Antimalarial Phenanthrene Amino Alcohols. 2.
LiAlH,. The mixt was stirred at room temp for 29 hr. The reaction was hydrolyzed with H,O and extracted with Et,O. The Et,O soln was evapd in vacuo to yield 3.0 g of crude product. Tlc showed a number of spots (silica gel-C,H,). The crude reaction product was chromatographed on a 28 X 3 cm column of silica gel (C,H, elution, 60-ml fractions). Fractions 6-12 gave 500 mg of the starting amino ketone (15%) (nmr, ir). Fractions 22-29 (10%Et,O) gave 500 mg of product (nmr, ir, elemental analysis of the HCl salt). Other fractions were unidentified, although final 100% Et,O elution gave 800 mg of material that appeared to be a trialkylamine. The HCl salt of the product was prepd in EtOH-Et,O as white crystals, mp 119-1 22" (15% yield). A 100-mg probe run had given a nearly quantitative yield of product 17.
Acknowledgment. The authors gratefully acknowledge many helpful discussions with Dr. R. E. Strube of the Walter Reed Army Institute of Research. Dr. Strube also
JournalofMedicinal Chemistry, 1972, Vol. 15, No. 7
775
suggested a number of the aryl substrates and made them available for this work. References (1) (a) G. R. Coatney, W. C. Cooper, N. B. Eddy, and J. Greenberg, "Survey of Antimalarial Agents," Public Health Monograph No. 9, Washington, D.C., 1953, p 13; (b) ibid., p 30. (2) F. Wiselogle, "A Survey of Antimalarial Drugs, 1941-1945," J. W. Edwards, Ann Arbor, Mich., 1946, pp 332, 333. (3) T. S. Osdene, P. B. Russell, and L. Rane, J. Med. Chem., 10,431 (1967). (4) E. L. May and E. Mosetig,J. Org. Chem., 11,105 (1946). ( 5 ) W. T. Colwell, et al., submitted for publication. (6) C. H. McMullen and C. J. M. Stirling, J. Chem. Soc., 1217 (1966). ( 7 ) E. H. Nodiff, K. Tanabe, C. Seyfried, S. Matsuura, Y.Koundo, E. H. Chen, and M. P. Tyagi,J. Med. Chem., 14,921 (1971).
An timalarial Phenanthrene Amino Alcohols. 2. Trifluoromethyl-Containing 9-Phenanthrenemethanolst J Edward A. Nodiff,* Andrew J. Saggiomo, Masafu Shinbo, Eugene H. Chen, Hirotaka Otomasu, Yasuaki Kondo, Toyolvko Kikuchi, Basant L. Verma, Shin Matsuura, Keiichi Tanabe, Mahesh P. Tyagi, and Shiro Morosawa Germantown Laboratories, Inc., Affiliated with The Franklin Institute, Philadelphia, Pennsylvanh 19144. Received November 29, I971
A series of mono-, di-, tri-, and tetrasubstituted 9-phenanthrene amino alcohols has been prepd in which each compd bears a t least o n e CF3 group. A number of these compds, tri- and tetrasubstituted with a combination of CF3 and C1 groups, are the most active, nontoxic amino alcohols to emerge from t h e vast primary screen (Plasmodium berghei, mouse) of t h e Army's Research Program o n Malaria. T h e most effective member of t h e series, 6,7-dichloro-2,4-bis(trifluoromethyl)-a-(di-n-propylaminomethyl)-9phenanthrenemethanol*HC1(159),is 100% curative a t 5 mg/kg and active a t concentrations as low as 1.25 mg/kg. Antimalarial enhancement of 9-phenanthrenemethanols by introduction o f CF3 groups or a combination of CF3 and halogen was described earlier.' In an effort to approach the optimal substitution pattern for this series we have synthesized the compds included i n Table I. Chemistry. The preparative routes were essentially those described in paper 1 .l Details have been tabulated in the Experimental Section. Biology. Table I includes murine antimalarial data for 48 new CF3-contg 9-phenanthrene amino alcohols. The distribution of these compds among the curative, active, and inactive categories, at each dose, is shown in Table 11. Most of the new compds were active or curative at doses as low as 10 mg/kg. Conspicuous exceptions were the derivs with one or m o r e nonhalogenic groups (125,126,127,131). In fact, the 6-CF3,3-COOH deriv (126)was the only one i n the entire series completely inactive at even the highest concentrations. It would seem that the preferred substituents are those which combine a positive Hansch n constant' with a positive Hammett u ~ o n s t a n t . ~ The most active compds (113,129,135-139,142,159), with 60-100% cures at 20 mg/kg, were mainly tri- and tetrasubstituted with a combination of C1 and CF3groups. The best of these (135,137,138,159), with 60-100% cures at 10 mg/kg, all had two of their substituents at positions 2 and 4. Among the side chains, the piperidyl, Pr, Bu, a n d Am derivs were all quite good. Compds w i t h the heptyl side ' ?This investigation was supported by the U.S. Army Medical Research and Development Command under Contract No. DADA1770-C-0101 and is Contribution No. 1029 from the Army Research Program o n Malaria.
