CA2155758A1 - Heteroaromatic compounds with antipsychotic activity - Google Patents

Abstract

The present invention relates to a group of piperazine and piperidine derivatives of formula (I), wherein Y is a heteroaryl group optionally sub-stituted by one or more halogen, nitro, C1-6alkyl, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, hydroxy, S(O)nR2 or S(O)nN(R2)2 where n is 0, 1 or 2, CN, CON(R2)2, COR2, CO2R2, CO-aryl, azido, -N(R2)2, -NR2N(R2a)2, -NR2N = C(R2a)2, -NR2(C =
O)CH(N(R2a)R2b, -NR2(C = O)R2a, NR2CO2R2a, C1-6alkoxycarbonylamino or PhN = N; with the pro-viso that Y does not include benzisothiazolyls or ben-zisozazlyis, V is -O- or S; Z is C1-8alkylene optionally interrupted by -O- or -S(O)n where n is 0, 1 or 2, C2-8alkenylene or C2-8alkynylene; X is N, CR3 or COR3-;
A is CR4 or N; B is oxygen, NR5 or S(O)n, where n is 0, 1 or 2; and R1 is hydrogen or one or more halogen, hydroxy, nitro, CN, NR62, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, or COR6, R, R2, R2a, R2b, R3, R4, R5 and R6, are each hydrogen or C1-6alkyl; or a salt, solvate, N-oxide or physiologically functional derivative thereof,to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular in the treatment of psychotic disorders.

Description

~ wo 94/18196 2 ~ 5 5 7 S 8 PCT/GBg4/00265 I

HETEROAROMATIC COMPOUNDS WITH ANTIPSYCHOTIC ACTIYITY

'I'hc prcsent invenIion relates to a oroup ol` piperazine and piperidine dcrivativcs~ to processes t`or their preparation. to pharrnaceutical compositions containin~ them and to ~hcir use in therapv~ in panicular in the tre.~tment of psychotic disorders.

Receptors for the chemical messenger doparnine are known to be located in the striatum :lnd the limbic brain area and such receptors have been classified as D I and D~ based on receptor bindin~ studies and on the presence or absence of a positive couplin~ between the receptor and adenylate cyclase activity. Activation of the D I -receptor is associated with stimulation of adenvlate cvclase, whereas the Do-receptor mediatcs dopaminergic effects that do not involve direct stimulation of this enzyme [see Kebabian & C~alne~
Nature,, _~7, 93(1979) and Harrold et al, J. Med. Chem., ~, 1631 (1987)~ . Although the distinct functions of the D I - and D~-receptors are not clear cut~ a strong correlation is believed to e,Yist between D~-receptor antagonism and antipsychotic activitv[see Seem~n. Pharrnacol. Rev.~ 3'~, 2'9(1981)~ Seeman etal, 13iochem Pharmacol.. 34, 151(1985). Creese et al, Science, 19~ 81(1976) and Levsen in Clinic.~l Ph~rmacolo~y in Psychiatry: ~leuroleptic and Antide~lessallt Research: Eds Usdin. DahL Gram and Lin~aerde. Macmill,m: Basin~stoke~ pp3~-5~(198'7)].

The chemical messenger 5-h,vdrox,v tryptamine (5-lIT) occurs widelv in the ccntral nervous svsIem and is known to be involved in the control ot' behavior. A number of dit'fercnt 5-1-IT receptors and rcceptor sub-types have been identified. In addition Io thc blockade of D~-receptors~ it has bcen postulatcd that 5-EIT~ receptor anta~Jonism is also desirable in ;m antipsychotic a_cn~lsee Jansscn eL al, J. Pharm. and F,~iper. Ther., ~(~'), t~85(1988)]. In particular it has bcen postulated that blocl;ade of central dopamine D~-receptors ma!~ control thc positive symptoms of schizophrenia (e.~n delusions and hallucinations) ~ hilst blockade o~' 5-I IT~ receptors mav assist in the amelioration of the nc~ative s,vmptoms of schizophrcnia (e._. apath,v ;md social withdra~!al). It has also been su(~ested th~t blockade of the ~-l1T~ rcceptor results in a reduction oi' the e,Ytrapvramidal side et'fects which arc l;nown to occur in the case ol` neuroleptic maintcnance therapv with man~ known antipsvchotic ;l'L~CIltS.

WO 94118196 21 S~ 7 ~ 8 PCT/GB94/00265 Psvcholropic benzisolhiazoles and ~cnziso.Yazoles arc dcscribed hl ~,'S~96879?.
EP035713~. EP019613'' and EP0511610. } urther .~nti-psychotic piperidines and piperazines are diselosed in EP03~9168~ EP037'76~7. El'001361~ and US5~?5~1' ~ .
A ~roup of novel piperazine ~nd piperidine derivatives ~s~ ~een discovered that are potent ant~gonists of dopamine O~ receptors,andt'or 5-~ r~cepLors ~nd are theret'ore ."", useful in the treatment of psychotic disorders ' ~

The present invention provides a compound of formula (1)~ a salt. solvate or physiologieally functional derivative thereof yJ~ N x--~a ~ )=( (I) R I

wherein Y comprises a hetero~ryl group optionall~ substituted by one or more halo~en. nitro~
CI 6alkyl. CI 6alkoxv. arvloYy. arvlCI 6alkvlenoxy hvdroxy, S(O)nR~ or S(O)nN(R2)~ where n is 0. 1 or 2, CN. CON(R')~ COR2~ CO7R'. CO-arvl. azido~
-N( R~)~. NR 'N( R~ . -NR~N=c( R7~)~ -NR2(C=O)CH(N(R 'ah)R~b, -NR'(C=O)R2~. NR CO~R'~. Cl 6alkoxvcarbon,vlamino or PhN=N; with the proviso lha~ Y does not include benzisothiazolyls or benzisoxazolyls;

V comprises O or ~i;
comprises C I galkYlene optionally interrupted by -O- or -S(O)n- where n is 0. 1 or C~ g~lkenvlene or C~ lkynvlenc:
~ comprises N~ CR3 or CoR3:
A comprises C~R~ or N:
B comprises oxyL~en. NR5 or S(O)n~ wllere n is O. I or '): and 1~ 1 comprises hydrogen or one or more halo~Jcn. hydrox- . nitro. CN, NR6~, (~1 6alkoxy.arvloxv.arylC1 6all;ylenoxv.orCOR(', ~WO 94/18196 ~ 2 1 5 5 7 5 8 ` ` PCT/GBg4/00265 R R2 R2a R2b R3 ~4. RS an~i R6 herein and R7, Rg R9~ Rl0 and Rl 1 herein~rter are h- dro(Jen or C 1 6alk- 1:

Compounds ot` torrnula (I? can torm solvates, in particular h~drates or partial h-drates.
and such solvatcs~ includin~J ph~siolo icall~ acceptable solvates, are also included within the scope o~` the invention The e~cpression -(R';)v should be taken to indicate the presence of v R~ variables each bein_ independenllv selected and not theref~re necessarilv identical.

As used herein~ the terrn "alk~l" as a ~roup or a part of a t~roup c~n be ,~ str~ight or branched chain all;yl group optionall~ substituted bv one or more halogens, h-droxy, nitro, CN, N(R7)~, C 1 6alko~cv or CoR7, for e~cample~ methyl, ethyl~ propvl, prop-~-yl.
but~l, but-~-~l or ~-methvlprop-~-vl. Alkyl groups are most preferablv methyl or ethyl.

As used herein, the terrn "alkylene" ret`ers to a straight, branched or C~ 6cyclic all;~lene group optionally substituted by one or more halogens. hvdro~cy. nitro, CN, N(Rg)~
C I 6alko~- or COR~ for e~ample~ methylene~ ethylene, butvlene, pentylene, he~ylene, cyclohe~c~lene, or -(CH~)mC3 6cycloalkyl(CH~)m- ~here m is 0 to ~, in particular where C, 6cyclo~1kyl is ,~ cvclopropvlene ~roup.

.~s used herein. the term "all;envlene" refers to a strai~ht. branchcd or c-clic all;en~l group havinn t`rom ~ to ~ carbon atoms optionall- substit-lted bv one or more halo(Tens.
h-~dro~;v, nitro, C~i, N(R9)~. C1 6all;o:;- or CoR9. SUCIl as, Ior e:;ample, ethen--lene.
propen~lene. butcn~lenc. pentenvle~e. he~cenvlene and the lil;e As used hercin. the teml ''all;~vn~lene'' reters to a strai~ht or branched all;~n~ roup havi}l(T t`rom ~ to .~ carb<)n atoms. optionall~ substituted b~ one or morc halooens, h~dro~;-, nitro, C~, ~(R10)~. Cl 6all;o~;v or COR10 sucll as, for c.~;ample, eth-nvlene.
pro~ n- Ielle. but~ n~ lene, pcn~! n~ lellc, hc:;~ n~ Icne and thc li~c \s uscd hcrein, thc tcrm 'all;o~ " reiers to .In -0;111~1. -O;lll;cn! l or -Oall~n~ l nroup WO 94/18196 PCTtGB94/00265 ~
21SS~58 .-~s used herein. the term "heteroaryl" reters to a monoc-~clic or bicvclic fused rin(g system comprisin~J 5- l O atoms ~wherein I or more ring atoms are independentlv selected l`rom nitrog~en. oxygen or sult`ur.
, Bicvclic heteroaryl groups may have one ot` the rin ~ ith complete or partial saturation. .~
:
As used herein. the terms "arvl" refers to phenvl. naphthalenvl optionallv substituted by one or more halo~ hydro.xy. nilro. cvano. trifluoromethyl, lower alkyl. Iower alkylthio or N(R 1 l )~ .

As used herein. the terms "arvlo~cv", and arylCl 6alkyleno:Yy retèr to an -Oarvl ~nd -OC l 6alkylenarvl group respectively wherein "aryl" and "al~yl" are as defined hereinbefore.

As used herein. the term "halo" refers to fluoro. ehloro, bromo and iodo.

As used herein. the term "physiologieally t`unetional derivative" means any physiolo_ieally aeeeptable ester, or salt of sueh ester. of a eompound of forrnula (I) or a compound whieh upon ~minictration to the reeipient is capable of providing (directly or indireetly) sueh a eompound or an aetive metabolite or residue thereot: Sueh physiologieally tùnetional derivatives e,m also be prodru_s of the eompounds of the present invention and ~re eonsidered to be within the seope of the invention.

The present invention ineludes all optieal isomers ot` compounds of t`ormula (1~ ,md mixtures thereof ineludin~g raeemic mixtures. Tlle invention also includes all 2eometric isomers of compounds of forrnula (I) including mixtures thereot:

The invention t`urther provides eompounds ol forrnula (I) and sal~s. solvates and phvsiologically t`unctional derivati~es thereot in ~hich the nitro~Jen ~tom shown in tormula (I) ~hich is adjacent to ~ and ~vhich is p~rt of the si~-membered rin~ is in its o.~idized t`orrn as N-o~ide.

Tlle present invention includes eompounds ot t`ormula (I) in the form ot physiologically ~ ceptable S,II~S thereot: ~uitable s,llts are~ in partieular~ Ieid addition salts ineluding _WO 94/18196 ~CT/GB94/00265 those t`ormed ~vith both or~anic and inor~anic acids. ~uch acids ~ill normallv be phvsiolo~Jically acceptable althou~h salts of non-phvsiolo~icallv acceptable acids can be of` utilit,~ in the preparation and purification ot` the compound in question Thus pre~'erred salts include those ~orrned from hydrochloric. hydrobromic. sulphuric. citric.
tartaric. phosphoric. Iactic.~pvruvic. trifluoroacctic. acctic. succinic. o~;alic. ~`um~ric.
maleic~ o.~;aloacetic. methanesulph~ni~ ~thanesulphonic. p-t~luenesulphoni&~;
bcnzenesulphonic and iscthionic acids. ~alts of compounds of formula ( I) can be made bv reactin~ the appropriate compound in the form o~`the t`ree base with the applu~,l;ate acid. Preterabl,v the salt is the hydrochloride salL or dih,vdrochloride salt, The present invention also includes within its scope compounds of formula (I) which are in the form of a salt!solvate(in particular h~drate or partial hvdrate), Base salts of the compounds of formula (I) are also included within the scope of the invention. Suitable base salts include those t`ormed with both organic and inor~anic bases Such bases will normallv be phvsiolo~ically acceptable althou~th salts of non-physiologicallv acceptable bases can be of utility in the preparation and purification of the compound in question. Thus preferred base salts include those formed from alkali metal(e ~.. sodium). ~Ik:lline earth metal(e.~., ma~nesium), ammonium and quaternary ammonlum.

Pre~`erred heteroaryl ~roups are p,vridinyl. pyrimidin,vl. pyrazinvl. pyrazolYI. pyrrolyl, r~-ridazin, l. quinolinyl. isoquinolinyl. imidazolvl. benzimidazole. t`uryl. benzofuryl, thienyl. benzthienvl. indazolyl. o~azolyl. thiazol! l. isothiazolyl. iso~;azolyl. purinyl, triazinyl. indol~ryl~ napthiridinyl. quinazolinvl, pyrrolopyridinyl~ tetrahydroquinolinyl, indolinyl. quino~calinyl, triazolyl or ~hiadiazolyl.

I~,lore preferred heteroarvl ~roups are pyridin-h pvrrolyl. quinolinyl. imidazolyl. furyl.
thienyl. benzthienyl. indolyl. napthiridinvl. quinazolinyl. tetrahydroquinolinyl and indOlin! l Tlte most pret`errcd hcteroaryl ~roups are pyridinyl. quillolinyl thienyl. benzthienyl.
indol~ l. tetrahydroquinolinyl and indolinyl ~ccordin~ to a prct'erred aspcc~ o~`thc present invcn~ion 'r' is substitu~ed -ith N¢R2)2

2~75~ ~

-~ccorain(~ to a t'urther pre~erred aspect ot`the present invcntion ~' is p~ridine. thiophene or benzThiopllene optionall~ substituted ~ith l~'(R2)2 .~ccordin(J to a more preferred ~spect ot` the prese,~r invention R is H or ~le ~' is p~ ridine. thiophene or benzthiophene option~ substituted ~vitL .~iH~ 'Hl~le or~~H.~c.

.~ccor~iinl7 to the most preferred aspect of the present invention R is H and Y is pyridine or thiophene substituted vith NH2.

.~ccordin~ to ~Irther preferred aspect o~` th~e present invention V is more preferably O! Z
is Cl 6 all~ylene and is mos~ pre~`erably C~ alL~ylene; B is -S- NH or -O-. is more preferL-Ibl~ -S- or-O- and is most pre~`erably -S~ is CH or N and is most preferabl~ N
and R I is H or F and is most preferably H.

