Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 921
ANTIMALARIAL PHENANTHRENE AMINOALCOHOLS.1
Antimalarial Phenanthrene Amino Alcohols. 1. Fluorine-Containing 3- and 6-Substituted 9-Phenanthrenemethanolsl EDWARD A. NODIFF,* KEIICHITANABE, CHRISTOPH SEYFRIED, SHINMATSUURA, YASUAKIKONDO, EUGENE H. CHEN, AND MAHESH P. TYAGI Germantown Laboratories,t Philadelphia, Pennsylvania
19144
Received March 18, 1971
A number of the title compounds are quite effective against Plasmodium berghei in mice. The most active members of this group are disubstituted and bear CFa groups or a combination of CF3 and halogen at positions 3 and 6. Many of these compds are curative at 40 mg/kg and some at 20 mg/kg. None of the 9-phenanthrenemethanols caused photosensitization in the test animals.
The appearance of drug-resistant falciparum malaria has stimulated the search for new antimalarials. In their monograph Coatney, et aE.,2 discussed the eficacy of many simple 9-phenanthrenemethanols against Plasmodium gallinaceum in chicks. The most active comCHOHCH2N(R),.HCI
6
5
4
3
pounds in this group were those which contained C1 or Br atom in positions 3 or 6 and in which R was an unbranched alkyl 4-7 C long. The best of these, 6-bromo-a-(di-n-heptylaminomethyl) -9-phenanthrenemethanol-HCl,3was used as our standard for comparison. The value of substituting F or F-containing groups for halogen or H in prototype medicinals has been demonstrated repeatedly in the past two decade^.^ In a logical extension of this work we have prepared a series of 9-phenanthrenemethanols with F or F-containing groups at positions 3 and/or 6. A number of these compds are considerably more effective than the standard. Biological Data. Table X includes comparison data (Rane mouse screen6) for the standard and our F-containing analogs. The most active members of this group are disubstituted and bear CF3 groups or a combination of CF3 and halogen at positions 3 and 6. Most of these compds are curative at 40 mg/kg and a number are curative a t 20 mg/kg. Among the monosubstituted compds only the 6-CF3 derivative (IXd) is significantly more potent than the standard. None of the phenanthrenemethanols caused Affiliated with the Franklin Institute. (1) This investigation was supported by the U. 9. Army Medical Research and Development Command under Contract DADA 17-67-C-7067 and is Contribution No. 903 from the Army Research Program on Malaria. (2) G. R . Coatney, U'. C. Cooper, N . B. Eddy, and J . Greenberg, "Survey of Antimalarial Agents," Public Health Monograph KO.9, Washington, D. C., 1953. (3) E. L. May and E . Mosettig, J. OrO. Chem., 11, 627 (1946). (4) The pharmacology of F-contg compds has been reviewed by F. Herr in "Aromatic Fluorine Compounds," A. Pavlath and A. Leffler, Ed., Reinhold. N.Y., 1962, p 682. ( 5 ) Tests were carried out in five mice, infected with a lethal dose of P. berohei, by Dr. L. Rane and coworkers, Malaria Screening Laboratory, University of Miami, Miami, Florida. For details of test procedure, see T. 6. Osdene, P. B. Russell, and L. Rane, J. Med. Chem., 10, 431 (1967). Test data were supplied by Drs. T. R. Sweeney and R . E . Strube of Walter Reed Army Institute of Research.
