?~,THYLCNEDIOSY
ASALOGSO F
Journal o j Medicinal Chemistry, 1970,
FCBRlFUGlSE
1'01.
iU, S o . 6 867
Structural Modification of Febrifugine. Some Methylenedioxy Analogs1 PING-LUCHIESAND C. C. CHENG .I1 idwest Research Institute, Kansas City, Xissouri 64110 Received April $7, 1970 Some methyleriedioxy analogs of febrifugine and related compounds have been synthesized. They were found to be active against Plasmodium berghei. Their toxicity in mice is much lower than that of febrifugine. The therapeutic indices of these compounds are comparable with those of the parent compound.
The emetic p r ~ p e r t y z - ~associated with febrifugine
(I) has limited its potential usefulness as a chemotherapeutic agent against ma1aria.j Suitable structural modification of this compound may reduce its undesired toxic effect. Some synthetic work in this series has been d e ~ c r i b e d . ~ -Side-chain ~ modification of febrifugine had not been found fruitful;6-10 on the other hand, mono- or disubstitution by certain groups on the quinazoline ring system, particularly at positions 5 , 6, and 7, resulted in increased antimalarial activity and, in some cases, also increased the chemotherapeutic index. U
I
The methylenedioxyphenyl group, an important moiety frequently found in natural products, has been reported to possess some interesting biological activities.ll-24 l:or example, higher antimalarial activity (1) This work was supported by Contract No. DA-49-193-AID-2749 with the U. S. Army Medical Research and Development Command. This paper is Contribution No. 802 from the Army Research Program on hlalaria. (2) R . K. Chaudhuri, B. K, D u t t a , and R . ?i. Chakravarty, Indl'un M e d . Gaz., 89, 660 (1954). (3) J. F . €3. Edeson and T. Wilson. T r a n s . Roy. Sue. T r o p . .bled. H y g . , 49, 543 (1955). (4) P. B. Russell in "hledicinal Chemistry," A . Burger. E d . . Interscience, New T o r k , N . Y., 1960, p 819. ( 5 ) I t is of interest t o note t h a t although Chang-Shan has been used in treating human malaria for a long time, no resistant strains of malaria parasites have been reported. (6) B. R . Baker, et ul., J . Org. C h e m . , 17, 35, 52, 58, 68, 77, 9 7 , 109, 116, 132, 141, 149, 157. 164 (1952); 18, 133, 138, 153, 178 (1953); 20, 118, 136 (1955). (71 (a) K . S. Dhami, H. S. Sachdev, and K. S.S a r a n g , J . Sci. I n d i u n Res., l S B , 690 (1956): (b) P . Singh, K . S. Dhami, G. A I . Sharma, and K . 8 . Narang, ibid., 17B 120 (1958); (c) M . S. D h a t t and H. L. Uami, i b i d . , ISC, 256 (1959); (d) G. R . Dave, G . S.JIemada, and G . C . .amin, J . I n d i u n C h e m . Soc.. 37, 595 (1960); (e) M. S. D h a t t , C u r r . Sci., 30, 179 (1961); (f) H. Singh, Ii. S. Bhandari. and K . S. S a r a n g , J . I n d i a n C h e m . Soc., 41, 715 (1964). (8) (a) 0. Y. Magidson a n d Y.-K. Lu, Z h . Obshch. K h i m . , 29, 2843 (1959); (b) Y.-K. Lu a n d 0. Y. Magidson, i b i d . , 29, 3299 (1959). (9) hl. Fishman and P. A . Cruickshank. J . M e d . C h e m . , 13, 155 (1970). (10) R. I. Hewitt, W. S . JVallace, E. R . Gill, a n d J. H. Williams, A m e r . . J . T r o p . Med. Hug., 1, 768 (1952). 1111 1%. C . FitliimIri(.k, .\iist.mlinn Pat,rnl 1:36,2nn ilnnnj: C h m . n h t r . , 46, 17% (lY5l). (12) N. Mitlin, J . B c o E'ntomol., ~ 49, ti83 (195tij. (13) W. F. Barthel a n d R. H. Alexander, U . S. D e p t . A g r . . A R S series 38-42 (1957); C h e m . Abstr., 53, 1621i (1959). (14) E. 0 . Esnac and .I. 1';. ('auida, .I. I n s e c t . Z'hydol., 14, !I13 (lO(i8). (15) (a) H . L. Haller, E. R . McGovran, L. D . Goodhue, and W. N . Sulli\.an, J . Ore. C h e m . , I , 183 (1942): (b) H . L. Haller, F. B. LaForge, and \I: N. . Sullivan, i b i d . , 7, 185 (1942). (16) A . S. Perry and W.JI. Hoskins, J . Econ. B'ntomol., 44, 839 (1961).
