QUISOXALINE ANTIMALARIALS
January 1970 T.mm X V a Exposure
Day
066b
converted to its cis isomer by the action of light, and that the cis isomer is only about 0.03 times as potent as the trans isomer.
f3M/f200
f20OC
That the apparent, isomerization of 76 is reversible is indicated by t,he continuat,ion of the experiment. The light-exposed solution was placed in the dark box, and was allowed to stand there a t room temperature for 2 weeks. The IIV spectrum was determined after 7 and 14 days in the dark. Although little change was observed after 1 week, it was apparent that by 2 weeks the original spectrum of the trans isomer was beginning to emerge (see Table XV). However, the uncatalyzed rate of conversion back to the trans isomer is too slow to account for the observed activity of the presumed cis isomer. In one effort to isolate the cis isomer of the free base 38, an oil was obtained; an attempt t o crystallize this material resulted only in the isolation of unchanged trans isomer.'* Thus, it. appears that whatever change 76 undergoes on exposure to light, it is readily reversible and is therefore unlikely to involve an oxidative cyclization or a similar irreversible change of structure. The common experience that light induces the isomerization of trans-olefins to the cis isomers and the analogy to pyrantel's reaction to light strongly suggest that the light-induced change in 76 is also to the cis isomer.
Light 1 20,600 8250 2.5 Light 3 10,200 7700 1.3 Light 10 10,300 7480 1.4 Light 17 8,250 7100 1.2 Dark 24 10,100 7050 1.4 Dark 31 13,000 7090 1.8 a Changes in the uv spectrum of trans-76 on exposure to (i) diffuse daylight, fluorescent, lighting for 17 days, and (ii) after exposure to light and storage in the dark for 14 days. Calculat,ed e value at 355 mp, a maximum in spectrum of 76. Calculated e value at 290 mp, another maximum in t'he spectrum.
TABLE XVIa Sample
76
a
Exposure
Ilark Light Pyrantel Dark Light Table is explained in the text.
% redn of S. duhzus --burden a t 25 mg/ky-Day 1 Day 3 D a y 17
99 99 99 99
93 90 99 78
82 89 96 15
Acknowledgments.-The authors \\-ish to thank llessrs. P. S. Gordon, R. B. James, G. F. Smith, R. W. Sumner, and T. F. Estabrooks of the Pfizer hIedical .Research Laboratories for valuable assistance rendered during the course of this investigation.
dramatic change in chemical structure. I n the parallel experiment, the pyiantel -elution lost activity upon exposure to light. From previow experience* it is known that pyrantel is readily
Quinoxaline Studies. XV.'"
119
(12) P. S . Gordon, private communication.
Potential Antimalarials.
Some
(RS)-~-(Dialkylaminomethyl)-2-quinoxalinemethanols1b HESRTR.~ I O R E K 4 SO D
HARRY
P. SCHULTZ
Department of Chewcisit yI I'niveTsitg of Xiami, Co/al Gables, Florida
S3lR4
Received September 5, 1969 Six (KS)-cu-(dialkylaminomethyl)-2-quinoxalinemethanols were prepared from 2-tetrahydroxybutylquiiioxaline cia, an eight-step sequence. IL'either intermediateb no1 target compounds (diethylamino through di-nheptylamino derivatives) possessed antimalarial activity against Plasmodium berghei i n mice.
