Bept. 2G, lib37 CHEMIBTRY A N D INDUSTRY 8.53

NEW DERIVATIVES OF. p-ARSANILIC ACID - . .. By SIR GILBERT MORGAN and ERIC WALTON

(Paper read before Section 6-Chemistry at the meeting of The British Association i n Nottingharn on September 2, 1937)

During tlic last few years nn csteusive group of INW organic arsenical conipounds has been prepured a t thc Chemicnl Resc;ircli r,:lboratory, Tcddingtoo. The objcct of this invcstigtition \\'as to discover arscuicals t o replace or supplenient tlic A~~icricaii drug, 'rryparsaniide (II), wliich is iiscrl iu tlic trcntincnt of lntc syphilis nud tropical slecping sickness.

It miiy be now added that, after testing soiiie JOrJ active co~i~poii~icls, inany of these substances appeared less toxic and more active than Tryparsiiaiidc in the aniiual tcst stages.

Tlic group of conipounds chosen €or prepmation had the, gencrnl forniula (I), ns shown in the first diagnm.

5u 0.2

W,.U. = iuitiinium luthnl dose in mg. per 20 g. mouse. X.C.D. = niitiiinuiii curative dose in mg. per 50 g. mounu.

>= - !d.L.D. 10-15 .\l.C.II. 6 5 --. . . --

DXAolIaal 1

It will be iioticetl that this structure brings together tlie acyl and ainidc groupings into one niolecular type.

I n adopting this configuration, the following points were borne in niind :

(1) It is well known t l i i r t ncylntion of p-iirsaniEc soid (I1 I) n t first dccrenscs its toxicity, whcrens nlkyl- ntion increiiscs its toxic iictivity. The figures nppcnded

1'-iirsanilic adid, yet, it is a i itlost ~~rtliiable drug in the brcntment of sleeping sickness tint1 ncurosypliilis.

(3) It wiis tliouglit dvisttltlc, therefore, to comhinc tlic nppnreritly non-t.oxic ncyl gronping with nil aliphatic iiniidc, such as is present in 'I'rypnrsninitle, by preparing n groiip of coinpunds of type (1).

The iiietliods cniploycd in the prepiiratioli of such IL

groiip varied consideriibly in detail, but., in general, the proccdiirc WIS to condcnsc p-:manilic acid with a dibnsic acid or its siriiplc clcrivntirc, nnd to trcnt the ester of t,lic resiilting compound with amnionin or an amine, ns shown in dingram 2.

T n this way :I considerable nuiiibcr of coin pounds of type (I) (diagmni 1) Iirivc bccn prepared, tlic following rndicnls being jnvoli-ed: osnlpl(~1 =O), malonyl(ri = l), succinyl ()I == 2), gliitiiryl ( I t = 3), nclipyl ( 1 1 = 4), piiiiclyl ( N = 5), siilmyl ( 1 1 = 6), nzclalyl ( 1 1 = 7), scbncyl (11 = 8). !l'\vo or three componnds of tlic Iiesnclccylcn~~dicnrlJoxylpl series with 11 = 16 have also hccn obtained, bu t here exceptionid difXcultics of prcpnriitioii and solubility h a ~ e I)cen met,, and as yet tliey have not bccn cxriniincd biologicidly.

Tlic first series, where '1 = (I, was readily obtnined by direct condensation of p i r s i i d i c acid with osnlic acid, followed by trentiiiciit. of the estcrifictl product with the appropriate aiuiiic (scliciiic a). I'hc third series, wiicre 16 = 2, was nlso ohtiiined Iy direct coriilcnsntion of p-arsanilic ncid with succinic ncid. The product, ~~-nrsonosiiccinnnilic :icitl, WIS ring-closed by the action of heat, and tlic resulting mil treated yith amines (scliemc 6 ) . Tlic reniiiiuing series (1 and 3 4 ) were, in goncrnl, prepared I J ~ contleiiuing jo-nrsnnilic acid with tho cstcr-acid ellloritlo of tlic, iip1xoprintc dihasic acid and proceeding as i n tlic other cases (scl~cinc c) .

~~icthylinnloiiyl series Iins also bccn prepred, but it has not Irccii incllirletl for disciission in tlic present paper,

above for pnrsiinilic acid, and its ncctyl (I\') uud mothpl (V) dcrivst,ives respcctivcly, will bear out this cotitontion.