chain retained considerable activity but were less effective
than the others. The compds 135,137,138,and 159 are the most active, nontoxic amino alcohols to emerge from the vast primary screen of the Army's Research Program on Malaria. Experimental Section$ 4,5-Dichloro-2-nitrophenylacetic Acid. Method A. Commercial 3,4dichlorobenzoic acid (Eastman), suspended in concd H,SO,, was nitrated with mixed acid (modification of the method of Claus and Bucher,) to give 77% of 4,5dichloro-2-nitrobenzoic acid. This material was identical with that obtd on oxidation (KMnO, in aqueous Me@) of authentic 4,5dichloro-2-nitrobenzaldehydegthereby proving its structure. This nitrobenzoicacid was converted to the corresponding nitrophenylacetic acid in the usual manner (Table ILI, footnote y ) ;mp 133-136" (C,H,-ligroin), yield 68%. Anal. (C,H,Cl,NO& C, H, N. Method B. To a mixt of 34 ml of HNO,(d 1.42) and 375 ml of mncd H,SO, at -20" was added, in one portion, 95 g (0.46 mole) of 3,4dichlorophenylacetic acid (Research Organic/Inorganic Chemical Corp., Sun Valley, Calif.).The reaction temp rose to -5" and was then maintained at -10' to -5" for 0.5 hr and at -5" to 0" for 1 hr. The resulting white mass was poured into 1.8 kg of aushed ice and the white solid was washed, dried, extd with boiling ligroin (ext discarded), and crystd from aqueous HOAc; yield 95 g (83%), mp 132-1 34". The ir spectrum of this material was identical with that of the analytical sample obtd via method A. 3,5-Bis(trifluoromethyl)benzaldehyde. A mixt of 3,5-bis(tri$Satisfactory spectra were obtd where required for structural detn; ir as Nujol mulls on Perkin-Elmer 137B Infracord; nmr (by Sadtler Research Laboratories, Philadelphia, Pa.) on Varian A-60A. Mp's were detd in capillary tubes in a n electrically heated ThieleDennis apparatus and are uncorr. Where analyses (Microanalysis, Inc., Wilmington, Del.) are indicated only by symbols of the elements analytical results were within 20.4% of the theor values.
776
Nodiff, et al.
Journalof Medicinal Chemistry, 1972, Vol. 15, No. 7
Table I. Antimaiarial Activitf CHOHR *HCl
No.
Substituents
143 113 114 115 116 144 117 118 119 120 145 121 146 147 148 122 123 124 125 126 127 128 149 129 150 151 130 131 132 133 134 152 135 153 154 155 156 157 136 137 138 139 140 158 141 159 142 160
R*
2-3 2CF 4CF 5CF 7 a 3 1-Br, 6 c F 3 2C1, 5 € F 3 2€1,70 7C1, 2 c F 3 7C1,4CF3 2-Br, 6 C F 2-Br, 6 C F 3 4-Br, 6 C F 2C1,6-CF3 2C1, 6 C F 3 2C1,6CF3 2,6-(CFJ, 4,6-(CF J2 3 a 3 ,6 0 , 3COOH, 6 € F 3 3-SOlCH3, 6 C F 3 7C1, 3 C F 3 1,2€1,, 6 C F 3 1,2€1,, 6 C F 1,3€1,, 6 C F 3 1,3€1,, 6 C F 3 1,3€1,, 6 € F 3 1,34CHJ,, 6CF3 l,3-Brl, 6 C F 3 2,3€1,, 6 C F 3 2,3-Br2, 6 4 3 , 2,4€1,, 6 C F 3 2,4€1,, 6 C F 3 2,4-Br2, 6 € F 3 3,4€1,, 6 C F 3 3,4€1,, 6CF, 3,4€1,, 6 C F 3 3,4€1,, 6 C F 3 3,4€1,, 6 C F , 6 4 , 2,4iCF3), 7-C1,2,4-(CFJl 2,4,6iCF$ 5,7€1,, 3 C F 3 6,7€1,, 3 C F 3 6,7C1,, 3 C F 3 6 , 7 4 4 , 2,4-(CFJ, 6 , 7 4 4 , 2,4iCFJ, 2,3-Br2,6 C F 3
