July 1969
, ~ X T I Y I A L A R I A L .4ND A N T I L E P R O T I C
REPOSITORY DRUGS. VI1
597
Repository Drugs. VII. N-Allylidene-4,4’-sulfonyldianiline and N-(Benzylideneand -l-Naphthylmethylene)-N’-methylene-4,4’-sulfonyldianilinePolymers with Prolonged Antimalarial and Antileprotic Action’ EDWARD F. E L S L A G E R , DAVIDB.
C A P P S , AKD
DOXALD F. WORTH
Departrnent of Chemistry, ilIedical and Scientific Affairs Division, Parke, Davis & Company, Ann
bor, lllichrgan 48106
Received March 14, 1969 Various ~-allylidene-4,4’-sulfonyldianiline polymers (Ia and b, 11), N-(benzylidene- and -1-naphthylniethylene)-N’-methylene-4,4’-sulfonyldianilinepolymers (IIIa and b, IT), and related substances were synthesized a b potential repository antimalarial and antileprotic agents in the search for water-labile sulfones whose activation and mobilization from the depot site might not, unlike DADDS, be enzyme dependent. The N-allylidene-4,4’wlfonyldianiline polymers were prepared from DDS, 4-sulfanilyl-o-toluidine, and 1,1,3,3-tetraethoxypropanein MeOH and HC1, while the N-(benzylidene- and -l-naphthylmethylene)-N’-methylene-4,4‘-sulfonyldianiline polymers were synthesized from DDS and the corresponding dialdehyde in i-PrOH or i-AmOH. Among them, polymeric N-allylidene-4,4’-sulfonyldianiline hydrochloride (Ia), N-allylidene-2-methy1-4,4’-sulfonyldianiline hydrochloride (Ib), and N-benzylideneN’-methylene-4,4’-sulfonyldianiline (IIIb), together with ?r’,N’-[sulfonylbis(p-phenylenenitrilopropenylene)]bis(4-sulfanilylaniline) (11), fulfilled the above requirements and protected mice for periods of 3.5-8.5 weeks against Plasmodium berghei and > 8 weeks against Mycobacterzum leprae.
I n previous papers it was reported that cycloguanil p a m ~ a t e , ~ a- ~ e d a p s o n e , ~ - and l ~ various 4‘,4“‘- [pphenylenebis(methylidyneimino-p-phenylenesulfony1) 1bisacetanilides, l 4 4’-[N-(benzylidene)sulfanilyl ]anilides, 4’- [N-(salicylidene)sulfanilyl]anilides,l and a{ [ p - (N-alkylsulfanilyl)phenyl]imino]-4,6-dihalo-o-cresols‘ exhibit remarkable repository antimalarial, antileishmanial, and antileprotic properties. The present communication summarizes the results of investigations aimed toward the development of water-labile, repository DDS polymers whose activation and mobilization from the depot site might not be enzyme dependent. Several of the polymers described herein satisfied these requisites and exhibited promising repository antimalarial and antileprotic action. The condensation of 1,1,3,3-tetraethoxypropanewith 4,4’-sulfonyldianiline and 4-sulfanilyl-o-toluidine in RIeOH and HC1 afforded polymeric N-allylidene-4,4’(1) Previous paper: D. F. Worth, E. F. Elslager, and A. A. Phillips, J . .Wed. C h e m . , 12, 591 (1969). (2) E . F. Elslager and P. E . Thompson, Abstracts, 9th National Medicinal Chemistry Symposium of the American Chemical Society, Minneapolis, Minn., June 1964,p 6A. (3) P. E. Thompson, B. J. Olsaewski, E. F. Elslager, and D. F. Worth, A m . J . T r o p M e d . Hyg., 11, 481 (1963). (4) CamolarB. (5) E. F. Elslager, Z. B. Gavrilis, A. A. Phillips, and D. F. Worth, J . M e d . Chem., 12, 357 (1969). (6) E . F. Elslager and D. F. Worth, Nature, 206, 630 (1965). Acedapsone is Hansolara. Dapolare is the acedapsone-cycloguanil pamoate combination. (7) P . E. Thompson, B. Olsaewski, and J. A. Waitz, A m . J . T r o p . M e d . Hyg., 14, 343 (1965). (8) (e) C. C. Shepard, Proc. Soe. E x p . Biol. Med.. 124, 430 (1967); (b) C. C. Shepard, D. H. McRae. and J. A. Habaa, ibid., 121, 893 (1966). (9) C. C. Shepard, J. G. Tolentino, and D. H. McRae, A m . J . T T O PMed. . Hyg., 17, 192 (1968). (10) P. E. Thompson, Intern. J . Leprosg, 86, 605 (1967). (11) (a) R. H. Black, W. B. Hennessy, B. MoMillan, B. B. Dew, and J . C. Biggs, M e d . J . Australia. 2 , 801 (1966): (b) A. B. G. Laing, G. Pringle, and F. C. T. Lane, A m . J . T r o p . M e d . H y g . , 16, 838 (1966); (c) K. H. Rieckmann, Trans. R o y . SOC.T r o p . M e d . H u g . , 61, 189 (1967); (d) W. Chin, G. R. Coatney, and H. K. King, A m . J . TTOP.M e d . H u g . , 16, 13 (1967); (e) W. Chin, P. G. Contacos, G. R. Coatney, M. H. Jeter, and E. Alpert, ibid., 16, 580 (1967). (12) D. F. Clyde, Abstracts, 8th International Congresses on Tropical Medicine and Malaria, Teheran, Iran, Sept 7-15, 1968,p 1380. (13) For recent reviews, see (a) E . F. Elslager in “Annual Reports in Medicinal Chemistry, 1965.” C. K.Cain, Ed., Academic Press, New York. N. Y.,1966, p 136; (b) E. F. Elslager in “Annual Reports in Medicinal Chemistry, 1966,”C. K. Cain, Ed., Academic Press, New York, N. Y., 1967, p 131. (14) E . F.Elslager. A. A . Phillips, and D. F. Worth, J . M e d . Chem., 12,363 (1969).
