REPOSITORY DRUGS. V
May 1969
collected by filtration and crystallized three times from MeCN to give 5.3 g (68%) of a bright yellow solid, mp 238-241 dec. 4’[(2-Acetamido-5-thiazolyl)sulfonyl]acetanilide (X).-A mixture of 29.7 g (0.10 mole) of N-(5-sulfanilyl-2-thiazolyl)acetamide,sz75 ml of HOAc, and 13 g (0.13 mole) of AczO was heated to boiling when a thick slurry formed. D X F (50 ml) was added and the mixture was heated under reflux for 1.5 hr. After cooling, the precipitate was collected by filtration and washed (H20). Recrystallization from DUF-EtOH gave 28.5 g (84%), mp 313314” dec. Anal. ( C I ~ H U S ~ O ~ C,SH, Z ) N. 3’,3”’-Sulfonylbisacetanilide (XI).-To a solution of 9.3 g in 100 ml of bIeLCO and (0.038 mole) of 3,3’-sulfonyldianiline~3 7.5 ml of pyridine was added dropwise 8.8 g (0.11 mole) of AcC1, keeping the temperature below 40’ by adjusting the rate of addition. After standing 24 hr at room temperature, the mixture was poured into 5% HCl, and the resulting precipitate collected. Recrystallization from EtOH gave 6.4 g (51%), mp 215-218’. Anal. (C&I~XZO~S) c, H, K. 3,3’- [Sulfonylbis(p phenyleneiminomethylene)]di- 2 thiazoliO
-
-
(32) L. L. Bambas, J. A m . Chem. Soc., 67, 671 (1945). (33) Tennessee Corp., Atlanta, Ga.
363
dinethione (X11).-A4 mixture of 24.8 g (0.10 mole) of DDS, 23.8 g (0.20 mole) of 2-thiazoline-2-thio1, and 18 ml (0.20 mole) of formalin in 500 ml of 2-PrOH was stirred and heated under reflux for 24 hr. The product was collected by filtration of the hot reaction mixture and recrystallized from DMF-HzO to give 18 g (355,), mp 225-226’. Anal. ( C ~ O H B S ~ OC, Z SH, ~ ) S, S.
Acknowledgments.-The authors wish to express their appreciation to Dr. Paul E. Thompson and coworkers of these laboratories for the antimalarial evaluation of these compounds and to Dr. Charles C. Shepard of the Communicable Disease Center, Atlanta, Ga., for the leprosy studies. JTe also thank Dr. David B. Capps and Dr. Leslie 11.Werbel for the preparation of several of the compounds described herein, Rlr. TYilliam Pearlman for the performance of the hydrogenations described, Dr. J. hl. T’andenbelt and coworkers for the spectral and solubility determinations, and Mr. Charles E. Childs and associates for the microanalyses.
Repository Drugs. V. 4’,4”’-[p-Phenylenebis(methylidyneimino-~-phenylenesulfonyl)]bisacetanilide (PSBA) and Related 4’,4”’-[Bis(imino-p-phenylenesulfonyl)]bisanilides, a Novel Class of Long-Acting Antimalarial and Antileprotic Agents’ EDWARD F. ELSLAGER, ANNETTEA. PHILLIPS, AND DONALD F. T ~ O R T H Research Laboratories, Parke, Daws and Company, d nn Arbor, Slachagan
48106
Recezved January 6, 1969 Various 4’,4”’-[bis(imino-p-phen~lenesulfonyl)]bisanilides(111-VI, VIII) were synthesized as potential repository antimalarial and antileprotic agents in a search for long-acting sulfones that would be less dependent on enzymatic deacylation for activity and afford higher blood sulfone levels than 4’,4”’-sulfonylbisacetanilide (acedapsone, DADDS). The compounds were prepared by condensing the appropriate phthalaldehyde or naphthalenedicarboxaldehyde with the requisite 4’-sulfanilylanilide. Among them, 4’,4”’-[p-phenylenebis(methylidyneimino-p-phenylenesulfonyl)]bisacetanilide(PSBA) (IS) fulfilled the above requirements and showed remarkable repository effects alone against Slycobacten’um Zeprae and alone or in combination with cycloguanil pamoate against Plasmodium beryhei in mice and Plasmodium cynomolgi in monkeys. Structureactivity relationships are discussed.