5
CHPBu, Pip Pip Pip Pip CH,NHep, Pip Pip Pip Pip CH,NBu, Pip CH,NBu CH,NBu CH,NHep, Pip Pip Pip Pip Pip Pip Pip CH,NBu, Pip CH,NBu, CH,”ep, Pip Pip Pip Pip Pip CH,NBu Pip CH,NBu, CH,NPr CH,NBu, CH,NAm, CH,”ep, Pip Pip Pip Pip PiP CH,NPr PiP Cfwrl Pip CH,NBu,
, ,
,
,
,
3.8 0.5 1.1
10 4.7
17.3 0.5
1c
10.3 1.8
17.2
5.3
7.5 0.3 1.1
0.7 7.1 0.4 0.6 5.5 6.9 5.1 1.3 10.3 4.1
0.3 1.9 5.3 13.5 12.3 0.4 10.0 0.3 0.3 7 .O 0.3 6.5 3c 8.9 5.5 12.3 7.5 0.9 11.5 3c 5c 1.9
0.5
1c
5ce
13.1 1.7 5c
1c 6.1
20 9.7 4c 1.7 2.1 0.5 1.o 2c 0.6
40 13.7 5c 4.9 8.3 5.1 6 .O 2c 9.2 5c
1c
1c
12.5 1c 1c 2 .o
3c 2c 9.6 lC 9.7 3c 1c 1c 0.3 0.1 2.7 4c 11.1 5c 4c 1.1 3c 0.9 3c 4c 1.9 20.1 5c 4c 2c 1c 5c 6.9 5c 5c 5c 5c 5c 4c 2c 5c 5C 5c
1c 1.9 1c
15.8 14.7 0.1 0.1 0.3 13.9 8.1 4c 2c 0.5 17.8 0.5
1c 1c
0.5 15.1 4c 13.3
1c
15.9 13.1 2.3 3c 5c 5c 3c 2c 2c 11.9 5c 3c 12.3
80 3c 5c 2c 3c 9.1 6.2 4c 14.7 5c 2c 3c 4c 10.6 2c 2c 4c 3c
1c
3.7 0.3 5.9 5c 14.3 5c 5c 4.7 5c 11.7 5c 5c 6.9 2c 5c 5c 5c 5c 5c 3c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c
160 5c 5c 5c 4c 1c
320
5c 5c 4c
1c
1c
5c 17.7 5c 5c 5c 5c
5C 5C 5c 5c 5c 5c 2c 4c 5c 5c 5c 5c 3c 0.3 5c 5c 5c 5c
1c
3c 3c 5C 5c
1c
9.5 0.3 13.1 5c 3c 5c 5c 2c 5c 13.7 5c 5C 3c 5c 5C 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c
5C 5c 5c 5c 5c 4c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5c 5C 5c 5c 5c 5c 5c 5c
640 5c 3cd 5c 5c 5c 3c 5c 5c 5c 5c 5c 5c 5c 5C 5c 5C 5c 3c 0.5 5c 5c 5c 5C 5c 5c 5c 5c 5c 5c 5c 5c 5c 5C 5c 5c 5c 5c 5c 5c 5c 5C 5c 5c
‘Tests were carried out in five mice, infected with a lethal dose of P.berghei, by Dr. L. Rane and coworkers, Malaria Screening Laboratory, University of Miami, Miami, Fla. For details of test procedure, see Osdene, e f a1.16 Test data were supplied by Drs. T. R. Sweeney and R. E. Strube of Walter Reed Army Institute of Research. bPip = 2-piperidyl. CAMST,mean survival time over controls (6.2 0.49 days); C, number of cures (mice surviving to 60 days); a compd is considered to be “active” when the MST of the treated group is more than twice that of the control group. dl and 2 toxic deaths at 320 mg/kg and 640 mg/kg, respectively (deaths occurring before day 6 after infection are attributed to drug action and counted as “toxic deaths”). eAMST at 2.50 and 1.25 mg/kg = 12.0 and 6.8 days, respectively.
*
Table 11. CF,€ontaining 9-Phenanthrenemethanols. Activity Distribution at Each Dose Dose, No. No. No. No. Dose, No. mg/kg tested curative“ active” inactive mg/kg tested 5 17 10 37 20 48 40 48 %ee footnote c, Table I.
1 7 21 31
3 14 13 8
13 16 14 9
80 160 320 640
48 48 48 43
No.
No.
curativea
activea
37 43 47 42
I 4 0 0
No. inactive 4 1 1 1
777
Journal of Medicinal Chemistry, 19 72, Vol. 15, NO.7
Antimalarial Phenanthrene Amino Alcohols. 2.
Table 111. Nitro aBhenylcinnamic Acidsaa COOH
No.
