Antimalarials. II. .alpha.-(2-Piperidyl) - American Chemical Society

8-CH3, -CH30, or -Cl substituents increased the survival time of mice infected with Plasmodium berghei, but they retained photosensitizing properties,...
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Antimalarials. 11." w(2-Piperidyl)- and cr-(2-Pyridyl)-2-trifluoromethyl-4-quinolinemethanols'b ROGERAI. PINDER AND ALFREDBURGER &pat lriient o j Cheiiiisliu, Cnzversity o j Virginza, Charlottesvzlle, Vzrgzniu 22901

Received October 12, 1967

X series of a-(2-pipeiid~-1)-2-t~ifluorometh~-l-4-qui1ioliiiemetha1iols %-assynthesized in the hope that replacerneiit of %-aryl by 2-CF3 would decrease the photosensitizing qualities of the 2-aryl analogs. ,411 of the 2-trifliioromethyl derivatives carrying 6- or 8-CH,, -CH,O, or -C1 sitbstit,iients increased the survival time of mice infected x-ith Plasrriodium berghei, but they retained photosensitizing properties, albeit less than the 2-aryl-substituted analogh. SCHEME I A number of cu-(2-piperidyl)-4-q~inolinemethanols~~~*~~ have high antiplasmodial activity in avian iiifectio~is.~ fi High activit,y is associated with a substituent' in the 2 position of the quinoline nucleus, particularly phenyl, which will prevent oxidation at that position; the cinchona alkaloids and related compounds are rapidly Iv I11 biotrarisformed in man to the inactive carbostyril derivatives.j The most promising compound, G,S-dichloro-2-phenyl-a-(2-piperidyl)--l-quinoline m e t h a n o l , was eighty times more active than quinine against Plasmodiui~ cathei?ierium in the duck,4 but' it produced severe photosensitivity and did not' find clinical use in man.6 There is renewed interest in this type of ant'imalarial, bot'h because it is firmly bound t o host tissues and slowly released and therefore has I I1 repository properties, arid because it has shown one of the highest' recorded activities against Plasinodiuni by hydrolysis, gave the pyridyl ketones (111). Cataberyhei in mice.' It' has been theorized that phot,olytic hydrogenation of I11 selectively reduced the cartoxicity arises because of the increased resonance conbonyl group and the pyridine nucleus without attacking jugation from the 2-ary1 group ;7 a trifluoromethyl the qurioline nucleus, giving the amino alcohols of type group in lieu of a 2-aryl group may modify this propI, while reduction with sodium borohydride gave amino erty arid still prevent oxidation to the carbost'yril. alcohols of type 11. We are t'herefore reporting the synthesis and ant'imalarThe 2- trifluoromethylcirichoriiriic acids (IV) were ial activit'y of a series of ~(2-piperidyl)-2-trifluoroprepared by the route outlined in Scheme 11. Coiimethyl-4-quinolinemethaliols (I) arid of the correderisatiori of a substituted aniline (V) with ethyl 4,4,4sponding a-(2-pyridyl) compounds (11)which represent trifluoroacetoacetate* in the presence of polyphosphoric a new type of analog. SCHEME I1 The synthetic approach t o amino alcohols of types I R\ R, nu arid 11, start'ing from t'he corresponding quinoline-4carboxylic acids (IV), is outlined in Scheme I and reduces the number of steps from six2,3to tu-o.la Addition of 2-lithiopyridine t o the acids at -GOo, followed