SHCOCH>
A systematic; search for various types of repository drugs in these laboratories led successively to the development of cycloguanil pamoate (1),2-4 a long-acting antimalarial and antileishmania drug; acedapsone (DADDS) (II),1,5-sa rppository antileprotic and antimalarial agent; and cycloguanil pamoate-acedapsone (DhDDS),1,5s6a combination antimalarial drug with protracted action against drug-resistant strains.9
00
(1) Previous paper: E. F. Elslager, 2. B. Gavrilis, A. A. Phillips, and D . F. K o r t h , J . M e d . Chem., 12, 367 (1969). (21 E. F. Elslager and P E. Thompson, Abstracts, 9th National hledicinal
Chemistry Symposium of the American Chemical Society, Mnneapolis, Jlinn., June 1964, p 6.4. (3) P. E. Thompson, B. J. Olszewski, E . F. Elslager, and D. F. Korth. Am. J. T r o p . .Wed. Hug., 12, 481 (1963). (4) Camolar@. ( 5 ) E. F. Elslager and D. F. Worth, Nature, 206, 630 (1963). (6) P. E. Thompson, B. Olszewski, and J. A. Waitz, A m . J . T r o p . .\led. Hyg., 14, 343 (1965). ( i ) (a) C. C. Shepard, Proc. Soc. E x p . Biol Med., 124. 430 (196i); (b) C. C. Shepard, D. H. McRae, and J. A. Habas, ibid., 122, 893 (1966). (8) Acedapsone is the nonproprietary name for 4‘,4“’-nulfonylbisacetanilide.
I n the biological literature acedapsone has also been referred t o as sulfadiamine, 4,4’-diacetyldiaminodiphenyl sulfone, 4,4‘-diacetylaminodiphenyl sulfone, N,N’-~iacetyl-4.4’-diaminodiphen~-lsulfone. and DADDS. H a n s o l a r a is a proprietary name for acedapsone. T h e proprietary name for t h e acedapsone-cycloguanil pamoate combination is DapolarB. (9) For recent reviews, see (a) E . F. Elslager in “Annual Report8 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 P o r k , N. Y . , 1967, p 131.
“2
I
NHCOCH, I1
Among the 4’-sulfanilylanilide congeners of 4.4’sulfonyldianiline iDDS) investigated p r e ~ i o u s l y , ’ ~ ~ 4’,4”’-sulfonylbisacetai1ilide (acedapsone, DADDS) (11) conferred the longest protection and has been studied extensively Loth in experimental animals and in man.5-12 (10) D. F. Clyde, Abstracts, Eighth International Congresses on Tropical Medicine and Malaria, Teheran, Iran, Sept 7-15, 1968, p 1380. (11) (a) R. H. Black, W. B. Hennessy, B. McMillan. 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 n . J . T r o p . M e d . H y g . , 15,838 (1966); ( e ) K. H. Rieckmann, T r a n s . R o y . SOC.T r o p . f i l e d . Hug., 61, 189 (1967); (d) W. Chin, G. R. Coatney, and H. K. King, A m . J . Trop. M e d . H y g . , 16, 13 (196i): ( e ) W.Chin, P. G. Contacos, G. R . Coatney, h4. H. Jeter, and E. Alpert, ibid., 16, 580 (1967). (12) C. C. Shepard, J. G. Tolentino, and D . H . JlcRae, ibid., 17, 192 ( 1968).
