[CONTRIBUTION FROM THE
DIVISION OF
PHYSIOLOGY, XATIONAL INSTITUTb, 08,&&ALTR]
ATTEMPTS TO F I N D NEW ANTIMALARIALS. IV.’s2 AMINO ALCOHOLS DERIVED FROM PHENANTHRENE AND TETRAHYDROPHENANTHRENE EVERETTE L. MAY
AND
ERICH MOSETTIG
Received January $6, 1946
We have shown in previous communications that a number of amino alcohols of type I (1) and type I1 (2) show a high antimalarial activity. We were interested to find out whether analogous compounds of type 111 (--CHOHCH2CHgNRs) would be of greater or lesser therapeutic value.
I
I1
The simplest way of arriving at phenanthryalkamines of type I11 consists in the reduction of the corresponding amino ketones, which in turn are obtainable by the Mannich reaction. Previously (3, 4), isoamyl alcohol was used to advantage as medium in this reaction. By employing a modification as specified by Fry ( 5 ) , the amino ketones were obtained in considerably higher yields. They were reduced catalytically in the form of their hydrochlorides. From the propylamino ketones upwards, fission in the alkamine side chain becomes more pronounced with increase in the size of the dialkylamino group, as shown by recovery of secondary amine hydrochloride and non-basic products. The Meerwein-Ponndorf-Verley method proved to be without value for the reduction of the amino ketones, since they were not stable under the conditions employed in this procedure. The tolerated doses (chicks) of the ‘Wannich-type” amino alcohols are consistently lower (0.1-0.3 mg. per g.) than those of the corresponding ethanolamines (1, 2) (Dr. Nathan B. Eddy, 6). This results in a rather unfavorable chemotherapeutic index, and though these compounds have a high effectiveness against Plasmodium gallinaceurn (Dr. G. Robert Coatney and Dr. K. Clark Cooper, 7), the study of this type was not further pursued. None of the drugs showed any activity towards sporozoite-induced gallinaceurn malaria (7). Acknowledgment. We are indebted to Mr. Edward A. Garlock, Jr. for carrying out the microanalyses. 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. 1 Studies in the Phenanthrene Series XXIX. 105
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E. L. MAY A N D ERICH MOSETTIG
SK 1804 8861 8862 8863 7310 1805 6824 6825 6826 7309 7308
9-(J-Dimethylamino-I-oxopropyl)-I ,2,S,44etrahydrophenanthrene hydrochloride. A mixture of 4.1 g. of dimethylamine hydrochloride, 1.5 g. of paraformaldehyde, 9 cc. of benzene, 9 cc. of nitrobenzene, and 2 drops of concentrated hydrochloric acid was stirred and boiled under reflux until the original solid became a light colored oil (ten t o fifteen minutes). At this point 11 g. of 9-acetyl-I ,2,3,44etrahydrophenanthrene was added and the stirring and refluxing resumed. At the end of another ten-minute period, amino ketone hydrochloride began separating, whereupon a water-trap was inserted and during the next twenty minutes 0.75 cc. of water was collected. The reaction mixture was cooled, diluted with ether, then cooled in the ice-box and filtered. The precipitate (11.5g.) was recrystallized from absolute ethanol-ether. The yield of hydrochloride melting at 187-189" was 9.8 g. (84% based on used ketone). After another recrystallization, the melting point waa constant at 189-190". Anal. Calc'd for CloH&lNO: C, 71.78; H , 7.61; C1, 11.15. Found: C, 71.11;H, 7.49;C1,11.47. was recovered. From the original filtrate 3 g. of 9-acetyl-I ,2,3,4-tetrahydrophenanthrene %(S-Dimethylamino-l-hydroxypropyl)-1,d,S,4-tetrahydrophenanthrene hudrochloride. Nine and five-tenths grams of the above compound (m.p. 187-189") absorbed one molecular equivalent of hydrogen in fifteen hours when shaken with 0.2 g. of platinum oxide and 110 cc. of 85% ethanol. The clear solution was filtered from catalyst, evaporated to dryness on the steam-bath under water-pump vacuum, and the syrupy residue dissolved in the minimum of warm acetone. After a few minutes the acetone solution of the amino alcohol hydrochloride was filtered from extraneous material, whereupon the compound slowly crystallized. It was cooled overnight in the ice-box and the material collected (6.2 g. of m.p. 150-162"). On recryst,allization from absolute ethanol-ether, 5.1 g. of white platelets of m.p. 16&169° was obtained. 3 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 to 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 wit.h that of quinine. All compounds listed in the Table were administered as hydrochlorides, except SN 1805 which was administered as base. 4 A11 melting points are uncorrected.