and lower toxicity are noted with 3-piperonylsydnones when compared with its analogous alkoxy derivatives. 2b Some psychotropic phenylisopropylamines are methylenedioxy derivatives. 26, 27 The enhancement of biological activity is believed to be due to inhibition of in uico drug metabolism through interference with biological oxidation of the effective agents by either inhibition of hydroxylation or hydride t r a n s f e ~ - . * " ~ *This ~ - ~ ~also explains the prolongation of hexobarbital-induced sleeping time in animals by methylenedioxyphenyl derivatives. 34 Based on this information, the preparation of the 5,&, the 6,7-, and the 7,s-methylenedioxy derivatives of febrifugine and related compounds was undertaken. The synthesis of the 6,7- and 7,s-methylenedioxy analogs Vb and Vd was carried out according to the following scheme (see Experimental Section). Preparation of the 5,6-methylenedioxy analog Ve was carried out 2s follon-s. Xitration of 3,3-methylenedioxybenza1dehyde"j (VI) gave a mixture of 2,3-methylenedioxy-6-nitrobenzaldehyde (VII) and the corresponding &nitro isomer VI11 in a ratio of 2 : 1, ai. estimated by nmr. These isomers can be separated by fractional recrystallization from either l l e & or lleOH. A more facile separation of the isomers in NeOH can be achieved in the next stage, wherein the aldehydes were oxidized to the corresponding acids (IX and X) by permanganate. 2,3-llethylenedioxy-6-nitrobenzoicacid (IX), which is much more soluble in NeOH than the corresponding 5-nitrobenzoic acid (X), was thus ibolated and esterified to give XIa. Catalytic reduction of X I a (17) R . .I. Hoffman, T. L. Hopkins, and .4, JY. Lindcluist, i b i d . , 47, 72 (1964). (18) (a) 13. H. Moorefield, Contrib. Boyce T h o m p s o n I n a t . , 19, 501 (1958); (h) H. H. lloorefield and 11.H. J. Keiden, i b i d . , 2 2 , 425 (1964). (19) SI. Rerosa and W. F. Iiarthel, J . A g r . Food C h e m . , 5, 855 (1957). (20) U. P. Aloore and P. S. Hewlett, J . Sei. Food A g r . , 9 , 666 (19581. (21) C. Wilkonson. R . L. Metcalf, and T. R. Fukuto, J . A g r , Food C h e m . , 14, 73 (19661. (22) E. AI. de Espanks and B. Weksler, Proc. Soc. E z p , B i d . J l e d . , 63, 195 (1946). (23) (a) K . W.Rosenmund, Ber.. 43, 3412 (1910); ( b ) \Y,I3utli, F , K u l z , and K . W. Rosenmund, i b i d . , 72, 19 (19391. (24) (a) S. Biniecki and L. Rylski, Acta Pol. P h u r m . , 11, 9 (19541; (b) L. Rylski, ibid., 15, 2 l i (1958); (e) S. Riniecki and \T, Zlakoirska, i b i d . , 21, 571 (1964). ( 2 5 ) 15'. H . S y b e r g and C . C . Cheng. J . .\fed. C h e m . , 8 , 531 (1965). (26) A. T. Bhulgin and T. Sargent. S u t u r e ( L o n d o n ] , 216, 1141 (1967). (27) F. Ilallacker. .lfonnts/i. Chem., 100, i 4 2 (1969). (28) I:. I I . S c l i m i r l l nnil 1'. .\. l)nlirrr, .I. IZcol. ISnfomol..49, i2!1 (1956). (29) Y . 1'. SUll nlld 1,:. I t . . l " l , l l ~ " r l , J . A g r . Poud < ' h P , , ! . , 8 , 3 1 ( I Y t i O ) . (30) W. 15'. Philleo, R. D . Schonbrod, a n d L. C. Terriere, ibid., 13, 113 (1965). (31) D . .I. Hpnnessy. ibid., 13, 218 (1965). (YB] I t . I,. Metcalf, i l n ~ ~/lei%. u . L r i t o m o l . , 12, 229 (19tii). (33) M. it-. hnders, B i o c h e m . P h n r m u c o l . , 11, 2367 (19681, and references cited therein. (34) B. C . Fine and J. 0. Molloy, S a t u r e ( L o n d o i i ) , 204, i89 (1964). (35) W.H . Perkin, J r . a n d T'. h f . Trikojus, J . C h e m . S o c . , 2925 (19261.