Ligaiitst Plasimtli i*vi Deryizei iiifectioiib in mice, a siiiglc 100 400-ing Lg sc close of D-kDDS almost iiivarial~l\ prer-eiitibtl or +troiigly suppressed patent infectioiis tliiougli (i-14 weelis. 1 siiigle 30-mg l;g in1 dobc 01 I)XIlI>S prevented patelit Plnsniodi m i c i / i z o ~ i o l iitfeti~/~ tioils i i i iuoiihe? s for 63 268 (:iveiage 138) (Liys :iiicI gently *uppress.ctl the 1xiiasitcnii:t for niaiij* eel;. loiigct . *Iconipurisoii ot IIAIDDS.cycloguaiiil panioatc Ill i Ii,l u n i t 1 :i 1 : 1 ryt~loguaiiilpniiio:zte -llA1lllXiiiisture 3-81 c; yieltl. Similarly, 4’,~”’-[u-gheii\.ie~is~i~iet~iyl:tg:uii>t lilies of I’ boqliei highly rcsistatit to either Dl>s idyneimiiio-p-pheii~leiicsulfoii)l)]bisacetanilitle (11) 19 01 e> cloguaiiil hy(1iochlontlc t1enioiistr:ltcvl t1i:tt tlir Table 11) aiitl 4’,4”’-(tZ,G-iiapl~th~Ieiiebis(ine~li~Iit~y~~~iiiixtuic’ lint1 I)roatlcr repositor! :ic*tioiiaguiiist the d u g imino-p-pheiij leiieiulfoiiyl)lbisacetaiiilide (Y) (10. rcw5t:uit litic~s tliaii cithrr thug : t l o i i c ~’ Iii ,tutlies Tahle IT) w r e prepared from 4’-sulfaiiilylaceta1iilitlr agaiiist ~~speriiiiciit:illepiu$j iiifectioiis i i i thc niousc‘. (3IADDS),’ plitl-ialaltlehyclt~.ant1 2,6-naphthnleiietli:1 hiiiglv 6-mg kg tlosc of II=\DIlS adiiiiiiisteietl a t 2-1iiuiitli iiitei\ a13 afforclctl 1ic:trly coiiiplete +uppressioti of Alli/cobacteriiw/ l r p i o t , \\-hilt 1:iigt.r doses \wrc conil)lctcl>* qjpresbiw ; Tlie :tiitim:il:tri:d propet tic+ oi the c j cloguntiil l)aiiio:itc> D-%I>TW niisturc h:i~(* k e i i evaluated 111 :I1)~)roXllll>ltel\ 1000 l l U l l l X l 1 3UhJt’ctS I “ l g a i i ist l ~ l u i ~ t u md ~I / I riotl> I\ (’re o1)ttiiiictl ( I; 5traiiis auiceptiblv to clilorguaiiitlr aiitl 1~~~iiniethaiiiitit~. 4 months; (2) \in+ rcsistniit to vlilorgu~iiiitlcniitl p j iiinetlianiiiie, :i. iiioiith>, :itit1 ( 3i +ti:uiis frorii soutlieast Asia resistaiit t o chlorgu:uiiclt~, Ijyrii~ietliaiiiiii(~.a i i t l the 4-ainilioqiiiiioliiic+, vnrinhlc, approxirnntclj 2 nionths. Thc rcsults of prclirninni\ cliiiieal trial n-ith DADIX aloiith carboxaldehyde’: iii 19 slid 435; yield, respectivelj-. lepiosy Iiave :ilso beell promising.’- 111 The condeiisatioii of 4,1‘-(etli~.leiiedioxy)berizaldehyde’” iigle 223-nig iiii dobe of DA%DDS atiminwith 2 equiv of 4,4’-sulfoiiyldiaiiiline(DDS) or 4‘istt~rctlovt~1~\77 d:iys WI> t4c’ctir.e as oral IlDS gi1 eii sulfanilylacetanilide (L5DDS)’ (procedure T7) gavt’ 1 1 1 ,I tlos~igeoi 100 iiig t1:tiIj O J :Lti’catniciit periotl oi X,N’-[ethylenebis ~osy-p-phei~l\’Ieneinethglidyiie~]bis( 448 n C t ’ I L \ Isulfanilylaiiiliiie) (12a) (11, Table 11) (96%) and 4’,4’”Iiia~iiiu(~l1 :is I>.1I>L>h I+ :tppareiitl\- tlepeiident upon tleucetylatioii for acti\ it>- m c 1 affordb oiilj extremelj, lo\\ d f o i i e Glootl Icvels, :I repositorj sulfoiie that ib le-s (Iqieiicleiit on eiizyinatita cleacylatioii for activity aiitl e1iLhles higher I~looci3ulfoiie lwels thaii IlhDDS niight iulfill a iirefiil iicetl. Therefore. atteiitioii via+ fclciioetl oti the tlesigii nittl syiithesis of iiovel sulfonc, \.IL1 li = H niolerulcs that niight uiiclergo olow, ~ioiienzyniatic ‘1 K = COC’H h j tlrol.