Preferred compounds of formula (I) include:
~-(1-(~-( I,'-Benzisothiazol-i-vl)-l-piperazinyl)butYI)-~-pyridinecarbo~camide;
~'-(4-( I-(l.~-Benzisothiazol-~-yl)-l-piperazinYl)but 1)-3-pyridinecarbo~camide:~'-(4-('~-(1 .~-Benzisothiazol-~-vl)- I -piperazinyl)butvl)-L~-pyridinec2rbo~;amide:
t-But~ -(N-(~ -( I .2-benzisothiazol-i-~Y i)- I -piperazinvl)butvl)carbamovl)-i-thienvl)carbamatc:
'-.~mino-~ -( I .'-benzisothiazol- .-~ piperazinyl)-b-ltyl)-i-p~ ridinec~rbo:;amide:
mino-~-( 1-(~-(1 .2-benzisothiazol-i-~ l)- I -piperazinyl)-butvl)-~-p! ridinecarbo~;amide;
mino-~'-( l-(~-( I .2-benzisothiazol-~-~ 1)-1 -piperazinvl)-butyl)- -.
p!-ndlnec~rbo~camldc: -mino-1~i-(4-(~-( I .2-benzisothiazol-,-~ l)- I -pipcrazinyl)-butvl)-~-p~ ridinecarbo.~;amidc:
i-.L~mino-~;'-(L~-(L~-( 1 .2-benzisothiazol-i-~v l)-1-piperazinvl)-b~ltvl)-')-~hi~phcllecarbo.~;ami(lc:
~- ~mino-~\-( 1-(~-~1 .2-hcn;zis(lthi lzol- .-~I)-I-pipcr~zinyl)-but~l)- .-t~ c.lrbo~

~WO 94/18196 A 2155 7-~ ~ PCT/GB94/00265 ~ -Amino-N-(4-(4-(1.~-benzisothiazol-3-yl)-l-pipcrazinyl)-butyl)benzo(b)thiophene-~-carboxamide:
'-Amino-N-(4~ -bcnzisothiazol-3-vl!- l -piperazinyl)-butyl)-,-thiophenecarboxamide;
~-~4-[4-(1.~-Benzisothiazol-3-:vl!-l piperazinyl]butyll-8-quinolinecarboxamide:
N'-[4-[ l-( 1 .~-Benzisothiazol-~-yl)- l--piperazinyl~butylI- l .~.~.4-tetrahydro 8-quinolinecarboYamide:
4-f4-( 1 .2-Benzisothiazol-3-vl)- 1 -piperazinyllbutyl]-7.3-dihvdro- I H-indole-7-carboxamide:
N-[4-[4-(I .~-Benzisothiazol-3-yl)- l -piperazinyI]butyl l- l H-indole-7-carboxamide;
and physiologically acceptable salts~ solvates physiologicallv f~tnctional derivatives and ~-oxides thereof.

More preferred compounds of formula (I) include:

3-Amino-N-(4-(4-( I .~ -benzisothiazol-3-yl)- 1 -piperazinyl)-butyl)-2-pyridinecarbo:camide;
3-Amino-N-(4-(4-( l ,~-benzisothiazol-3-yl)- l -piperazinyl)-butyl)-~-thiophenecarboxamide;
N-(4-(4-( 1 ,2,Benzisothiazol-3-vl)- I -piperazinyl)butyl)-2-pyridinecarboxamide;
N-(4-(4-( 1 ,2-Benzisothiazol-3-vl)- 1 -piperazinyl)butvl)-3-pvridinecarboxarnide:
;md physiologically acceptable salts. solvates physiologically functional derivatives artd N-oxides thereof.

Tlle most preferrcd compound of formula (I) is:
mino-~1-(4-(4-( 1.~ -benzisothiazol-~-y I )- I -piperazinyl)-butyl)-~ -pyridinecarbo~;amide:
and phvsioloTically accept tble salts solvatcs physiolo~ically functional derivatives and N-oYides thereof.

~;alts of` compounds ol` formula (I) arc prct`erabl~ the ~ICl salts and solvates arc pret`erablv hvdrates 'I`hc compounds of formula (I) show an advantagcous prot'ilc ol` pharrnacological activity and are usct'ul in thc trcatmcnt ot` a numbcr ol` conditions 'rhe compounds sl~o-~. I`or e~;amplc an.Yiolvtic. ccntrally-actinT musclc rclaYant. and antidepressant 21S5~

activity Thev are also useful in thc trcatment o~` aPgression associated wilh senile demen~ia~ borderline personality disorders and as a broad-spectrum an~iemelic. In particular the compounds are uset'ul in Ihe treatment ot` psychotic disorders such as r schizophrenia.

I'oten~ial antipsychotic acti-ity can be assessed by~t,l~i~ability ot`a compound to block ;Ipomorphine-induced climbin~ in the mouse~see Qnren etal, E~lr J. Pharmacol., 1', ~9(198~), Iversen. Science. 188, 1084(197~ and Gudelsky & Moore, 3 ~eural Transm., 8, 95(1976!). The tendency ot a compound to induce catalepsy and its ability to blocl; apomorphine in~IIced stereotypes are behavioural measures which indicate the potential of n compound to induce e~ctrapyramidal side effects.

The compounds of formula (I) are potent anta~onists at dopamine D~ receptors nd at ~-HT~ receptors and have utility as antipsychotics. This profile of activity has been confirmed by the potency of compounds of formula (I) in the mouse-climbin~ assay and by good ratios of the dose required for potency in this assay to the dose required t'or the induction of catalepsy.

Compounds of formula (I) are also potent agonists at the 5HTIA receptor. This activity has been associated with anti-depressant and an~ciolytic effects as vell as with a reduction ot e~ctrapyramidal side-et`fects. The combination ot` potent dopamine D~
receptor antauonism and ~-HT~ receptor anta onism with S-HTIA receptor agonism wllich is to be found in compounds of formula (I) is a particularly advantag~eous profile of activity for an anti-psychotic agent and. in particular. for a drug for use in the treatment of schizophrenia.

According to a further aspect. the present invention also provides a method for the trcatment or prophyla:Yis in a mamm~L such as a hum~n. of a disorder selected from the folk~win~:
an~icty. muscle spasm. dcpression. ag~nression associated with senile dementia.
borderline personality disordcrs. emesis ~nd psychosis which comprises ~lministering to tllc mammal an effective trcatment amount of` a compound of forrnula (I) or aphvsiologicallv acceptablc salt. or sol-ate or physiologicall~ t'unctional derivative therEo~: In particular a method t`or the ~rcatment or prophyla~is in a mammal ot` a ps!chotic disorder which comprises administering to 'the mammal an anti-ps-chotic ~WO 94/181g6 215 5 7 ~ 8 PCTlGs94loo265 el~ective trealmenl amoullt ot`a compound ol`f`ormula (I) or a physiolooicall~ acce?lablc sall or solvate thereof or a physiolooicall~ tùnctional derivative or N-o~ide thereor`. In particular. the invention provides such a method wherein the ps-cho~ic disorder is schizophrenia.

Accordin(J to a ,vet further~aspee~; thc,~ples.~nt irlverlIion ~,rovides a e~m,rQunLL~of.torm~
( I) or a phvsiolo~Ti~eally acceptable salt or solvate thereot: or a phvsiolo(Jicallv tunclional deriative or N-oxide thereof for use in therap,v. in particular the therap,v or prophyla~cis ot a ps~chotic disorder such as schizophrenia. Tlle invention also provides the use of a eompound of formula (I) or a physiolo~Tieallv aeeeptable salt or solvate thereof t`or the manufacture of a medicament for the treatment or prophylaxis of a ps,vchotic disorder such as schizophrenia.

Whilst it ma,v be possible for the eompounds of the present invention to be ~l~lmini~tered as Ihe raw ehemieal, it is pret`erable to present them as a pharrn~reutieal eomposition.
According to a furthcr aspect, the present invention provides a pharmaceutical eomposition eomprisin~ a eompound of formula (I) or a physiolo~ieallv aeeeptable salt or solvate thereof or a physiolo~ieally funetional derivative or N-o~cide thereof tooether with one or more pharm~re-ltieally aeeeptable earriers theretor and optionall~ one or more other therapeutieall,v active ingredients, The earrier(s) must be 'acceptable' in the sense of beino compatible with the other in(Tredients ol the composition and notdeleterious to the recipient thereot:

Tlle compositions inelude those suitable l`or oral. parenteral (includin~ subculaneous, transdermal. intradermal. intramuseular and intravenous). reetal and topieal (ineludin~, dermal. bueeal an-l sublin~ual) administration althou~h the most suitable route can depend upon for e,Yample the eondition and disorder ot the recipient. Tl-e eompositions ean con-enientlv be presented in unit dosa~e torm and ean bc prepared b!- an~ of the methods well l;no-vn in the art ot pharmac,v. All methods include the step ot~ brin~in_ into assoeiation a compound of the present invention as herein deFIned or a pharrnaeoloLTically aeeeptable salt or solvate thereof ("active in_redient") ilh the carrier w hich constitutes onc or more accessor~ inoredients,. . I n oeneral Ihecompositions are prepared b~ unitorml~r and intimatelv brin~inL~ into associalion Lhe acti-e inoredient with li~luid earriers or t;nelv divided solid carriers or both and then. ir ncccss;lr~. shapin~ thc pro(lucL into the desired composiLion, WO 94/18196 PCT/Gs94tO0265 ~1$575~ _ (:'ompositions of` the present inven~ion sui~ble for oral administration can be presented as discrete units such as capsules~ cachets or tablets each containing a predelermined amounl ot the active ingredienl: as a powder or ~ranules; as a solution vr a suspension in an aqueous liquid or a non-aqueous liquid: or as an.oil-in--vater liquid emulsion or a ~vater-in-oil liquid emulsion. The active ingredien~"can also b~.,presented as a..bolus electuarv or paste. , !

A tablel can be made bv compression or mouldin_~ optionally witi1 one or more accessorv ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free^flowing form such as a powder or granules~
optionallv mi~ed with a binder. Iubricant~ inert diluent~ lubricating, surt`ace active or dispersing a~ent. Moulded tablets can be made b,v moulding in a suitable m~chine a mi,Yture of the powdered eompound moistened ~ith an inert liquid diluent. The tablets can optionally be coated or seored and ean be f`ormulated so as to provide slo~v or controlled release of the aetive ingredient therein.

Compositions for ~a~ te~dl ~-lmini~tration include aqueous and non-aqueous sterile injection solutions which can contain anti-o:;idants, buffers, bacteriostats and solutes ~vhich render the eomposition isotonie ~ith the blood of the intended recipient: and aqueous and non-aqueous sterile suspensions vilich ean inelude suspending agents and thickening a~ents. The composilions can be presented in unit-dose or multi-dose containers~ for eYample sealed ampoules and ials. and can be stored in a freeze-dried ( iyophilised) condition requiring onlv tile addition ot the sterile liquid carrier~ tor e~;ample. ~ater-t`or-injeetion. immediately prior to use. E.Ytemporaneous injeetion solutions and suspensions can be prepared trom slerile powders, granules and tablets of the kind previously described.

Composi~ions for transdermal administr~tion can be delivered b,v p.assive diffusion or by electrically assisted transport. i`or e:;ample. iontopheresislsee. ior e~;ample,I~h.lrmaceutical Research ' (6). ,18 (1986)l and tvpically tai~e the f`orm ot an op~ionally but`fered aquevus solution ol a compound ot` tormula (I) or .1 salt or acid derivative thcreot. ~uitable compositions comprise citrate or his/tris butt`er (pH6) or clll;mol/~ater. .Such cotnpositions call optionally comprise a Iysosomal upta~;e-illhihiting a(ccnt.

_WO 94118196 215 5 7 5 8 PCT/GB94/00265 ~ I

~`ompositions for rectal administration can be presented as a suppository with the usualcarriers such as cocoa butter or polvethylene lvcol.

~ompositions t`or topieal administration in the mouth. Ior e.Yample buceally or sublinlTuallv. include lozen~es comprising, th~ active ingre(1ient in.a tlavour.ed basis such.
as sucrose and acacia or tra~Taeanth, and pastilles eomprisino the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

Preferred unit dosaoe compositions are those eont~inin~ an effeetive dose, as hereinbelow reeited, or an appropriate fraetion thereof: of the aetive ingTredient.

It should be understood that in addition to the ingredients partieularly mentioned above, the compositions of this invention can include other agents conventional in the art having regard to the type of composition in question. t`or e:cample those suitable for oral ~mini~tration ean inelude tlavouring agents.

The eompounds of the invention are pret`erably used to treat psyehotie disorders sueh as schizophrenia by oral ~-lmini~tration or injeetion (intl~ualellteral or subeutaneous). The preeise amount ot` eompound administered to a patient will be the responsibilitv o~` the attendant physieian. ~lowever the dose employed will depend on a number of t`aetors.
includin the age and se~ of the patient. the precise disorder being treated. and its severit~. Also the route of administration ean vary dependin~T on the condition and its severity .

Tl~e compounds of the invention are tvpically administered orally or via injection aL a dose of from 0.0~ to 50.0 m~/l;g per da!,. 'I`he dose range ~`or adult humans is (Tenerally l`rom 1.~ to 3~00 mgida and preferably between ~.8 to 1 7~0mg/day. more preferabl~ 7 to 700m(T/da!

Ille present in~ention also provides processes tor the preparation ot` compounds of formula (l) ;3nd physiolooicallv accept,lble salts and sol~ates thereof and physioligicallv l`unctional derivatives thereot: In s encral thc compounds of formula (I) can be prepared h~, anv process l;no-vn in the prior art ~`or the preparation ot` analogous compounds In thc ~`ollo~in ~ descrip~ion~ the ~roups Z .Y. V~ ,~ L3, R~ R~ R~a~ R~b, R'. R~. R', WO 94/18196 ~ PCT/GB94/00265 ~
21~ 55'~ 5'8 R6. R7. Rg. R9~ R~ md Rl l ha~e thc mearlin(Ts ascribed to thern in forrnula (I)unless otherwise stated.

.L~ccordinlT to a i`irst ~eneral process ~ compounds oi` i'orhlùla (I) can bc prepared bv reaction of a compound of tormula (II) y NH (Il) -- F~
~vith a compound of formula (III) L Z t`l x~a <~_ ~ (III) where L is a leaving group. for e~cample~ a halogen such as bromine. chlorine or iodine.
an alkyl- or arvlsultonvlo~cv such as meth~n~slllfonyloxy or p-toluenesulfonyloxy, in the presence of an appropriate solvent and base.

Thc process can be carried out either at room temperature or at elevated temperature such as 60 ')C to 140 C. Suitable solvents include N.~-dimethvlformamide, acetonitrile. benzene. toluene, ~cylene etc. and appropriate bases can be chosen from or~anic bases such as triethyl amine. pyridine etc.. alkali metal carbonates or bicarbonates such as sodium carbonate, potassiuim carbonate. sodium bicarbonate.potassium bicarbonate etc.. or alkali metal hvdrides such as sodium hvdride. potassium hvdride etc.

,L~ccordinl~ to a second ~eneral process (B). compounds ot formula (l) vherein Z is -(CI-~ -or-~CH~)s- can be prcpared by rcaction ot a compound of formula (II) with a ~ompound ot` t`orrmula ( l V ) ~WO 94/18196 215 ~ 7 5 8 PCT/Gsg4/00265 w-x~
'--~' \l (IV) where W is a suitable ~nion. such 2S a halogen. for example. bromine or chlorine, sulphonic acid esters such as mesylate or tosvlate and Rl~ is -(CH~)4- or -(CH~)s-, more particularly -(CH~)4-. The conditions of reaclion can be the same as those described for ~eneral process (A! above. Additionally a complexing agent such as1.4.~, l O~ 13.1 6-hexaoxacvclooctatecane( 1 8-crown-6) can be included.

According to a third gener.ql process (C) compounds of formula (I) can be prepared by reaction of a compound of formula (~/ ) ,1~ (V) Y N __~
R

in which L is as hereinbefore defined. ~ith a compound of formula (VI) HN X--~ B
/ ~/
(VI) ~1~

rhc proccss can be carried out as dcscri~cd ~`or ocncral proccss (~) above WO 94/18196 215 5 ~ S ~ - PCT/GB94/00265 ~ccoraing to a fourth oeneral proccss (Dj. compounds ol` lormula (I) in which ;'~; is ~\i c.~n be prepared b~ reaction of a compound of f`orrnul~ (VIT) v y , 1 7~ NH (Vll) with a compound of tormula (VIII) L~A~3 (VIII) in which L is as hcreinbctore defincd.