I'i>:iti~ii
11:). S =6.7-OCH-O 11. X = 7.8-OCH-0 c. S = 36-OCH-O
i'OICH,CH=CHL
I\
I
li 1
111
I\.
1
li. I
ti. I li. I ti.?
ti. 2 ti. 2
ti . 2
IVn.X=6.7-OCH.O h. 9 = 7,8-OCH-O c , X = 5.6-OCH.0
Y
RO*
6.2 ti . 2 ti .2 ti .2 ri . 2 (i.2 ti.2 I;.?
li,2 Ii.2
V a X =6 7-OCH-0, R =CH 11 X = 6.7-OCH-0, R = H c X = i.8-OCH-0 R = CH d X = 7 8-OCH.0, R = H c S=iB-OCHOR=CH
yielded methyl 2-amino-3,ti-meth~leriedioxyberizoute (XIb). The latter was heated nith HCOSH? or il mixture of HCOSH, and HCOOH to form the intcrmediate 5,6-methylenedioxy-4-quitiazolone (IIc), albeit in low yield. The Ale ethcsr of 3,G-meth) lenedioxj febrifugine (Ve) was prepared from IIc and 111 in the same fashion as described for the other two isomers.
-r
ro
0 y k ~ C H o
O&HO0
+
'
\
( r I qo C H O
LO h0 \'I11
L I1
VI
1
Ih\li 0
r
h\lnO,
r
O
o&R;
0
:"O?'
e
NO XIa.K=OCH,,X=KO 11 R = O C H , X = S H
x
The side-chain intermediate ~ b r o n i oketone 111was prepnrcd by the method of Baker arid A l c E ~ o except >~ that oiio of itb intermedi:itcs, :3-li?-droxS.-cr-picoline (SI1I), was otit:iinrvl by hydrogetiolysis of N-(3-
1 -
I
s 11
ti. 1 ti. I (5. I
li.1 ti. I (i.1
(i.I 0 .I li. I
li.I
(i.I ti. I
(i.I ti . I ti. I ti. I
0.2 li.2 li 2 ti , 2 li.2 ti . 2
Test results were obtained by Dr. Leo Iiane, University 111 AIiami School of 3ledicine (Contract D,4-49-193-311)-2218), :md provided hy 1he Ilivision of 3lediciIial Chemistry, Walt el, I:eed Army Iiistit,iite of Ileseitrch. * Mice were infect,ed wit11 :t lethal dose of I-'. hc'rghei 3 dnys prior to administration of chemical (subcut;ineously i n oil) at each dose level. ( l i ( 3
SO
IY
ti 2 ti I ti. I
SI11
hydrox~-%-picol~l)trimeth~lammotiiurn iodide ( X I ) rather than by the action of KH,OH on 2-acetofuran at
high temperature under pressure, as reported ,)k thew investigators.'j Test results ot nitthj lcricdiox;\*:iriuiogs of' I'okmfugiiic~ :uid the Ale rthers :ig:iiii,t I). OCrqhei art~listcditiTaI)l(~ 1 l?or compiirison, twt rtwilts of fcbrii'ugiiic~:tg;iin.st thc, hame system are tt1,o iricluded. Toxic deathss6 v ~ r ( b observed at 10 mg/kg for febrifugine (I). On theother hand, no toxic deaths were encountered vith doses of 320 mg/ kg for Va, 40 mg/kg for Vb, 160 mgikg for TTc, 20 mg Lg for Vd, and SO mg/kg for Vr. Thv (:$ti) Ileatlia occurring O I L days 2-6 after infection are attiil)iircii t u ilriix action and counted aa "tnxic dratiis." Control animals do not die hefort: day 6.