(2) Tryl'arsnniido (1'1) may 110 considcrcd ns contrrining tho inoio tosic NLI.Cl1, group, also present in A'-motliyl-

us this would teud to brcnk tlic coutinuity of tlic figurm quoted.

li'iill nccouuts of tho cliciriistry of tliesc sulrstnnccs h a w lieon published by 11s froiii t h e to tinic in the Jourricil of I l c Chctiiicd Sociely ( 1931-1936).

854 CHEMISTRY AND INDUSTRY Sopt. 26,1037

I l = 0 1 2 3 -I 5 G 7 6

Sviiintnr!j of 1r.d.s oit inice

l ) l . W I l A ~ l 3 Figurcs denote doses i n uig. per 20 6. iiioiiso Xininium lethal doso on left eidc of dingonnl line JLiiiinium curntirc dose on riglit side of dingoiinl linc

* Estendcd trinls on rnbbittl in iitldition to tliosc. on Inice.

omo curntive nctioii o curntivc nction - ? \

It will be noticed that of the 45 sodiuin salts of ninidcs tnbulnted between the Iiorizontnl double lines in the dingram, only 2 are inactive ; 16 arc feebly activc; while 27 arc definitely curative. T n sonic cases the curative amount is only one-tenth of the niiniinum letlial dose. l n these anininl tests, tlie cured inice rcinniiied free froin trypnnosoiiics throughout a period of a t lenst 28 days. It is thus apparent t ha t tlierapeutic activity is manifested fairly generally liy this group of conq~ounds.

Apart froin this fact, it itiust he admitted t l i n t the figures show very little correlation a t first gli~iice, bu t this is unfortunately quitc ti usiml characteristic of chcmo-therapeutic results. Attention iiiay be directed, however, t o the fact that, iipart froin tlie osalyl series,

Oxnlyl .... Jlnlonyl .... Succinyl Glutaryl Atlipyl .... Pimelyl Suberyl Azclayl .... 60baayl Mean ....

which is csccptionally poisonous (as might be espccteil), the tosicity tends to rise as we ascend froiii one series to the nest. This is rather surprising in view of tlic lower arsenic eontcnt, but lower rates of cliininatioii and/or detosication would account for tlie discrepancy.

The nes t diagram (‘1) depicts an atteinpt to corrclutc t,he therapeutic ratios. Tlic latter have been arcraged both horizontally and vertically with a view to :isscssing the relative values of the snnie amidcs of different acidic series on the one Iiand, and the diflcrcnt nmitlcs of a particular series on thc otlier.

-idniittedly the figures vary widely, Gill there seems to be some indication that those compounds with tlic best ratios arc to be found nmong tlic lower suhstitutcd amides of the succinyl, glutnryl and adipyl series.

The selection of a few active compounds from this group for further therapeutic trials was made in collabora- tion with the Liverpool School of Tropical hledicine, due regard being paid both to tlic biological activity and the ease of ninnufncture of tlic drugs concerned. The compounds starred in dingrain 3, iinincly soiZiio)b t~iuZoi~aitiloelli~lnI,liile-1,-rc~sotttrle, (I) ()L = 1 ; R, = 3 i , R, = EE), sodiurii st~cci~i~tii i l o , , i e ~ ~ i ~ ~ a i ~ i i J c - ~ ~ - c i ~ s o ~ t ~ i ~ e

deni i t l i~lni~~i~e-p-(~rsoica~e ( i t = 3 ; R, = Me, 13, = JIc) were crcntually choseii, and we :ire inilcbted to Pro€. Yorkc for tlic following figures, showing the rcaults of tests on rabbits, coinpared with those for ‘rrjytrsamidc. It will be seen that, on this showing, tlic drags selected appear to be slightly niorc active than Tryparsauiidc.

As the result of these t,rials, sodium succinauilo- mcthylaniidc-~~-arsonatc, now known as Neocryl, wns eventually selected for human trials. The manufacture of this h u g was a t first undertaken on a small scale :it the Chemical Research Laboratory, Teddington, hut i t has now lieen taken over by Pharmaccut ical Speciulities (Nay LV, Baker), Ltcl., of 1)agenhnni.