sulfonyldianiline hydrochloride (Ia) (90%) and Sallylidene - 2 -methyl - 4,4’sulfonyldianiline hydrochloride (Ib) (84YG),respectively (Table I). Treatment of
L
R Ia, R = H b, R = CH3
Ia with KaOH in AleOH converted Ia to a fragment which analyzed correctly (C, H, K,S, H 2 0 ) for S,S’[sulfonylbis(p-phenylenenitrilopropenylene)lbis(4 - SUIfanilylaniline) monohydrate (11). Polymerization of
I1
4,4’- sulfonyldianiline and 2,3,5,6 - tetrachloroterephthalaldeh~de,’~ terephthalaldehyde, 1,5-naphthalenedicarboxaldehyde,l0 and 4,4’-(ethy1enedioxy)dibenzaldehyde” in i-PrOH or i-AmOH gave X-methy1ene-X’(2,3,5,6tetrachlorobenzylidene) - 4,4’ - sulfonyldianiline a,4-polymer (II Ia) , N-benzylidene-N ’-methylene-4,4 ’sulfonyldianiline polymer (IIIb), S-methylene-S’-( 1-
r L
x’ ‘x
1,
IIIa, X = C1 b,X=H
naphthylmethylene)-4,4’-sulfonyldianilinea,5-polynier (IV), and S-methylene-S’- [p-(?-phenoxyethoxy)beii-
1v (15) 2,3,5,6-TetrachloroterephthaIaldehydewas generously supplied I]? Mr. Charles E. Granito, Diamond Shamrock Corp., Painesville. Ohio 44OTT. (16) 1.5-Naphthalenedicarboxaldei~yde was generously supplied by 111.. B. H. Klanderman. Research Laboratories. Eastman Kodak Co., Rocliehtrr, N. Y. 14650; see B. H. Klanderman. J . Org. C h e m . . 31, 2618 (1066). (17) JV. J. P. Neish, Rec. Trau. Ciidm.. 66,435 (1947).
KO.
K
Ia Ib 1118 IIIb IV
H CII, H H I-r H
z
Mp,
"('
X=CHCH=CHNH 258-262 dec h-=CHCH=CHKH 257-229 dec N=CH-p-C6Cl,CH=N >400 N=CH-p-CsHICH=N >400 S=CH- 1,5-CioH6CH=Kb Sinters 240 ( S=CH-~-C~HIO),( CHz)? 3.58-367 der v a Compounds range from yellow t o red. C& represents naphthyleiie.
zylidene]-4,4'-sulfonyldianiline polymer (V), respectively (Table I), in 49-89% yield.