~-ticscissioii tlirectl?- up011 contact with I~otlj ti*siii+ iiiitl fluicl.. This report ilesciibes the SJ iithcsib [eth~lenebis~ox~-p-plieuyleiiernet hy lidy iieiiiiiiio-p-pli~~iiaiitl pioperties of v‘ti ious ~’,I”’-[l~isiiiiiiiio-~i-~)lietiyl~~iic.~leiiesulfon~~l)]bisaccta~iilide (1%)(12, Table 11) (54C; I . sulioii~~l)]Lie~uiilicl~~+, ~ C ’cI r d ot \I hich fulfill thc M ~ O eT S.S’ - ( 1 ~- PhenyleiiecliriictliZ.Ii~lyiie)~is[4 - S - allylr~~c~lllrc’llli’llts. sulfaiiilyl)ai~iliii(~] (\TI) \\-as obtained in 67‘ ;yieltl 1)j1‘2ic~ wiideiisntloii of 1 eyuir- of tereplithalaldeliytlc, 2,3,3,ti-tetrnchlorotcreplitlialaldeliy~le,13 or 2,3,5,G-tetrariic.tli~ltereplitlialal~~eliy~le with 2 equiv of 4’-sulfanilylf o r ni ani 1i d E ( 11F D D S) , 4 ’- s u 1fan il y1a c e t an il i de (1L5IlDS) , I 4 ’-sulfaiiilZ.lpropioiiaiiilide, 4 ’-sulf anilylIicptaiiaiiilidc,I or 4’-sulfanil~llauraiiide’ in EtOH, aMIH. or 2-AinOH afforded the corresponding 4’,4”’[ /~-phciijlencbis(methylid~i~eimi~io-p-phenglenesulfoiq-l)]l~isaiiilitles (111) 11-7, Table I) (procedures 1-111) in \‘I1 %
(91
( I 3) A 3 j,6-Tetrachloroteiephthaialdeh~ de was geneiously supplied b\ Xlr Chnrles E. Granito, Dianiond Shamrock Corp., Pamesville. Ohio 44077 (14) 2 3,5,6-Tetrameth>lterephthalaldehqde was generously suppiled b\ Di l3 H Klanderman, Research Laboratories. Eastman Kodak Co , Rochestrr Y T I 4 h j 0 , see B H. Klanderman, J. Ora Chem 31,2618 (1986)
(1.5) 2,6-Saphthalenedicarboxaldeh& de was generously supplied by DI. 1’. \V. Storms, Marathon Oil Co., Denver Research Center, Littleton, CToio.; w e 1’. W. Storms and P. R. Taussig, J . Chem. Eng. Data, 11, 272 (19fitj). (1G) I\-,J. P. Neish, Rec Trau. Chim., 66, 435 (1947).
365
REPOSITORY DRUGS. V
May 1969
TABLE I 4’,4”’-[ ~ - ~ € l E ~ Y L E N E B I S ( ~ ~ E T € l Y L I D Y N E I ~ l I ~ O - ~ - P l l E ~ Y L E ~ E S ~ L F O ~ Y L ) ] B I S . ~ S I L l D E S a
I 2 3
4 5 6
7 a
s,
R
so.
LIP,
Yield Puriicn purifd, % Procedure solvent*
cc
H H > 300 CH3 ”3, 5,6-C14 290 CHI H >300 Ci” H > 300 2,3,5,6-(CH3)4 CHs 280 (CH2)jCH; H 272-275 (CH2hoCHs H 265-268 Compounds are yellow solids. A, EtOH; B, &OH; C,
*
.halyses23
Formula
C, H, S C, H, S,H,O C, H, S, HzO C, H, S C, H, ?;, H?O C, H, N C, H, S
I rl C34H?6140& I1 B C36H26C14~406S2 ’ HzO C ~ B H B O S’ 1.5HaO ~O~S~ I -1 I C C38H34s406Sa 67 I1 D C.iCH3J106S2 ‘0.4HpO 3 I11 E C46HjOS406S2 0.67H?O 50 I F CjsHi~?;?OsSa DMSO; D, i-PrOH; E, Et?O; F, dioxane. 81 72 76 26
TABLEI1 OTHER ~’,4”’-[BIS(IMIXO-p-PFIEXYLESESULFO~YI~)]BIS ISILISES I S D A\SILIDESa
KO.