‘In Liverpool, Ncocryl seemed to net very bcneficinlly on several cases of both early and late syphilis, and, from Nigeria, Lester has reported good results in tlic treatment of sleeping sickness. For details of these trials, a pnblicntion in tlic British iIleiZiciil Jotrnrd (1936) by Yorltc, Alurgatroyd, and others should be refcrred to, but perhaps i t niay lm permitted to quote from the siiiiiinary of this paper :

“ In man, h’eocryl was well tolernted in closes which it is customary to cinploy for Tryl)nrsaiiiidc-ii:iiiiely in weekly amounts of froiii 2 to 4 grains. Tlie usual course consisted of tlie administration of this cunount weekly until a total quantity of froin 30 to 36 grains had been given. A nuiiiber of patients had sercrnl such courses,

(1) = 2 ; R, = €1, It, = XC), ~ l d sotlit(i)L ~ l ~ t t ~ ~ i ~ i l i / o -

~ I A O l t A J I

Cketnotherupeufic rafioa. (Approximate) Coin pound Amido BIctliylamido L)imothylnxniiIc litliyliin~iclr . . . . . . . . . . . . . . . . 1 0 3 I‘ . . . . . . . . . . . . . . . . 6 . . . . . . . . . . . . . . . . 3 14 3 1 . . . . . . . . . . . . . . . . 1 - 13 8 . . . . . . . . . . . . . . . . 4 4 7 4 . . . . . . . . . . . . . . . . - 3 2 2 . . . . . . . . . . . . . . . . 4 3 7 1 . . . . . . . . . . . . . . . . 0 1 1 - . . . . . . . . . . . . . . . . 1 1 0 . . . . . . . . . . . . . . . . 1.0 3.1 4.4 9.2

1 1 1. 9

9

-

Scpt. 15,1037 , CHEhlISTHY AND INDUSTRY 856

l)IAGftA>f 5 Bioi~//iury o/ rulbil t d s ,.

i\retllotl of trcntniciit nntl Socliiiin ii~nloiiniiilo- Sodium succinnnilo- Sodiuiu glutnrnnilo- Trypnrsnniidc dose in g. pcr kg. rnhbit etli~lniiiiclc-p-nrsollnte ~~ietliylnmiclc-p.nrso~~~it~ dii~ietliylamidc-p.nrsonnte - . -

So. t,rentctl So. ciirctl S o . trmtc.tl 4 0.25 aiiiglc tlovo .... .... - -

0.6 single close .... .... 0.15 foiir doses .... .... .- -- )

!I 0.25 foiir closes .... .... - - 0 . 4 four closes .... .... 6 6 5

the total quantity rilltging froni GG to 1.1 I grniiis, ~vltilc onc pnticnt hnd an unintcrruptcd course of G9 bptns, witliout sliowing nny toxic signs. Aport froni vcry occnsionril nriitscn :ind roniit,ing, tlic only toxic signs o\)scrvcd were niild nrscnicnl dernintitis it1 two pnticnts and temporary jaundice in two or three w r y nclrnnccd cnscs of ncurosypliilis after prolongcd courses of thc drug. Visual tlisturbnnccs h n w not been cncoiintcrctl, I ~ u t it. would I)c unwisc to nssiiiiic t l in t tlicrc is no risk of their production with Ncocryl in vicw of the closc rclntioiisliip of this drng to other quinqncrnlcnt nrscnicnls kno\vn to prodircc siicli disturbances. In further trials, tlicrc- forc, tlic snnic unrc1:isetl nttcntion mill h a r e to t ic givcn t o the possibility of this danger.

'* Ncocryl exhibitcd in n prononnccd ilcgrce the stiinUInt,ing nction wliieli onc is accustomcd to associnte with 'l'ryl)~irsnniidc rind the other qitinqucvnlcnt :troinat.ic arscnicnls.

ii In contrast witl i 'l'ryp:Lrs:iniidc tlic nc\v driig exerts n rlcfiiiitc action in prininry, secondary niid tertiary syphilis. In prjninry sypltilis, Ncocryl by itself is inndcqiintc since, alt,lioiigh tlic lesion clcnrcd i t p rnpidly, secondary niniiifestations subsequently tlctdopcd. \\'lien Ncocryl was conil)inetl with bisniutli the cffccts on priinnry syphilis secnicrl t o IIC niorc pcrinnncnt, :ind so fnr none of oiir pnticnts t,rcntctl in this wny ltns rcl:ipscd.

h'eocryl ]ins n wry tlcfinitc nction on tcrtiary mnni- festations of syphilis, tlic lesions dis:ippcnring cotiiplctcly in twenty ortt of twcnt8y-fivc ctiscs.

ri In curly nciirosypliilis and in tdJCS, Ncocryl g r i m wry sntisfnctory results.