photosensitization6 in the test animals. The intermediates listed in Tables I to VI1 and in Table VI11 were all inactive. Chemistry.-The antimalarials in Table X were prepd by standard sequences. Thus, the Perkin reaction between the appropriate phenylacetic acids and benzaldehydes in the presence of Et3N (method A)7-9 or KzC03(method B)s provided the nitrocinnamic acids (I). Reduction to the corresponding amino acids (11) was effected with ammoniacal FeS04 (method A)sI9 or FeS04 and NaOH (method B). I n the latter method the Na salt was often isolated rather than the free acid. This expedient permitted simpler work-up and in the case of the 2'-amino derivatives minimized concomitant lactam (IIA) formation. Pschorr cyclizationsvg of the amino acids or amino acid salts gave the phenanthroic acids (111). Sequential conversion of these acids to the acid chlorides (IV), the diazomethyl ketones (not isolated), and the bromomethyl ketones (V) was r ~ u t i n e . ~ Reaction of the ketones with alkaline methanolic IVaBH410 and treatment of the resulting ethylene oxides (VI) with the appropriate dialkylamines produced the a-(di-n-alkylaminomethyl)-9-phenanthrenemethanols (VII) (method A) .11.12 I n another approach to VI1 the bromomethyl ketones (V) were converted to the amino ketones (VA, not isolated) and reduced [Al(O-i-Pr)3 (method B)13 or NaBH4 (method C) ].lo The a-(Zpiperidy1)-9-phenanthrenemethanols (IX) were made from the acids (111) via the pyridyl ketones (VIII) by the Boykin p r o ~ e d u r e . ' ~ * ' ~ Experimental Section16 4-Trifluoromethoxyphenylacetic Acid.-The reaction between O~H, 4-F3COCeH&OC1 (from 25 g of commercial ~ - F ~ C O C B H ~ C60 ( 6 ) Phototoxicity evaluation was carried out by Col. William E . Rothe, Division of Medicinal Chemistry, WRAIR, Walter Reed Army Medical Center, Washington, D. C. 20012. For details of the test procedure see W. E . Rothe and D. P. Jacobus, J . M e d . Chem., 11, 366 (1968). (7) M. Pailer, A. Schleppnik, and A. Meller, Monatsh. Chem., 89, 211 (1958). (8) D. F. DeTar, Org. React., 9, 409 (1957). (9) P. H. Leake, Chem. Rev., S6, 27 (1956). (10) S. W . Chaikin and W. G. Brown, J . Amer. Chem. Soc., 71, 122 (1949). (11) R. E. Lutz, et al., ibid., 68, 1813 (1946). (12) S. Winstein, T. L. Jacobs, R . B. Henderson, J. H. Robson, and B. F. Day, J . Ow. Chem., 11, 157 (1946). (13) E. L. May and E . Mosettig, ibid., 11, 1 (1946). (14) R . M. Pinder and .4.Burger, J . M e d . Chem., 11, 267 (1968). (15) D. W. Boykin, Jr., A. R. Patel, and R. E . Lutz, ibid., 11, 273 (1968). (16) Melting points mere determined with an electrically heated ThieleDennis apparatus and are uncorrected. Elemental analyses mere carried out by Schwarzkopf Microanalytical Laboratory, Woodside, PIT. Y.,and Microanalysis, Inc., Wilmington, Del. Where analyses are indicated only by symbols of the elements anal. results were within &0.4% of the theor values.
NODIFF,et al.
922 Journal of Medicinal Chemistry, 1972, Vol. 14, YO. 10
TABLE I NITRO~-PHENYLCINKAMIC ACIDS
Phenylcinnamic acid
No.
