llurch 196s
ASTIMALAI~IAL FLUOI~INATED ~-QUINOLISEMETHANOLS
To a solution of the foregoing ester (0.06 mole, 18.32 g) and ethyl 6-ben~amidocaproate~" (0.061 mole, 16.06 g) in 50 ml of dry C6TT6, N a S H 2 (0.073 mole, 2.93 g) was added. The mixture was heated at 90' with vigorous stirring for 24 hr. iZfter cooling the mixture to .%", 32 ml of concentrated H2SO4 in 50 ml of H2O was added and refluxing was cont'inued for 65 hr. The C,& was then distilled off azeotropically and the residue was made alkaline with 30% aqueous NaOH keeping the temperature below 40". The mixture was then extracted with C6H6. After drying ( MgSOd) the solvent was removed under reduced pressure. The ir Fpectrum of the solid residiie indicated that the N-benzoyl group was not cleaved. The material was t'herefore suspended again in a solution of 30 ml of concentrated H2SO4 in 50 ml of IT20 and the mixt,ure was refluxed for 64 hr. After cooling it was made alkaline as before and extracted with CeH6. The dried CsFTe solution iipon concentration in vacuo left an oil to which 23 g of 4 8 7 HBr was added. Upon standing for a short while a yellow precipitate was obtained and filtered: the yield of 6-[6-methyl-2ip-tolyl~cit~cho~ii~i~l]-n-amylamir~e dihydrobromide was 5.5 g (84'; based on recovered acid).': The aqueous alkaline phase was acidified with concentrated FICl and the resulting precipitate was filtered, washed with a little EtOH, and dried. The weight, of recovered 6-methyl-2(p-tolyl)-4-cinchoninic acid from the unreacted ethyl ester was 7.8 g. The foregoing amine dihydrobromide (0.008 mole, 4 g) was dissolved in hot l8Yc HBr and treated rapidly with a solution of Br2 (0.008 mole, 1.28 g) in an equal volume of 487, HBr. The crude product was filtered and dispersed in 40 ml of boiling 95% EtOH, and H20 was added until a clear solution resulted. Cool(15) This intermediate and the ones which follow en route t o 60 mere used directly in t h e next synthetic step without characterization; c/. ref 9 and 14.
277
ing gave a light yellow precipitate. Concentration of the mother liquor yielded some additional product'. The total yield of 6-bromo-6-[6-methyl-2-(p-tolyl)cittchonii1~l]-n-amylamine dihydrobromide was 3.95 g (84(x). The foregoing product (1.5 g) was dissolved in 50 ml of 93% Et013 and 7 ml of 14% aqueous Na2C03was added. The mixture was shaken for 1 hr in a stoppered bottle and then hydrogenated over 20 mg of PtO2 in a Parr hydrogenation apparatus. The react,ion mixture was filtered and washed (Et,OH, hot CHC1,). The solvents were removed in vacuo. The residue was dissolved in hot CHC13 and filtered. Evaporation of the solvent left a brown residue. This was dissolved in absolute EtOH and the solution was saturated with dry HCI. After standing fnr a short while, Et,O was added and t,he precipitate was filt'ered to yield 0.5 g of t'he hydrochloride. A small amount, of this salt was converted into the free base 53. The ir spectra of the free base 53 and its hydrochloride salt were idelltical with those of t>heproducts obtained by catalytic reductions of the pyridyl ketone. 2-Aryl-4-quinolinecarboxylic Acids (Cinchoninic Acids) (I) (Table IV).-A11 of the substituted cinchophens reqiiired as starting material were synthesized by the Pfitzinger'e condensation. In general, it was found that better yields were obtained when the mixtures of the appropriate isntins and substituted acetophenones in EtOH-KOH were refluxed for 30 hr; shorter periods of time gave poorer yields.
Acknowledgment.-The authors wish t o thank Professor A. Burger for fruitful discussion before and during the course of this work. (16) IT-. Pfitzinger, J. Prakt. C h e n . , 66, 283 (189i).
Fluorine-Containing 4-Quinolinemethanols as Antimalarials' ANDREW J. SAGGIOMO, KAZUO KATO,AKD TOYO KAIYA Research Institute of Temple University, Phdadelphia, Pennsylvania 19144 Received September SO, 1967 Various fluorine-containing ~-dialkylaminomethyl-2-phenvl-4-quinolinemethanol derivatives have been prepared for evaluation against Plasmodium berghei in mice. Preliminary biological data indicate the fluorine compounds to be more potent at comparable doses than the corresponding chloro derivatives. a-Di-n-butylaminomethyl-2-(4-chlorophenvl)-7-trifluoromethvl-4-quinolinemethanol when administered to mice in a single . " ' subcut,aneous dose was curat,ive a t 40 mg/kg.