Phenylacetic acid
Phenylcinnamic acid
H
Benzaldehyde
COOH
Temp, "C
Yield, %
Mp, "C (solvent)
Formulabb
2'-NO,, 3 C F , 2-NO; 3cFt 95 174-175 (C6H6-petr ether) 63 16H I$ Po! 343: 2-NOza 2-N02, 3'cF, 100 116-117 (C6H6-hexane) 59 C16H1$g04 2-N0,, 4€F$ 2-Bf 80 250 (aq EtOH) 57e C16HJ%rF,N04 2-Br, 2'-NO,, 4'CF, 5C1, 2-N02, 3 ' 4 3 3€F: 5€1,2-N0; 20 157.5-158.5 (aq AcOH) 63 16H9cIF Y04h 5€1, 2-NOZx 3cFt 2'-NO,, 5 ' 4 , 3CF, . 60 188-190 (aq EtOH) 65 C, ,H,ClF,NO,' 3-Br, 2'.N02, 4'cF,] 2-N02, 4 c F f 3-Bf 45 177-179 (aq MeOH) 88 '1 s H S r F 4cF,c 72 1' 6H PrF go4 5-Br, 2-N0,, 4'CFf S-Br, 2-NOZk 100 218-220 (C6HJ 5C1, 2-N0,, 4'427, 4 c F ,c 5C1, 2-NOZa 50 189-190 (C6HJ 64 1 6H 9'lF go4 2'-NO,, 3,4'-(CF+ 3cFt 2-N0,, 443: 50 209-210 (aq EtOH) 63 1 $p gNo 4 4CH,, 2'-NO,, 4 &, 2-NO,, 443: 4CHt 70 222-224 (C6HJ 38 1$1 ZF f i 0 4 11 4-S0,CH3, 2'-NO,, 4 ' € F 3 2-N0,, 4 c F P 4-SO,CH,I 70 182-183 (aq EtOH) 56 'l$l ZFyo6' 12 5'€1,2'-NO,, 4 C F , 5421, 2-N02X 4cFt 65 202-203 (C6H6-ligr0in) 95 1' 6H9clF YO4 13 2,3€1,, 2'-NO,, 4'CF 2-NO,, 4 C F t 2,3€1,' 80 223-225 (AcOH) 89 1' 6H8C12F P O 4 16H8C12F 14 2,4€1,, 2'-NO,, 4 ' c F , 2-N02, 4 C F P 2,4€1," 65 243-244 (C6HJ 84' 15 2,4-(CHJ2, 2'-NO,, 4'CF, 2-NO 4 C F 2,4-(CHJ; 70 222-224 (aq EtOH) 22 1EH 14F f i 0 4 16 2,4-Br2, 2'-NO,, 4'437, 2-N02, 4 C F > 2,4-BrZU 61 233-235 (C6HJ 47 1' 6H BBrZF Po4 4,5€1,, 2-NO: 60 195-198 (C6HJ 62 C16H8C4F go4 4cF,C 17 4,5€1,, 2-N0,, 4'-CF, 18 4,5-Br2, 2-N0,, 4'-CF3 4CFt 4,5-Br2,Z 2-N02 77 196-198 (AcOH) 65 1' BBBrZF PO4 19 3,5€1,, 2'-NO,, 4'€F3 3,5Cl/ 90 212-214 (C6HJ 86 C16H8C1p$04 2-N0,, 4 C F 20 3,S-Br , 2'-NO,, 4'€F, 60 217-218 (C6HJ 57 1 Ffio4' 2-NO,, 4CF3d 3,5-Br,' 21 4'C1, I'-NO,, 3,54CFb2 4C1, %NO$ 3,5-(CFJif 60 228-229 (C6HJ 72 C1$8CF6N0,' 22 5'C1,2'-NOZ,3,5-(CFJ, 5C1, 2-NOZx 3,5-(CFJ,f 55 212-213 (C6HJ 75 Cl$H,C1F, NO, 23 2'-NO,, 3,4',5-(CFJ, 60 185 (C6HJ 2-N02, 4 C F P 3,54CfJf 63 C18H8F9N04 24 3',5'€1,, 2'-NO,, 4 C F , 3,5€1,, 3-N02; 4 c F 75 234-236 (EtOH) 60 c16H8c1Pfi04 25 4',5'€1,, 2'-NO,, 4 C F , 4,5€4,2-N0 4CFib 45 186-187 (aq EtOH) 66 1' 6H8C12F 3'4 26 4',5'-C1,, 2'-NO,, 3,5(CFJ2 4 , 5 4 4 , 2-NOZf 3,5-(CFJ2f 80 210-214m 80 I $7C4F dm 27 2'-NO,, 3,4,5-Br3, 4'CF, 2-N0,, 4CF?- 3,4,5-B1,~ 60 257.5-258.5 (CHC1,-hexane) 58 1' 6H7Br $ 4 'Aldrich Chemical Co., Milwaukee, Wis. bPrepd via adaptation of method desaibed in ref 5. Tierce Chemical Co., Rockford, Ill. dSeeref mp 114" (MeOH). Anal, 6. %alated as a by-product was the decarboxylated compd, 2-bromo-2'-nitro4'-trifluoromethylstilbene, (Cl,H9BrF,N0& C, H, N. Jkxperimental Section. gC: calcd, 56.89;found, 57.50. hH: calcd, 3.77; found, 3.30. T:calcd, 51.70; found, 51.23. ICompds 6 and 7 are both intermediates in the synthesis of 2-bromo6-trifluoromethylphenanthrene-9-carboxylic acid (37). Although prepn of 7 involves the relatively expensive p-trifluoromethylphenylacetic acid, use of 7 instead of 6 eliminates isomer possibilities during subsequent prepn of 37. %ee ref 7. 'See ref 8. W s e d without purification. "Eastman Organic Chemicals, Rochester, N. Y. OAt looo, the yield was 72%. PSee ref 9. QH: calcd, 2.83; found, 3.29. 