-rhe process can be carried out ~s describcd tor oeneral process (A) abovc.

f~ccordin~ to a si.Yth ~cneral process (F)~ compounds of forrnula (I) can be prepared b~
rcaction ot`compounds ot` forrnula (IX) ~I (IX) YJJ~LI

~WO 94/18196 -15 21 S 5 7 5 :8 PCT/GB94/00265 ~vnerein Ll is ~ h2iogen(e.~.. Cl. Br). OMe Qr OH. or. in the case vher~ Y in the com~ound of formuia l'i) is ~o 5e subs~lhted ~t ,t le2s; one of the ?osliions or-ho to the am.iae or thioarnide w;th an - I~HR2 gro~p by re~c~.on of ~ comcouna of l"or;r.ul~ ( IXa).

r~
/
~ / ~v and wherein Y,V and R~ are as previousiv desc..bed. vith a compound or` forrnula (~) /~A, i~

Rl in a suitable organic solvent with or without the addilion or a suitable base at or below room te~ LLIre or at elevated t~ yc~ es (e.~ 0 C to 1 ',LO C). Suitable solven~s include ~ dimethvlforrn~rnide. ~c_tonitriie. dichloromethane. ber~ene. toluene.
tetranvdronlran. .Yylene e~c. and a~lO,LJli~ bases c~n be chosen from or,anic bases such as trieth,vl arnine. p,vridine elc.. aL~;aii met~l carbonates or bicarbonates such as soduum carbonate. potassiuirn carbonate. sodiurn bicarbona~e. potassiurn bicarbonate etc.. or alkali met ~I hydrides sucA as sodium h,vdride. po~assiurn hydride e~c.Additionally, catalysts or couplin(J rea~ents such as trimethylalnminllm isobulvlchloroformale or 1.3-dicyclohe.Yyicarbodiimide~'DCC! c~n also be included.

~hen L is OH and ~' is subs~itu~ed ~,ith ~n ~HF~ ~roup adjacen~ lo the caroonyi or thiocarbonyl (Jroup. the process can be car~ied out in the presence o~` silicon te~rac'~lloride in a retluYinn solvent ~uch as ar~n- drous pyridine. [Kornen ~I.J.
J Het-rocyclic Chern.. 2~), lO~(199~)].

WO 94/lX196 215 5 7 5 8 : PCT/GB94/00265 .~ccording to a seventh _eneral process~ ). compounds of tormula (I) in wllich Y is a thiophenc group c.ln be prepared by trcatment o~` a compound ot` ~`ormula (,Ya) v ~
NCJI~N Z--N X--~ B
R ~;/ )=( (Xa) with 1~4--lithi~ne-2.5-diol~Walser~ A. et al. J Het Chem.. 28, 1 l~ l( l99 l)~.

Compounds of formula (I) can also be prep:~red from other compounds of formula (I).
The following constitute e.Yamples of such intercon-~ersions.

Compounds of formula (I) in vhich Z is C~ galkylene can be prepared by reduction of a compound of formula (I) in which Z is C~ galken~lene or C~ galkynylene. Reduction c~n be achieved b,v catalvtic hydrogenation with h~dro~en in the presence of a suitable catalyst such as palladium. platinum. nickel. rhodium etc. in an appropriate solvent such as ethanol. tetrahvdrofuran. methanol. ether. ethyl ~cctatc. benzene. toluene. hc.Yane etc.
The reaction can bc carried out at atmospheric or elevated pressure and at room or elevated temperatures such as ~0 to 100 ~C'. Partial reduction ot` an acctylenc (-C-C-) to the aliiylene (-C=C-) can bc accomplished bv reduction using a poisoned catalyst such as Lindlar cat~l,vst.

Compounds of forrnula ~I) which are optionallv substituted bv one or morc hydroYy can be prcpared from thc corresponding mctho:;v derivatives b~r known methods [For c.Yample. bv treatment ~vilh a I,e-vis acid such as boron tribromidc or aluminium trichloridc in a sol-~cnt such as dichlormethane at room temperature lMcomie. J.F.W.
~nd West. D.E. ()rg ~nth. ('oll Voi V, ~,1'(197~).. Lillard. R.D. _al.. J.Me(l Chem 76S-~ 77S( I 99 1 ) 1 l~ro 94/18196 _ 21 5 S 7 5 8 PCT/GB94/00265 Compounds ot` tormula (I) which are optionall- substituted by one or more N(R~ or \iRN(R-)~ can be prepared bv hydrolvsis ot` thc corresponding alko.Yycarbon-lamino dcrivatives b~ l;nown methods~ f`or e,Yample. hv Ireatment ol` a (tert-buto~c,vcarbonyl)-amino derivative witll an acid such as trifluroacetic acid. and a t-butvl cation sca~en~er suchas anisole or tiliophenoI in a ~olvent such as chl.orQl`o~L,at, .
room temperature ~Lundt. B.~. Int. J PreT~t. I'rotein Res. 1~, ~58(1978)1.

(~ompounds of t`ormula (l) which are optionally substituted bv one or more l\iH~ can also be prepared by reduction of the correspondin~ nitro derivatives bv known methods.
~For e:cample bv catalvtic hydrogenation with hvdro~en vith a catalvst~ e,g., platinum, palladium. ranev nickel~Q~. ~h., ~9, 1 16( 1969), J.i\~led.Chem., 16, I0~3(I973);
J.Org.Chem., 38, 60(1973)1 Compounds of t`orrnula (I) which are optionall,v substituted by one or more -NR2(C=O)R~)a. -NR2CO ~R2a or -NR2(C=O)CH(NR2a)2R~b can be prepared by acet,vl~tion of the corresponding arnino derivatives by known methods. [For example t-y treatment with an acid chloride such as acetyl chloride or ethyl chloroformate and an organic base such as triethvlamine in a solvent such as dichloromethanel.

Compounds of formula (I) where R is Cl-6 ~Ikvl can be preparcd b~ alkvlalion of the correspondin~ secondary amide bv l;nown methods(for e.Yample. b- treatment ~ith a base such as sodium hvdride in a suitable solvent such as dimethylt'ormamide. I'ollo-ved b- trcatment ~vith an ~ latit1~, aocnt such as meth,vl iodide).

Compounds ot tormula (I) where V rcprcscnts sulphur. can be prepared by treatmen~ ot`
compounds of formula (I~ vhere V rcpresents o~ en. with a sulfonatin~ rea~ent such as Lawesson's rea~ent ~2. l-bis(~-metho:~vphenvl)-l.~-dithia-2.~-diphosphetane-7.~-disulfidel in a solvent such as toluene at an ele- ated temperature.
~.Synthesis, 9~1 (1979): Tetrahedron, '~, 2~ ¢1979).

(~ompounds ot` tormula (I) wllich arc optionall- substituted b! one or~ more ~'IIN=C'(R~)~ can be prepared t'rom the correspondin~ h-dra~ine derivatives all(i the applu~l;ate lietone~ b- I;nown mt:tllods.

WO 94/18196 ' ' PCT/GB94/00265 _~
2~,ssrl 5 ~

(`ompounds of fommula (I) where the nitrooen is o~cidized to the N-oYide can be prepared bv oYidation of compounds ot' t'ormula (I) with an o,Yidizin~T rea~ent such as m-chloropero~;vbenzoic acid in an appropriate solvent such as clichloromelhane.
,~
Compounds of fommula (11) are either ~no- -n compounds or can be prepared b~v standard methods linown in the art. ,~ ' Compounds of forrnula (IIl) can be prepared bv al~,vlation oi` ~ compound of formula (VI) with a compound of fommula (XI) L Z L (~r) where L is a le~ving group such as for e,Yample a halogen such as bromine ehlorine or iodine. an all;yl or an arvlsulfonvlo,Yy sueh as methanesulfonyloYv or p-toluenesulfonylo~y.

In some cases, for exarnple when both L ~roups are halo~en and Z is Rl~. partieul~rly (CH )4~ the same reaetion can lead to the compound of fomnula (IV) ~J.Med.Chem., ?9, 359-369 (1986)].

Compounds of fommula (V) can be prepared by al~;ylation of the appropriate compound ot` t`ormula (Il) with a compound ot` formula (~ ltemativelv the compound ot l'ormula (V) can be prepared bv conversion of the hydro.Y,vl ~roup in a compound of forrllula l Xll) Y N 7 OH ( ~II) into a lea-in~T croup. L as hereinbct'ore defined. by ~;nown metllods. 'I`he compound ot' lormula (XII! can in tum be prepared h,v condensation ol`a eompound of t'ormula (l~) ~,ith ;In aminc) aleohol ot` formula (Xlll) ~VO 94/18196 215 5 7 5 ~ pcTlGs94loo265 H2~ z ~H
(~

or bv treatment of a compound of formula (II) with a compound of forrnula L-Z-OH.
1-hc process can be carried out eithcr at room tempcrature or at elevated temperature such as 60 C to 140 C Suitable solvents includc N.N-dimethvlforrnamide.
acetonitrile. benzene. toluene. ~cvlene etc. and applupliatc bases can be chosen from or~anic bases such ~s triethvl amine. pvridine ctc.. alkali metal carbonates or bicarbonates such as sodium carbonate~ potassium carbonate, sodium bic~rbonate.
potassium bicarbonate etc . or alkali metal hvdrides such as sodium hydride. potassium hvdride etc.

Compounds of forrnula (VI) are either known compounds or can be prepared by knowmethods. for e:~arnple:

when X=N.A=NandB=S:
Yevich et al, J. Med. Chem., _9, 359-69 (1986)~
US 4,590.196;

whenX=C.A=NandB=S:
US ~.5~8.~9~:

vhen X = ~1. A = I\~ ~nd B = O:
J Med Chcm.. ~9, 3~9-69 (1986):

vhenX=C.A=NandB=O:
.1. Med Chcm.. '~, 761-69 (198~):

when X = N. A = N and B = SO~:
J Med. C'llem., 3~, 3316-33~8(1991). Alternativelv this intermediate can be prepared b~ the trcatmcnt ot 3-chlorobcnzisothiazole-1.1-dio~;ide (Eur. P~t. Appl.
O 196()96) with piperazine in a solvent such as toluene at elevated temperaturessuch~s I~ 16()~C;

WO 94/18196 pcTlGs94loo26 2~SSrls~ ~0 ~hcnX=N.A=N~ndB=S(O):
.1. Med. Chem. 3~ ,3 16-33~8(1991 ):

when~=C.A=CandB=NR5:
~JS 4~,, 5 1 27 US 4~7 1 0~500:

whenX=N.A=CandB=S:
can be prepared ~ccording to th~ following reaction schemc; by heating applo~.,ately substituted aminobenzo[b]thiophenes with piperazine in a solvent such as l-methyl-2-pyrrolidinone. The requisite aminobenzo[b]thiophenes can be prepared by Ire~tment of appropriately substituted ~-~luorobenzonitrile with the~nion of methyl thioglycolate followed by dec~bolllethoxylation of the resultingbenzo[b]thiophene;

Rl ~CN Rl ~C02M~

~N~

p~; ~ R

whenX=C~A=CandB=S:
I;R 2~5~519:

whenX=N~A=NandB=NR5:
IJS ~.957~916:

whenX=C~.~=NandB=NR':

~0 94/18196 21 5 5 PCT/GB94/00265 can bc preparcd bv deprotcction ot N-protected piperinylindazolcs obtained from the re.-ction ol` ;m appropriately substituted ~-( 7-~luoroaroyl )piperidine [J.~led Chem., ~8, 761.(1985)] with a hydr~zine in a reflu:cin(T solvent such asn-butanol accordino to the followin~ scheme:

N--R~

whenX=C~A=CandB=SO~:
JP 037645~3 A~;

when X = C~ A = C and B = NR5:
DE ~500898 Al.

Compounds of forrnula ~VII) can be prcpared by alkylation of piperazine with a compound of formula (V).

Compounds of` t`ormula (VIII) ~re either ~;nown compounds or can be prepared b-known methods~ t`or e:~ample:

~vhenLisCl.A=NandB=S:
[JS~590 196:

wl1el1 L is Ch !'~ - N alld B = ():

WO 94/18196 ; PCT/GB94/00265 215~758 - 22 -J. I; ~ed. Chem.. 'q, "9 ( l 9~o`):

wnen~ sCl ~=~'andB=S3~:
~? 019~096 .~

Compcunds of forinuia (I.~) or ~I~Ya) ~re -ither,k~io-~-n compounds or can be prep.~red bv kno~n methods.

For e.Y mple compounds ot` formula ('l~a') can be prepared bv the Irea~ment of the appropnale ~-amino-subslituled acids vith phosaene or a phosgene subslilute (e.~.
trichloromethyl chloroformate) in an appropriàte solvent such as benzene or dio.Yane [J.He~.C'nem. 1', ~6~(197~); J..~mer.C~.em.Soc., 7~, ~S~7.(1950): J.Or~,Chem. 11, ~070fl976!]. The compounds of formul~ ;a) vhere 'v' represents o.Yv~en can also be prepared bv treatment o~ the approprialel,v substituted ~nhydrides of forrnula (~L~? vith azido~rimelhylsilane in an appropriate solvent such as chloroform. The correspondin~
thio derivalives of the formula (I~a) where V represems sulphur c~n be prepared by treatmem of the correspondinc~ o~o derivalive with phosphorus pentasulfide in rerluYing ~cylenes.

(Y) y ('~

Compounds of formula (~') wherein R=H can be ob~ained by cl-avat7e of the corrcspondino phth~limides of r`orrnuia (~-b!

j~ N _--N X--o R~

~VO 94/18196 21 5 5 7 ~ 8 PC T/GB94/00265 w,ith hvdrazine hydratc in methanol. Compounds of formula (Xb) can be prepared b~
hc alkvlation of compounds of formula (Vl) with compounds of forrnula (XX) ~ (XX) wherein Z and L are as defined hereinbefore.

Compounds of formula (XX) are either commercially available or can be prepared by the alkylation of phth~limide with a compound of formula (Xl).

Compounds of formula (X) wherein R=Cl-6 all;vl can be prepared trom compounds otformula (Xc) N Z N X _~ B
P~ /
6~ (XC' wherein P is a protectin(~ (~roup. for e:~ample tri~luoroacetate. b- removal ot` thc protcctin(T oroup b- I;nown metho(ls. Ior e:cample aqucous potassium carbonale WO 94/I8Ig6 ,, PCT/GB94/00265 ~15S~ S ~
Compounds of t`orrnula (Xc) ~vherein R=C I f, all;~ 1 can be prcparcd t`rom compounds of l'orrnula iX). wherein l~ I. by protection of the amino ~roup. I`or e~;ample as the tritluoroacetamide. followed by alkvlation of the resultin~ protected amine with a CI-6 alliyl halide~ for e,Y~mple methyliodide.

Compo~mds of formula (Xa) can be prepared~by couplin~ compounds of formula(X) ~vith cvanoacetic acid in the presense of ~a suitable coupling rEa~7ent such as 1.3-dicvcloheYvlcarbodiimide(DCC) in an appropriate solvent such as N.N'-dimethvlformarnide BIOI,OGICAE DATA

A. ~nti7,~svchotic Antagonism of apomorphine (Smg/kg s.c.) - in~luce~i climbin~-7 in the mouse is a measure of dopamine receptor anta~onism in the mesolimbic brain region and in turn reflects potential antipsychotic activity.

Compounds were ~lmini~tered orally to the mice I hour prior to scoring.
3-Amino-N-(4-(4-( 1 .~-benzisothiazol-3-yl)- 1 -piperazinyl)butyl-~-pvridinec~rbo~camide (E:;ample S) anta~onised apomorphine-induced climbin~ in the mouse at an EDso = 5 7 m~7/k~. p.o and 3-Amino-I~1-(4-(4-( 1~- benzisothiazol-3-yl)- 1 -piperazinyl!butyl)-~-thiophenecarbo:Yamide(E~ample 8) at an EDso=9 7m~7/Li~ p.o. ~Costall. B.. Navlor. R.J.and Nohria. V. Climbin~ behaviour induced bv apomorphine in mice: ~ potential model for the detection ot' neuroleptic activity~ European Joumal of 1'harmacolo~y, 50, 39-50( 1 97~)]

Pharmaceuti cal Composi tions The followin~ e~camples illustrate thc preparation ot~pharmaceutical compositions in which the active in~redient is a compound of formula (1~ or a physiolo~7icallv acceptable s,alt or solvate thereo~; for c:~ample thc compound 3-Amino-i\~ benziso~hiazol-3-,vl)- 1 -piperazin,vl)but~ 1-'7-pvridinecarbo~amide.
'rhesc e,~ mplcs arc not to hc construed as limitin(7 ~hc invention.