ATTEMPTS TO
FIND
ANTIMALARIALS.
IV
107
Anal. Calc'd for ClaH&lNO: C, 71.33; :K, 8.19. Found: C, 71.05; H, 8.18. 9-(3-DimethyEamino-l-hydroxypropyl)pherianthrene hydrochloride (S). The intermediate amino ketone hydrochloride for this compound was prepared like the previous tetrahydrophenanthrene analog. The yield from 11 g. of 9-acetylphenanthrene was 10.5 g., m.p. 169171" (3). A mixture of 2.4 g. of this amino ketone hydrochloride, 0.07 g. of platinum oxide and 20 cc. of methanol absorbed 1.2 molecular equivalents of hydrogen in three t o five hours. As described in the previous reduction, 1.7 g. of amino alcohol hydrochloride melting a t 158163" was obtained from acetone. Two recrystallizations from absolute ethanol-ether brought the melting point t o the constant value 164-166'; prisms. Anal. Calc'd for ClBH&lNO: C, 72.26 H , 7.03. Found: C, 71.89; H, 7.25. 9-(3-l)iethylamino-l -hydroxypropyl)-l,2,3, 4-tetrahydrophenanthrene hudrochloride. A 0.8 g. stirred and refluxed mixture of 5.5 g. of 9-acety1-l22,3,4-tetrahydrophenanthrene, of paraformaldehyde, 2.8 g. of diethylamine hydrochloride, one drop of concentrated hydrochloric acid, 4 cc. of nitrobenzene, and 11 cc. of benzene became almost clear after one-half hour. A small amount (about 0.1 g.) of paraformaldehyde was then added and the reaction continued one-half hour. Thirty cubic centimeters of ether was added to the cooled reaction mixture, after which it was extracted three times with 50-cc. portions of water. The water solution was made alkaline and the liberated amino ketone base shaken into ether. The dried ether solution (Na2S04)was freed of solvent, the residual base dissolved in about 40 cc. of acetone and 3.5 cc. of 25% alcoholic hydrogen chloride and a little ether were added. The yield of amino ketone hydrochloride was 4.1 g. (4970), m.p. 140-143'. It was pure enough for the subsequent reduction. Seven grams of this product, with 0.2 g. of platinum oxide and 75 cc. of methanol absorbed one molecular equivalent of hydrogen in five hours. From acetone as described for the lower homolog, 5.0 g. of amino alcohol hydrochloride was obtained. After a recrystallixation from absolute ethanol-ether the melting point was constant a t 200-201"; white needles, yield 3.9 g. A n a l . Calc'd for C21Hd21NO: C, 72.47; H , 8.69. Found: C, 71.96; H, 8.68. 9-(3-Diethylamino-l-hydroxypropyl)phentcnthrene hydrochloride (8). A mixture of 11 g. of 9-acetylphenanthrene, 1.5 g. of paraformaldehyde, 5.6 g. of diethylamine hydrochloride, 2 drops of concentrated hydrochloric acid, and 25 cc. of benzene was refluxed and stirred for one hour and forty minutes. The amino ketone hydrochloride resulting was isolated as its tetrahydrophenanthrene analog above. The yield was 7.5 g. (80% based on used ketone), m.p. 133-135" (3). Five grams of 9-acetylphenanthrene was recovered. When ten grams of the hydrochloride of m.p. 133-185" mas shaken under hydrogen with 0.2 g. of platinum oxide and 80 cc. of methanol, i t absorbed 1.05 molecular equivalents of hydrogen in five hours, when uptake ceased. The yield of amino alcohol hydrochloride, isolated as above, was 6.9 g. From absolute ethanol-ether, 5.6 g. crystallized as fine white needles of m.p. 180-1S3°. S n a t . Calc'd for Cz,H&NO: C, 73.31; H, 7.62. Found: C, 73.28; H, 7.75. On examination of the filtrates of the ainino alcohol hydrochloride, some