Spiranes. XII. Azaspiranylalkylphenothiazines1 - Journal of Medicinal

Spiranes. XII. Azaspiranylalkylphenothiazines1. Charles H. Grogan, Rafael Kelly, and Leonard M. Rice. J. Med. Chem. , 1966, 9 (5), pp 654–656. DOI: ...
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Spiraiies. XII. i~zas;~ivan~lalkylpheiiothiazines'

.Ilthough plieriothiazine has long been uwd a i ai1 ctfec*tive inqectiridc arid anthelniintic, it war not until thc iyiithcsii of proinazine2 and proniethazine? b y Vliarpwti(+ in 1914 arid the elaboration of the potent a~itihistaiiiini(*properties5 of tliesr 10-dialkylanii~io;tlkylplieIiothiazirie~ that the phenothiazine niicleus hecwiit~ of' iiiiportaricbe in medicma1 rheinistry. ('ontin,icd iiivestigatiori of 10-substituted phenothiazines" Ird to tlic. synthesis of (*hlorpromazine7and the disc*ovcryof its potent C ' S S deprcwarit propertiei.E * i s :I. r ( 4 t of the iiivestigationr of t h e 1:rencah I\ orkers 011 thr iyiitheqi. and application of phenothiazine dcrivativey i i i t h r treatment of iiierititl Iiuiidred. of permutations of thv b:iiic active structurt~, I, liar(>c ~ o l v e t liii the last two dec*ades. l l a n y of the i r i i t i:il v:iriatioiis wcrc perfornictl by C'harpcnticr.l?

c ~ l e r t r o ~tlcii.iiy, i such a* halogen. trifluoroiiiri Iiyl, cliniethylaiiiiiio*ulf~Iiyl, nc*yloxy. :illtoxy, allrylthio, preferably :it the 2 position. When R is cthylciie 01' the tertiary aiiiitie iiioiety is substituted at the 2 poqitioii of a triiiiethylene chain, aritilii,ctamirii(~aud ~spasinolytir properties a r inore ~ pronounced. Sinrc UT hat1 rcmitly synthe.izetl :i lie\$ group ol vvoridary :iiiiiric., the azaspiraiiesl'j 11, it w:ts of i i t torest to iiir-eitigate the type of activity and potciicay of thc phenothiazine derivatives in wliich the tertiary :milie iiioicbty of I x i s itii azahpiraiiyl group.

11, n

=

1or 2; m = 1-4

Thc ollly reporti of :I piranylalkylpheno t hiuiiicthe 1iteraturc : ose of Aloffett, ef a / . , ' $ who rvported the bynth of lo-(a , a-polyIiiethylenespiropyrrolidino)alkylp thiaziiiei in which the pyrrolidirie nitrogen atom wab a to tlie spiro curboil. It ha* l m i i our experieiiw 111 t hc phsrinacological evaluation of :L heries of CSS depressants (w-azaspirariylbut.r.rop2ieiioIiei13) that when thc ring nitrogen atom \\-a* 01 t o the spiro c~arboii.activity \vas greatly decrrased o i :ibolishe(l as cmnparetl to thc potent activity of ihoiiicrir c1crivatir.c~I I I which the zpiro carbon wa* @ 01 y to the ring nitrogm. The S X I ~ I Ctypcl of obscrv:itioir. oxt criilcd to a groul) of em-nit rogcii-whst itut ed *pi r:ii 1 ~ i t i c ~ l c(aniiiiospirarit i '). Wheii tlw aniino group \\:i* d or y to the 5piro c on atom, potent analgesir. loc*;il :iiiestlietic, arid rcqiiratory stiinulants resulted, wliil(~ i ~ o n i ~ r a-subst i(~ I trit ed :iininospiranes exhibited Iittlo or no phariiiacological artivity in these areas. 1Ioffettl clxiiiictl only that t lie lO-(a,a-polyniet hylc~iiespiropyrrolitli~io)alkylplieiiothiazinesincreased tho -Iceping tiiiic of micc :uhinistered hexobarbital, :uitl 110 specific C ' S S pIinri~ixc~olog.ic~al acstivity was caitctl. 111