A high degree of antimalarial act'ivity was discovered in the 4-quinolinemethanol series during the World War I1 program supported by the government. Reviews2 of this work indicated that the most notable changes in activity in this series n-ere caused by substituent variations in the aromat'ic rings. A considerable number of the chlorine-subst'ituted a-dialkylaminomethyl-2-phenyl-4-quinolinemethanolsshowed pronounced antimalarial action. In the past two decades pharmacological investigations have revealed that the replacement of chlorine and hydrogen in biologically active compounds by fluorine and fluorine-containing groups has provided in many cases highly potent fluorine-containing therapeut,ic agents. We now report the synthesis and potent antimalarial activity of various fluorine-containing 4-quinoline(1) This investigation was supported by the U. S . Army RIedical Res?arch a n d Development Command under Contract Dd-49-193-MD-2950 and is Contrihution KO.290 from the Army Research Program on Malaria. Survey of Antimalarial Drugs. 1941-1945," (2) (a) F. T.Wiselople. ".i J. IT. Edwards. Ann Arbor. Ilich.. 1946: ( h ) G. R . Coatney, I\-.C. Cooper, N. U. Eddy. a n d J. Greenlierp, "Surveg. of .intimalarial Agents," Public Health Monograph No. 9, Washington, D. C., 1953.
methanol derivatives. These compounds were prepared as part of a program to develop new and moreeffective agents to combat drug-resistant malarial parasites. Chemistry.-Our synthetic plan essentially paralleled those routes described previously for the preparation of 4-q~inolinemethanols.~~~ The general route to the fluorine-containing 4-quinolinemet'hanol derivatives commenced with the preparation of the appropriately substituted cinchophens (2-phenylcinchoninic acids). The latt'er (Table I) were obtained (a) from readily accessible anilines via the Sandmeyer isatin synthesis516 and the Pfitzinger r e a c t i o ~ i and ~ * ~ (b) ~ ~ through the Doebner-AIiller r e a c t i ~ nbetween ~ ~ ~ ~the ~ ~appropriate anilines, benzaldehydes, and pyruvic acid. (3) R . E . Lutz, el a?., J . An.Chem. Soc., 68, 1813 (1946). S.Winstein, et a?., i b i d . , 68, 1831 (1946). ( 5 ) T. Sandmeyer, H d u . Chim. Acta, 2, 234 (1919). (6) R . C. Elderfield in "Heterocyclic Compounds," Tol. 3 , R . C. Elderfield, E d . , John Wiley and Sons, Inc., New York. N. I-., 19.52, p 208. (7) IT. Pfitzinger, J . Prafct. Chem., 66, 283 (1897). (8) For excellent r e v i e w . see ref 6, Vol. 3, p 222; Vol. 4, p 17. (9) 0. Doebner, Ann., 242, 265 (1887). (10) For a review, see ref 6 , Vol. 4, p 25. (4)
RZ
279
Rlarch 196s TABLE IV FLUORINE-COXTAILYIKG 2-PHEXYL-k)UISOLYL COCH,
1\IErHYL
KETOKES
Ri
R? Recrjstn s o h ent
hIV! Cornpd
R1
18 19 20 21 22
7-CFr 8-CF3 6-C1 6-C1 6-c1
Coinpd
R1
1% 2
Rz
H H 8-C1 8-C1 8-CF3
R3
"C
1%3
4'-C1 4 '-C1 3'-CF7 4'-F 4'41
LIP, OC
123 .j-124 178-179 14.5-146.5 137-138 209-209.3
Kecrystn solvent
I ield,
70
4'-C1 157-1.X CsH, 86 6-F I€ 125-127 Ligroiii 68 4'-C1 7-F H 194-196 C,Hs 73 4'-C1 A-CFJ H Ligroiii 90 8-C1 3'-CF3 136-138 6-C1 8-c1 4'-F 141-143 C6Hs 67 6-C1 193-196 5 CaHs 94 2X 6-C1 8-CF3 4'-CI Elemental analysis of these compounds was generally omitted. I r spectra of the acid chlorides indicated the C=O absorption band a t 5.7 p, whereas the ciiichoninic acids displayed the C=O peak at 5.9 ~ 1 . 23 24 23 26 27
Q
Yieid,
70
EtOH
.i4
Me&O-HiO EtOH EtOH EtOAc
80 36 12 33
formula
CisHii C l F J i 0 CisHnClF3SO CisHioClnFsNO Ci7HioC12FSO CisHioCllF3XO
lnal,>es
C , TI, s C, H , S C , 11, ?; C, H , N C, H , X
taining 4quinolinemethanol derivatives possess potent antimalarial action arid are curative in mice. Compound 45 was found to be significantly more active than the corresponding chloro derivative. None of the intermediates tested were active. Photosensitization effects of 4quinolinemethanol derivatives were described in an earlier review.2a Recently, the phototoxic potency of a number of quinolinemethanols, including compounds 45 and 48, has been reported by Rothe and Jacobus.'*
Experimental Section13 The object of this research was to prepare as quickly as pussible the pure target compounds in sufficient quantity for antimalarial t'esting. Consequently, the experimental conditions described herein do not necessarily represent the optimum. Occasioiially the isolation, extensive purification, or elemental analysis of an intermediate was omitted. Physical and analytical data are found in Tables I-VIII.