y

(1)(a) Paper I : D. I T - . Roykin, J r . , .A. R . Patel, R. E. Luta, and .A, ](urger, J . Heterocycl. C h e m . , 4, 459 (1967). (b) This JTork was supported b y the U. S. Army Medical Research and Development Command, Contract KO. D.\-49-193-AID-2955, Contribution S o . 297, A. Burger and R. E. Luta co-responsible investigators. ( 2 ) A . D. Ainley and H. King, Proc. Rou. SOC.(London), B126,60 (1538). ( 3 ) R. F. Broivn, et a!., J . A m . C h e m . Soc., 68, 2705 (1916); E. R. Bucliman and D. R . H o n t o n , ibid., 68, 2718 ( 1 9 4 6 ) ; E. R . Huchman, H. Sargent, T. C. Myers. and D. R . Howton, i b i d , 68, 2710 (1916); E. R . Huchman, H. Sargent, T. C. Myers, and J. .\. Seneker, ibid., 68, 2692 (1946); J. 13. Koepfli, 11. 11. Rapport, .L E. Senear. and J. F. Mead, ibid., 68, 2697 (1916): R . 1:. Lutz, et aZ., ibid.,68, 1813 (1Y46); J. F. >lead Koepfli, ibid., 68, 2708 (1916): H. Sargent, %bid.,68, 2687 (1946); R . -1. Seibert, T. R. ir-orton, -1.A. Henson, and F. I\-. Bergstrom, i b i d . , 68, 2721 (1946): A . E. Senear, H. Sargent, J. F. Mead, and J. B. Koepfli, zbid., 68, 2655 (1546); S. Winstein, T. L. Jacobs, E. F. Levy, D. Seymour, G. B. Linden, and R. R . Henderson, ibsd., 68, 2714 (1946). (4) F. T. TYiselogle, "d Survey of Antimalarial Drugs, 1941-1945," J. R-. Edwards, Ann Arbor, blich., 1946. ( 5 ) R. T. I\-illiams, "Detoxication 3Iechanisms." John TT-iley and Sons, Inr., Nrn. Yurk, N. Y,, 1059, p 655. (6) T. N. Pullman, 13. Craig, A. S. Alving, C. 11.TYhorton, R. Jones, and L. Eicllelberger, J . Clin. Inuert., 27 (Suppi.), 12 (1948). ( 7 ) D. P. Jacobus, Abstracts, l58rd National LIeeting or the .iinerican Clieiuical Society, Miami Beach, Fla,, .ipril 1967, 1\18.

p

R

VI1

VI11

i

1.BuLi 2.C02

N (8) J . Burdon and

IX V. (2. K. AILLouglilin,

T r t r o h e d r o , i , 20, 21Ci3 (lYb4).

- I

,

.1

S.7 li Teats were c:iri,ied o i i t i i i iiiic,e iiifected with I'. krqhei.1; 'rest resiilts were slipplied by \\-alter I:eed h r n i y Itistitrite of I t r search, iVashiiigton, I). c'. 15iihaiicemetit iii stirviva1 time of treated animals is regarded :is evidetice of ailtimalarial activity. A c~clrnporitidi- cotisidereti active if the iiieatli sitrvival time of t h o tre:ited gloiip is more 1hati tloitble the meaii ,siirviv:il time (7.IJ & 0.5 days) of the coiilrol grolip: it i s >aid t o he ciirative w-heii I tie :itiinial aiirvives tip t o 60 tlays.

E l O I I , yield ill g.

2-Trifluoromethylcinchoninic Acids (Table IV).

A.

111:I

TAULE VI 2 - T l ~ I ~ L ~ U l ~ O ~ ~ E T H Y L Q U I N O L I N E ~ - R I L)EItIVITIVES ETH.\~OL

CHOHX

d

R& It

.\lethod

Tieid, %"

LIP, "Ch

FormulaL

Yield,

63,5l 196-197 C,iH,F3NO? R Xa 67 215-216 C ~ ~ H ~ F ~ N O LH Pip H Pyr 51 8-CHj B 199-200 CI,H~F~SOI Pip ~-CHJ 62,685 224-226 Ci3HioF3XOi A, B 6,8-(CHj)~ Pyr 6-CH3 226-227 C11H&1F3?r'Oid A, B 72,74 6-C1 Pip 8-CH3 8-c1 B 18 210-212 C ~ I H , C I F I S O ~ ~8 C H 3 Pyr 6-OCIIz A 63 238-239 C~IH~F~NO~ 6,8-(CHa)2 Pip a Yield from seqiierice B is based on the starting 4-chloro6,8-(CH3)2 P y r See footnote b, qilinolines. b Itecrystallized from EtOAc. Table 111. C: calcd, 47.93; found, 47.36. e No N analysis. Pip 6-CI

91 60 100

254-255 115-116 254-256 189-140 284-286 120-122

55 86

279-280 128-129

45

6-Cl

Pyr

89

266-266 149-150

8-CI 8-Cl

Pip Pyr

28 78

218-250

6,84219 6,8-CI?