Certain quinolinemethanols,* long used as antimalarial agent's, frequently have less activity toward newer st'rains of malaria organisms. Because of the similarity of quinoline and quinoxaline, as well as the presence of t'he quinoxaline moiety in some broad spectrum (but toxic) antibiotic^,^ it was hoped that quinoxaline analogs of quinoline antimalarials would exhibit antimalarial act'ivity. The purpose of t,his paper is to report the syndhesis of a series of (RS)-a-(dialkylaminomethyl)-2-quinoxalinemethanolsJ incorporating diethylamino through di-n-heptylamino groups, for testing as ant'imalarials. Chemistry.-The desired synt'hetic objective was at'tained cia the sequence D-arabino-2-tetrahydroxybutylquinoxaline (1),4 2-quinoxalinecarboxylic acid (2), 4 2-quinoxaloyl choride (3),42-diazoacetylquinoxaline (4) , 2-chloroacetylquinoxaline ( 5 ) , (RS)-a-(chloromethy1)(1) (a) Paper SIX' of this series: S. Gerchakov a n d H. P. Schultz, J . .bled. Chem., 12, 141 (1969). (b) Contrihution No. 691 from the Army Research Program on Malaria, supported b y t h e U. S. Army Medical Research a n d Development Command cia Contract DADA li-6T-C-7064. (2) G . R . C o a t n e r , W.C. Cooper. N . B. E d d y , a n d J. Greenberg, Survey of Antimalarial Agents, Public Health Monograph No. 9, G . S . Government Printing Office, \f-ashington, D . C., 1953. ( 3 ) H. Otsuka a n d J. Shoji, T e t r a h e d r o n , 23, 1535 ( 1 9 6 i ) , a n d references therein. (4) S. Gerchakov, P. J. K h i t m a n , and H. P. Schultz, J . M e d . Chem., 9, 266 (1966). 2-Quinoxaloyl chloride i s nom commercially available.
2-quinoxalinemethanol (not analyzed) (6), (RS)-2quinoxalinepoxyethane (7), and (RS)-a-(dialkylaminomethyl)-2-quinoxalinemethanols(8). 2-Quinoxalinecarboxylic acid was prepared from 1 b y a considerable improvement of existing procedures, the material being isolated and purified a i its S a salt. Treatment of 3 with CHJ2 gave 4 (not isolated), which was transformed by standard methods into 5. A variety of reaction coiiditions failed to transform secondary amines and 5 into the corresponding amino ketones; only red, irresolvable tars were obtained. The reduction of 5 with XaBHA gave 6, unstable, flaring within 1-10 hr of drying to black ash. from which small flake. of 2-acetylquinoxaline were i.;olated manually. Konetheless, freshly isolated 6 was treated immediately with EtJH in an attempt to form a target compound 8, either aia a substitution reaction on 6, or via transformation i n situ of 6 into 7, which in turn could react with E t z X H to yield 8. However, only 2acetylquinoxaline was obtained, possibly by a reaction mechanistically related to the hydramine fission (Scheme I). Alternatively, elimination of HCI from 6 may have been spontaneous (vide s u p m ) , or promoted by basic X atoms of the quinoxaline nucleus. The amino ketone or chlorohydrin (6) derivatives of quirioxaline were thus eliminated as direct intermediates
QUISOXALISEAISTI3IALARIALS
January 1970
121
TABLE I ~ ~ ~ ~ ~ ) - ~ - ( L ) I . ~ L K ~ ~ L . ~ ~ ~ I S O J I E T H P L ) - ~ - ~ L ~ I ~ O ~ . ~ L I S l ~ ~ ~ ~ ~ T H . ~ ~ ~ L ~ " ~ c
Q~J-J-CHOHCH~NR,R,
so.