diethylamine hydrochloride and non-basic material were found. $-(9-Dipropylamino-l -hydroxypropyl)-1 ,: I , $ , 4-tetrahydrophenanthrenehydrochloride. A mixture of 11 g. of 9-acetyl-l,2,3,4-tetrahydrophenanthrene, 1.5 g. of paraformaldehyde, 6.9 g . of dipropylamine hydrochloride, 2 drops of concentrated hydrochloric acid, and 25 cc. of benzene became clear upon refluxing and stirring for fifty minutes. After a n additional twenty-five minute period the reaction was interrupted, cooled, and 20 cc. of ether was added. The small amount of oil which separated was dissolved by adding a few cubic centimeters of acetone and the solution was cooled in the ice-box for one-half hour. A
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E. L. MAY AND ERICH MOSETTIQ
white solid separated, was collected (3.3 g.), and washed with a little acetone-ether mixture. The filtrate and washings deposited 8.9 g. of white, almost pure, amino ketone hydrochloride on standing two to three hours i n the ice-box. The 3.3 g. above yielded on fractional crystallization from absolute ethanol-ether 1.2 g. of dipropylamine hydrochloride as a first fraction and 1.1 g. of amino ketone hydrochloride. From all of the filtrates an additional 0.8 g. of the latter was obtained making the total yield 10.8 (58%). It crystallized in leaflets with an indefinite melting point. Four grams of this compound and 0.1 g. of platinum oxide in 40 GC. of methanol absorbed 0.95 molecular equivalents of hydrogen in 2.75 hours, when reduction ceased. From acetone-ether 3.0 g. of a white solid separated on cooling in ice. Upon recrystallization from absolute ethanol-ether 0.3 g. of dipropylamine hydrochloride (leaflets) separated first and W&B filtered quickly. From the filtrate 2.2 g. (m.p. 166-171") of the desired amino alcohol hydrochloride crystallized after two hours at room temperature. An additional 0.2 g. was recovered from the filtrate. A second recrystallization gave 1.9 g. of m.p. 182.5-184". The analytical sample melted at 183.5-184.5'. Anal. Calc'd for C:sHdlNO: C, 73.46; H, 9.11. Found: C, 73.19; HI 9.26. 9-(S-DipropyZamino-l-hydroxypropyl)phenanthrene hydrochloride. The amino ketone for this compound was prepared as the foregoing tetrahydrophenanthrene analog except that the reaction time was one hour. The yield of almost pure amino ketone hydrochloride (from 11 g. of 9-acetylphenanthrene) as i t crystallized from the benzene reaction mixture after dilution with ether, was 13.3 g. (71%). A mixture of 2.0 g. of this product, 0.05 g. of platinum oxide, and 20 cc. of methanol absorbed 0.9 molecular equivalents of hydrogen in ninety minutes. From acetone-ether, a small amount of dipropylamine hydrochloride separated at 0". This was filtered, whereupon a white crystalline hydrochloride began t o separate from the filtrate. After standing at room temperature overnight and one hour in the ice-box, 1.0 g. of amino alcohol hydrochloride of m.p. 131-138" was collected. After two recrystallizations from absolute ethanol-ether 0.85 g. of compound separated as fine white needles of m.p. 144.5-146.5' (turbid melt). Anal. Calc'd for CzoHsoClNO: C, 74.27; H, 8.13. Found: C, 73.88; H, 7.86. 