Because of the over-all interest in polymers l a , 11, arid I I I b as repository antimalarial and antileprotic agents, these drugs were also supplied to Dr. Charles ('. Shepard, Communicable Disease Center, Atlanta, Ga., for evaluation against Mycobactetium leprae i l l L mice. Each polymer was completely suppressive wlieii administered subcutaneously in single 200-400-mg 'kg doses in BBCO a t 2-month intervals. The DDS content of the polymers IIIa and b, IT.', Comparative antimalarial , antileprotic, and metaand V was measured by a uv assay (Experimental Secholic data 011 DDS, X U I D S , DADDS, PSBA. ant1 tion). These results, together with the microanalyses three DDS polymers (Ia, 11, arid IIIb) in mice and rat5 (Table I), indicate a nearly 1:l ratio of DDS to aldeis presented in Table II.8a,ioThe duration of protechyde moiety. Problems associated with the insolubiltion against challenge with I-'. beryhei afforded by a ity and instability of these polymers in suitable solvents single subcutaneous 400-mg 'kg dose of these polymers precluded the use of solution methods for molecular ranged from 3.,5 to 8.5 meeli-. By contrast, each sulweight determination. fone protected mice against A I . Zrprae infections for >8 The r\T-allylidene-4,4'-sulfonyldianiline and N-(benweeks following a single 200 -4OO-mg/kg dose, thus rezylidene- and -1-naphthylmethy1ene)-S'-methyleneflecting earlier observations that LII.Zeprae is more senqi4,4'-sulfonyldianiline polymers described in the present tive t o DDS than P. b e i y h d O t l The pattern of urintuy communication were supplied to Dr. P. E. Thompson cscretion in rats also was iiitermediate between DDS arid coworkers of these laboratories for evaluation as and. DADDS. These rehult:, imply that polymers Ia, potential repository antimalarial agents against Plasmo11, and IIIh might provide :Lrelatively more intense, dium bergheiin the mouse. As in previous :ilbeit less prolonged, cheniotherapeutic effect than a n drugs were suspended in 5 ml/kg of benzyl benzoate quivalent dose of DLIDDSor PSBF, arid be much safcr castor oil (BBCO, 40:60) and given to groups of 15-33 drugs than UDS. albino mice in a single 400-mg/kg sc dose. Subgroups of treated mice were subsequently challenged with P. berghei trophozoites a t weekly or biweekly intervals. Experimental Section16.19 Assessment of repository action was based on the period Uv Assay for DDS Content of Polymers IIIa and b, IV, and of protection against patent infections afforded by I V.--A sample of the polymer was dissolved in 0.5 N IICl iii single dose of the drug. Activity is expressed as the MeOH with warming if necessary. After solution was complete, number of weeks 50% of the mice were protected. an aliquot was removed and an appropriate dilutioii was made illto MeOH containing sufficient KOH to neutralize the acid. The ;h;-allylidene-4,4'-sulfonyldianiline hydrochloThe spectrum of the solution, which now contained free DDS, ride polymer (Ia) exhibited very long acting repository was determined. The DUS coilrelitration was then obt,ained antimalarial effects. A single, subcutaneous 400-mg using an E: of 1180 a t 296 m p , except for 1. which exhibited kg dose of Ia protected 50% of the mice for approxirelatively strong absorption from the aldehyde l e i d u e where readings at 310 nip were used (Table 111). Polymers la and 1) mately 8.5 weeks against challenge with P . beryhez. Polymeric r\'-allylidene-2-methyl-4,4'-sulfonyldianiline could not be assayed in this fashion due to their relat,ive btability methanolic'HC1. hydrochloride (Ib) , X,N'- [sulfonylbis(p-phenylenenitri- in theN-Allvlidene-4.4'-sulfonvldianiline Hvdrochloride Polymer lopropenylene) Ibis (4-sulfanilylaniline) (II), and the S- (Ia).-To solution of 24.8 g-(0.10 mole) 4,4'-sulfonyldianilirie benzylidene-N'-methylene-4,4'-sulfonyldianiline poly(DUS) in 11. of MeOH was added 24 ml (0.10 mole) of 1,1,3,3tetraethoxypropaiie followed by 8.6 ml (0.10 mole) of conceiimer (IIIb) protected mice from challenge with P . berghei trated HCl. After heating under reflux for 20 min the orange for approximately 3 . 5 4 weeks, a period intermediate Drecioitate was collected bv filtrat ion and washed thorourrhly between the short-acting DDS and the very long acting k t h hleOH. DADDS and PSBF.10~14 These results suggested that N-Allvlidene-2-methvl-4.4'-sulfonvldianiline hvdrochloride polymers Ia and b, 11, and I I I b should provide higher polymer (ib) was prepared from 4-~ulfanilyl-o-t~luidinearid blood levels than DADDS or PFBF and still afford pro(18) Melting points (corrected) were taken on a Thomas-Hoover capil. tection for reasonable periods of time. By contrast, the lary melting point apparatus. (IS) Where analyses are indicated only b y symbols of the elements or S-methylene -X'- [ p - ( 2 - phenoxyethoxy)benzylidene]functions. analytical results obtained for those elements or fonct,ions were 4,1'-sulfonyldianiline polymer (V) failed to protect :ill within f0.4Y0of the theoretical values. Water determinations were by t h e of the mice for even 1 week. Karl Fischer method.
a
I
.
I
"
July 1969
h T I M A L A R I A L AND
AXTILEPROTIC REPOSITORY DRUGS. VI1
599
TABLE I1 COMP.iR.iTIVE ANTIMALARIAL, ANTILEPROTIC, A N D ~ ~ E T A B O L IDATA C O N DDS, MADDS, DADL>S, PSBA, AND SELECTED 4,4’-SULFONYLDIANILISE P O L Y M E R S ~ ~ ’ ~ ~ Urinary excretion
% exWeeks mice protected creted P. M. in 30 bergheia lepraeb days
Structure
Comprl H h-(F&
DDS
so +\H.
9
13.8
3.9
50
32
1.3
1.2
>8
7
>200
0.2
0
>8
40
,>*I
--
0.4
0.2
>8
32
25
>8
34
39
>8
50
30
2
3.5
DA4DDS
12
PSBA
3-7
In
L
Peak methemoglobin levels. g/100 ml
Peak blood level, rg/ml
57