Ri, R2
k'ormula
Reaction time, hr
Reaction solvent, reflux
----yo Base
yield-Parnoate
Parnoate m p dec, C c
Antimalarial act.. life span increase, days. mouse, 640 mg/kgP
Et&H 38 Ci,HigTsO 3.3 0.4 Etd 100-1 30 0.2 Ilioxane 68 29 9 . .5 CsHeN608 n-Pr CC1, 62 43 80-130 0.3 CigH;oN&b 29 n-Bu CC1, 47 28 78-10.? 0.9 38 CsjH jsS& n-Pe Dioxane 26 13 7.;-92 0.3 CG7H86S602 16 ) n-Hex 13.5 Dioxaiie 89 41 63-83 0.0 CjlHB43605 6 n-Hep Uv spectra of pamoates were as expected; average X,.,[mp (e)] 237-238 (153,000), 278-279 (10,600), 289-390 (13,700), 301-302 (12,600), 318-321 (13,700). b H nmr spectra of bases were as expected; average 6[ppm(CC11)] 4.19 (s, 1 H, HCOH), 4.88 (9, 1 H, HCOH), 8.05 (m, 4, H, aromatic), 9.18 (s, 1 H, heterocyclic); average 6 (ppm) for Ohc derivatives: 5.98 (t, 1 H, HCOAc), 7.86 (m, 4 H, aromatic), Products, except the diethylamine compound, were iso8.84 (s, 1 H, heterocyclic); also present, complex peaks of alkyl substituents. lated and analyzed as the diammonium pamoate salts. All analyses were C, H, and S ; values were within +0.4% of the theoretical Uv spectrum, Amax [mp ( e ) ] 236 (26,400), 310 (5600), 318 (6700); n 2 3 ,D5 1.5700. e Average life span of control mice infected values. with Plasmodium bcryhei, 6.2 days. 1 2 3 4
(1
14.7-147' dec. The material was dissolved in 40 ml of 9 :I-HCI, treated with decolorizing carbon and filter aid, and filtered into 80 nil of H,O to give 3.94 g (95%) of 5 , mp 148-148.5' dec. Reci,ystallizatioii of 5 from C6H6-hexane (1:2, 15 ml/g) gave 1.66 209 mp ( e 15,500), 240 g (407,) of 5 : mp 147.5-148' dec; A,, (%1,100),'251 i24,300), 310 (6900), 319 (7300). Anal. (GOHjCISjO) C, H, C1, S . (RS)-2-Quinoxalineepoxyethane (7).--8 suspension of 20.7 g of 5 iii 200 ml of THF-EtOH (1: 1)was cooled to 0". With stirriiig, 1.6 g of NaBH4 was added; after 13 min, 1.6 g of i\;aBHc was added; after 45 min 400 ml of C6H6 %-as added; aft'er 1 hr 1 1. of €I& was added. The organic layer was washed three t,imes with 100-ml portions of H20, dried (IIgSO,), treated with decolorizing carbon, filtered, and concentrated. The residue was triturated with 40 ml of IIeOH, filtered, and washed with 10 ml of AIeOH. The filtrate was evaporated t o dryness, and the semisolid residue war trit,iri,ated with 10 ml of AIeOH, filt,ered, and washed with 5 nil of AIeOH. The combined solids were dried (vacuum desiccator, XaOH) to give 13.6 g ( 6 3 % ) of 6, mp 104-105O dec. Although uiistable when dry, slid flaring to a black ash whhin 1-10 hr, 6 could be stored nnder ligroin at 0" for 2 weeks. To a stirred suspension of 12.34 g of 6 in 90 nil of 95yo EtOH Y NaOH was added 10 nil of 6 - \ S a O H ; after 5 miii 10 nil of 6 i was added; after 20 miii the react>ioiisrispension was poured into 1.2 1. of H20, from xvhich 7 was extracted five t'imes with 250-ml portioiis of Et,O. -1fter drying (hIgS04) arid removal of Et,O, the reaidlie was d i s d v e d in 100 ml of c6H6, dried (AIgSO,), treated with decolorizing carboii and filter aid, filt'ered, and conceiitrated. The mlid residiie was triturat,ed with 20 ml of ligroin (bp 35-60') and filtered to give 9.4 g (9175, based on 6 ) of 7, mp 94-93". For analysis 7 was sublimed (8U", 0.1 mm): 9 4 . 5 5 209 mp ( e 9900), 239 (26,500), 320 recovery; nip 9.5.5-96'; A, (4900); pmr (CCl,), 6 (ppm) 3.12 (m, 2 H , CH,), 4.08 (9, 1 H, C H ) , 87.86 (m, 4 H, aromatic), 8.62 (s, 1 H, heterocyclic). Anal. (CIOH~NPO) C, H, N. 2-Acetylquinoxaline.-h solution of 1.8 g of 6 in 50 ml of Et,SH was stirred for 70 hr at 25" and refliixed for 22 hr. Filtration of t,he reaction mixtiire gave 0.8 g of Et*?iH?+ C1-, and conceiitration gave 1.15 g of semisolid residue, only 0.1 g of HCI. The remainder was extracted which was soluble in 1 with 90 ml of hot ligroiii (bp 37-53"); the ligroin solution was clarified, filtered, and concentrated to give 0.83 g ( 5 7 % ) of 2(8)T l l i r ; f I u a s coiipled with t w o adjacent iliastereotopic 11; tile i l i i a r t e t actually 2 i i o u h l e t ~. ,J A B = 5.3 Hz.