9-(S-Dibutylamino-l-hydrozypropyl)-I,8,3,4-tetrahydrophenanthrenehydrochloride. The "Mannich" product for this compound was prepared essentially as described for the dipropylamino derivatives above. The reaction time using 11 g. of ketone was forty-five t o sixty minutes. After diluting the reaction mixture with two-thirds its volume of ether and cooling in the ice-box, 3.4 g. of dibutylamine hydrochloride was collected. From the filtrate 9.4 g. (46%) of amino ketone hydrochloride (m.p. 129-132") was obtained. Six grams of this compound, 0.1 g. of platinum oxide, and 50 cc. of methanol absorbed the calculated amount of hydrogen in two hours, when uptake came to a standstill. From acetone-ether, dibutylamine hydrochloride (0.4 g.) separated. The filtrate deposited overnight, at room temperature, the desired amino alcohol hydrochloride in a yield of 2.5 g., m.p. 131-134". After a recrystallization from acetone-ether and one from acetone, the product crystallized in blade-like needles of m.p. 138-139". Anal. Calc'd for C*&H&lNO: C, 74.32; H, 9.48. Found: C, 74.14; H, 9.63. g-(S-Dibutylamino-l -hydroxypropyl)phenanthrene hydrochloride. The Mannich reaction with 11 g. of 9-acetylphenanthrene and 8.4 g. of dibutylamine hydrochloride, carried out by a procedure similar t o that described in the three foregoing experiments, required two hours. The yield of crude product was 14.5 g., which on recrystallization from absolute ethanol-ether gave 13.1 g. (77y0 based on used ketone). Two and five-tenths grams of 9acetylphenanthrene was recovered. Eight grams of the recrystallized product absorbed 0.95 molecular equivalent of hydrogen in eighty minutes when shaken with 0.15 g. of platinum oxide and 75 cc. of methanol.
ATTEMPTS TO FIND AX'TIMALARIALS.
IV
109
The residue from filtration of catalyst and evaporation of solvent in vacuo was dissolved in 20 cc. of acetone and this solution diluted with 40 cc. of dry ether. After two hours in the ice-box 2.3 g. of dibutylamine hydrochloride separated. The filtrate was seeded with amino alcohol hydrochloride (crystallized by one week's standing and tedious manipulations), and on cooling in ice, 3.2 g. of hygroscopic product melting at 80-90" (with bubbling) was obtained. After two recrystallizations from acetone-ether 2.8 g. of white rectangular plates of m.p. 94-98" (frothy melt) was obtained. The compound was very hygroscopic and was dried in a vacuum desiccator before analysis. C,J 72.29; O H : H, 8.86; CH,OH, 7.4. Anal. Calc'd for C ~ ~ H ~ ~ C ~ S O . C H Found: C, 72.49; H , 9.00; CH30H, 7.9. The solvate methanol was determined by drying to constant weight a t 77" in vacuo. 9-(S-Dzarrtylamino-i-hydroxypropyl)-l,f?,3,~-tetrahydrophenanthrene hydrochloride. The Mannich reaction in this experiment was tarried out with 11 g. of 9-acetyl-1,2,3,4-tetrahydrophenanthrene as described for the foregoing dipropylamino and dibutylamino analogs and required ninety minutes. After diluting with a n equal volume of ether the reaction mixture was cooled in ice for two hours and filtered from 2.0 g. of diamylamine hydrochloride, Since the amino ketone hydrochloride would not crystallize, the filtrate was evaporated to dryness and the residue washed twice with dry ether, 11.5 g. of crude oilymaterial remaining. This was reduced in 75 cc. of methanol with 0.3 g. of platinum oxide, absorption 1.05 moles, 3 hours. From acetone-erher, diamylamine hydrochloride (2.2 g.) separated. The filtrate deposited gradually 3.6 g. of amino alcohol hydrochloride of melting point 100-105". The substance was recrystallized twice from acetone-ether and appeared as clusters of long white prisms (3.0 g.) of m.p. 104-105.5". final. Calc'd for C2,H&lIVO: C, 75.05; H , 9.80. Found: C, 75.08; H, 9.G1. 