'C: calcd, 46.36;found, 47.00. SFrom commercial 2,5dichloronitrobenzene in 33% yield, via adaptation of method of Simet;6 mp 164-166" (aq EtOH). Anal. (C8H6ClNOJ C, H, N. 'See ref 10. ref 11. ',See ref 12. WSee ref 13. XPrepd from commercial 5-chloro-2-nitrobenzoic acid in usual manner (see footnote y), mp 156-158" (sublimation at 135-140°, 1 mm). Anal. (C8H6CWO&C, H, N. Yprepd from 3,5dichloro-2-nitrobenzoic acid14 via the method described for 4-trifluoromethoxy phenylacetic acid in paper 1;l mp 163-164" (C6Hd. Anal. (C,H,Cl,NOJ C, H, C1, N. ZObtd in 66% yield by nitration of 3,Wbromobenzaldehyde in an adaptation of the method of Alford and Schofield,'' mp 105-107" (hexane). Anal. (C7H$r,N0,) C, H, N. aaThe compds in this table were all made via method B (Ac,O + K,COJ of paper 1.' bbAll compds were analyzed for C, H, N. 1 2 3 4 5 6 7 8 9 10
,
,
Table IV. Phenanthrene-9-carboxylic Acids COOH
No* 28 29 30 31 32 33 34 35 36 37 37 38 39 40 41 42 43
starting material 1 1 2 2 3 4 4 5
5
7 6 6 8 9 9 10 11
Substituents
Mu, OC (solvent)
2CFt 4CF 5CF 7CF: 1-Br ,6€F 2421, 5CF,3e 2C1, 7CF,e 7€1,2cF 7€1,4cF e 2-Br, 6 € F 2-Br, 6-CFjf 4-Br, 6 C F j f 2€1,6CF 2,6-(CF J] 4,6-(CF&$' 3CH3, 6-€F3 3 6 0 ,CH 3, 6 C F
214-216(C6Hd 228-230 (C6Hd 219-220 (C6HQ) 247-249 (C6H6) 287-288 (i-ROH) 239-240.5 (Me$0)' 215-255 (Me,CO)e 206-230 (EtOH-ligoin)e 206-230 (EtOH-ligroin)e 288-289.5 (EtOH) 289.5-290.5 (EtOH) 246-247 (AcOH) 276-277 (C6H6-EtOH) 288-289 (aq AcOH) 211-211.5 (aq AcOH) 278-279 (dioxane) 314-315 (AcOH)
, ,
,
Yield ,% 31 6 12 12 36 20 20
Formulam 32 ' 1'
6H9F 32' 16H9F 2 ' 3 16H9F 32 '
C16H8BrF0 C ,H,ClF :O :d 1
2 ' 3
6H8ClF302 C16H8ClF302
1'
51 65 65 79 20 40 40 40
C16H8BrF302 16H8BrF 1'
32 '
6H8BrF302 32 '
1
C1$8F602 1$SF
62'
1$1 2 lF ' 3
C1$11F$04
778
Nodiff,et al.
Journal of Medicinal Chemistry, 1972, Vol. 15, No. 7
Table IV. Continued
__
_______.
Start ing" material
Yield, 72 Formula" 58 C16H8CF302 44 12 45 13 45 C16H7C1ZF302 46 14 37 16H,C1ZF 3'2 47 15 43 I SH12 P ' 3 48 16 71 1' 6H$r ZF 32' 49 17 31 16H,C12F302 50 18 33 1 6H$r ZF 32' 69 1' 6H,C12F 32 ' 51 19 52 20 35 1' 6H$rp 3'Zh 53 21 60 1 7"/cF602. 54 22 72 c1$7cF60: 55 23 52 Cl,H,F,O, 56 24 17 C16H7C12F302 57 25 45 1 6H,C12F 3'2! 58 26 45 1 $6C1ZF 60ik 59 27 43 1 6H6Br 3F 32' "The nitrocinnamic acids (Table 111) were reduced to the corresponding amino derivs using method B (FeSO, + NaOH) of paper 1.' The resulting Na salts were subjected to Pschorr cyclization without purification. bThese isomeric acids were sepd by fractional crystn from C,H,, the 4 isomer (29) being the less sol fraction. %ee footnote b; 7 isomer less sol. dC: calcd, 59.20; found, 59.74. eObtd as mixt and used as such in the pyridylation step at which stage isomer sepn was effected. fcyclization of 6 gave a mixt of the isomeric acids 37 and 38. Isomer sepn was initially effected by repeated frac crystn from AcOH. It was later found more expedient to carry the mixt through to the target compds 145 and 146 and to make the sepn at that stage. gSepn of 40 and 41 was carried out by extg 40 from the mixt with Et,O. k : calcd, 42.87;found, 43.35. 'C: calcd, 51,90;found, 52.45. ]Used without purification. kH: calcd, 1.15; found, 0.70. 'H: calcd, 1.96; found, 2.72. mAll compds were analyzed for C, H.
No.