Phenylacetic acid
Benaaldehyde Method
Temp, OC
Yield, hlp, “ C (solvent)
YO
Formulaa
41 194-195 (HOAc) 77 CijHioFNO4 4-Fc A 2-K02h 4-F, 2’-NO2 2’-NO2, 4-CF3 2-NO,b 4-CF3d A 20 177.5-178 (aq Et0I-I) 76 C~BHIOF~NOI 82 CisHioFN04 70 179.5-181 (EtOH) 4-Fc 2-K0,* -4 IC 4‘-F, 2-NO2 ht? 155.5-158 (CBHO) 63 Ci6HioF3NOif 2-N02* A 4-CF3C Id 2-NO2, 4’-CF3‘ B 20 176-179 (ligroin-C&,) 58 ClaHloF&”d Unsubst 2-NO,, 4-CF30 Ie 2’-NOp, 4’-CF3e 73 C~~HIOF~NO~~ B 43 141-142.5 (aq MeOH) 2-NO,b 4-CF30h If 2-NO2, 4’-CF,O 185-186.5 (aq HOAc) X3j Cl&BrF3NOa B 40i 2-NO2, 4-CF38 4-Brb Ig 4-Br, 2’-N02, 4’-CF, Ih 4-C1, 2’-NO,, 4’-CF3 2-NO2, 4-CF38 4-CIb B 100 201-202 (aq EtOH) 69 C16HgClF3NO4 80 CI~HSF~INO~ I3 6,; 193-194 (ligroin-C&6) 4-Ik 2-NO2, 4-CF38 Ii 4-1, 2’-NO2, 4‘-CF3 194-195 (CsHe) 60 C16H9BrF3N04m 4-CFad 100 4-Br, 2-N0Z1 Ij 4’-Br, 2’-N02, 4-CF3 203-20j (aq EtOH) 82’ Ci6HgCIF3NOa B 45” 4-C1, 2-NO2“ 4-CF3d Ik 4’-C1, 2’-1J02, 4-CF3 176-178 (C6H6) 71 Ci?HgF&Oa 4-CF3d B 100 11 2’-NO2, 4,4’-(CF3)2 2-NO2, 4-CF3v British Aldrich Chemical Co., lIilwaukee, Wis. Pierce Chemical Co., Rockford, Ill. 4 All compds were analyzed for C, H, N. Patent 870,541 (June 14, 1961). e Compounds Id and Ie are both intermediates in theprepn of IIId. Use of I e instead of Id eliminates the need for expensive p-trifluoromethylphenylacetic acid. C : calcd, 57.00; found, 57.54. 8 L. Simet, J . Org. Chem., 28, 3580 N : calcd, 3.97; found, 3.35. I .4t 20, .50, and 80”, the yields were 58, 66, and 41y0,resp. Sapon Labora(1963). h Experimental. Used without tories, Oceanside, N, Y . 1 From 2,5-dibromonitrobenzene (.4ldrich) via adaptation of method of Siniet (footnote 9 ) . anal. n From commercial 2,5-dichloronitrobenzene as in ref 1. o A t 23 and 80” the yields were 65 and 55%, resp. Ia Ib
TABLE I1 Yield,
No.
Substituents
M p , O C (solvent)
A. AMINO
IIa IIb TIC IId IIe IIf
Ik IIh IIi IIj 11%
I11
2’-NH2, 4-F 2’-NH2, 4-CF3 2-NH2, 4’-F 2-NH2, 4’-CF3 2’-NH2, 4’-CF3 2-”2, 4’-CF30 2‘-NH2, 4-Br, 4’-CF3 2’-NH2, 4-C1, 4‘-CF3 2’-NH2, 4-1, 4’-CF3 2’-NH2, 4’-Br, 4-CF3 2’-NH2, 4’-C1, 4-CF3 2 ’-N Hz, 4,4 ’-(CF3) z
a-PHENYLCINNAMIC
a, h (EtOH)
b (EtOH) 202.5-203.5 (EtOH) 208-210 (C6H6) h (C6HB-ligroi11)
h (CHC13) h
h
%
Method
Formula
Analyses
ACIDS
A A A A A B B B B B B B
69 72 87 67 67 91 98 88 92 63 79 80
B. 3-Benzalo~indoles~
H IIAa 4’-F 193-194 (EtOH) 235-236 (EtOH) IIAb 4‘-CF3 IIAg 234-235 (EtOH) 4’-Br, 6-CF3 IIAh 211-213 (EtOH) 4’-C1, 6-CF3 231-232 (EtOH) IIAk 6-C1, 4’-CF3 On a large scale this material was used without crystn because boiling in EtOH caused cyclodehydration and formation of IIAa. * Rapid conversion of this compd to the corresponding lactam, on heating, made the mp indefinite. c Isolated as Na salt. Used as free amino acid without purification. e Isolated as by-products in the synthesis of the corresponding 2’-amino-a-phenylcinnamic acids.