~WO 94/18196 21 5 5 7 ~ ~ PCT/GB94/00265 ~5 -.~. T:lblets .~ctive in_redient I ~Omg Lactose ', ~OOm I\!laize Starch ~Om_) Polvvinvlpyrrolidone ~ ~mg) ~lagnesium Stearate ~mg) ) = contents per tablet.

The active ingredient is mixed with the lactose and starch and gr,tntlktted with a solution of the polvvinylpyrrolidonc in water. The resultant granules are dried~mixed with magnesium stearate and compressed to give tablets, B. Injections Injection I

Thc salt of a compound according to the invention is dissolved in sterile water for injection.

Intravenous injection composition 11 ~ctive in(Tredient O.'Og Sterile. p,vrogen-free phosphate buf~`er (pH9.0) to I Oml The activc ingredient as a salt is dissolved in most o~` the phosphate bu~`er at0 C~ then made up to volume and filtcred through a sterile micropore i`ilter into sterile lOml glass Vi,lls (TVpC 1) which are sealed ~,vith sterile closures and ov erseals.
C. (`apsule compositions ,, ", ~`aps~lle C`ompositi-)n I

2 i5 5 ~ PCTIGB94/00265 - ~6 -Composition I can be prepared bv admixina the ingredients and fillin_ Iwo-part hard ~elatin capsules ~ ilh the resulting mi.Yture.

'mg/capsule .
(2) ACtiVC in~7rcdient~50 (b) Lactose B.P. 143 (c) Sodium Starch Glvcollatc ~5 (d) ~\ilagnesium Stearale ~0 Capsule Composition 11 mg/capsule (a) Active Ingredient ''50 (b) ~vlacrogel 4000 Bl' 350 Capsules can be prepared by melting the Macrogel ~000 BP, dispersing the active ingredient in the melt~ and filling two-part hard gelatin capsules therewith.

Capsule C,omposition 111 (Controlled release capsule) m~7icapsule (~) Active Ingredient ~50 ~b) ~licrocr~stallinc Cellulosc1'?5 (c) Lactose Bp 1~s (d) Eth,vl Cellulose 1'~
~13 The controllcd-rclease capsulc composition can be prcpared by cxtruding mixed inaredicnts (a) to (c) using an eYtruder. then spheronisin~7 and drving thc c.Ytrudatc. Tllc dried pellcts arc coated ~ ith cthvl ccllulose (cl~ as a controllcd-rcleasc membrane and t'illcd into t~vo-part hard ~elatin capsulcs.

~WO 94/18196 _ 2 I S 5 7 5 ~ PCT/GB94/00265 -- _7 --n ~;~ r~ comrosition ~ctive ingredient () '5000 ~orbitol Solution 1 50000 Glvcerol l OOOOg ~odium~enzoate () 0050~, Flavour O O l ~5ml Purified Water q s to 5 Oml The sodiurn benzoate is dissolved in a portion of the purified water and the sorbitol solution added The aetive inoredient is added and dissolved The resulting solution is miYed with the glyeerol and then made up to the required volurne with the purified water E. SLI~POSjtOrV eomposition mo/suvpositorv Active in~Tredient (63ml) * 50 Hard Fat~ BP
(Witepsol H15 - Dynamit Nobel) l 770 ~0~0 * The active in~redient is usel as a po-vder ~-herein at least 90% of the particles are ot 63mm di~meter or less One fit-th ot the Witepsol l-I15 is meleted in a steamjacl;eted pan at ~5 C
maYimum The active inredient is sifted through a ~OOmm sie-~e and added to the molten base with miYing, usin(g a ~ilverson fitted vith a cutting head until a smooth dispersion is achieved Maintainin ~ the mi~ ture at ~5 ~C~ the rem ining ~hitepsol H15 is added to the suspension ~vhieh is stirred to ensure a homogenous miY 1 he entire suspension is then passed throu~h a ~50mm stainless steel screenalld -ith continuous stirring allowe(l to cool to ~ C ~t a temperature of '~-10 C ~ uots ot`the mi ;ture are t`illed into suitable plastic moulds and ~hc supposit-)rics allowed to cool to room temperaturc WO 94/18196 -. ~ PCT/GB94/00265 ~
215~7 ~ 8 ~

~. Transdermal ('ompositinn C ompositions suitablc for transdermal :-rlministration can be presented as discrete patchcs adapted to remain in intimate contact with thc epidermis of the recipient for a prolon~ed period of time. Such patches suitablv c'Ontain the active compound I ) in an optionallv buffered. aqueous solution or ~ ) dissolved in an adhesive or 3) dispersed in a polvmer. .~ suitable concentration of the active compound is about I % to '0%.
preferablv about 3% to 15%. As one particular possibility. the active compound must be delivered from the patch bv iontophoresis as (Jenerallv described in Pharmaceutical Research. (6), 318(1986).

The invention is further illustrated b~ the following E,xamples which are not to be construed as limiting thereofi E.xperimental Section C`,eneral Unless other vise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as dimethyl formamide (D~IF).
tctrahvdrotùran (THF). dichlorometh~ne. toluene. pyridine, and dimethyl sulfo~ide (D~fSO) ~ere obtained from Aldrich Chemic~l Company in surc scal bottles.
Triethvlamine was distilled t`rom calcium h~dride prior to use. All reactions involving air- or moisture-sensitive compounds ~vere perforrned under a nitronen atmosphere.
I:lash chromatoEraphy [Still, W. C. etal. J.Or(nChem..~3, '~9'~3(1978)] and Flush chromatographv ~ere pcr~ormcd using EM Science silica gel 60 (~30-~0() mesh .~ST~1). Thin-layer chromatonraphv (TLC) was performed with Analtech silica _el FG
l LC plates ( ~50 mm). I H NMR and 1 3C NMR were determined with superconducting, ~T NMR spectrometers operatins~ at ~00. 300, and 500 ;~ z. Chemic~l shifts are e.xprcssed in ppm downficld from internal trimethvlsilane. Si~nificant IH NMR data arc reported in order: multiplicit~ (s, singlet; d doublct: t, triplet: q. quartet: m, multiplet). numbcr of protons. and couplin~ constants in Hz. Elemental analvses ~vere rerforrned b- either /~tl~ntic i\~licrolab. Inc.. Norcross Geors~ia~ or Galbraith l.al~oratories. Inc.. I~noxville. Tennessee. Mcltin~ points ~vere determined ith a lllonlas Hoover capillarv mcltins~ poin~ apparatus`and arc uncorrectcd. The piperazinc ~WO 94/18196 215 5 7 S 8 PCT/GB94/00265 ~9 ~ ~ -benzisothiazole interrncdiate. .-(1 -piperazin~ l )- I .~-benzisothiazole was prcparcd accordin_ to ~;nown procedurcs~Yevich. J.P. et :11. J.~led.Chcm.~ ~9, 359-369(1986)1.

E~;amples ~-~ample I

(;l) Pre~aration of ~-(4-(4-(1.2-benzisothiazol-3-vl)-l-piperazinvl)butvl) phthalimide hv drochl~ridc.
N-(4-Bromobutyl)phth~limide (3.50 g~ 0.0124 mol), 3-(1-piperazinyl)-1.2-benzisothiazole (2.7~ ~, 0.0124 mol. 1.0 eq), triethvlamine (2.24 mL. 0.0161 mol.
I .3 eq ) and acetonitrile ( I ~.0 mL) were added to a 100-mL. round-bottomed flask. The cloudv oMnge solution was heated under N7 at re~lux for 17h. The mixture was allowed to cool to room temperature ~nd diluted with dichloromethane. The or~Tanic solution was washed with saturated K ~CO ,. dried over M~SO4, filtered. and concentrated to ~ive 5.48 g of a li~ht oran~Te solid. This crude material was recrvstallized from acetonitrile and dried in a vacuum oven to give 4.35_ o~ a tan powder. The hydrochloride salt was prepared bv the addition of lN HCI in ether md recrvstallized from 95% ethanol to give 4.53 C! (82%) of thc title compound as an off-white powder. mp: 258-260 C (dec). I H NMR (DMSO-d6): ~ 1.72 (m, 4), 3.~0 (m.
~). 3.54 (m, 6). 4.02 (brd. ''. J = 13.7). 7.44 (ddd. 1. J = 8.1, 7Ø 1.1). 7.57 (ddd~ 1. J =
.1. 7Ø 1.0), 7.85 (m. ~). 8.09 (dd. 2. J = 8Ø 4.5). 11.18 (br s, I ). 13C NMR (Dl\~ISO-16)~ 0.5~'. ~ 5. 36.8~. 46.30. 50.~. 5~.98. 1 ~ 1.1 ~. 1 '~''.98. 1 ')~ .94. 1 ~.56. 1 ~6.90.
1 ~.06. 1 ~ 1.58. 13~.33. 15~.0~. 16~.16. 167.93.

Anal. Calcd for C-~3~ N4O~S I~CI: C. 60.4~; H. 5.51: N. 12.76. Found: C. 60.46:
H. ~.55: N. 12.17.

(h) Preparation of .-(~-(4-aminobutvl)- 1 -piperazinvl )- H2-hcn7.isothiazole Hvdrazine hvdratc (~ldrich Chcmical Compan~.85%)(2.6'' ~. 1.5 eq) ~as added to asolution of 2-(~-(4-(1.2-bcnzisothiazol-3-vl)-1-pipera_inyl)but~l)phthalimide (1'.46~,.
0.0'796 mol) in methanol (30.0 mL). I hc rcactioll mixture vas heatcd at reflux f~r 3.5 h and allo-ved to cool to room tcmperaturc. IN HCI (59.() mL,) ~vas added to the solution and thc resultin~ hitc prccipitant as filtercd and ~ashe(l witll water. rhe filtratc ~vas m.ldc basic b~ thc additioll o~` ~0/O NaOH .md extractccl ~vi~ll dichloromethan~:. l'hc' WO 94/18196 , PCT/Gs94/00265 215S~S~

or( anic l~,ver ~s dricd o~er .M ~ , I`iltered. ;3nd conccntr~ted witll ~ rot~r~ c~porator to ~i~e 8.1 ~ (9~%) of the titl~ compound as an oran~Jè-brown oil. I H NMR (CDCI ):
~1 1.38 (br s. 2). 1.55 (m. ~). 2.~5 (t. ~. J = 7.~ .6~ (t. 4. J = 5.()). ~.74 (t. 2, J = 6.8)t ..57 (l~ 4~ J = 5.0)~ 7.35 (ddd. 1 .J = 1.1 7Ø 8.1)~ 7 ~Ç (ddd~ 1, J = 1.1. 7.0, S.l), 7.81 d~ I J = 8.1)~ 7.91 (d, I . J = 8.' ). 11~is cry4s ~mine ~v~s uscd without tùrther ~urificalion.

(~ ) I'reparation o~ -(4-(4-( l .~-hen7,isothiazol-3-~, l )- 1 -r)ipera7.invl)hutvl)-3-pvridinecarbo:Y~mide hydrochloride Nicotinoyl chloride hydrochloride (Aldrich Chemical Company) (1.1 g, 6.1 mmol) was added portion-wise to an ice-cold. stirred solution ot 3-~-(4-aminobutyl)-1-piperazinvl)-l.~-benzisothiazole (1.8 ~. 6.0 mmol) and triethylamin~ 5 mL. 17.9mmol. 3.0 eq) in dichloromethane (~5~0 mL). The resultinc suspension was allow~d to stir at 0 C for 0.5 h and at room temperature for 2 h. The cloudy reaction mi~;ture was diluted with dichlorom~th:-ne (~5~0 mL) and washed with satur,~ted NaHCO3 (' X 50 mL)~ The ornanic layer was separ~ted, dried over Na7SO4. filtered~ and concentrated with a rolarv e~aporator to give an oft:white foam~ The crude material was dissol~ed in isoprop~nol (20~0 mL). chilled with an ice water bath and treated dropwise with HCI
(6.0 ml of a IN solution in ether) with swirling. The mi~cture was diluted with ether (~0.0 mL) and the resultin~ ot~:white solid ~as filtered and vashed with ether ( ~ 10 mL). The salt W,lS rccr,vst~llized trom 95~O ~thanol to civc 1.47 (57%) ot the ~itle compound as olt:wllite crystals. mp: '29-231 C. 1 H NMR (Dl\~SO-(16): ~ 1.64 (m~
81 (m. 2)~ 3.'7 (m~ 3.47 (m~ 3~6~ (br d~ ~ J = 11.5)~ ~.10 (br d~ '~ J = 13~ 1), 7.56 (m~ 7.6~ (t~ 1~ J = 7.6)~ 8.14 (t~ '~ J = 6.8)~ g.'3 (d~ 1~ J = 6.')~ 8.73 (d~ 1~ J =
.5)~ 8.81 (br t~ 1. J = 6.')~ 9.05 (s~ 10.8~ (br s~ 1). 13C NMR (DMSO-d6): (S ' 1.76 '7.33~ 39.58~ ~7.53~ 51.61~ 56.~5~ 35~ 1 '4.57~ 1'5.16~ 1'5~7~ 1'8.11~ 1~9~'8~
131~1û 136.15 1~9.55~ 15~.88~ 153.~6~ 163.39~ 165.9'. Mass spec (CT/CH~ 50 mA/sec)~ m/7.: ~1 ~ I (396).

An~l. C~lc(l for ~ 125NsOS HCI: ~`~ 58.39: H 6.07: N 16.'1: S~ 7.4~: Cl~
I`ound: C~ 58.~7: H~ 6.1 ~: N~ 16.1~: X~ 7.~9: Cl~ 8.1~.

r~ pl~

~WO 94/18196 215 5 7 ~ 8 PCT/GB94/00265 - 31 - = ~ =

rep,arl[ion of \i-(~-!4-~ hcnzisothia7OI-3-Yl)-l-piperazin~l)hut~l)-~-p~ridinecarhoYamide h~drnchloride This compound ~ as prep~red~ accordin~ to the method described in E.Yample (Ifc)), bv emplovin(J isonicolinovl chloride hvdrochloride (Aldrich Chcmin,~l CQmp,~v). ~L~6 1 mmol). 3-(~ aminobutvl)- 1 -piperazinvl)- I .~-benzisothiazole (E.Yarnple I (b)) (1 8 ~. 6.0 mmol) tmd triethvl~mine (~.5 mL. 17 9 mrnol. 3.0 eq) in dichloromethane (~5.0 mL). The crude h~drochloride s tlt ~,as recrystallized from 95% EtOH to ~ive 1.20 g (~6%! of the title compound as off-white crvstals. mp: ~3g-240 C. IH NMR
(D~ISO-d6): o 1.6~ (m. ~). l.g0 (m, ~). 3.~9 (m. 4), 3.46 (m. '), 3.61 (br d. ~. J = 10.5), ~.10(brd.2.J= 10.5),7.19(t. 1.J=76),7.6~ J=76)~7.8o(d ~J=5.g!~g.ls - (t, 2. J = 6.7), ~.75 (d, 2. J = 5.8), 8.90 (br t, 1. J = S.S), lO.gO (br s. 1). 13C N~v~R
(DMSO-d6): S ~1.76. ~7.~4. 39.68. ~7.53, 51.61. 56.2~ 6. 1~2.~5, 125.17, 1~5.7g, 12~.11. 1'~9.~8, 1~.56, 151.30. 153.26. IG3.39, 165.7~. A~lass spec (CI/CH4.
50 rn~sec), miz: ~1 + I (396).

Anal. Calcd for C~IH~5N50S ~ICI: C, 55.39: H. 6.07: N, 16.71: S. 7.4~: Cl, 8.'71.
Found: C, 58. i7; H. 6.11: N. 16.12; S. 7.38; Cl. g.lS.