Journal of Medicinal Chentistry, 1970, Vol. 13, .Yo. 5 869
~ I E T H Y L E X I ; L )AXLLOGS I O X T OF FEBRIFUGINE
toxicity of the methylenedioxy compounds are indeed much lower than that of febrifugine but the therapeutic indices remained about the same. Because the activity pattern of the free alcohol and the n4e ether in the other two isomer pairs are nearly identical, no further effort was made to cleave the Me ether Ve to yield 5,6-methylenedioxgfebrifugine.
Experimental Section
was evaporated to dryness under reduced pressure. The residue was treated with concentrated HC1 and again was evaporated to dryness. The residue was twice recrystallized from EtOH to Anal. (C17give 0.8 g (387,) of white crystals, m p 235-237'. HinNxOj.2HCl) C. H. N. - - 2,3-Methylenedioxy-6-nitrobenzaldehyde (VU) and 2,3Methylenedioxy-5-nitrobenzaldehyde (VIII).-A mixture of 60.7 g (0.44 mole) of 2,3-dihydroxybenzaldehyde,38.4092 g (0.53 mole) of CH2Br2,62 g (0.45 mole) of anhyd KPCOB,and 4 g of Cu041 was heated in 400 ml of D M F a t 125-130' under NP for 2 hr. The solids were removed by filtration and were washed with AleOH. The combined filtrate was diluted with 1.3 1. of H t 0 and extracted with a total of 1 1. of CHC13. The extract was washed with H20, dried, and evaporated. On distillation in oacuo, 41.7 g (63%) of 2,3-methylenedioxybenzaldehyde(VI) was collected as yellow liquid, bp 68-70' (0.05 mm), lit.35 mp
All melting points (corrected) were taken on a Thomas-Hoover melting point apparatus. The uv absorption spectra were determined with a Beckman DK-2 spectrophotometer. Where analyses are indicated only by symbols of the elements, analytical 34". results obtained for those elements were within &0.4% of the To 150 ml of concentrated HNOa was added, with stirring and theoretical values. cooling (ice bath), 16.5 g (0.11 mole) of VI in 10 min. Stirring 6,7-Methylenedioxy-4-quinazolone(IIa).-A mixture of 9.75 g (0.05 mole) of methyl 2-amino4,5-methylenedioxybenzoate37 was continued for another 10 min and the reaction mixture was poured into 700 ml of HPO. The precipitated crude product was and 50 ml of HCONHz was heated a t 100-110" for 1 hr and then collected by filtration. It was recrystallized 3 times from Xe&O a t 190-195" for 0.5 hr. The precipitate, which formed on coolto give 4.5 g (21%) of VI1 as yellow needles, mp 144-145'. I t s ing, wa> collected by filtration and washed with LIeOH to yield nmr spectrum (CDC4) exhibits two singlets at 7 3.67 (2 H ) and 6.3 g of crude product. The filtrate was diluted with 300 ml of -0.42 (1 H), and two doublets centered a t 2.97 and 2.10, reH20 whereupon additional 0.7 g of solid was obtained. The spectively (1 H each; J = 9 cps). Anal. (CaHjSOj) C, H, x. combined product was recrystallized from DLIF t o give 3.1 g (337,) of pure IIa as white crystals: mp 317-319" dec; if::" From the mother liquor the other isomer VI11 was isolated. I t was purified by recrystallization (bIe2CO) t'o give yellow 236 ( e 48,000), 286 (48,000), 311 (5700), and 323 mp (5400). needles: mp 150-151'; nmr 7 3.58 (s 2 H ) ; 2.10 (d 1 H, J = d n d . (C9HsS2Oa)C, H, N. 3-[2-Oxo-3-cis-(l-carboallyloxy-3-methoxy-2-piperidyl)pro- 2 cps), 1.58 (d, 1 H, J = 2 cps) and -0.27 (s, 1 H). Anal. ( C S H ~ N OC,~ )H, iX. pyl] -6,7-methylenedioxy-4-quinazolone(IVa).