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 923
ANTIMALARIAL PHENANTHRENE AMINOALCOHOLS.1
TABLE V
TABLE I11
9-BROMOACETYLPHENANTHRENES
PHENANTHRENE-9-CARBOXYLIC ACIDS
p-COCH2Br Yield,* No.
3
Yield,
No.
Substituents
Mp, "C (solvent)
%
Formula"
267 (EtOH) 67 CijHeF02 IIIa 3-F 234-235 (aq EtOH) 37 ClsHsFsOz I I I b 3-CF3 34 CisHsFOz 270-272 (EtOH) IIIc 6-F IIId 6-CF3b*d 259-260 (C&) 30 CisH~F30z 259-260 (aq EtOH) 41 C1eHgF302 IIId 6-CF3cJ 234-235 (aq HOAc) 57 CleHgFa03 IIIf 6-CFsO 67 C16HsBrF30~ IIIg 3-Br, 6-CF3 280-281 (dioxane) 61 CieH8ClFaOz I I I h 3-C1, 6-CF3 268-270 (EtOAc) 54 CieH,gFaIOz IIIi 3-1, 6-CF3 285-286 (EtOH) IIIj 6-Br, 3-CF3 264-267 (CeHs) 69 C1~H8BrF30~ IIIk 6431, 3-CF3 256-257 (EtOH) 52 CiaH&IF3Oz 1111 3,6-(CF3)z 272-273 (as EtOH) 42 CI~HSFBOZ From IId. From IIe. 5 All compds were analyzed fer C, H. d The ir spectra of IIId obtd from I I d and IIe were identical.
TABLE IV 9-PHENANTHROYL CHLORIDES p-COCl No.
Substituents
Mp, O C (solvent)
IVa 3-F 136 (CeHe) IVb 3-CF3 146-147 (CeHe-petr ether) IVc 6-F 130-132 (sublimation) IVd 6-CF3 127-130 (C&) 41Va was used without anal. The remaining analyzed for C, H.
Formulaa
ClaHsClFO CleH&lFsO CiaH&IFO CieHsClF30 compds were
Substituents
Mp, "C (solvent)
Yo
Formula'
Va 3-F 144-145 (EtOAc) 71 CleHlaBrFO Vb 3-CF3 119-120" 61 C17H1oBrF30 VC 6-F 104-106 (CsHe) 51 ClaHlpBrFO Vd 6-CF3 133-135 (C6He-ligroin) 50 C17H10BrF30 Vh 3-C1, 6-CF3 147-149 (EtOH) 77 C17HgBrCIF30 Vi 3-1, 6-CF3 173-174 (EtOH) 92 C17H9BrFJ0 Vk 6-C1, 3-CF3 142-144" 82 C17HgBrClF30 V1 3,6-(CF3)z 166-168 (EtOH) 50 ClsHSBrF60 a All compds were analyzed for C, H except Vb and Vk which were used in the next step without crystn. bBased on the corresponding phenanthroic acid (Table 111).
TABLE VI 9-PHENANTHRYL ETHYLENE OXIDES~ 0
/ \
p-CH-CHz Yield,
No.
Substituents
Mp, 'C (solvent)
%
VId 6-CF3 120-125 (crude) 64 VIi 3-1, 6-CF3 151-152.5 (MeOH) 606 VIk 6 C1, 3-CF3 150 (ligroin) 66 a These compds were generally used without analysis. b Isolated as a by-product was a compd whose elemental [(Cl7Hl2FaIO) C, HI and ir analyses indicated that it was most probably the methyl carbinol (9-CHOHCH3)(VIi'); mp, 178-179.5' (CeH6ligroin).