R
8
COCH,
z
Llp, OC
S=CHCH=CHSH
217-225 dec
Yield Propurlid, % cedure
46
IT
Purifcn solventb
A
.haI?-ses23
Formula
CJiH:8S40&.
C, H, C1, S, H20 C, H : Sc C, H, S
a Compounds range from yellow t o red. represents naphthylene.
A , 1IeOH; B, i-PrOH; C, EtOH; D, DNF-i-PrOH.
the reaction of N-allyl-4~4’-sulfonyldianiline17 and tereph t halaldehy de in Et OH. 4’,4”’-[ 1-Propen- 1-y 1-3ylidenebis (imino-p-phenylenesulfonyl)]bisacetanilide monohydrochloride (VIII) (8, Table 11), which contains an aliphatic side-chain interruption between the two
FH
.HCI
C, H, S C, H, S S :calcd, 8.15; found, 7.50.
C10H6
two compounds exhibited noteworthy repository action. 4’,4”’-[p-Phenylenebis (methylidyneimino-p-phenylenesulfonyl)~bisformanilide (PSBF) (1) was very long acting and protected mice for >9 n-eeks against challenge with P. berg hei. 4 ’,4 ’’’-[p-Pheny lenebis(methylidyneimino -p-phenyleiiesulfoii-yl)]bisacet anilide (PSBB) (IS) protected mice for 5-7 weeks, depending on particle size (fine to medium), a period intermediate between the short-acting DDS and the very long acting
VI11
sulfone moieties, was prepared from 1equiv of 1!1,3,3tetraethoxypropane and 2 equiv of 4’-sulfanilylacetanilide (MADDS)’ in MeOH and HCl in 46% yield (procedure IV). The 4’,4’”-[bis (imino-p-phenylenesulfonyl) Ibisanilides described in the present communication were supplied to Dr. P. E. Thompson and coworkers of these laboratories for evaluation as potential repository antimalarial agents against Plasmodiuna berghei in the mouse. As in previous ~ ~ r k , l -drugs ~ were suspended in 5 ml/kg of benzyl benzoate-castor oil (40 :BO) (BBCO) and given to groups of 15-25 albino mice iii a single 400mgikg sc dose. Subgroups of treated mice mere subsequently challenged with P. berghei trophozoites at meekly or biweekly intervals. Among the 4’,4”’-[p-phenylenebis (methylidyneiminop-phenylenesulfonyl) Ibisanilides (111) (1-7, Table I),
IX
DADDS.18 These results suggested that PSBA should provide higher blood levels than DADDS and still afford protection for reasonable periods of time. S o n e of the bisanilides (4, 6, 7, Table I) derived from higher molecular weight acids exhibited promising repository activity. As a group, the 4’,4”’-[bis(imino-p-phenylenesulfonyl)Ibisanilines and anilides summarized in Table I1 were also less promising than PSBA and PSBF, and compounds VI-VI11 failed to protect all of the mice for even 1 week. Expanded repository antimalarial studies with PSBA were carried out utilizing P. berghei in rats and P. cyno-
(17) B. R. Baker, 11.V. Querry, and A . F. Kadiah, J . Org. Chem., 15, 402 (1950).
(18) P. E. Thompson, Intern. J . Leprosy, 35, 605 (1967).