-This compound 2,3-Methylenedioxy-6-nitrobenzoic Acid (IX) and 2,3-Methywas prepared from 9.5 g (0.05 mole) of IIa and 0.05 mole of I11 by lenedioxy-5-nitrobenzoic Acid (X).-To a hot solution of 7.9 g essentially the same procedure as described for the preparation of (0.05 mole) of K1In04 in 200 ml of H?O was added 5.85 g (0.03 the corresponding febrifugine intermediate.6 Recrystallization mole) of VI1 in 130 ml of hIe2CO in 20 min. AIezCO was then of the crude product (mp 147-153' dec) from EtOH gave 8.0 g distilled on a H 2 0 bath. The residual aq suspension was heated (53';) of IVa.HC1 as white solid, mp 134-156' dec. Absorption on a steam bath for 20 min and filtered and the filter cake was thorbands of spectra (uv, ir) were a i expected. -4nal. (C;dH2,oughly washed with HPO. The combined filtrate was acidified S k h . H C 1 ) C, H, Y, C1-. with HC1 to give 6.0 g (95%) of IX, mp 183-186'. I t was puri3- [2-0xo-3-cis- (3-methoxy-2-piperidyl)propyll-6,7-methyfied by recrystallization from aq MeOH or Me2CO-Skelly F as lenedioxy-4-quinazolone (Va) .2HCI.-The product was obyellow crystals, mp 188-189". Anal. (CaH5 N06) C, H, N. tained in 80% yield by boiling 9 g (0.019 mole) of IVa with 100 The 5-nit,ro isomer X was prepared in a similar manner. I t ml of 6 .Y HC1 as described for the corresponding febrifugine intercould also be obtained by oxidation of the crude nitration prodC, niediate,G mp 22.5-227' dec. Anal. (C18H~lN~O~.2HC1) ucts of 2,3-methylenedioxybenzaldehyde followed by trituration H, N, C1-. of the oxidation products with MeOH, wherein X is much less 3- [2-0xo-3-cis-(3-hydroxy-2-piperidyl)propyl]6,7-methysoluble than IX. X crystallized from NeOH as yellow needles, lenedioxy-4-quinazolone (Vb) .2HCI.-A mixture of 6.3 g (0.0146 mp 204-206'. Anal. (CsHjNOs) C, H, X. mole) of Va'2HC1 was heated with 60 ml of 48T0HBr a t 135" for Methyl 2,3-Methylenedioxy-6-nitrobenzoate(XIa).--A mix20 min. The solution >vas evaporated to dryness under reduced ture of 10.6 g (0.05 mole) of I X and 20 ml of SOClZ was heated in pressure and evaporation %vasrepeated after addition of 30 ml of 120 ml of CHCL under reflux for 30 min. The clear solution was EtOH. The residue was boiled briefly with 10 ml of EtOH then evaporated to a syrup under reduced pressure. I t was saturated with dry HCl. The resulting solid was collected by treated with 50 ml of MeOH and the mixture was allowed to stand filt,ration and recrystd from MeOH to give 4.3 g (707,) of white a t room temperature for 30 min before it was evaporated. The als, mp 228-231" dec. Absorption bands of spectra (uv, solid residue thus obtained was recrvstallized from MeOH to irj were as expected. Anal. (C17H19Na05.2HC1)C, H, X, C1-. give 9.02 g (80%) of XIa as yellow nkedles, mp 97-99". Anal. 7,S-Methylenedioxy-4-quinazolone(IIb).