissolved in acetone, from which the amino alcohol hydrochloride separated in long white prisms (1.8 g.), m.p. 180-186". From the mother liquor 0.3 g. of unchanged amino ketone hydrochloride was recovered. It was not attempted to prepare this amino alcohol by the aluminum isopropoxide reduction method which was subsequently found more advantageous in this series of compounds. Preparation of amino alcohols 8 , 9,4,6,6,7,8.9w-Bromoacetylphenanthrene (1 molecular equivalent), the appropriate secondary amine (2 molecular equivalents), and dry ether (5 cc. per gram of bromo ketone) were mixed and the suspension shaken mechanically until all bromo ketone had disappeared (two to ten hours). After cooling in the ice-box for one t o two hours, secondary amine hydrobromide was filtered off and the ether evaporated (the last few cubic centimeters in uacuo). T o the oily residue was added 3 N aluminum isopropoxide (3.5 cc. per gram of bromo ketone employed in the preparation of the amino ketone) and the reduction carried out essentially by the procedure of Lund [See paper I (1)l. It was found advantageous when working with small amounts of material t o use steambath heating and to replace liquid which distilled from the reaction mixture by dropwise addition of isopropanol. The time required for the reductions was one t o two hours. Finally the isopropanol was evaporated in Vacuo and the residue was partitioned between a n excess of 10% sodium hydroxide and ether. The ether layer was washed twice with water, dried over sodium sulfate and the solvent evaporated. The dark-colored residue was evaporatively distilled at 190-210°/0.05 mm. The straw-colored distillate was dissolved in dry ether and the solution made slightly acidic with about 15% alcoholic hydrogen chloride. After some time (1 t o 24 hrs.) the amino alcohol hydrochlorides crystallized. The yields ranged from 40% t o 75%, based on bromo ketone. 9-(S-dl-trans-Decahydroquinolino-I-hydroxyethyl)phenanthrene. Thirty grams of 9wbromoacetylphenanthrene, 28 g. of dl-trans-decahydroquinoline (7) and 150 cc. of U.S.P. ether were mixed, the whole was shaken mechanically for two hours and cooled in the icebox. The trans-decahydroquinolinehydrobromide which separated was filtered off (21.5 g.) . On standing overnight in the ice-box the ether filtrate yielded 25 g. of amino ketone melting at 93-95". Twenty-two and five-tenths grams of this compound was reduced with 100 cc. of 3 N aluminum isopropoxide solution as described above. After about 3 hours the acetone test was negative. Upon distilling the solvent and partitioning the residue between a n excess of 10% sodium hydroxide and about 100 cc. of ether, a crystalline solid separated in the ether layer. It was filtered off and the filtrate (X) was put aside. The precipitate (12 g., m.p. 143-145") was suspended in acetone and treated with 11 cc. of 15% alcoholic hydrogen chloride. Overnight 5.7 g. of amino alcohol hydrochloride separated as clusters of fine white needles, m.p. 243-245'. One recrystallization raised the melting point to 249250.5", which did not change on further recrystallization. This compound is designated Isomer A. The corresponding base melted a t 140-142". The acetone filtrate of hydrochloride A yielded, on cooling in the ice-box, a 2.7 g. fraction of amino alcohol hydrochloride. By evaporation of the resulting filtrate to dryness and trituration of the residue with acetone, a n additional 1.5 g. was obtained. These two fractions were combined and recrystallized from an absolute ethanol-ether mixture. The substance appeared in clusters of blade-like plates of m.p. 203-207" (Isomer B). It still contained a small amount of A which could be removed by conversion to the base (m.p. 154.5-156") and recrystallization of the latter from alcohol. From the original ether filtrate X additional amounts of A (2.0 9.) and of B (1.5 9.) were obtained by acidification and fractional crystallization as described above. Thus the total yield of A was about 7.5 g. and of B about 5 g. of practically pure material.
AMINO ALCOHOLS FROM PHENANTHRENE
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13
14
EVERETTE L. MAY AND ERICH MOSE!ITIG SUMMARY
A series of amino alcohols carrying the side chain-CHOHCHpNh in position 9 of phenanthrene has been prepared. The evaluation of these compounds as antimalarials is discussed. BETHESDA 14, MD. REFERENCES (1) MAYAND MOBITFIG,J . Org.Chem., 1 1 , l (1946). ( 2 ) EDDY,Unpublished results. (3) COATNEY AND COOPER, Unpublished results. (4) WRIGHT, Unpublished results. (5) BACHMANN AND BOATNER, J . A m . Chem. SOC.,68,2097 (1936). AND VAN DE KAMP,J . A m . Chem. SOC.,66,3448 (1933). (6) MOSETTIC (7) ADKINS AND CRAMER, J . Am. Chem. SOC.,62,4349 (1930)