X single 400-mg kg sc dose of PSBX protected rats against challeiige with P. berghei iriolqi in rnoiikeys.ls I"
for 1 ~veek aiid had strong suppressive action a t 3 It should be recalled that a coinparalde dosc of IIADDS iii this species failed t o provide protcctioii, prcsuniably due hi part to tlic slower rate of mobilizatioii of DADDY a t the iiijectioii site, ancl partly because tlic rat appears to be deficient iii enzymes which reinon; at least m e of the acetyl groups from DADDS.fi This prewmptive evideiicc that the scission of PSBA is iiot tliizj me dependent is corroborated by physical-cheniiral c h t n (Experirnental Sectioii) which indicates that PSBA is iery labile iii aqueous iiieclia. In rhesus monkeys, ;i siiiglc 50- or 100-nig kg ini dose of fiiie pnrticle size PSBA in BBCO protected against challeiigc nitli tiophozoitcs of P. eyioviol(/L for an average of 11-13 11wks :~iid greatly suppressccl the 13:irasitcniia for s(~i.cra1 weehs longel,. The iiieaii duration of protection after 5t siiigle 5O-nig kg iin close of nietliuiii particlc s i x PdBd raiigetl from 4.4months in isopropyl nijristatc-peanut oil (2.5 i 5 ) (IILIPO)to 5.1 rrioiithsiii RBCO. 111 therapeutic tests in mice aiid rats, a siiigle 400nig kg sc dose of PSB-i proclucetl stroiig suppressioii oi the para:,iteinia within 48 lir a i i t l all aiiilnd5 lint1 iieg:itive tliicli and thin siiiears oil clays (5- 7 aftcr tlokiiig. -\ 50-mg kg irn dose of PSBA suppressed pat ciit iiifectioiis of I-'. c y ~ r r ~ o l in g i moiiheys as rapidly a9 :t subst:tntial intraniuscular tlose of DI)S.i'i Tests agaiiist resistant lilies of 1'. beryhei iii inice iiitlivate that PFBAi,lilie D;lDDS, is effective agaiiist sti:iin:, rcsistaiit to cbycloguaiiil but not against strains taiit to DDS. Hon.e\ei~,a 1:l mixture of cycloguaiiil painoate aiid PSUA n ;is effective against Goth the cycloguaiiil- aiict DDS-rtsistaiit 1iiic.s.l' Iii view of the o - i e i d l potriitial of PSBA as n repository aiitirna1:irial aut1 aiitilepiotic agent, the drug was supplied 1o 111. C'linrlcs C'. Shepard, Coiiiiiiunicahle I>i:,c:ise Center, -4tlaiita. (;:I.% for emluatioii agailist JI. k p r a e iii inicc. The thug \vas coiiipletely suppressive i t lieii atliiiiiiistci.ed w1)cutaiieously hi ii *ingle 400-mg kg ( 1 o v iii BR('0 a t 2-nioiitli ilitc1rvals.'" PSI3h also c.sliil,itecl iiiotlest rcpositorj aiititubcrculosis activity :igniii>t Jlycobnctcriiii~f u b c , ~ i i l o ~ s iHj;Iiv b iii iiiice ~vlieii atlniiiiisterctl subcut aiieousl\- iii n siiigle 400-800-iiig lip do\(. in I?\IE'O.-" -1summary of coinparativc ant ininlarial, antilcprotic. a l i i 1 inetal,olic datu 011 DTX, lIXDDS, DADDS, PSBX, a i i t l PSBF iii mice aiid rat5 i:, prewited iii Table 111.' Ih \I cdis.'Y
,-
Diup
Structuie
I)DS JIADDS DADDS
~-H~SC~H~SO*CGH*-~-SH~ ~-H?SC~H~SOZC~H~-~-SHCOCH~ 11"
PSBA
I S C
111, R = H, S n = H" PSBF Estimated number of weeks 5056 of mice were protected following n single 400-nigilrg 5~ dose of drug suspended in Ixnzyl ben~o;iiecastor oil (40:60). Drugs given as a single subcutaneous dose of 400 mgikg in a volume of 5 ml 'kg of 1 5' pectin and 0.1 Tween 60 See text for structure. in distilled water. ____
-... .
(19) P. E. Thompson, A. Bayles. and J. A. n'aitz, manuscript in preparation. (20) For a description of the test method, see L. RI. Werbel, E. F. Elslager, h l . K.Fisher, Z. B. Gavrilis, and A. 3. Phillips, J. M e d . Chem., 11, 411 (1968).
(21) D. H. Kaump, .i.T. Blata, \V.L.Ebiiigrr, R . A . P'i:Li,tt, ,I. I:. lFiIzgrald, D. L. Hentz, S. 11. Kurtz. T . F. Reutner, D. E. Roll, a n d .J. I.. Sch:irdein, i~nprihlisheddata in the files of Parke, Davis a n d Co., A n n :\rbor, h l i c h .
-. .