9-(S-Diamylamino-l-hydroxypropyl)phenanthrene hydrochloride. The amino ketone hydrochloride obtained from 11 g. of 9-acetylphenanthrene (ninety minutes reaction time) was isolated in the following manner. The benzene reaction mixture was evaporated to dryness in vacuo, the residue dissolved in 40 cc. of acetone and ether added carefully until no more unchanged diamylamine hydrochloride (3.0 g.) precipitated. After cooling the filtrate overnight in the ice-box 11.6 g. (60% based on used ketone) of the diamylamino ketone hydrochloride was obtained. Two grams of 9-acetylphenanthrene was recovered. Fourteen grams of this hydrochloride when shaken with 100 cc. of methanol and 0.2 g. of platinum oxide absorbed 0.9 molecular equivalent of hydrogen in two hours. From acetone-ether 4.0 g. of diamylamine hydrochloride and 6.5 g . of amino alcohol hydrochloride were obtained. The latter melted at 112-118', and after a recrystallization from acetoneether, the yield of product melting a t 122-L25" was 5.0 g.; clusters of plates. Anal. Calc'd for C*;H3&1SO: C, 75.77; H, 8.95. Found: C, 75.44; H, 8.87. g-(d-Piperidino-l-oxopropyl)-1,%,3,4-tetrahydrophenanthrene hydrochloride. A mixture of 10 g. of 9-acetyl-lJ2,3,4-tetrahydrophenanthrene, 7 g. of paraformaldehyde, 5.5 g. of piperidine hydrochloride, and 50 cc. of isoainyl alcohol was boiled under reflux for one hour. The two-layered reaction mixture was cooled and diluted with ether, whereupon the amino ketone hydrochloride crystallized (5.3 g. or 33% of crude material). After two recrystallizations from absolute ethanol-ether, the melting point was 187.5-188.5'; white needles. Anal. Calc'd for C.xH2&1?;0.H20: C, '70.29; H, 8.04. Found: C, 70.70; H, 7.91. The material was dried at 100" in. vacuo for two to three hours. Anal. Calc'd for Cz2H?8ClNO: C, 73.82; H , 7.89. Found: C, 73.34; H, 7.77. 9-(d-Piperidino-l-hydroxypropyl)-l,%,b,4-tetrahydrophenanthrene.The 5.3 g. of hydrochloride above, with 0.2 g. of platinum oxide and 100 cc. of 950/, ethanol absorbed the calculated amount of hydrogen in 24 hours. The residue remaining after filtration from catalyst and evaporation of solvent was partitioned between a n excess of dilute sodium hydroxide
110
E. L. MAY AND ERICH MOSETTIG
and ether. The dried ether layer (NazSO,) was concentrated t o 15 cc., whereupon the base crystallized. After cooling, 1.8 g. of amino alcohol was obtained, m.p. 114.5-115.5". The melting point was not changed by a recrystallization from ether; white needles. Anal. Calc'd for C I ~ H ~ ~ NC,O 81.69; : H, 9.04. Found: C, 81.31; H, 8.77. SUMMARY
A series of amino alcohols derived from phenanthrene and tetrahydrophenanthrene, and carrying the side chain -CHOHCH&H&R2 in position 9, has been prepared. The evaluation of these compounds as antimalarials is discussed. BETHESDA 14, MD. REFERENCES (1) MAYAND MOSETTIG, J . erg. Chem., 11, 1 (1946). (2) MAYAND MOSETTIG, J . Org. Chem., in press. (3) VAN DE KAMPAND MOSETTIG,J. Am. Chem. Soc., 68, 1568 (1936). (4) MOSETTIG, SHAVER, AND BURGER, J . Am. Chem. SOC., 60, 2464 (1938). (5) FRY,J. Org. Chem., 10, 259 (1945). (6) EDDY,Unpublished results. AND COOPER,Unpublished results. (7) COATNEY