E~; tmple (a) Preplratioll o~ -hcn7is0thia701-~-~l)-l-r-iperl7invl)hut~
r~! ridinecarhoYamidc h~ drochloride Picolinic acid (1.~ (7. 9 7 mmol! (Aldrich Ch~mical Compan~ ) and potassium h~dro~;ide (0.56 o. 10.0 mmol) ~ere dissolvcd in distilled ~ater (~.0 rmL) The ~vater ~as removed ~vith a rot.~r e~,aporator and thc rcsultin ~ ~vhite solid rcsidue ~v~s treated ~vith benzenc (~5.0 mL). The solution was concentrated and dricd undcr hi~h vacuum. The rcsLIltill~ potassiunl salt ~v;lS suspcnded in bcnzene (15 0 mL) and coolcd in ~n icc ~vatcr bath. O.Y IIVI chloride (1.0 mL. I l ~ mmol) ~aS addcd drop~isc to this co~led solution Tlle reaction miYture ~as allo~ed to ~ lrm to ro( m tcmper;lturc alld oraduall~ to ~v,~rm to a ~entle retl~; Tllc rcsultino ~ inc-red hlacl; solution ~as cooled and addeddlop~visc IO a cooll~-i solLIti(ln (icc ~tcr bath) ol .-(~ -aminobut~l)-l-piperazin!,l)-1.2-bcll~isotlli;l7Olc ~ mplc I(l )) ( ~ () (n I() U nllnol). .Ind tricth~lamillc (~.~ mL. 17 9 WO 94/18196 PCT/Gs94/00265 ~
2~S5~ 5~ - }~

mmol)~ in dichloromethane (10.0 mL). The reaction mixture was allowed to warrn to room temperature and stir overni~ht. Thc dark suspension vas concentrated with a rotar- evaporator to give a black oil. The residue~ as dissolved in dichloromethane and ~ashed with saturated NaHCO ,. I lle organics ~ere dried over Na~O4~ filtercd~ and concentrated in vacuo to give S.01 ~ ot a aark oil. The crude material was purified by ehrom~tocraphy on flash silica gcl vith a gradient eluant chlorotorm (100%)/chloroform-acetone-methanol (28:~: 1)/chloroform-acetone-methanol ( I ~:2: 1) to give 1.80 g of the free amine. The product was taken up in dichloromethane. treated ~ ith HCI (4.6 mL of a IN solution in ether) and diluted with ethyl acetate. A dark colored precipitate was filtered from the solution and the filtrate was allowed to stand t`or three davs. The crystals that formed upon standing were filtered and dried to give 1.15 ~J (27%) of the title compound as off-white crvstals. mp: 231-234 C. I H ~MR
(D~SO-d6): ~ 1.61 (m, ~), 1.76 (m. ~). 3.18-3.38 (m~ 8), 3.57 (m, 2), l.10 (m. ~). 7.~7 (tm. 1. J = 7.6), 7.61 (m, 2), 8.0'7 (m. ~). 8.12 (t, ~. J = 8.1), 8.65 (dt, 1, J = ~.7~ 1.7), 8.92 (t, 1, J = 6.2), 10.30 (br s~ 1). 13C NMR (DMSO-d6): ~ 21.79, 27.54, 39.31.~7.51. 51.61~ 56.32, 1'~-7.36, 1~3.0''. 1~5.15~ 125.78~ 127.61, 128.10. 179.78. 138.94~
149.50, 151.16~ 153.24~ 163.37~ 165.04. Mass spec (CI/CH4 S0 mA/sec)~ m/z: M +
I/base (396).

Anal. Calcd for C~lH25NsOS HCI: C~ 58.39; H~ 6.07, N, 16.')1; S, 7.42; Cl, 8.21.
Found: C, 58.10; H, 6.10; N, 16.04: S. 7.39: Cl, 8.09.

F-.Yamples ~ and S

(a) Prep~ration of 3-~7~is~toic anhvdride ~nd 6-a.7aisatoic anhydride mixture of 3- and 6-~7~ic~tQic anhydride was obtained from ~.3-pvridinedic~rboxylic anhydride (Aldrich Chemical Company) (11.~ c. 76 mmol)~
azido~rimethvlsilane (Aldrich Chemical Company) (11.~ mL. 86 mmol. 1.1 eq). and chlorot`orm (S0.0 mL) accordin_ to the method described bv D. J. Le Court and D. J.
I)ewsbury~ ~iynthesis~ I l. 97~(198~). The precipitant oblained trom the reac~ion mi:~ture was filtered and dried to gi-~e 6.10 g (~S%) of a ):1 mi.~;ture of the title compounds as a ~,hite solid. mp: ~07-~10 C (dec). 11~ NMR data for the 6-isomer(minor) are given in square braci;cls~ JMR (I)~fSO-d6): ~ 7.~9 fdd. I. J
= ~.'). 7.S). ~7.5~ (dd~ l~ J = 1.~ 5~.6)1~ [7.69 (dd. R J = ~.S. 8.6)1. 8.~9 (dd. 1~ J = I.S.

7.8')~ ~gH9 (dd. I. J = 1.-. 4.5)]~ 8.64 (-Id. I. J = 1.8. 4.9). ~11.53 (br s~ 3 I'br s~

(h) Preparation o~' 2-amino-.~V-(4-(~-( I .~-hcnzisothia7.01-'-vl )- I -piperazin~ l')hu~ 1)-3-pvridinecarbo~amide hvdrochloride and 3-amino-~V-(4-(4-(1.2-benzisothiazol-3-~rl)-1 -piperazinvl jbutvl)-~-pvridinecarbo~mide hvdrochloride A 2:1 mi.Yture o~'3-azaisatoic anhvdride and 6-a7~ toic anhydride (~ . 6.1 mmol) was added to a stirred solution ol' ~-(4-(4-aminobutyl)-1-piperazin~1)-1,2-benzisothiazole (E.Yample l(b)) (1.8 ~, 6.0 mmol) in tetrahydro~uran (~0.0 mL). The reaction mi:cture was allowed to stir under nitrogen at room temperature for 0.5 h. The sol~enl ~as removed with a rotar~ e-~aporator. ~nd the resulting crude residue was purified by chromatography on flash silica gel with a gradient eluant: dichlorome~hane (100%!/dichloromethane-methanol (98.5: I .S)/dichloromethane-methanol (97:3)/dichloromethane:methanol (93:7) to aive 1.48 g (91%) of ~-amino-N-(~-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-pyridinecarboxamide as a foam and 0.54 g (66%) of 3-amino-N-(4-(4-(1,'7-benzisothiæol-3-yl)- 1 -piperæinyl)butyl!-2-pyridinecarboxamide as a foam. The hydrochloride salts of each isomer were prepared independently by dissolving the t'ree amine in dichloromethane (20.0 mL)~ filterino, and treating the filtrate with HCI (I equi~. o~ a IN solution in ether). The solutions vere diluted with ethvl acetate and allo-ved to stir at room temperature for I h. The resultin~
white cr--stals were collected by filtration and dried in a vacuum oven to~ e the corresponding hydrochloride salts.

E.~mple ~: 2-Amino-/V-(4-(4-(1,~-benzisothiazol-3-vl)- 1 -piperazinv l )but~ 1)-3-pyridinec~rbo~amidc h-drochloridc. TLC: silic~ ~cl. methanol/chloro~orrn 1:9 (R~ =
0.25). mp: 2~0-222 ~C. IH NMR (DMSO-d6): (~ 1.59 (m~ 2), 1.75 (m. 2). 3.~' (m, 8),3.57(m,2),4.0X(m.2).6.60(dd. I.J=4.8.7.7)~7.10(s,2)7.47(t, 1,J=7.6).7.60 (t, I . J = 7.5)~ 7.93 (dd. I . J = 0.8. 7.6). 8.07 (dd, 1. J = 1.3, 4.7). 8.1~ (t, ~, J = 8.0). 8.54 (br t. I . J = 5.5). 10.55 (br s. 1). 13C NMR (DMS()-d~ 0.84, ~6.30. 38.45. 46.6'.
~0.71. ~5.38. 110.97. 111.59, 1 ~ 1.51. 1 ~.3~ .9~ 7.~ 8.~5, 138.10. 1 ~9.18.
152.47. 1~8.05. 16~.58. 167.33. Mass spec ICl/C'H~. 50 mt~lscc), mlz: M + I (411).

.~n~l. C'alcd tor ~ 6N(,()~ ~ HC`I: ~`. 56.43; Il. ().()9: N. 18.8(): S~ 7.17: ~`1. 7.93.
~ und: C. 56.3(): ~1. 6.14: N~ 18.75: ~. 7.1'): Cl. 8.()',.

WO 94/18196 PCTIGs94/00265 ~ s~ 4 ~ ;ample ~ Amino-.~ -ben~iso1hiazol-~ l)-l-piperazinyl)butyl)-~-pvridinecarbo.Yamide hvdrochloride. TLC: silica (~el. methanolichlorot`orrn 1:9. (Rf=
().47). mp: ~8-~0 C. Iil NMR (DMso-d(~)~ o:l.59 (m. ') 1.74 (m, ~ .30 (m. ~).
.58 (m. 2), 4.08 (m. 2). 6.84 (br s, ~). 7.15 ('dd` 1, J = 1.~. 8.~). 7.24 (dd. 1, J = 4.~.
X.~). 7.~7 (tm. 1. J = 8.0). 7.60 (tm. 1~ J =,~0). 7.79 (dd. 1. J = 1.~ 4.~)~ 8.1'~ (t. ~. J =
8.~). 8.69 (br t. 1 J = 6.~-). 10.~0 (br s. 1). 13C NMR (DMSO-d~ 0.77. ~6.55.37.68. 46.47. 50.56. 55.'9. 1~ 7. 1~4.07. 1~4.53. 1~.70~ 1~7~0'~. 1''7~24, 128~19.
128 91. 135.49~ 146.32. 15~.17. 16 .~8, 167.56. l\/lass spec (CI/CH4. 50 mA/sec), m/z:
M + 1 ~411).

Anal. Caled for C~21H26N60S HCI: C, 56.43; H, 6.09; N, 18.80; ~, 7.17; Cl, 7.9~.
Found: C, 56.36; H, 6.12; N. 18.70; S, 7.1''; Cl, 7.85.

E~.Yamples 6 and 7 (a) Preparation of 4-~7~is~toie anhydride and 5-~z~is~toie anhydride ,~nhydrous chloroform (50.0 mL), 3.~-pyridinedicarboYylic anhydride (11.5 g, 77.1 mmol~ and .azidotrimethvlsilane (10.1 g 88.0 mmol. 1.14 eq) were added to a ''50-mL.
round-bottomed flasL~ and placed under N~. The resultin~ ereamy suspension was (~entlv warmed to iniliate the re.lction. Thc reaelion was eYotherrnic and nitroaen ~as was evoived. ~tter IU min the ~ s evolution subsided and the solution was heated at reflu,Y t`or 0.75 h. ,~s the re.action proceeded thc solids dissolved, resulting in a clear pale yellow solution. The reaction miYture was allo-ved lO cool to room temperature and ethanol (~.5 mL. 77.1 mmol. 1.0 eq) was added in one portion. Solids immediately preeipitated out of solution upon this addition. The mi.Yture was allowed to stir at room temperature 'ror 15 min and the solids vere tiltercd. washed with chloroform and dried in a vacuum oven at room temperature to (~ive 1~.6 ~ ol`a li~ht vellow powder. This material w~s stirred with aeetonitrile (1()0 mL) and the undissolved solids were tlltered.
Tlle l`iltrate was heated at rctlu~ for 0.~ h. The solution w.lS allowed tO cool tO room temperature and cooled tur~her in an iee bath the solids that t`ormed vere tlltered and the liltrale w.1S concentraled wi~h a ro~ar- evaporator lo ~ive I.~0 ~ ol`a vellow powder. ;~
secon(l crop ol produc~ as oblained hy tritur.llin(~ all ol the undissolved solids in ~ W0 94/18196 21 5 S 7 ~ ~ PCT/GB94/00265 - ~5 - `.

boilino ;Icetonilrile 11()0 m~ ) tc r l .~ h The mi.~;ture ~ as tiltered hot and the t`iltrate w,as concentr~ted to providc an addiLiollal ~ 'l ,, total) o~ the title compounds as yellow solids. The crude product ~as l:l mi.Yture oi ~- and ~-azaisatoic anh~dride as indicated bv inteor~tion ot` the correspondino si(~nals in ~he ~ IR. lH Nl~IR
(Di~IS0-d~,. 300 MHz): ô 7ØY (d. 1. J = ~.h). 7.80 (dd. I J = ~.~. 0.7). 8.~ (d. 1. J =
.8!. 8.~ (s l ). 8.66 (d, 1. J = '.6). 8.96 (s. I). 1'.08 ( br s. ~). This material was used ~,ithout filrther purification.

(h) Preparation of i-amino-\~ -(1.7-benzisothiazol-.-~l)-l-piperazinvl)hlltvl)-~-pvridineearboYamide dihvdrochloride hvdrate and ~-aminc)-.~'-(~-( l-( l .~-benzisothiazol--vl)-l-piperazinvl)butvl)-~-pyridineearboYamide dihvdroehloride A l:l mi.Yture o1 ~-~7~iC~toic anhydride and ~-~7~ic~toie anhvdride (~.71 g. 28.7 rnrnol) was added to a stirred solution of 3-(4-(-l-aminobut~,l)-l-piper~zin-1)-1,2-benzisothiazole (E.Y~mple l (b)) (~ g ~8.7 mmol. 1.0 eq) in anhydrous tetrahydrofuran ( lO mL). The reaction miYture ~-as allo~,~ed to stir under nitrogen at room temperature for l h. The solvent ~vas removed with a rotar~ evaporator. and the resulting crude residue was purified b~ chromato~raphy (~ ~c) on ~lash silica c~el: onee ~,vith 5:9~ methanol:diehloromethane and 0.1 % trieth~larnine as eluan~ and once with ~:97 methanol:diehloromethane and 0.1 % triethylamine as eluant to (Jive ~.l l g (~G /0) of ~-amino-l\i-(~ -( 1 .2-benzisothiazol- .-yl!- l -piperazinYl!butvl pvridineearbo~;amide as a tan powder (TLC: silica ~el. methanolidiehloromethane 9~
Rf = (). l l) and 2.'?9 ~ 'o) oL ~-amino-.t\l-( I-~-(l.'-benzisothiazol-,-yl)-l-piperazin~,l)butyl?-~-p-ridinecarbo:~;amide as an oran e solid (TLC: silica ~el.methanol/diehlorome~hane 95:~. Rt-= 0.~2?. The hydrochloride salts ot eacll isomer ~vere prepared indepen(len~ly by treatment with l~? ether~al HCI. T~le salts were reerystallized trom either e~l1anol/elher/EtO~c or 9~ ~0 etl1.~nvl and dried in a vacuum oven.

F.~ mple f ~ mino~ 1-( I .2-b~n7.isothia,zol-~-! l )- I -piperazin~ l )butyl)-~-pvridineearbo~;amidc dih~ droehloride hydrate. mp: 22'~-', l ~C l I l ~\l;\ IR ([)i~,lS0-d6 ,0() ~II lz)~ ( n~. ~). }, ~ (m. ~). 1 (!6 (br ~ . J = 1,.2).
7~( (t. I. .l - 7.~,). 7 5'~ (dt. l. ! = ,~ l. () .'~). ~.0~ (s. 2). ,~.l' It. 1. J = ~.l). ~..~l (s~
(hr ~ (hr ~. I ) l -(` i\.';~ll~ (I)~lS0-d~ Il-lz): ~ ~0.7.

WO 94/18196 5S~ S ~ PCTIGB94/00265 '6.0~. 3~.~7. 46.~. 50.64. 5~.'6. 1~1.5,1. 1~.32. 1''~.93. 1'6.~8. 1~6.~0 1~7.0~.
g. 1''8.~-L. 130.62. 146.83. 15~.~6~ 16'.59. 165.~3.