S V R ~
acetylquinoxaline, mp 76.5-77.5". Sublimation of 0.5 g at 50" (1 mm) gave 0.33 g (4057 total yield) of yellow crystals: nip 79-79..i0 ; positive haloform, negative Tollens t,est; Amax 210 nip ( e 9900), 247 (22,100), 311 (4500), 320 (4500); pmr (CCl,), 6 (ppm) 2.72 (s, 3 H, CH,), 7.90 (m, 4 H, aromat'ic), 9.34 (8, 1 H, heterocyclic). Anal. (CIoHsSZO) C, H, N. Di- (RS)-a-(di-n-butylammoniummethyl)-2-quinoxalinemethanol Pamoate (8).--$ solution of 110 ml of CCla containing 5.17 g of 7 and 3.88 g of Bii2SH was refluxed under K2 for 29 hr, iuitil pmr data indicated the reaction was 757, complete. The cooled soliition x a s treated with 0.71 ml of h e 2 0 in order to transform urireacted BriPNH into BL~?SAC.After 15 miii the solutioir was extracted three times with 50-ml portions of 0.3 S HC1; the combined aqueous extract was treated with decolorizing cahon arid filter aid aiid filtered. The filtrate was brought t o pH 9-10 and extracted t.hree times with 50-ml portions of CC1,. The combined CCI, soliition was counterextracted wit.h saturated NaC1, dried (hIgSO,), treated with decolorizing carbon and filter aid, and filtered. Removal of the solvent, gave 5.83 g (64.5%) of oily yellow prodiict. The oil was redissolved in CCl, and again purified as outliiied above. Removal of CC1, gave 5.6 g ) of clear oil whose prnr spectrum proved it to have the d btructure. The oil was dissolved in 100 ml of 0.183 iY HC1, treated with decolorizing carbon and filter aid, aiid filtered three times and the filt,rat,ewas diluted to a final volume of 20U ml. A soliitiou of 3. g of disodium pamoate in 50 ml of HzO was likewise prepared, then diluted to 200 nil. The two solutiolis were simultaneously dripped int,o 400 ml of stirred water, giving iiistantaiieous precipitation of 6.3 g (437,) of product. In some instances acceptable analyses were obtaiiied only after liberation of the fi,ee base wit,h NaOH from the pamoate salt, repurification of the free base (alumina column), and reprecipitatioii of the pamoate salt. Physical data for all target compounds (8)are listed in Table I. Di-( RS)-~-fdi-n-butylammoniummethyl)-2-quinoxalinemethanacetoxide Parnoate.-.$ sclntion of 1.1 g of 8 ( S B L Icom~ poiirid) and 0.31 ml of Ac,O in 10 ml of CClastood 12 hr under Sn at 25". The prodiict \+-aspruified and transformed into ita pamoate salt by the same serie3 of steps as outlined for the parent 8 : 237 m p (E 150,600), yield 0.95 g (48.45,); mp 80-140"; A,, 279 (8.500), 291 (11,700), 302 (10,100), 319 (7200); pmr average data, see footnote b, Table I. Anal. (Cs3H74Ne0,0) C, H, N ,
Acknowledgment.-The aut'hors are indebted t o 3Ir. John Oatis, Jr., for his skilled techriicul :issist:mce.