Pip

PJ r

33 82

262-264 138-139

6-OCH3 6-OCH3

Pip Psr

52 100

241-242 1i2-173

A, B A

H 6-CH3

T.IBLEV 2-'~RIFLUOROhlETHYL-4-PYRIDOYL$UINOLINES

R

Yield, 70

AIp,

O c a

Analyses

I1

C, H, N

G-CHJ

c, H

63 130-132 60 125-126 8-CHa 64 98-99 6,8-(CH3)3 73 119-120 6-Cl 48 152-133 8-c1 31 116-117 6,8-C1> 34 138-139 6-OCH3 67 132-133 Recrystallized from EtOH.

C, H,

c,H

C, H C, H C, H, N C, H, S

trifluoromethylcinchoninonitrile (23.6 g, 0.1 mole) and a soliitioii of NaOH (12 g, 0.3 mole) in H,O (50 ml) and EtOH (120 ml) was stirred under reflns for 12 hr. The solution was evaporated to dryness, and the residue was dissolved in HXO and filt,ered throiigh Celite. The clear filtrate was acidified by dropwise addition of AcOH, and the white precipitate was collected and recrystallized from EtOAc, yield 20 g. 2-Pyridyl 4-Quinolyl Ketones (Table V).-To an ethereal solutiori of n-butyllithium (0.05 mole) a t -60" was added rapidly 2-bromopyridine (8 g, 0.05 mole), and the brown mixture was stirred at -60" for 1 hr. Finely pox-dered 6-methoxy-2-trifliioromethylciiichoiiirii(~ acid (6.4 g, 0.02 mole) was added all a t once arid the mixture was htirred at -60" for 2 hr. It was allowed to warm to room temperature and then hydrolyzed by addition of H20. The ether layer was dried (LlgSO4) and distilled

Mp, 50 80 66

O C

12-1-126

CF,

Recrystn solvent EtOH RIeOH EtOH EtOH EtOH LIeOHC6H6 EtOH AIeOHCsH6 EtOH EtOH-petr etherd EtOH MeOHCsHs EtOH EtOH-petr etherd EtOH MeOH

Pip = 2-piperidyl; Pyr = 2-pyridyl. Table 111. c PI': calcd, 7.33; found, 7.80.

I'ormuiab CisHi1FsNz0. HCI C~HiiFaN20 C I I H I O F ~ NHCl ?~. CnHnFsN20 CiiHioFa?;?O. HCl CnH13F3N20 CisH?iFaN20. HCI C~aHlsFd20 CisHisCI123N?O'HCI C1sHioClFaN20 CisHieCIFsKtO. HCI" CisHiaClFa?;?O CisHisChFaN20' HC1 CisHoChFaN,O C I ~ H I O F S N ~HCI O?. CiiHl~F~S202 d

See footnote b, Bp 30-60".

to give a yellow solid, which was recrystallized from EtOH as yellow needles, yield 4.7 g. a-(2-Piperidyl)-2-trifluoromethyl-4-quinolinemethanols (Table VI).-A solution of 6-methoxy-2-trifluoromethyl-4-quinolyl2pyridyl ketone (4 g) in EtOH (300 ml) containing 1 molar equiv of HC1 was shaken with PtOI (200 mg) at 2.8 kg/cm2 under H,. The reduction was stopped when 4 equiv of HZ had been absorbed; the catalyst was filtered off, and the residue was concentrat,ed until crystallization began. Recrystallization from EtOH gave white needles, yield 2.2 g. a-(2-Pyridyl)-2-trifluoromethyl-4-quinolinemethanols(Table VI).--NaBH4 (0.26 g, 0.007 mole) was added portionwise to a stirred solution of 6-methoxy-2-trifluoromethy1-4-quinolyl2pyridyl ketone (2.2 g, 0.007 mole) in LIeOH (200 ml), and the mixtiire was stirred at room temperature for 2 hr. LIeOH was removed under reduced pressure arid the residue was taken up in ether, washed (HgO), and dried (llgSO4). The ether was distilled, and the residue was recrystallized from lIeOH, yield 2.3 g.

Acknowledgment.-This study has profited from frequent and helpful discussions with Professor R. E. Lutz and Drs. D. W. Boykin, Jr., arid A. It. Pate1 of the University of Virginia.