-A mixture of 5.85 ,H. g (0.03 mole) of methyl 2-amino-3,4-methylenedio~ybenzoate~8 ( C Q H ~ S O ~ ) CN. Methyl 2,3-Methylenedioxy-6-aminobenzoate(XIb).-.4 soluand 33 ml of HCONHI was heated, with stirring, a t 130-140" tion of 5.63 g (0.029 mole) of XIa in 120 ml of EtOH vas shaken for 1 hr, 140-170" for 1 hr and finally a t 170-175" for 2 hr. Sepunder H2 in the presence of loyoPd-C for 1 hr in a Parr hydroaration of some solids was noted a t the end of this period. The genator. The catalyst was filtered and the solution evaporated reaction mixture was poured into 600 ml of H20. The resulting to dryness to leave a yellow solid. Two recrystallizations from precipitate was collected by filt,ration, washed with H 2 0 , and NeOH gave 3.41 g (70%) of XIb as yellow needles, mp 104-106". dried in air to give 4.6 g (817,) of product, mp 325-330" dec. dndl. ( C Q H ~ N O C,~H, ) N. A n analytical sample was prepared by recrystallization from 5,6-Methylenedioxy-4-quinazolone@IC).-A mixture of 5.85 g DAIF to yield off-white solid: mp 329-333" dec; 251 ( e (0.03 mole) of XIb, 10 ml of 90% HCO?H, and 25 ml of HCONH2 :38,000),311 mp (4200). Anal. (C9HsSs03) C, H, K. \vas heated, with stirring, at 125-135" for 1 hr, then a t 130-185" 3- [2-Oxo-3-cis- (3-methoxy-2-piperidyl)propyl] -7,s-methyfor 1 hr, and finally for 3 hr a t 185-190". The mixture w a s lenedioxy-4-quinazolone (Vc).HC1.-The condensation of I I b poured into 400 ml of H20. The resulting precipitate was with I11 to yield IVb was carried out as described for its 6,7-isocollected by filtration, washed with H20, and dried. The crude mer IVa. Hydrolysis of IVb with 6 A- HCI gave 2.3 g of Vc as product was recrystallized from DMF-MeOH to give 0.34 g (6%) off-white solid, mp 183--195° dec, believed to be the unstable of pure IIc as off-white crystals, mp 279-281' dec. Repeated dihydrochloride. On furt,her recrystallizations, the monohvdroruns gave yields in this reaction ranging from 5 to 10%. Anal. chloride was obtained as white crykals, mp 247-249" dec. Anal. ( C Q H ~ N ~C, O SH, ) K. (CiaHziNaOs.IIC1)C, H, N, C1-. 3- [2-0xo-3-czs-(1-carboallyloxy-3-methoxy-2-piperidy~)3-[2-0xo-3-cis-(3-hydroxy-2-piperidyl)propyl] -7,s-methypropyl]5,6-methylenedioxy-4-quinazolone(IVc).-This comlenedioxy-4-quinazolone (Vd) .2HCI.--A mixtiire of 2 g of Vc. HC1 ttiid 20 nil of 4X:; ITRr was heated a t 130-140° for 20 miii. If
-
(33) H . ICondo, Japanese Patent 7220 (1951); C k e m . Abstr., 48, 726 ( 1Y .34). (JS) I'. Uallacker, Justus Liebigs A n n . Chem., 633, 14 (1960).
139) 11. Parill-. K . Schrll)el, and IC. Lockemann, i b z d , , 383, 28s ( l u l l ) . (40) IC. W. Mera and J. Fink. Arch. f h n r m . . 289, 3 4 i (1958). (41) Af. Tomita and T. doyapi, Chem. Pitarm. Bull. (Tokyo), 16, 523 (1968).