Of clcvcn cwcs of Xigcrinn slccping sickncss trcntctl by n single course of Neocryl ten licciiiiic clinic:illy norturil nnd tlic otlier \viis inipro~~cd. 15iglit of tltcsc cases lint1 n t tlic tiinc of trcntntcnt pathologicnl spinal Iluicls ; in tlircc of tlicni tlic fliiicl lint1 bccoinc norniril riftcr the single coiirsc of trcritincnt ; in two i t 11:id Ixconic considcrnblp iiiipro\wl : nntl i n onc pnt1tologic:il changes lind nppnrcntly incrcnscd, tliougli clinicnlly thc pnticnt Itad bccoiiic qiiitc norninl ; tlic other two criscs tlbscontlctl owing to tlicir cliiiicnl iniprovrnicnt beforc

- - i ) . -

Xo. ciiretl So . trented KO. ciiretl So. trcnted No. cured 0 3 0 3 0 4 6 3 6 3 - B 1 I 9 1 2 1" 9 6 8 7 0 ' 6

thc coni~~letion of thc trcntmcnt. 111 addition, R twe1ft.h very ndvanccd cnsc, which had failed to react to very fill1 courses of 'rry~~n.rsn~nidc, of Bayer 20.5 and of Antrypol, fnr sonic rcnson or otlicr improved rcmarknbly after n coiirsc of Neocryl.!'

Neocryl has :tho bccu subjectcd to an iutcresting test I J ~ Hawlring, I-fennclly, nnd Qunstcl n t Cnrdiff (1937), involving tlic cstiiiiiition of thc trypnnocidal activity itnd nrscnic content of tlic ccrebrospinal fluid after :dministr:ition of arsenic compouncls. Thcsc workers snggcst that the cllicicncy of drugs used for syphilis and trypnosoiniasis may be estimated in this way.

In t.11cse tests, Ncocryl prodnccd only R slight tryptinocidnl activity in thc C.F.S., ns compnrcd with that obtained by 'I'ryparsamidc and a few other quinqucvnlcnt arsenicals. Thc totnl arsenic content of tlic C.S.P. wit.11 NeocryI, liowcvcr, WRS wcll up t o the standard nttnincd by other drugs, and if anything more pcrsistciit,.

'rhc subject is vcntilntcd in ii leading nrticlc of tlic I,u//cel of J ~ l y 10, 1937.

Neocryl is a t present bcing given a clinical trial on a lilrgc sctilc under the auspices of the Thcrapcutic Trials Coniiiiittec of tlic JIcdicnl Research Council. Interim rcports indicntc sonic diff crcncc of opiuion in regard to- its value compnrcd with Tryparsainide. JIost morlrcrs ngrce, Itomc\~er, iu finding Ncocryl considorably less toxic than Tryparsamidc, but i t is still much too early to givc i t fincil verdict on the clinical possibilities of the drug.

-

Chcniicnl Rcscnrch Laboratory (Dcpnrtmcnt of Scientific nnd hdi i s t r id Hesearch)

!l!cdd i ngt on, 31 i tld lcscs

BIBLIOGRAPHY I-inwkiiig, I?., Hciinolly, T. J., nncl Quastcl, J. H. : Journal

o/ I%cir/tirtcology ciiid Ezperiiiienlul Il'herupeulies, 1037, 159, 167. Jrorgiiii, c. T. nnd \\'nlton, E. : Jortrrtnl ojtheGiieiiiieu2 Gociety,

l!Y3l, 618; 1931, 1743 ; 1032, 276; 1033, 91 : 1933, 1004;

S'orlcc, \\'., Murgntroytl, F., iiiitl others ; British ilfledical 11)95. 290 ; 1!l36,~02.

Jonr,itr/, l!)36, vol. 1, 104%

TRACKING DOWN A DEFICIENCY DISEASE ,.I \ I : I j . r h * q J , p By D. SANDYS WUNSH, M.A. . t ',

For sonic twenty-five or tliirty yciirs II diseiisc hits I)ccn prcvnlcnt ninong sliccp in ccrtriin nrerts of South- Iiind, N.Z., \vlticli nppcrirctl to bc grritlunlly sprcrttling i i i i d incrcusing in viriilcncc. Tho Reriousncss of t l io troublc vnricd niucli froiii ycrir to yerir, wet ycnrs 1)cing w r s c t t inn dry.,/Soniu locrilitics werc rc~guliirly inorc

subjcct to i t tluin others. L'crliiips tho worst itrca wns tlic district of Morton JInins, whence tlic discnse took its custonirtry but incorrect nnnic of * ' Norton BInins I)isetisc "-incorrcct bccnusc it iniplictl n IiniitiLtion to this nciglibourhood, diemis , ns will bo sccn Intcr, its incidoncc ivns frir niorc widcsprcutl.