~nal. Calcd for C~IH~6N6o~ ~HCI ~) 3~jH~O: C, 51.~ H. 5.94: N. 17.07: Cl, 0: H~O. 1.82. Found: C. 51.02: H, 6.05. N. 16.98: Cl, 14.09; H~O, 1.~

~:~ample 7 ~-Amino-N-(4-(4~ -benzisothiazol-3-yl)- 1 -piperazinvl)butvl)-3-pvridinecarbo~camide dihydrochloride. mp: 1''')-130 C (effervesces). 1H NMR
(D~lso-d6~ 200 MHz): ô 1.6~L (m. ~) 1.79 (m. ~), 3.07 (m. ~), 3.30 (m, 8). 3.7~ (br s.
'~). 6.93 (d. 1. J = 6.6). 7.48 (t. 1, J = 7.5), 7.61 (t, 1, J = 8.7.4), 8.1'7 (m, 1). 8.~4 (br d.
~). 8.7~ (s. 1), 8.97 (br t. 1. J = 5.6), 1~.40 (br s. 1). 13C NMR (DMSO-d6. 50.~9 MHz)~ 1.1'). 26.07. 38.30. 46.95. 50.83, 5~.51, 111.05. 111.14. 1'71.'~7. 1~1.07 1'~.6~ 7.06, 128.13. 1~1.5~ .36. 15~.11. 157.68, 162.50, 165.'~.

An,~l. Calcd for C21H26N60S ~HCI: C. 5 17; H. 5.84; N, 17.38. Found: C. 5?.'75;
H. 6.17: N. 17.31.

E~ample ~

(a) Preparation nf 3-amino-lV-(4-(4-(1.'7-benzisothiazol-3-vl)-l-Diverazinyl)butvl)-~-thiophenecarbo~camide hydrochloride 3-( l-(1-Aminobut,vl)-l-piperazinyl)-l.~-benzisothiazole ('2.83 ~. 9.7~ mmol) (E~;ample l(b)) and ~nhvdrous chlorot'orm (~OmL) were added to a ~50-mL. round-bottomed flasi;. and stirred under N~. Trimethvlaluminum (~.8 mL. 19.6 mmol. '.01 eq) ~AIdrich Chemical Company, ~'.0 M in toluene) was added dropwisc and the reaction mi:Yture was stirred for 0.5 h. ~ solution of methvl-3-amino-~-Lhiophenecarboxylate (1.66 g.
10.~6 mmol, 1.08 eq) ~AIdrich Chemical Company) in anhvdrous chlorofonn ('~ mL) was added and the oran~e solution was heated at 45-50 C for 5 d. The reaction mi:;mre was slowiv added to cold I N hvdrochloric acid (100 mL). The pH ot` the mi~;turc vas adjusted to pl-l = I() with saturated ~;~C03 and thc mi:~ture was transt'erred to a separatory t'unnel. Chlorot`orm vas added to 'the separatory ~'unnel and thc lavers were separated. The or~anic layer vas washed ~ ith water (~ 00 mL). The aqueousla- crs ~vere combined an(l c.~;tracted w ith chlorotorrn. Tlle or~Janic la- crs ~vcre eoltlbined. v~shcd ~'viLh SaLUraLcd NaCI. dried over ~I~rSO~. liltcred and concentratcd to ~WO 94tl8196 _ 215 5 7 ~ ~ ` PCT/GlB94/00265 ~ivc ~ o~` the crude product as a thin iark brown-oran~e oil. 'I`he l`ree base ~ as purit`ied b~ ~lash chromato~raphv wilh dicl~loromethane followed b~ dichloromethane:
mc~hanol (9~: ~) t e,ive 1.3'' ~ ot`a tan solid. 'I~he f`ree base (1.~3 ~. '.06 mmol) ~ as dissolved in dichloromethane and I N ethe~eal HCI (3.06 mL. 1.0 eq) was added. The h~drochloride salt was recrvstallized from e~hanol / water to give 0.93 g (~1~o) ot' the title compound as a tan solid. mp: ~0-~3~ ~C. I i~ NMR (DMSO-d6): S I .5 ' (m. '),.
1.75 ~m. '). 3.')6 (rn. 6). 3.~8 (m. '~). 3.61 (br d, ~. J = 11 1!. 4.10 (br d. '7, J = 1'7.5).
6.~ (br s. 1). 6.60 (d. 1, J = 5.3), 7.40 (d. 1. J = ~.3). 7.55 (m, ~), 8.15 (br t, ~. J = 6.9).
10.51 (br s, 1). 13C NMR (DMSO-d6): .j ~1.65. '77.61, 38.86~ ~7.~0~ 51.~8. ~6.~.102.19. 1' 1.90. 1~.16. 124.97. 1'75.6'~, 1'7.9~. 128.59, 1'~9.1~, 153.06. 1~.08, 163.18. 16~.53.

Anal. Calcd for C~0~2sNsos~ HCI: C, 53.1L}; ~I. 5.80; N, 15.~9. Found: C. 53.~:
Il. 5.86: N. 15.36.

EYample 9 (a) Pre~aration of methyl 4-((tert-buto~vcarbonyl)amino)-3-thiophenecarboYylate Methvl- l-aminothiophene-3-carboxylate h~drochloride (6.57 ~. 33.9 mmol) (~la~bridge Chemical Companv). I,~-dioxane (25 mL) and ~% Na~C03 (~5 mL) were combined in a ~00 mL. round-bottomed ~lask. and the mixture was cooled in an ice-water bath.svlution o~~ di-tert-butvl dicarbonate (18.6 ~7. 85.~ mmol. ~.51 eq) (Aldrich Chemical C'ompanv) in l.~-dioxane (~5 mL) ~as slowlv added to the reaction mixture. The icc-water bath was removed and the reaction mixturc was allo-ved to ~varm to room temperature ~or 18 h. .~n additional portion ol` di-tert-butvl dicarbonate (1.86 ~.
17.7mmol. O.5~eq) in l,~-dioxane (lOmL) vas added and the rcaction mixlure was stirred at room temperature t'or ~6 h. The reaction mixture was trans~'erred to a separator~ l'unncl. Water and ethvl acctate were added to thc reaction mi:cture and the or~anic la-er was separated. The aqueous la~cr was e.Ytractcd ~vi~h ethvl acetate. The or~anic la~ers were combincd. washed t~vice with water, dricd over ;~ ,SO~. t'iltered and concentrated to ~i~e a red-brown iiquici. The crudc product was partiall- puri~'icd b~ ~lush chroma~o~Traphv witil a ~radient cluallt ol' hc~ancs (10()-9~~ cth~ l acc~te ") to (TiVC ;I colorlcss liquid. 'I'hc Li~lc com~0und prccipitated upon standin~ tO 'Ti~'C

2J~-~S~S~
09 (r ( ~ 6) of the desired product mr): 1()0-10~ "C I I-I ~MR (D.;~,lSO-d~s. 60 C):
Is ')). ~ ~ (s. '). 7 ~3 (d. 1. J = 3 ~)~ 8 ,~ (d. 1. J = 3 ~) '3 ()1 (br s. 1) 13C
~IR(CDCI,): d'~.69.5~.~7.gO9~. 1()774. 1~1 7~'96. 1" 74. 153.4'3. 164./S.

.-~nal-~sis Calcd for C~ 15NO~S: C 51.3~ 8. ~ . Found: C. ~1.'8; E~.
90: H. 5.~8.

( b ) Preparation ot ~-(( tert-huto~- carhon~ l )amin~ -thiophenecarbo~ l ic acid .~vfeth~l ~-((tert-buto~vcarbonyl)amino)-~-thiophenecarboYylate (~.Og ~, 8.08 mmol), 9~% ethanol (40 mL) and 50% sodium hvdro~cide ( 10 mL) ere added to a ~00-mL.
round-bottomed flas~. and heated at ~ C for 1 h. The reaction mi,Yture vas allowed to cool and the pH vas adjusted to pH = ~ bv the addition of 1 N HCI The reaction mi.Yture was transferred to a separator~ ~`unnel and eYtracted with dichloromethane. The or~anic laver was separated and the aqueous la~er ~as e~tracted with dichloromethane.
The organic layers vere combined. dried over M~SO~. filtered and concentrated to ~ive a white solid. The product was dried a second time. as described above. and dried in a ~acuum oven, to ~ive 1.83 g (93%) of the title compound as a white solid. mp:
167-16S C (effervesces). lH ~MR (D~ISO-d6!: ~ 1.50 (s. 9). 7.~ (br d. 1. J = ~.i?.
S 3? (d. 1. J = 3 5!. 9.31 (br s. 1). 1 `C N~R (D;~,-ISO-d6): ~ ?~ ~5 ~1.07. 10~.30.
1''.~3. 1~.94. 1~7.~ 9. 166.~0 .~nal. C21cd ~or C 1 oH 1 ~O~S: C. ~9.37: H. 5 39: ~. ~ 76. Found: C. ~9.30: ~I. 5.~:
~i, 5.7' (c) I'reparation , ~` t-h~lt~ f 1-1 1-(1 ?-ben7is0thiazol-3--1~-l-piperazin~ l)hutvl )carhamo -thien~ l ~c~rb~m~te I-l(tert-E3uto~:vcarbonvl)amino)-3-thioph~nec;lrbo~;~lic acid ( I ~9 ~T 6 1' mmol). 3-(~-~-aminobut~l)-l-r)ipera~in-l)-l.~-benzisothiazole ('.09 T, 7 '0 mmol. 1.18 cq) I ~;anlple l(h)) and anh-dro-ls ~ ~i-dimeth~ ormamide ('O mI.) ~ere combined in a ~0~)-1llL roun(l-hottome(l tlasl;. :~ solution ~-t l.~-~lic!~lohe~;!lc;lrhodiimidc (1 6~)(n , 7~ mlll~ 7 e~ Idri(:h ~hcmical ( omp.ln~ ) in anll!-drous ~ WO 94/18196 215 5 7 5 ~ PCTlGss4loo265 dimeth~ lforrnamide ('5 mL ) ~as add~d drop~vise to the re~ction mi.~ture ~nd ~he solution ~s ,tirred undcr N7 t'or 0.~1~. I-H~dro.Y-benzotri~zole h-(lra[e 11.0 (~ 7.~() mmol.
I .' I 4) (~Idrich C'hemic~l Comp~n~ as added to the solution ;md th~ re,~ctionmi.~;~ure ~ as s[irred under N~ at room temper~ure t`or '.75 d. The susp~nsion was fil[er~d ~nd the filtrale ~as concentraled to ~7ive an oranoe oil. Th~ crude ~'ree base was dissol~ed in dichloromethane :~nd the solution t ~s tr~nsr'erred to a s~parator~ tunnel.
The organic phase was w~shed ~ ith saturated N~aHCO,. The or~anic la~er vas separated and the aqueous la~er ~ as e~ctracted vith dichloromethane. The ornanic la~ers ~ere combined, ashed ~ith saturated ~iaCI, dricd o~er .~ 5O4. filtere(l and conc~ntrated to gi-e an oran~e oil. The f~ee base as partiall~ purified b- tlash chromatograph,v ~vilh dichloromethane follo~ed b~ dichloromethane: methanol (96: 4) as eluant to give a cloudv orange oil. The oil was dissolved in dichloromethane. filtered and concentrated to give a less cloud~ orange oil. The crude free base ~-as dissol~ed in eth~l acetate. filtered nd concentrated to give '.7~ n (S6%) of the free base as a clear orancre oil, A portion of the fiee base was isolated as the h-drochlorid~ s~lt upon recr-stalliz~tion from ethanol. mp: 116-119 C. IH NMR (D~ISO-d6): ~ 1.4~ (s, 9), 1.60 (m, 2), 1.7S (m, 2), 3.29 (m, 6)~ 3.44 (tm, 2, J = 12.1). 3.57 (d. ~, J = 11.9)~ ~.05 (d, ~, J = 13.~), 7.~5 (t~ 1. J = 7.6). 7.~9 (brs, 1), 7.5~ (t. 1~ J = 7.5), 5.09 (d, 1~ J = S.'), S.l~ (d, 1, J = S.~), S.35 (d. 1, J = ~.~), 8.g2 (br t, 1. J = 5.6). 10.17 (s. 1). 10.6~ (br s, 1).
I'C ~ R (D~lSO-d6): )'1.58. 27.02. 2g.g9. ~S.S9. ~7.~6. 51.'7. 56.06~ S0.6~, 107.69. 1~'.16. I'~.g5. 1'~.97. 1~ 9. 1'7.9i. 1~9.09. 1~9.i~ 7.gl. 1~.01.
1~,.09. 16~.1S. 16~.g9.

.~n~l. Calcd ~`or C~l-l . ,N~O .~ ~ HCI H~O: C. 5'.66: H. 6. ~6; N. I'.'S: ~f~O. ~.16 ~ound: C. ~.76: H. 6.~6: N. I~.,S: H~O. 2.90.

~;amrle In a) Pre~aration oi ~-amino- ~ -( 1 -rl-( 1 .~-hen7.isotllia701- ~-~1)- i -r)irera7in~ l~hut~
tlliophenec;lrho~;ami(ie h~lrochloride ~-But! l N-( 1-(1\ -( 1-(~( 1 2-benzi~c ~hiazol -~-~ l )- I -pip~razill! l )bu~ l )carb:lmo~
thiell! l)carh;llll;l[~ 6 ()7 mmoi) ( L`~;alllple ~ )) tritluoro;lc~tic aci~ mL) (E;.~l ~ iell~:e) allh~lrou~ anisol~ mL ) ~ lricll r`llenli(~ ompan! ) an~i anh~lro~l~

21S5rl5g PCT/GB94/0026~ ~

chloroform (50 mL ) ~vere combined in a "0-mL. round-bottomed flasl;. and stirred under ~i~ at room temperature for '0 min. Thin laver chromatography indicated that the rcaction as complete. I~he rcaction mi:~lure was concentrated to give an oran~e liquid.
Thc crude product was dissolved in dichloromethane and trans~èrred to a separatory ~`unnel. The or~anic phase w~s vashed with,sàturated NaHCO3 and separated. The ;lqueous layer was e~{tracted with dichlorornethane. The organic la,vers were combined, dried over l\/I_SO4~ filtered and concentrated to give an oranPe liquid The crude free base was purified b,v flash chromatography with dichloromethane followed bv dichloromethane: methanol (96: ~) as eluant to give 1.57 g of the free base as a pale orange oil. The free base 1.40 g (3.37 mmol) was dissolved in ethyl acetate and 3.~ mL
of I N ethereal HCI (1.0 eq) was added. The hydrochloride salt was ~iltered and dried to ~ive 1.01 g (37%) of the title compound as an of i:white solid. mp: 70~-706 C. I H
NMR (DMSO-d6): o 1.58 (m, '), 1.79 (m, . ), 3.00-3.80 (m, l0), 4.0~ (m, 7), 5.80 (br s, ~),6.10(d 1,J=3.3),7.49(ddd,1,J=1Ø7.0 8.1).7.62(ddd.1,J=1Ø7Ø8.1), 8.03 (d I . J = 3.5), 8.15 (br t. 7, J = 6.8). 8.40 lbr t. 1. J = 5.5). 1 3C NMR (DMSO-d6):
o 71.70. 27.79, 38.70. 47.46. 51.51. 56.16. 97.85, 1'7.18, 124.98, 1'5.59. 125.87.
177.93. 1'8.16, 129.09, 148.60, 153.06, 163.2~. 165.04.

Anal. Calcd for C70H2sN~OS7 HCI: C. 53.14; H. 5.80; N, 15.~9. Found: C. 53.70;1-1. 5.8~}; N. 15.34.

E!;~mpie I I

(~) Preparation o~ methvl 3-aminoben7oiblthiophene-~-carbo~vlate Tllis compound was prepared accordin(~ to the method of J.R. Beck[J Org Chem., 37, 3~4(197~)1 bv emplovin~ '-nitrobenzonitrile ~50.0 g, 0.338 mol) (Aldrich Chemical Company), meth~l thioglycolate (33. ' mL. 36.~ g. 0.343 mmol. 1.11 cq) (Aldrich Chemical CompanY). N.N-dimethvlform~mide (400 mL) and aqueous ~COH
(37.~ g/l 87 mL water) to give 36.1 ~ %) o f the titlc compound as a pale beige solid.
11-1 N;\/IR (CDC13): 3.90 (s~ 3). ~.9 ' (br s. ~). 7.37 (ddd. 1. J = 1.3. 7Ø 8.'). 7.~8 (ddd.
1. J = 1.5. 7Ø 8.7)~ 7.6~ (~dd. 1. J = () 8. 1.5. 8.0). 7.74 (ddd. 1. J = 0.8. 1.~, 8.0).