Na salt of the amino acid either sepd spontaneously or was forced out by addition of solid NaCl or solid NaOH. Phenanthrene-9-carboxylic Acids (Table III).-A mixt of 0.05 mole of the Na salt of the aminophenylcinnamic acid (Table 11), suspended in 200 ml of EtOH and 0.17 mole of i-AmONO, was ethanolic HC1 during 60 min. ml of C & . , and 250 ml of SOC12) and 750 ml of ethereal CHZNZ treat.ed a t -5" with 160 ml of l,i70 The mixt was maint.ained at - 5 to 0" for an additional 2 hr and (from 50 g of N-nitrosomethylurea) carried out in the usual manslowly poured int.0 a mixt, of 0.5 mole of NaHzPO2,2.3 g of Cu ner'? gave 20 g of 2-diazo-4'-trifluoromethoxyacetophenone as 3 drops of concd HrS04,and 80 ml of HzO a t 40". After ) pale yellow crystals, mp 48-49' (petr ether). Anal. ( C ~ H ~ F ~ N Z O Zbronze, C, H. To a mixt of 2 g of AgzO, 3 g of NaZSz03, 5 g of Na~C03, 1 hr t,he resulting cryst,als were collected. The free amino acids in Table I1 were cyclized to the correand 200 ml of H20, a t 50-60°, was added 5 g (0.022 mole) of the sponding phenanthroic acids in an identical manner. diazoacetophenone in 30 ml of dioxane.'7 After 1 hr a t 50-60' 9-Bromoacetylphenanthrenes(Table V).-A mixt of 0.03 mole the mixt was maintained at reflux until N2 evoln ceased (ca. 2.5 of phenanthrene-9-carboxylic acid (Table 111), 150 ml of dry hr). A small quantity of black solid was filtered from the cooled CeH6, and 150 ml of SOC12 was heated under reflux for 3 hr. mixt and the filtrate was acidified with dil HCl to give 3.3 g The solvent and excess SOCl2 were removed, and the residual (7oY0) of the phenylacetic acid as off-white solid, mp 82-84'. acid chloride (qnant) was used without further piirification. A colorless anal. sample was obtained by vac sublimation. Anal. (Data for some of the acid chlorides are included in Table IV.) (CgH~F303)C, H. To a mixt of 90 ml of 40y0 KOH and 400 ml of EtzO, at O-S', Nitro a-Phenylcinnamic Acids (Table I). Method A.-A mixt was added, in portions, 30 g of N-nitrosomethylurea. The yellow, of 0.3 mole of the phenylacetic acid, 0.3 mole of the benzaldehyde, ethereal CH2Nz layer was sepd, dried over KOH pellets (4 hr), 300 g of AczO, and 30 g of Et3N was stirred a t the listed temp for and dild with 50 ml of CeHe. To this soln a t 5" was added, during 24 hr, poured into 1.8 1. of warm Hz0 and stirred. The resdting 1.5 min, 0.03 mole of the acid chloride. The mixt was stirred a t crystals were washed, dried, and recrystd. .iofor 2 hr and at room temp overnight. The resulting pale yellow Method B.