REPOSITORY DRUGS. V
May 1969
367 TABLEI V
Experimental Section22$23 4’,4”’- [p-Phenylenebis(methylidyneimino-p-phenylenesulfony1)lbisanilides (111) (Table I) and Other 4‘,4”’- [Bis(imino-pphenylenesulfonyl)]bisanilines and -anilides (IV-VI, VIII) (Table 11). Procedure I. 4’,4’”-[p-Phenylenebis(methylidyneimino-p-phenylenesulfonyl)]bisacetanilide(PSBA) (IX).A hot, filtered solution of 6.7 g (0.05 mole) of terephthalaldehyde (Aldrich) in 200 ml of EtOH was added to a hot, stirred solution of 29.0 g (0.10 mole) of 4’-sulfanilylacetanilide (MBDDS)’ in 2 1. of EtOH. The solution was heated at reflux for 3 hr, then concentrated to 1 1. over an additional 2.5-hr period, at which time the product began to precipitate. The mixture was kept at room temperature overnight and filtered to give 10.5 g of a first crop. Concentration of the filtrate gave two additional crops weighing 11.5 and 5.5 g, respectively. The crops were slurried in boiling EtOH, recovered by filtration, and dried at 75” in vacuo; total yield, 27.0 g (7600). -411 three fractions were pale yellow and melted above 300”. The uv absorption curves ( D M F ) showed maxima at 347 mp ( E :550)and 287 mp ( E : 740) after correction for H20. A convenient uv assay method for determining the amount of RIADDS in PSBA involves treatment of the Schiff base with 0.5 N HCl in RleOH. After solution was complete, an appropriate dilution in MeOH was made weakly alkaline with a minimum amount of KOH solution. The spectrum of the solution, which now contained MADDS and the tetramethyl acetal of terephthalaldehyde, was determined and compared to a standard spectrum of MADDS (E:920 at 294 m p ) . Typical results were within *3‘5 of that expected. This procedure was generally applicable to the assay of the sulfone moiety of the other Schiff bases described herein. In an effort to determine the solubility of PSBA in aqueous media, a 50-mg sample was agitated in 10 mi of a 0.1 N pH 7 phosphate buffer for 1 hr. After centrifugation a uv absorption curve was obtained from the clear supernatant solution. The absorption at 350 mp showed a concentration of < 0.001 mg of PSBAlml; however, there were weak maxima at 289 ( A = 0.61), 272 (d = 0.68), and 258 mp ( A = 0.73) from the hydrolysis products. An absorption curve obtained from the insoluble residue showed only intact PSBB. Because of the difficulties inherent in obtaining consistent uv absorption curves in H 2 0 or even l\leOH-H20 mixtures due to lack of solubility and stability, mixtures of DhIF and HzO were chosen for the estimation of the hydrolysis rate, since this allowed for complete solution in partially aqueous systems. Solutions of PSB-4 (0.0025 ) were prepared and kept at room temperature in the solvents indicated (Table IV), and the half-life of PSBA was estimated from the periodic examination of the decrease in absorption at 350 mp. Table IT’ shows the dramatic decrease in the stability of PSBA in solution with increasing concentrations of H20. Eesides the decrease in the absorption at 350 mp, these curves showed a peak emerging at 298 mM which was consistent with the formation of RIADDS and/or DDS. Visual examination of a DMF-H20 (70:30) solution of PSBA after 27 hr by tlc (silica, EtOAc) indicated the predominant hydrolysis product to be MADDS. 4’,4”’-[p-Phenylenebis(methylidyneimino-p-phenylenesulfonyl)]bisformanilide (PSBF) (I).-To a solution of 5.53 g (0.020 mole) of 4’-sulfanilylformanilide (MFDDS)’ in 300 ml of boiling EtOH was added a solution of 1.34 g (0.010 mole) of terephthalaldehyde in 50 ml of EtOH. After heating under reflux for 2 hr, the solution was concentrated to 200 ml and allowed to cool to room temperature. The precipitate was collected and dried in vacuo at 75’to give 5.28 g (81%) of yellow crystals, mp >300”. Compounds 4, 7,and 10 were prepared in a similar manner and were crystallized from the solvents indicated in Tables I and 11. (22) hfelting points (corrected) were taken on a Thomas-Hoover capillary melting point apparatus. (23) Where analyses are indicated only by symbols of the elements or functions, analytical results obtained for those elements or functions were within *0.4% of the theoretical values. Water determinations were by the Karl Fischer method.