TAHLE VI
FLUORIXE-CONT.UNIXG a-BROMOMETHYL 2-PHEXYL-4-QUINOLYL KETOXES COCH2Br
Cornpd
Ri
R2
R3
Prepn methoda
hip, O C
Recrlstn 601%ent
Yield,
70
29* 6-F H 4 '-CI A 243-246 dec AcOH 8tj 4'-C1 B 239-241 dec 30* 7-F H AcOH 53 B 169- 171 EtOH 31 7-CF3 H 4'-C1 93 4'-Cl A, B 162-164 32' 8-CF3 H ?rIeOH-HLO SSd 3'-CF3 A, B 168-169 33~ 6-C1 8-CI EtOH 9.id A 173-174 841 4'-F 34 6-CI EtOH 89 EtOH 35 6-C1 8-CF3 A, B 193-196 8gd 4'-C1 a Refers to methods A and B in the discussion. b Isolated and analyzed as the hydrobromide salt. llixture melting point was riot depressed and ir spectra of both products were identical. Yield based found, 47.22.
Tormula
lnalgaeu
C17H11Br2C1FN0 C , H,?; C1;H1,Br2C1F?;0 C, H , ?; C18HloBrClF3KO C , H , N C18HloBrC1FdS0 C, H, S C18H9BrCI2F3NO C , H , S CI;H$BrCl,FNO C, H, N C I ~ H S B ~ C I I F ~ SH O , K ; C" Prepared L K L methods A and B. on method 9. e C: calcd, 46.68,
lethal dose of Plus??&iu.yy~belyhei 3 days prior to adMaterials.-& and 4-Fluoroaiiiliiie, 4-trifluoromethylaiiilitie, ministratior, of the ,,hemicai. ~ , ~ ~ the t i,,hemicai ~ ~ ~ l4-chloro-2-trifluoromethylaniline, ~ , 4-chloro-;S-nitrobeiizotrifl~ioride, was administered subcutaneously in oil at, each of three dose levels, namely at, 40, 160, arid 640 mg/kg. The mean survival time of infected control mice is 6.5 ==I 0.5 days. Extension in survival time of the chemically t,reat,ed mice is interpreted as evidence of antimalarial activity. The number of mice surviving (out of five) a t 00 days post infection are considered cures. preiimiIlary arltimalarial test data are reported in Ta8bleIX. The results indicate that the fluorine-con-
3'-trifluoromethylacetophenone, and 4'-fluoroacetophenone were purchased from Pierce Chemical Co,, 2- arid 3-trifluoromethylanilirie were obtained from Maumee (12) W. E. Rothe a n d D. J. Jacobus, 1 5 4 t h National LIeeting of the American Chemical Society, Chicago, Ill., Sept 11-14, 1967, p 37. (13) Melting points were determined with a n electrically heated TiiieleDennis apparatus and are uncorrected. Elemental analyses were carried o u t by Schwarzkopf Alicroanalyticai Laboratory, IYoodside, X. Y..and Micro-analysis, Inc., Wilmington, Del. Where analyses are indicated only b y symbols of the elements, analytical results obtained for those elements \vere witilin +0.4% of +,lie theoretical values.
"SO
Hc;' OH c H 2x