-A mixt of 0.3 mole of phenylacetic acid, 0.3 mole diazo ketone was suspended in 75 ml of dioxane at room temp and of benzaldehyde, 0.17 mole of KzC03, and 0.75 mole of AczO was treated with 30 ml of a 1: 1 mixture of 48y0 HBr and dioxane. slowly raised to the listed temp and maintained a t this temp for Aft,er 0.5 hr, the brown soln was stirred with a mixt of 20 g of 24 hr. To the hot soln were added 400 ml of HzO and 200 ml of NazCOs in 150 ml of HzO to give the bromoacetyl deriv. 10% HC1. The mixt was stirred a t room temp for 2 hr and 9-Phenanthryl Ethylene Oxides (Table VI).-To a siispension filtered. of 0.015 mole of the bromomethyl ketone (Table V) iii 52.3 ml of Amino a-Phenylcinramic Acids (Table 11). Method A.-To NeOH was added a t room temp, diving 15 min, 0.03 mole of a mixt of 70 g of FeS04.7H20, 146 ml of HzO, and 146 ml of NaBH4. The mixt was stirred a t room temp for 10 min, treated concd NHIOH, at 7O-XO0, was added a soln of 0.03 mole of the with 10 ml of 12% NaOH, allowed to stand overnight, and evapd nitro acid (Table I ) in 70 ml of warm dil N H 4 0 H (1: 1). The to dryness. The epoxide was exM with C6H6. mixt was maintained a t 70-80" for 2 hr, filtered, and acidified a-(Di-n-alkylaminomethyl)-9-phenanthrenemethanol Hydrowith AcOH. chlorides (Table VII). Method A.-A mixt of 0.008 mole of Method B.-To a soln of 0.5 mole of FeS04.7Hz0 in 130 ml of the epoyide (Table VI) and 0.024 mole of the R2NH was heated H2O was added a soln of 1.5 moles of NaOH in 600 ml of HzO. a t 110" overnight. The cooled mixt was dild with 400 ml of To this mixt a t 80" was added a soln of 0.05 mole of the nitro EtzO and treated with ethereal HCl t,o remove RzNH.HC1. acid (Table I ) in 0.075 mole of warm 2y0 NaOH. The mixt was Continued addn of Et20-HC1 gave the target compd. maintained a t 100' for 30 min and filtered hot. On cooling, the Method B.-A mixt of 0.023 mole of the bromo ketone (Table (17) E. W. Bachman and W. S. Struve, Org. React., 1, 38 (1942). V), 200 ml of Et20, 50 ml of MezCO, and 0.046 mole of RzNH
924 Journal of Medicinal Chemistry, 1971, Vol. 1.4, No. 10
NODIFF,et al.
TABLE VI1 a - ( D i - n - a L K Y L A ~ I s O M E T H Y L ) - g - P H E N ~ N T H R E E E T H . ~ N O LHYDROCHLORIDES
YHOHCH,N(R)2*HCI
Yield,
RIP, O
Substituents
NO
VIIa VIIa' VIIb VIIb' VIIC VIIc' VIId S'IId' T'IIh VIIh' VIIi VIIi' S'IIk T'IIk' VI11 VII1' a N : calcd,
3-F 3-F 3-CF3 3-CF3 6-F 6-F 6-CF3 6-CF3 3-C1, 6-CF3 3-C1, 6-CF3 3-1, 6-CF3 3-1, 6-CF1 6-C1, 3-CF3 6-C1, 3-CF3 3,6-(CF31 2 3,6-(CF3)2 2.87; found, 3.29.
C
(solvent)
188-189 (EtOAc) 145-146 (EtOAc) 180-1 8 1 (C&,-ligroin ) 149-151 (ligroin) 187-188 (EtOAc-CHC13) 157-159 (EtOAc-CHC13) 223-226 (EtOAc) 195197 (EtOAc-CHC13) 229-230 (EtOH) 183-186 (EtOH) 215.3-216. -5 (ligroin-GHs) 160-163 (aq EtOH) 223-226 (EtOH-EtiO) 182-184 (;\Ie2CO-Et?O) 243-244 (EtOH) 221-223.6 (CsHs)
Method
%
C B B B B B B A C C
55 73 36 34 17 40 50 27 43 58 36 82 28 28 17 19
A
,4 A A
B B
TABLE VI11 2-PYRIDYL 9-PHENANTHRYL KETONES
NO.