Substituents 7C1,3€F3 1,2€4,6CF 1,3€1,, 6 C F 3 1,3-(CHJ2, 6 4 F 3 1,3-BrZ,6 4 F 3 2,3C4,6CF3 2,3-Br,, 6-CF3 2,4C12, 6-CF 2,4-Br,, 6 4 3 , 6C1,2,4-(CFJZ 741,2,4-(CF& 2,4,6-(CFJ3 5,7€4, 3 4 F 3 6,7ClZ, 3 C F 3 6,7€1,, 2,4-(CFJ2 2,3,4-Br, 6 4 F ,
Mp, "C (solvent) 308.5-310 (dioxane-hexane) 297-298 (EtOH) 287.5-288.5 (aq EtOH) 308.5-309 (AcOH) 298-300 (aq EtOH) 320-323 (EtOAc) 318-320 (dioxane) 238-239 (aq EtOH) 250-251 (aq dioxane) 218 (C,Hd 252 (c,H,) 215 (C,H,) 284-286 (EtOH-dioxane) 339-340 (dioxane) 252-25 3 (AcOH) 278-279 (C,Hd
Table V. 9-Bromoacetylphenanthrenes
Table VI. a-Bromomethyl-9-phenanthrenemethanols
COCHSr
6
No.
Substituents
91 92 93 94 95 96 97 98 99 100 101
2CF 1-Br, 6 C F 3 2-C1,6CF3 1,2ClZ,6€F3 1,3€1,, 6 C F , 2,4€1,, 6CF, 2,4-Br,, 6 4 F , 3,4€1,, 6 C F 6,741,, 3CF, 6,741,, 2,4+CF&, 2,3,4-Br3, 6 C F 3
,
CHOHCH,Br
3
3
6
MD, "C (solvent)" 65-67 (petr ether) 168-170 (aq dioxane) 172-173 (CC1,) 161-1 63 191.5-193 (EtOHC,HJ 164-165 (aq EtOH) 172-1 73 (C6H6-hexane) 135-1 37 (EtOH) 204-210 145-1 60 117-119 (hexane)
Yield, % 78 71 86 78 62 49 80 57 75 78 76
"Compds 94,99, and 100 were used without purification. The remaining compds were crystd but used without analysis.
No.
102 103 104
105 106 107 108 109 110 111 112
Substituents 2CF, l-Br, 6 € F , 241,6CF, 1,2€1,, 6 C F 3 1,3€1,, 6 C F , 2,4ClZ, 6CF, 2,4-Brz, 6 4 F , 3,4€1,, 6 C F , 6,7€1,, 3€F, 6 , 7 4 4 , 2,4iCFJz 2,3,4-Br,, 6 C F ,
Yield, %
Mp, "C (solvent) 115-120 175-176(EtOH) 137 (EtOH) 151-156 (H,O wash) 172.5-1 74 (EtOHC,Hd 146-148 (C,H,-hexane) 130-1 35 140-142 (hexane) 193-200 125-1 27 138-143 (H,O wash)
100" 87b 65 81" 66b,c 85 84" 92b 82" 50" 87"
"Used without purification. without analysis. CIsolated and used in the next step as the epoxide.
Table VII. a-(2-Piperidyl)-9-phenanthrenemethanolHydrochlorides
No. 113 114 115 116 117 118 119 120 121 122 123 124
Substituents 2CF 4 e 3 5CF3 7CF3 2C1, S C F , 2C1,7CF3 7C1,2€F3 7C1,4€F3 2-Br, 6 € F 2C1,6CF3 2,6-(CFJ2 4,6-(CF J
,
Mp, "C (solvent) 301-303 (aq MeOH) 270-272 (MeOH) 305 (aq EtOH) 269-270 (C,H,-petr ether) 304-305 (EtOH) 292-29 3 (Me@) 327-329(EtOH) 312-31 3 (EtOH) 320-322 (aq EtOH) 313 (aq EtOH) 302-304 (EtOH) 264-265 (Me,CO)
Yield. % 35 37 50 55 56 64 58 58 33 71 75 33
Formula
Analyses
bi
Journal of Medicinal Chemistry, 1972, Vol. 15,No. 7
Antimalarial Phenanthrene Amino Alcohols. 2.
779
Table VU. Continued No. 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142
Yield, %
Mp, "C (solvent)
Substituents
Formula
Analyses
262-264 (EtOH) 320-321 (EtOH) 316-318 (EtOH) 329-330 (aq EtOH) 350 (EtOH-10% HC1) 326-327 (aq EtOH) 283-283.5 (EtOH-2% HC1) 311-313 (MeOH) 325-327 (aq EtOH) 322-324(EtOH) 325.5-327 (aq MeOH) 294-295 (EtOH-10% HCl) 327 (EtOH) 338 (EtOH) 295-296 (EtOH) 301-303 (EtOH) 345-346 (EtOH) 332-334(EtOH)
3CH, 6 C F , 3COOH, 6 C F , 3S02CH,, 6 C F 3 7 4 , 3CF3 1,2C12, 6 C F , 1,3€1,, 6CF, 1,3-(CHJ2, 6 C F 3 l,3-Br2, 6 C F , 2,3C12, 6 4 3 2,3-Br2, 6 C F 3 2,4€1,, 6€F, 3,4C12, 6 C F 3 6C1,2,4-(CFJ2 7C1, 2,4-(CFJ2 2,4,64CFJ3 5,7C12, 3CF, 6,7C12, 3CF, 6,741,,2,4iCFd2
,
%alated and analyzed as the hemihydrate. bH:calcd, 5.47; found, 6.11. 'C: calcd, 63.71;found, 63.11. dC: calcd, 62.29; found, 61.65. eC: calcd, 56.97; found, 56.49. fIsolated and analyzed as the monohydrate. Also isolated wasa hemihydrate (141A), mp 354-356".Anal. C, H.