I

Ytl.ui*t~lrul teuturcs Ilecess:Lry tor opt1111:tl ('Sd effect\ are. briefly, as follon-s. Subrtituent X oii posit i o i l 1 (i9 lis< littlc rfTt-'c+t o i i artivity, I3 is a three-

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I

1 3 1 ( 11 lfcd Lhirn

lj] I 1 I t, ij

\I

(rroQd1,

Ltri

(

\I 1:

iltrli

and 1

71

il3(8.4 g, O.O(i tills of K I wore refIiise(1 for 30 1ir i i i IO!) nil eci re:tvlioii mixturf, w:is diluted with :: V(JI ( J f et,her ant1 kppt ovrriiight :at 5'. 8-Azaspiro[4.5]decane hydrobromide13 ( 5 g, theory 6.fj g ) W:I> rcmcivetl hy filtmt i o i i : ~ i i ( l washed with et,her. T h e filtrate :in11 \\-:t.liing-: w t w -triIipeti of wlveiit at, t h e \rater pump until :I o i l s oil rcxi:iiiiecl. Ail material hoilirig i i p to 10oo (0.2 n i n i ) W:LS di-tilled: th(>rcsidunl oil was d i s d v e d i i i 300 nil of c,ther and x i t i i r : i t d iritli I€C!l

Benzocyclobutene Derivatives.

Oximes with Muscle Relaxant Characteristics'

A iiiimber of l-acylberizocyclot)iitelle., their oxime,, a i d several oxygeii-piibst it,iited oximes were prepared arid screened for potential mephenesin-like miiscle relaxant act,ivitg. The compounds Rere obtained from a common precursor, 1-cyanobenzocyclohiteue. which xras made from o-chloroliydrociriiiariioiiitrileby an improved method. The most effective material iri the tests employed &-as the oxime of l-acetJ-lbeii~ocyc,lohutene,ahich WELS cornparable in milligram potency to tlie comparative standard, chlorzoxazone.

c~>niaiiiiiig:I c.arhoriyl group adjacent, to a c~yc~l0:tlliyl To date, our study of the biological properties of com:tud their pourids containing the bicyclo[~.2.0]oc,tti-l,:~:.5-triciie ring, :I nunibcr of I-ncylbenzocyclobut~~es oximes werv 111:iclc~ for wreening as potential niu~c.lcrering system has in(-luded t>heprepar:tt,ion of several 1laxant$. Scwr:il oxygen-substituted derivatives of O J I P aniinoniethyl-2 and various I , 1-disubstit'utetl benzoof the morc intcre\ting materials, l-acetylbenzocyclocyclobutenes. Since slieletal inuscle relaxant, activit'y buterie oxiiiic, also werc prepared. The synthesis nritl had been reported for the oximes of 2-acetyl-l,4pharniacological ev:tluation of these compounds iiro benzodioxane4 : ~ n ddicgclopropyl lietone,j compounds described in the present report. I 1) I'rebanti~rl i n liar1 befow [lie l J i v i 5 t u n of lledicinal Chemistry, 1.51~1 The ketones were made from l-cyanobenzocycloNational Sleeting of t h e a m e r i r a n Chemical Society, Pittsburgh, Pa., butene ( l ) ,whic.l.1 was prepared as shown in Scheme I. I I a r r h 1968. ( 2 ) .J. .i. ,Skorcz and J. E. Robertson. J..lfed. ChPm., 8 , 2.55 (l!lliJi. o-Chlorohydroc~iiiiiitllloliitrile( 2 ) , obtained in an owr(3) 3 . A. Skorrz a n d F. E. Kaminski. ihid.. 8 , 7 3 2 (1965). :dl yield of 53%) from o-chlorobenzyl chloride :ml (4) C . I. .Judd, J . Freedman. a n d .I. F:. Robertson, .\bstructs, 149th S a methyl cyanoacetatc, n-as converted t o 1 by a modificatiunal Meeting of t h e I m e r i r a n Clieinival Society, Detroit, lficli., 1 p r i l 1Hti.5, p 2 2 N . tion of the proc.cdure of Bunnett and Sliorcz.fi Thii ( - 5 ) I,. 17. lilockus, G . 11. Everett, an(1 11. 1;. Ridiariis. l'