Substituents
Mp, "C (solvent)
Yield, %
VIIIb 3-CF3' 153-154 (EtOH) 70 VIIId 55 6-CF3 164-166 (EtOH-AIe2CO) VIIIf 6-CF30 151-152 (EtOH) 47 VIIIg 3-Br, 6-CF3 198-199 (aq Me2CO) 47 VIIIh 3-C1, 6-CF3 32 193-195 (aq EtOH) VIIIi 3-1, 6-CF3 209-210.5 (aq hIe2CO) 56 VIIIj 6-Br, 3-CF3 41 260-263 (CsHs) VIIIk 6-C1, 3-CF3 230-231 (dioxane-1IeOH) 82 VI111 243-245 (EtOH) 74 3,6-(CF3)2 a All compds analyzed for C, H, N. * Reduction of VIIIb with NaBHagave 39% of a-(P-pyridyl)-3-trifluoromethyl-9-phenanthrenemethanol (VIIIb'), mp 168-169" (MeOH). Anal. (C11HlrF3NO) C, H, N . c C : calcd, 65.38; found, 64.85. C: calcd, 65.38; found, 64.68. was btirred at room temp for 4 hr and R2XH HBr was removed. The filtrate was concd to a syrup and dild with 200 ml of Et'zO,and add1 RzNH.HBr was removed. The filtrate was concd to an oil and treated with a mixt, of 30 g of freshly dist' Al(i-OPr)3and 300 nil of i-PrOH. The mixt, was gently heated under reflux for 0.5 hr and the solvent was t,heri slowly dist'd (Vigreux coliimn, bat,h temp 100') until hIe2C0 was no longer evident in t,he dist,illate (0.75 hr). The bath temp was raised to 110' and dist was contd for 0.5 hr. The remainder of the solvent was removed under reduced pressure and the residue was extd with 2 1. of Et2O. The ext wu washed with H20, dried (lIgSO,), and treated with .-)00 ml of Et?O satd with HC1 gas. The pale brown s o h was filtered and concd. Method C.-A mixt of 0.01 mole of t'he bromo ketone (Table V), 0.02 mole of the R2NH, Id ml of dry Et,O, and 3 ml of l f e 2 C 0 was stirred at, room temp for -5 hr. The mixt, was filtered to remove R2KH' ITBr and the filtrate was evapd to dryness in z~acuo. The residiie was dissolved in 60 ml of MeOH and treated with 0.01 mole of SaBIT4. Two ml of 0.2 XaOH was added and the
mixt was stirred for 1.3 hr. The AIeOH was removed under reduced presbiire, and the residue mas made alk with 2 S NaOH and extd with EtiO. The ext was dried (MgSO,) and treated with Et20-HCl. 2-Pyridyl 9-Phenanthryl Ketones (Table VIII).-To a vigorously stirred mixt of 32 ml (0.05 mole) of l5Y0BuLi in hexane (Foote 31ineral Co., Exton, Pa.) and 50 ml of dry EtZO, cooled t o -60", was added 0.05 mole of 2-bromopyridine (Aldrich Chemical Co.). The brown soln was stirred a t -60" for 1 hr and a suspension of 0.02 mole of the phenanthrene-9-carboxylic acid (Table 111) in 150 ml of EtpO, cooled to -60°, was added all a t once. The mixt was stirred at -60" for 2 hr, allowed to warm to room temp, and hydrolyzed with H20. The Et20 lager waq dried (MgSO1) and evapd. a-(2-Piperidyl)-9-phenanthrenemethanol Hydrochlorides (Table IX).-A mixt of 0.01 mole of the ketone (Table VIII), 2.50 ml of EtOH, and 2 ml of concd HCl was hydrogenated for 1hr over 0.2 g of Pt02, a t 40 psig. The mixt was filtered and coned. A n attempt to reduce the iodo pyridyl ketone (VIIIi) in this
ANTIMALARIAL PHENANTHRENE
AMINO
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 925
ALCOHOLS.1
TABLE IX a-(2-PIPERIDYL)-g-PHENANTHRENEMETHANOL HYDROCHLORIDES
B
l
H*HCI
3
6
Yield,
No.