Table VIII. cu-(Di-nalkylaminomethyl)-9-phenanthrenemethanolHydro chlorides CHOHCH,N(R) *HC1
& No.
Substituents
R
143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160
2€F, 1-Br, 6 0 , 2-Br,6a3 4-Br, 6 C F , 2C1,6€F3 2€1,60, 1,2€1,, 6 0 , 1,3C12, 6 C F , 1,3€1,, 6 4 3 , 2,4€1,, 6 C F , 2,4-Br,, 6 C F , 3,4€1,, 6 C F 3 3,4C12, 6 0 , 3,4C12, 6 C F , 3,4C12, 6 C F , 6,7C12, 3 C F 3 6,7€1, 2,4-(CFJz 2,3-Br,, 6-CF3e
Bu HeP Bu Bu Bu HeP Bu Bu HeP Bu Bu
Pr Bu Am HeP PI
Pr Bu
MD. 'C (solvent) 179-180 (C6H,-hexane) 194-195 (C$I,-lipoin) 248-249 (Me@) 207-208 ( C a d 253 (Me,CO) 226-227 (Me,CO) 239.5-241 (C,H,-hexane) 263-264 (hexaneCHClJ 223-225 (aq EtOH) 235-236 (C,H& 236-236.5 (C,H,) 234-235 (EtOH-10% HC1) 191-192 (C,H,-hexane) 140-1 42 (C6H,-hexane) 128-1 30 (C,H,-hexane) 282-283 (EtOH) 222-223 (Me,CO-Iigroin) 234-235 (C6H&
Methoda
Yield, %
B B Ad Ad A A B A A B B B B B B B B B
18 44 13 13 63 35 27 41 38 29 24 48 22 18 17 81 85 23
Formulab
8' 3$rCF Po ,$IcF Po 30CJF Po
C25H31CF
C 3,H42BrClF$0 C25H C25H
C31H42ClZF$0
c25H29c1$$0 CZ5H29C1$
$O
C31H41C1$f10 C25H29C1$$0
$O
C25H2$rZCF
c23H2Sc1P
8 '
C2,H29C1$ $0 c2'$33c1$$0c C31H41C1$$0
c2$25c1$80 2dC1$
'2dH
gNo
C25H29Br2CF
J0
uMethods A and B used epoxides and bromohydrins, respectively, as starting materials. bAll compds were analyzed for C, H, N. 'C: calcd, 58.86; found, 59.36. H: calcd, 6.04;found, 5.54. dIsomers sepd by frac crystn from C,H,. eThis compd was obtd when 4debromination occurred during routine treatment of 112 with Bu,NH. Table IX. 2Pyridyl9Phenanthryl Ketones
6
No. 60
61 62 63 64 65 66 67 68
Substituents 2CF3 4CF 5CF3 7CF, 2C1, 5 C F 3 2C1, 7 C F 3 7C1,2-CF3 7C1, 4 € F 3 ~ - B I6-CF ,
5
4
3
Mp, "C (solvent) 121-123 (petr ether) 114-115(hexane) 115-116 (hexane) 139-141 (aq EtOH) 147-148 (EtOH) 201-202(EtOH) 193-194 (EtOH)b 142-153 (EtOH)b 215-217 (aq EtOH)
Yield, % 76 70 50 49 72 52 34 25 73
Formulau ' 2 lH 1ZF
C21HlPPO
c ,,Hi ZF flo c 2 IH 12F $0
CZlHllCF $0 '2
lH 1lcF
C21H11CF3N0
C~,H,,BrF,NO C21Hl ,cF3N0
780
Nodiff, et al.
JournulofMedicinal Chemistry, 1972, Vol. 15, N o . 7
Table 1X. Continued No.