STABILITY OF PSB.4
IN
A~~~~~~~
Solvent, % H?O in DWF
0
10 20 30 40 50
DIMETHYLFORMAMIDP. PSBA half-life, hr
> 2000 400 120 5.2 1.2 06
Procedure 11. 4:””-[( Tetrachloro-p-phenylene)bis(methylidyneimino-p-phenylenesulfonyl)]bisacetanilide (a).-Solutions of 0.27 g (0.001 mole) of 2,3,5,6-tetrachloroterephthalaldehyde~~ in 10 ml of AcOH and 0.58 g (0.002 mole) of 4’-sulfanilylacetanilide (JIADDS)’ in 30 ml of AcOH were mixed and heated on a steam bath for 15 min. The precipitate which formed was collected by filtration, washed successively with AcOH and i-PrOH, and dried zn vacuo at 65” to give 0.60 g (72%) of a pale yellow solid, mp 290’. Compound 5 was prepared in the same manner, except that the AcOH was removed on a rotary evaporator, and the residue was crystallized from i-PrOH. Procedure 111. 4’,4”’-[p-Phenylenebis(methylidyneimino-pphenylenesulfonyl)]bisheptananilide (6).-Solutions of 5.4 g (0.015 mole) of 4’-s~lfanilylheptananilide~and 1.0 g (0.0075 mole) of terephthalaldehyde in 80 ml of z-.4mOH were combined and heated under reflux for 2 hr. After cooling, the solution was diluted with Et20 and the resulting pale yellow precipitate, mp 272-275”, was collected by filtration and dried. Procedure IV. 4’,4”’-[l-Propen-l-yl-3-ylidenebis(irnino-pphenylenesulfonyl)]bisacetanilide Monohydrochloride Dihydrate (VIII).-To a solution of 14.5 g (0.050 mole) of 4’-sulfanilylacetanilide (AIADDS)’ in 1500 ml of MeOH there was added 6.6 ml (0.028 mole) of 1,1,3,3-tetraethouypropanefollowed by 2.2 ml (0.025 mole) of concentrated HC1. After heating for 1 hr under reflux, the mixture was cooled to room temperature, and the orange crystals, mp 217-225”, were collected and dried. Procedure V. N,N’- [Ethylenebis(oxy-p-phenylenemethylidyne)]bis(4-~ulfanilylaniline) (VIa).-A solution of 5.96 g (0.020 mole) of 4,4’-sulfonyldianiline (DDS) in 400 ml of i-PrOH was added to an 2-PrOH solution of 2.70 g (0.020 mole) of 4,4’(ethylenedioxy)dibenzaldehyde.le When no immediate reaction occurred, a few crystals of p-toluenesulfonic acid were added and the mixture was boiled under reflux for 2 hr. The precipitate which formed was collected from the hot mixture, washed with i-PrOH, and dried 18 hr zn vacuo to give 7.0 g (96%) of a pale yellow solid, mp 272-275”. Compounds 9 and 12 were prepared in the same manner, except that EtOH was used in place of i-PrOH as the reaction solvent. N,N’-( p-Phenylenedimetl~ylidyne)bis[4-(N-allylsulfanilyl)aniline] (VII).-N-~Allyl-4,4’-~ulfonyldianiline’~ (5.75 g, 0.02 mole) and terephthalaldehyde (1.34 g, 0.01 mole) were allowed to react in 360 ml of EtOH according to procedure I. The product was obtained as yellow- crystals from EtOH or MeCS, 4.5 g (67y0), mp 245-249’. Anal. (C,,H,&‘,O&) C,H, X.
Acknowledgments.-The authors wish to express their appreciation to Dr. Paul E. Thompson, Dr. J. A. Waitz, Dr. A I . W.Fisher, and Dr. D. H. Kaump, and coworkers of these laboratories for the antimalarial, antituberculosis, and toxicological evaluation of these compounds, and to Dr. Charles C. Shepard of the Communicable Disease Center, Atlanta, Ga., for the leprosy studies. We also thank Dr. David B. Capps for assisting in some of the chemical work described herein, Dr. J. M. Vandenbelt and coworkers for the spectral determinations, and Mr. Charles E. Childs and associates for the microanalyses.