IXb IXd IXf m 3 IXh IXj IXk 1x1
Substituents
3-CF3 6-CF3 6-CF30 3-Br, 6-CF3 3-C1, 6-CF3 6-Br, 3-CF3 6-C1, 3-CF3 3,6-(CF3)z
Mp, OC (solvent)
%
314-316 (EtOH) 311-313 (aq EtOH) 298.5-299.5 (MeOH) 317-319 (MezCO-5% HC1) 312-315 (aq MezCO) 348-352 (MeOH) 314-315 (aq EtOH) 324-327 (aq EtOH)
37 30 80 45 40 60 77 67
Formula
CziHziClFaNO CziHziClF3NO CziHziClFaNOz CZ1H~oBrC1F3NO CziHzoClzF3NO CzlH~oBrCIFaNO CziHzoClzFsNO CzzHzoClFeNO
TABLE X ANTIMALARIAL ACTIVITY~
yHOHR*HCl
AMST or Cb----
c
--Dose,
No.
Standard VIIa VIIa’ VIIb VIIb’ IXb VIIC VIIC’ VIId VIId‘ IXd IXf IXg VIIh VIIh’ IXh VIIi VIIi‘ IXj VIIk VIIk’ IXk VI11 VIIl‘ 1x1 a See ref 5 .
Substituents
6-Br 3-F 3-F 3-CF3 3-CF3 3-CF3 6-F 6-F 6-CF3 6-CF3 6-CF3 6-CF30 3-Br, 6-CF3 3-C1, 6-CF3 3-C1, 6-CF3 3-C1, 6-CF3 3-1, 6-CF3 3-1, 6-CF3 6-Br, 3-CF3 6-C1, 3-CF3 6-C1, 3-CF3 6-C1, 3-CF3 3,6-(CF3)2 316-(CF3)2 3,6-CF3 AMST, mean survival time over controls
10
20
40
2.1
4 .R 0.2 0.6 2.4 0.5 5.5 1.1 4.7
6.7 0.2 2.8 7.8 5.9 12.9 2.1 4.9 9.4 10.4 2 c 1.8 2 c
0.4
0.3 3.9
4.7 4.7 0.2
1c
3.4 5.0 6.5
1c 8.1 0.2 1.4 7.3 0.3 2 c 11.o
1c
7.8 3 c 11.9 4.6 4.8
7
mg/kg-
80
1c 1.2 3.6 8.4 13.3 16.9 3.3 8.7 13.0 2 c 11.2 2 c
1c
5 c
1c
160
3 20
640
3 c 4.6 5.6 11.0 14.5 3c 7.7 10.9
4 c 5.2 7.6 13.2
4 c 6.4 12.2 2 c 5 c 5 c 13.3 5 c 5 c 5 c 5C 5 c 5C 5 c 5 c 5 c 5 c 5C
1c
3 c 4 c
1c
5 5 3 5 5
c c c c c
1c
5 c 9.3 15.1 4 c 5C 2 c 5 c 5 c 5 c 5 c 2 c
9.8 1c 4 c 5 c 5 c 5 c 1c 5 c 0.5 5.3 8.3 10.7 5 c 5 c 1.5 5 c 5 c 5 c 5 c 5.0 2 c 2 c 3 c 3 c 5 c 5 c 5.9 1c 5 c 5 c 9.1 18.9 2 c 5 c (6.2 =k 0.49 days); C, number of cures (mice surviving to 60 days). 0.2 2.7
manner gave only the corresponding pyridyl carbinol (VIIIi’), mp 219-220’ (aq EtOH). Anal. (C,,HI3FJNO) C, H ; ir as expected. The same compd (VIIIi’) was obtained on reduction of VIIIi with methanolic NaBH4.
5 2 5 5 5 5
c c c c c c
No attempts were made to isolate the two possible racemates of the ~ ( Z p i p e r i d y l )analogs. For 1x1 this was subsequently
accomplished by Dr. Edward E. Hamel, Aerojet Solid Propulsion Company, who will publish his results shortly.