~WO 94/18196 215 5 7 5 ~ PCT/GB94100265 (h) Prep,~r~ n ~ mino- \ -(4-(~-( I .?-bcn~iso~hia7OI-3-~ l)- l -piper~zin~ l )butvl )hen70( h )Ihiophclle-'-carl~o~ami(lc h~ droch loridc -Aminobul~l)-l-piperazinyl)-l.?-benzisothiazole (~.6 o, 8.96 mmol) (E~cample l~b)) and anhydrous chlorot`orrn (~0ml,) were ad(led to 2 100-mL. round-hottom~d ~lask and stirred under i~ . A solution ot trimethylaluminum (~.6 mL.
9.~ mmol. 1.03 eq) (Aldrich Chemical Compan~ '.0 M in toluene) was slowlv added to the reaclion mixlure and the pale yello-v solution was stirred under N~ for ~0 min.
,-~nother portion o~ trimethvlaluminum (~.6 mL, 9.? mmol. 1.03 e~l) was added to the reaction mi.Yture. ~ solution ot methyl 3-aminobenzo~b~thiophene-2-carbo~cylate (1.86 ~. 8.98 mmol. 1.0 eq) in anhydrous chloroform (10 mL) was added to the reaclion mixture and stirred under N? at room temperature ~or 0.5 h. The golden-yellow solution was heated at 40 C for 4 days. The oil bath ~,vas removed and the dark oran~e solulion ~,vas allowed cool. To the slightly warm reaction mixture was slowlv added I N HCI
(~0 mL). The acidic reaction mi.Yture was heated at 40 C ~`or 0.~ h. The re~ction mixnlre u as allo-~,-ed to cool and saturated K~CO3 was added. The re,action mi,Yture was transt`erred to a separatory ~`unnel and eYtracted with dichloromethane. The organic phase vas dried over MgSO4. filtered and concentrated to cive the crude product as an orange liquid. The free base was purified by flash chromatography with a ~radient ~lu~nt of dichlorometh,~ne (100-9~%): meth~nol (0-5%) to cive 1.14 g (~7%! of the ~ee base as an orange oil. The free base 1.05 g (?,~ mmol) was dissolved in eth~ l acetate and ~.~5 mL ot I N ethereal HCI (1.0 eq) uas added. The hydrochloride salt ~v~s rccrYstallized trom ethanol / uater to give 0.82 ~ %) o~ the title compound as a beige solid. mp~ C. 11-1 NI~IR (DMSO-(16): ~ 1.58 (m. ~). 1.76 (m~ '). 3.10-3.50 (m~ 8). 3.59 (br d. '. J = 11.~ .08 (br d. ~. J = 13.~), 7.07 (br s, ~). 7.38 (ddd. 1. J =
1.1. 7.1. 8.1), 7.~7 (tm. '. J = 7.G), 7.60 (ddd. 1. J = 1.1. 7.1. g.'), 7.68 (br t. 1. J = 5.6).
7.83 (d. 1. J = 7.7). 8.03 (d. 1. J = 7.9). 8.1~ (t. '. J = 8.3). 10.39 (brs. 1). 1 'C NMR
(DMSO-d~ 1.61. '7.61. 39.10. ~7.33. 51.4(). 56.16. 99.33. 1''.16. 1~3.48. 1~3.9~.
1~.7~ .98. 1'5.59. 1~7.93. I~g.~9. 1~9.08. 133.38. 137.89. 1~8.~9. 1~.09.
1~)3.~0. 166.1~.

Anal.C;llcdt`orC~ 7N~OS~I{CI: C.57.~1:11.5.6':N. 13.9~. Found: C.57.~:
.68: i~'. 13.9~

WO 94/18196 ,~$~ PCT/GB94100265 1--Ç~.Yamr)le 1~

la) I'reparation ot` ~-cyano-\~-( I-r4-(l~-ben7isothia70I-.-vi)-I-pipcra7.invl)butyl)acctamide '-(~-(4-f~minobutvl)-I-piperazinvl)-1~'-benzisothiazole (~.~3 ~ 7 69 mmol (I~Yample l(b)), cyanoacetic acid (0.76 (~ 8 93 mmol~ 1.16 eq) (Aldrich Chemical(:`ompanv) and N~N-dimethylformamide (~0 mL) were addcd to a ~50-mL. round-bo~tomed flasl;. and stirred under N~ ~ solution of l~-dicyclohexylcarbodiimide ( 1.86 g, 9.01 mmol. 1.17 eq) (Aldrich Chemical Company) in N. N-dimethylforrnarnide ~ mL) ,vas added drop-vise to the reaction mi~cture. I-Hydroxvbenzotriazole hydrate ( 1.~4 ~~ 9.18 mmol. 1.19 eq) (Aldrich Chemical Company) was added and the reaction mi~;ture was allowed to stir at room temperature under N~ l'or ~3 h. The suspension ~as filtered and the solid was washed with N. N-dimethylformamide. The filtrate was concentrated to give an orange oil. The crude t'ree base was dissolved in ethyl acetate ~nd filtered. The filtrate was applied directly to a silica gel column and partially purified by flash chromatography with a gradient eluant of ethyl acetate (90-~0%):
methanol ( 10-20%) to give ''.92 g of the crude product as an orange oil. The crude free base was dissolved in dichloromethane and washed with saturated K~CO3. The orL~anic layer was separated and the aqueous layer was e~tracted with dichloromethane. The or~anic layers ~,vere combined. dried over M~SO4~ ~'iltered and concentrated to nive 1.93 ~ (70 % ) ot'the title compo~md as a pale bei(~e solid. IH NMR (CDC13): d. 1.63 ~brt.~.J=3.3).'.~7(brt.'.J=6.7).~.69(brt.~.J=~.9).3.36(m.~).3.37(s.~).3.~7 ~hrt.~.J=4.9)~6.66(brs. 1).7.3G(cldd. I.J= 1 ~.7Ø 8.1). 7.47 (ddd. 1.J= 1.~.6.9.
8.'). 7.8' (dt. 1. J = 7.8. 1.1)~ 7.91 (dm. 1. J = 8.0).

(h) Preparatinn o~' ~-amino~ -henzisothi~zol-3-yl )- l -pipera7invl~b-ltvl )-3-thior11lenec~rho~amide ~-Cyano-,V-(4-(~-( 1.~-bcnziso~hiazol-3-yl)-1-pipcrazinyl)bu~yl)ace~amidc ( 1.8, ~.
I'mmol). 1.4-dithianc-~.~-diol (I 79O 11.8 mmol. '.30e~ Idrich Chcmical ~omp~ny). tricthylamine (1.7()mL,. 1.~3(u l'.~mmol. ~.38cq) and cthanol (30mL) ~crc ad(lcd to a ~()()-mL~ round-bottolllc-l tlasl;. ~nd heatcd al 6()-6~ ~C` ull~lcr a nitro(~en allllospl1crc l`or ' h. 'I'hc oil hatl1 -as rcmoved alld thc rcaction mi~turc ~vas allo- cd to ~ WO 94/18196 21 5 5 7 ~ 8 PCT/GB94/00265 conl. ~'ater and dichloromethane ~vere added and the reaction mi.~cture ~1 as trans~`erred ~o a separator~ funn~l. The or~.mic layer ~ as separated and thc ayueous la~er ~as e.~;tracted with dichloromethane. 'rlIe or~nic la-ers ~vere combined. dried o-er .\~ SO~
t`iltered ~nd concentrated to 7ive a red-brown residue. The crude ~'ree base vas partially puri~'ied by ~lash chromatouraphv with a Jr~dient eluant ot`ethyl aeetate (100-98/o ):
meth~nol ~0-~%) to ~ive - partiallv solidified oran~7e oil. The ~`ree base ~vas dissolved in eth~l acetate and filtered. The filtrate was partially coneentr~ted to oive ~ suspension.
The pale tan solid was filtered and dried to ~ive 0.~39 17 (11%) of the title compound.
mp~ 9 C (dec). IH N~rR (CDC13): ô~ 1.68 ('br s ~) ''.~8 (brs~ '.68 (brs~ ~) 3.42 (m 2). 3.~8 (br s ~)~ 5.84 (br s. 1)~ 6.07 (br s. ~). 6.')3 (d 1. J = ~.8) 6.71 (br d 1 J = 5.8) 7.35 (ddd. 1. J = 1.1 7Ø 8.1) 7.46 (ddd. 1. J = 1.1 7Ø 8.1). 7.81 (d 1! J
= 8.~). 7.90 (d. 1 J - 8.~). I'C N~rR (DMSO-d6): o ~3.80. ~7.~7. 38.~6 49.61. ~2.~3 ~7.61 10~.69. 107.~ 1.09. 1~4.18. 124.~ 1''7.~0 1~7.89 1~.06. 161.0~.
163.~'. 16~.'}~.

An~l. Calcd for C20H2~ os~ 3/20 C4HgO ~- 0.3 H~O C. 56.98; H. 6.'~ N. 16.1~.
Found: C 56.70: H. 6.15:~. 16.26.

E~ample 13 (;l) Prep~ration o~ Ben7isothia701- ~ iper~zin~ l]butvl quinolinee~rbo~c~mide h~ drochloride .~nhydrous ~ limeth~l lt'orm~mide (~0 mL`). ~ uinolinee~rbo~vlic acid (1.0~ ~n 6.01 mmol! (Aldrieh Chemical Company). I-h-dro~ybenzotriazole hydrate (0.898 ~.
6.G~ mmol~ l.l l eq) (.'~ldrieh C'hemieal Compamy) and ~ -aminobutvl)-l-piperazinyl)-l.'-benzisothiazole (i.7~ ~n 6.V3 mmol. 1.0 eq) (E.Y~mple l(b)) ~vere combined in a ~0-mL round-bottomed flasi;. The reaetion mi~ure ~v~s cooled in ~nice-~vater bath and stirred under N~. A solution o~ -dic~ clohe:;vlc~rbodiimide (1. 7 -. 6.6~ mmol. 1.1() cq) (Aldrich Chemical ('ompan~) hl ~nh~drous -dimeth~lt'orm~mide (1~ mL) ~vas added drop~vise to the reaetion mi~;ture. The iee-~vater hatlI ~v~s removed ;md the reaetion mi~ture ~-as stirred at room temper~ture~'or '0 1-. ~I'he suspensiolI ~vas eoncelItrated i~7 -~lC~O and the er~lde produel ~vas partitioned l-el~veen eth- l acct~e ~n~i s~turated ~ [CO- . Tl1e I ~ ers ~vere sep;lrated and the a~l~lcous la~er ~V.IS e~;tr;lcted ~vitl1 eth~l aeetate. 'l'lle or~-~nie l;lvers ~vere combined.

WO 94/18196 ~ PCT/Gs94/00265 ~,~551~ 4 ~

dried over M~JSO4. filtered and concentrated to c~i-e ~ mixture of finclv dispersed soiids in an oranoe oil. Ethvl acetate was added to the mi~cturc ;md tllc suspension as fillered. 1`he filtrate was concentrated to aive ~.98 ~ ot` the crude product as an orange oil. Thc crude product was purified by llash chromato_raphy with dichloromethane.
dichloromethane:methanol (99:1) and dichlorometh,ane:methanol (97:3) as eluant. The appropriate ~`ractions were combined. concentrated~ redissolved in dichloromcthane.
t'iltered ~nd concentrated to give 1.46 ~ of the ~'ree base as a yellow oil. The ~'ree base was dissolved in dichloromethane and IN ethereal HCI (3.~8 mL. 1.0 eq) was added.
The solvent was removed in vacu(7. Tlle resultin~ hydrochloride salt vas dissolved in methanol and the solution was filtered throuah fluted filter paper directly inlo rapidly stirred ethyl acetate. The suspension was filtered to give 0.265 g of the title compound as a pale beige solid. Tlle filtrate was concentrated and recrystallized ~`rom meth~nol to give a second crop (0.447 o) for a total yield of 0.712 g (25%). mp: 187-189 C. IH
NMR (DMSO-d6): ~ 1.68 (m. 2), 1.91 (m, '7), 3.10-3.4~ (m~ 4), 3.56 (m. 6). 4.03 (br d~
~ J = 11.8), 7.~3 (t, l. J = 7.5). 7.56 (t. L J = 7.6!. 7.65 (dd~ 1. J = 4.3. 8.3), 7.7~ (t, l. J =
7.7). 8.09 (t, ~, J = 7.7). 8.17 (~, 1. J = 8.1), 8.54 (dm, ~, J = 7.6), 9.09 (dd. 1. J = 1.4.

4.1!. 10.87 (br t, 1, J = 5.5), 11.55 (brs. 1). 13C NMR (DMSO-d6): ~ 21.~4. 76.95, 38.85. 46.72. 50.82, 5~.~9~ 1'71.52, 1'~1.90. 1'~4.35. 124.94, 1~6.66. 1'7.31. 1'~8.44.
1'~8.56. 179.67, 132.38, 13~.72, 138.30. 14~.99. 150.8~ .43. 162.60. 16~.41.

E~ample 14 (~) Preparation o f 1.~.3.4-Tetrahydro-~-quinolinecarbo~ lic acid This compound was prepared according~ to the method describcd bv Coppola. G.M. (J.
~teroc~clic Ch~m.. 1978, 15, 645) by employing 8-quinolinecarboxylic acid (1.73 g, 9.99 mmol) (Aldrich Chemical Company). platinum o.~;ide hydrate (0.18~ g~ (EM
Science) and ethanol (30 mL). The mi~ture was hydro~enated on a Parr hvdrogenator at 50 psi for ~ h. The reaction mi~cture w~s filtered through a pad of` celite and the f~ltrate ~vas concentrated to ~ive 1.76 ~ (99%) ot'the title compound :~s a pale vellow solid. mp:
158-160 C. ~lit. mp: 165-167 Cl 1~1 NMR (DMSO-d6): ~S 1.77 (quin. ~. J = 5.9),~69(t.~.J=6.~).3.33(t.'~.J=5.5).6.36(t, 1.J=7.5),7.00(d. I.J=7.0).7.54(d. 1.
.1 = ~.0). I'C NMR (DMSO-~ 1.46. ~.3~. 41.6~. 109.59~ 114.17. 1~.73.
130.5~ 13~.5~ 149.13. 171.~4.

~WO 94tl8196 ~ 2 I 5 5 7 ~ 8 PCTtGB94/00265 - 4~ -Anal. C;31cd for CloHI IN()~: C. 67.78: Il. 6.~6: ~ 7.90. Found: C. 67.56: H. 6.3~:
~, 7.8~.