69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90
Substituents 2C1, 6 C F , 2,6-VJ2 4,6-(CFJ2 3CH,, 6 C F , 3COOH, 6 € F , 3-S0,CH3, 6 C F , 7C1,3-CF3 1,2424, 6 C F 1,3€1,, 6-CF 1,3-(QHJ,, 6 4 3 , 1,3-Br2, 6 C F 2,3€1,, 6-CF3 2,3-Br2, 6CF, 2,4-C&, 6 C F , 2,4-Br,, 6 C F , 3,4€1,, 6-CFl 6C1, 2,4-(CF,), 7C1, 2,4-(CF,), 2,4,6-(CF3), 5,7C12, 3CF, 6,7€1,, 6 C F , 6,7€1,, 2,4-(CFJ2
, , ,
Mp, "C (solvent) 205 (EtOH-C,H 6) 226-227 (EtOH) 166-167.5 (EtOH) 209-210 (C6H6) 275-278 (EtOH) 250-252 (EtOH) 231-232 (aq Me,CO) 227-228 (EtOH) 233-234 (aq Me,CO) 187-188 (EtOH) 237-238 (C6H& 251-254 (C6HJ 248-250 (C6H6) 211-212 (aq Me,CO) e 176-177 (EtOH) 188 (EtOH-C,H,) 187 (C$& 134 (hexane) 174-177 (H,O wash) 265-268 223-227
Yield ,5% 42 54 53 36 d 88 60 75 63 60 40 69 16 67 45 51 26 36 59 76 33
Forrnuh'l C21H11CF3N0 C22H11F6N0 '2ZH1
lF
C22H14FP
yo3
C22H14F3N03SC
'2LH
,IcF
1H O C G
c2 1 C21H10C12F3N0
a'
C23H16F$0 '21H ioBr ZF
C21H10C12F3N0
CZlH 1 uBr2F P O '2
c
lH1 OCIZF
3N0
H 1 OBI ZF $0
21
C21H10C12F3N0
'WH
1 OcF
C2~H10CF6N0
'2
3H 1
$5"'
C21H10C12F 2 l H 1OCIZF
C,,H,Cl,F ,N@
aAll compds were analyzed for C, H, N except 65 which was analyzed for C, H, Cl. bThe crude reac prod deposited 66 from EtOH. Concn of the filt provided 67. These compds were used without analyses. Tyridylation of the Et ester of 43 was more effective than pyridylation of 43 itself;mp of the ester, 217-218" (EtOH). Anal. (Cl9H1$,O4S) C, H. 74 was used without analysis. dObtd by oxidizing 72 Experimental Section). eAttempted synthesis of this compd (83) via pyridylation of 5 2 in THF gave only the 4debrominated compd (68). We are grateful to Dr. Richard E. Strube of the Walter Reed Army Institute of Research for providing the starting material 3,4dichlorod-trifluoromethylphenanthrene-9-carboxylic acid. gUsed without crystn.
J
fluoromethy1)benzoic acid (52 g, 0.2 mole) (Pierce Chemical Co.) and SOCl, (118 g, 1 mole) was heated at reflux for 2 hr. Excess SOCl, was removed under reduced pressure, the residual acid chloride was dissolved in diglyme (200 ml) and the soln was cooled to -70". A s o h of LiAl (ferf-OBu)$ (48.3 g,O.19 mole) in diglyme (200 ml) was added dropwise during 1 hr. The reaction was allowed to warm to room temp and poured into 10% HC1 (1.4 1.). Vac distn of the resulting oil gave 32.5 g (72%) of the aldehyde, bp 47-48' (0.2 mm), which was analyzed as the oxime; mp 86-87" (hexane). Anal. (C,H,F6NO) C, H, N. 2Pyridyl 3-Carboxy-6-t1~uoromethyl-9-phenanthyl Ketone (73). Routine treatment of 72 (Table IX)with 00,-H,SO, gave 58% of 2-pyridyl 3-formyl-6-trfluoromethyl-9-phenanthryl ketone; mp 195-196" (EtOH). Anal. ( C z 2 H l , F ~ 0 2C,) H, N. Oxidn of this aldehyde with KMnO, in aqueous Me@ (2 hr, 25") afforded 60% of 73.
References (1) E. A. Nodiff, K. Tanabe, C. Seyfried, S. Matsuura, Y. Kondo, E. H. Chen, and M. P. Tyagi, J. Med. Chem., 14,921 (1971)
(paper 1). (2) A. Leo, C . Hansch, and D. Elkins, Chem. Rev., 71,525 (1971). (3) H. H. Jaffe,ibid., 53, 191 (1953). (4) A. Claus and A. W. Bucher, Ber., 20,1621 (1887). (5) BritishPatent 870,541 (June 14,1961). (6) L. Simet, J. Org. Chem., 28, 3580 (1963). (7) L. C. Behr,J. Amer. Chem. Soc., 76, 3678 (1954). (8) B. Eistert,Ber., 97,1470 (1964). (9) P. Ruggli, H. Zaeslin, and F. Lang, Helv. Chim. Acta, 21,1247 (1938). (10) G . Lock and E. Bock, Ber., 70,923 (1937). (11) J. Blanksma, Chem. Zentrabl., I, 260 (1910). (12) B. Bogoslovskii and T. Yakovenko, Zh. Obshch. Khim., 24, 1043 (1954). (13) J. Blanksma, Chem. Zentrabl., 11,1964 (1912). (14) F. Asinger, Monatsh., 63,385 (1933). (15) E. J. Alford and K. Schofield, J. Chem. Soc., 2102 (1952). (16) T. S. Osdene, P. B. Russell, and L. Rane, J. Med. Chem., 10, 431 (1967).