(h) PreT~aration oi' .~ 4-('1.~-13enzisothiazol-3-vl)-1-piperazin~ hutyl~ 3.~-tetrahvdro-8-q~linolinecarbo~;amide This compound was prepared accordin~ to the method described ~`or E.Yample 13(;3) bv emplo,vin~ .3~4-tetrahydro-g-quinolinecarbo.Yvlic acid (1.06 o. 5.9g mmol)~I-hydroxvbenzotriazole h,vdrate (0.90 o, 6.66 mmol. 1.1 eq) (Aldrich Chemical Compan~). 1.3-dic,vclohe~lcarbodiimide (1.~7 ~,. 7.1~ mmol. 1.~ eq) (Aldrich Chemical Company). 3-(4-(4-aminobutyl)-1-piperazinyl)-1,~-benzisothiazole (1.8~ g, 6.~7 mmol. 1.05 eq) (E:;ample l(b)) and anh~drous N.N-dimethylforrnarnide. The reaction mixture was allowed to stir at room lemperature l'or 18h. concentrated in vacuo, and the crude product was partitioned between dichloromethane and saturated NaHCO3.
The finel,v dispersed solids were filtered and the filtrate vas concentrated to _ive the crude free base. This material was purified b~ fl~sh chromato~raphy as described in E~ample (13a!. The purified f'ree base (~.~8 g. 5.07 mmol) was dissolved in dichlorometh~ne and IN ethere~l HCI (5.07 mL. 1.0 eq) was added. The solvent wasremoved in vacuo and the resulting hydrochloride salt was dissolved in MeOH. Thesolution was filtered throu~h a ~luted filter paper directly into rapidl~ stirred ethvl ~cet~te. The suspension vas filtered to oive 0.~8 g (9%) of the title compound as an oran~e-beige solid. mp: 138-1~'' C. II-I N;\~R (DMSO-d6'): S 1.55 (m. ~. 1.77 (m. 4).
'.69 (t. '. J = 6.0). 3.'1 (m~ 8). 3.~7 (t. '. J = 1'.9). 3.56 (d. ~, J = 11.6`). 4.05 (d. ~. J =
13.4). 4.46 (br s. 1). 6.~4 (t. 1. J = 7.5). 6.96 (d. 1, J = 7.0). 7.37 (d. 1. J = 7 8!. 7.46 (t.
1. J = 7.5). 7.5S (t~ 1. J = 7.5). S.l I (t~ ''. J = ~.~). S.3~ (br t. 1. J = 5.3). 10.91 (br s. 1).
13C NMR (DMSO-d6)~ 1 54. ~1.86. '77.43. ~S.~7. ~9.11. 41.75. 47.56. 51.6~. 56.i4.
115.1~. 115.19. 1~.37. 1'3.35, 1~ . 1'5.7g. 1~7.35. I~g.10. 1~9.'9. I ~.S~.
1~6.19. 1~ 6. 163.~5. 170.~0.

Anal. Calcd for C~s~131N~OS 1.5 IICI ().35 ~I~C): C. 5S.SI: H. 6.55: N. 13.7~: Cl.
1().11: H~O. 1.~3. Found: C. 5g.47: ~I. 6.6~: N.l .4': Cl. I0.18: ~I~O. 0.85.

2~SS7'~ --mr~le IS

(~) I'rc~aration ot`~ 3-Dihvdro-I~ indol-I-vl)oiyoxvlo~l chloride This compound was prepared accordin~ to the procedure described bv Welste ld, W.J..
~/ al. (.J. .l~d. Chem. 1979, '', 107~) with modifications. Oxalvl chloride (102.1 c~
0.8()~mol) (Aldrich Chemical Compan~ ~nd anhvdrous dichloromethane (400mL) ~ere added to a 2-L. 3-necked round-bo~tomed fl~sk. Thc tlask was equipped with a mechanical stirrer. addition funnel and N7 inlet. A solution of indoline (48.0 ~.
().403 mol) in anhydrous dichlorometh~ne (350 mL) was added dropwise to the stirred rcaction mi.Yture over a 2h period. The reaction mixture was stirred at room temperature tor 3 h and then allowed to stand overnight. The resultin~ red-bro-vn solution was concentrated and diethyl ether was added to the residue. The suspension was filtered and the filtrate was concentrated to give 56.75 g (68%) of the acid chloride as a yellow-~reen solid. The crude acid chloride was used without filrther purification. IH NMR
(DMSO-d6): ~3.19(t.~,J=8.3)~4.17(t,2,J=2.3).7.1~(t, 1,J=6.9),7.24(t, I~J=
7.1),7.33(d, 1,J=7.0),8.01 (d, 1,J=7.6).

('b) Preparation of 4.S-di~ydropvrrolo~3 .'7.1 -hilindoline- I .~-dione Alrlminllm chloride (12.7 t~ 95.'7 mmol. 5.0 eq) (Aldrich Chemical Company) and 2-(~.3-dihydro-lH-indol-l-yl(glyo,Yvloyl)chloride (4.00 g. 19.1 mmol) were added to a 300-mL round-bottomed flask equipped with a m~rJnetic stir bar and N2 inlet. ThemiYture was quicklv heated to 100-1~0C and allowed to stir for 20 min. Thc oil bath vas removed and the mi~ ure was allowed to cool to room temperature. The resultin~
~olid ~as broken up with a spatula and added to icc-water (600 mL). The aqueousmiYture was stirred t'or I hr and e.Ytracted with chlorot`orrn. The organic layer was dried o~,cr M~SO4. filtered and concentratcd to ~ivc an oilv red residue. The residue was triturated with acetone and tiltered to ~ive ().71 g (~%) of the title compound as a red solid. mp: '~03-207 C ~lit. (Welstcad. W.J.. ~t al., J. i~le~l. Ch~m. 1979, 77, 1074) mp:
~06-~08 C]. I H NMR (DMSO-d6): ,~ 3.36 (t, ~. J = 7.9), ~.06 (t. ~, J = 7.9), 6.95 ('t~ I
J = 7.~. 7.'~4 (d. 1. J = 7.6). 7.~G (d. 1. J = 7.1). 13C NMR (DMSO-d6!: ~ 31.3~.
~6.~S. 113.03. 1'''.7'. 12~.7~. 12G.~ . 13~.1G. 156.~5, 160.67. Ig~.71.

;~n;li. Calcd for C101-17NO~: C. 69.36~ .07: N. 8.09. ~ound: C. 69.09: H. ~.10: N.
~.()0.

~WO 94/18196 21 5 S 7 S 8 PCT/GB94/00265 (c) Preparation of indoline-7-carho~;vlic aci(l .~ solution ot` sodium hvdro.Yide (1.~ ~T in ~ ML, oi` water) an(l 4~5-dihvdropvrroloL3.~ hi]indoline-1.~-dione ( 1.() g. ~.Y? mmol) wcre combined in aI ()0-mL round-bottomed tlask and stirred at room temperature for 30 min. A solution of hvdrogen pero~ide (1.8-? mL of 30% H~O~ in 1~.~ mL H-)O) was added dropwise and the reaction mi:cture was allowed to stir for 3.5 h.' The reaction mi~ture was transi`erred to a separatorv funnel and washed with benzene. The aqueous layer was separated. the pH was adjusted to 6-7 by the addition of IN HCI ~nd the solution was e~ctracted with chloroform. The pH of the aqueous laver was adjusted to 4-5 by thc addition of IN HCI
and extracted with an additional portion of chloroform. The organic layers were dried over MSO4. filtered and concentr~ted to give a Qold-tan solid. The crude product was triturated with benzene:isooctane (3:1) to ~ive 0.54 ?0 (57%) of the title compound as a tan solid. mp: 164-166 C. [lit. (Welstead, W.J.~ et ai.. J. .l/leu?. Chem. 1979, 7~, 1074) mp: 164-168 C]. I H NMR (DMSO-d6): o ~.93 (t, ~, J = 8.6), 3.55 (t. ~. J = 8.6)~ 6.44 (t, 1, J = 7.0), 7.13 (d, 1. J = 6.9). 7.36 (d~ 1, J = 7.5). 13C NMR (DMSO-d6): o '~8.19 46.70~ 1 07.95~ 1 1 5.49~ 1 8. 1 ~ 1 28.43~ 1 3 1 ._6, 1 54.48~ 1 68.73.

Anal. Calcd for CgHgNO2: C, 66.-?5; H~ 5.56: N~ 8.58. Found: C~ 65.98; H~ 5.51; N, 8.48.

(d) Preparation of ~V-~4-~4-( 1~ 7-Benzisothiazol-'-yl)- 1 -pipera~invll~utvll-~3-dihvdro-I H-indole-7-carbo~amide This compound was prepared according~ to the method described t`or ~.~ample 13(a) by cmplovin(7 indoline-7-carbo~cylic acid (0.86 ~ 5.'7 mmol) 3-(~ -aminobutyl)-1-piperazinvl)- I .~-benzisothiazole ( 1.60 17~ 5.~ 1 mmol~ I ,05 eq ) ( E.~ample I (b)), I-h~dro~;ybenzotriazole hydrate (0.78 g~ 5.77 mmol~ 1.10 eq) (Aldrich Chemical Company)~ 1.3-dicyclohe:cvlcarbodiimide (1.35 g~ 6.54 mmol~ 4 eq) (Aldrich Chemical Company) and anhydrous N.N-dimethylformamide. The reaction mi~cture was allowed to stir at room temperature tor ~4 h~ and the solvent was removed in ~?CICIlO.
F,thvl acetate was added to the residue and the mi.~ture was filtcred to remove thc insoluble material. The filtrate was vashed witll saturated Nal~CO ,. The onganic laver was dried over M'?SO4~ filtcred and concentrated to give 3.1~ g ot'the crude product as an oranoe oil. Tlle cmde material vas purit`ied bv tlash chromatograph,v with ethvl ;~cctate:methanol (')9:1 ) tollowed by eth,vl acctalc:metllanol (97:3) as eluant. l'he ar)propriate ~`ractions wcrc combincd~ conccnlraled~ rc(lissolvecl in dichloromcthane~

WO 94tl8196 PCT/GB94/00265 ~,~Ss~5~ - 48 -tlltered and concentrated to ~Jive 0.96 ~ (4'' %) of the title compound as an oranoe oil.
I H ~\iMIR (Dh~ISO-d~ .51 (m. ~ .36 (t. ~. J = 6.4). ~.~6 (br t. 4. J = 4.~ .89 (t.
~. J = 8.6). 3.~'~ (brq. ~. J = 6.()). 3.41 (brt. 4, J = 4.~). 3.~1 (t. ~. J = 8.6). 6.4~ (t. 1 J = 7.~). 6.3~ (s, 1), 7.07 (d. 1. J = 7.~). 7.3~ (~. 1. J = 8.1). 7.~1 (tm. 1. J = 7.~). 7.~3 tm. 1.J=7.5).8.02(d. 1.J=8.1),8.03(d. i.J=8.'~).8.11 (t. 1.J=~.6).

F!~ample 16 ( a) Preparation of I H-indole-7-carboxvlic acid This compound was prepared ,according to the method described bv lL;an~ R.
and Rapaport, E. (Te~rahedron. 1967, ~3~ 38''3) by employing indoline-7-carboxylic acid (3.0 g~ 18.1 mmol) (Example 15(c))~ 10% Pd on carbon (0.75 g) (Aldrich Chemical Company) and xylenes (150 mL). The reaction mixture was heated for ~ h. The hot solution was filtered through a pad of celite and the filtrate was concentrated to give 1.5~ g (52%) of the title compound as a red-beige solid. mp: 202-~01 C [lit. 20~ C].
I H NMR (DMSO-d6): o 6.52 (dd, 1~ J = ~.0, 3.0), 7.08 (t~ 1, J = 7.7), 7.3~ (t~ 1, J =
~.8) 7.74 (dd, 1, J = 1.7. 7.5), 7.81 (d. 1, J = 7.9)~ 11.05 (s~ 17.98 (br s~ 'C
NMR(DMSO-d6): ~ 101.80~ 113.83. 118.70~ 1'74.13, 1~5.97, 127.16. 1'79.61. 134.90.
16S.31.

~ ) Preparation of .V-~4-~4-(1.~ en%isothia~ol-3-vl~-1-piperazinvl~ tyll-1 H-indole-7-carbo~cam ide This compound was prepared according to the method described for E.Yample l~(a) b-emplovingJ ll'~-indole-7-carbo:cylic acid (1.3~ g. 8.19 mmol). 3-(4-(4-aminobutvl)-1-piperazinyl)-l~-benzisothiazole ~2.~7 ~, 8.~1 mmoh 1.04 eq) (E.~ample l(b))~
I-h~dro.~;vbenzotriazole h~,dratc (1.~0 g. 8.88 mmol. 1.08 eq) (Aldrich Cllcmical Companv). 1.3-dicvclohe:cylcarbodiimide (1.87 ~n 9.06 mmol. 1.1 eq) (Aldrich Chemical Companv) and anhvdrous N.N-dimethvlformamide. The reaction mi:cture was al}o-~ed to stir at room temperature t`or }6 h and thc so}vent ~vas removed in lacz~c.
~th~ l acetate ~vas added to the residue and the suspension ~vas filtered. The filtrate was washed ~vith saturated Na}lCO3 and the lavcrs ~lcre scparated. T}le organic laver wlas dried over MgSO4~ ~`iltered and concentrated to ~ive thc crudc product as an oran~e oi}.
Tllc crude free base was purified b~ flash chromatonraph~ ~vith ethvl acetate. ethvl acetatc:mcthallol (')9:l ) and cth~l acctate:mcthanol (97:,) :~s eluant to ~ivc`~.'7 .~
"',) ot thc title compound as a vello~ oil. 1 ~1 Ni\~lR (D~ISO-~ 7 (m~ 4)~ ~.39 (t.

WO 94/18196 . PCT/GB94/00265 ~I5575~

1~ J = 6.9) '.57 (br t. 4. J = 1.~). 3.3~ (m. ~ .4 ' (br t. 4. J = 4.~ ). G.46 (t. I . J = '.9).
7.04 (t. 1. J = 7.6)~ 7.3~ (t. 1. J = ~.9), 7.41 (tm. 1. J = 7.6). 7.~ (tm. 1. J = 7.8). 7.64 (d.
1 J = 7.5) 7.70 (d. 1. J = 8.1). 8.0~ (d. 1. J = ~.1) 8.03 (d 1. J = 8.7)~ g.5~ (t. 1. J =
.6) 11.13(s,l).

Claims (14)

1. A compound of formula I.

(I) wherein Y is a heteroaryl group optionally substituted by one or more halogen, nitro, C1-6alkyl, C1-6alkoxy, aryloxy. arylC1-6alkylenoxy. hydroxy, S(O)nR2 or S(O)nN(R2)2 where n is 0, 1 or 2. CN, CON(R2)2, COR2, CO2R2, CO-aryl, azido, -N(R2)2,-NR2N(R2a)2, -NR2N=C(R2a)2, -NR2(C=O)CH(N(R2a)2)R2b, -NR2(C=O)R2a. NR2CO2R2a, C1-6alkoxycarbonylamino or PhN=N;
with the proviso that Y does not include benzisothiazolyls or benzisoxazolyls.
V is O or S;
Z is C1-8alkylene optionally interrupted by -O- or -S(O)n- where n is 0, 1 or 2 C2-8alkenylene or C2-8alkynylene;
X is N. CR3 or COR3;
A is CR4 or N;
B is oxygen, NR5 or S(O)n, where n is 0, 1 or 2; and R1 is hydrogen or one or more halogen. hydroxy. nitro. CN, NR62, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, or COR6, R, R2, R2a, R2b, R3, R4, R5 and R6, are each hydrogen or C1-6alkyl:
or a salt, solvate, N-oxide or physiologically functional derivative thereof.

2. A compound, salt, solvate, N-oxide or derivative according to Claim 1 wherein the heteroaryl group is selected from the group comprising:
pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridazinyl, quinolinyl,isoquinolinyl, imidazolyl, benzimidazole, furyl, benzofuryl, thienyl, benztheinyl, indazolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, purinyl, triazinyl, indolyl, naphiridinyl, quinazolinyl, pyrrolopyridinyl, tetrahydroquinolinyl, indolinyl, quinoxalinyl, triazolyl or thiadiazolyl.

3. A compound, salt, solvate, N-oxide or derivative according to either of Claims 1 and 2, wherein the heteroaryl group is substituted with N(R2)2.

4. A compound, salt, solvate, N-oxide or derivative according to any of Claims 1 to 3 wherein the heteroaryl group is pyridine, thiophene or benzthiophene, optionally substituted with NH2, NHMe or NHAc and R is H or Me.

5. A compound, salt, solvate, N-oxide or derivative according to any of Claims 1 to 4 wherein R is H and the heteroaryl group is pyridine or thiophene substituted with NH2.

The compounds:

N-(4-(4-(1,2,Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide;
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-pyridinecarboxamide;
N-(4-(4-(1,2,Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-pyridinecarboxamide;
t-Butyl N-(4-(N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)carbamoyl) -3-thienyl)carbamate;
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-3-pyridinecarboxamide:
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-pyridinecarboxamide;
4-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-3-pyridinecarboxamide;
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-4-pyridinecarboxamide;
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-thiophenecarboxamide;
4-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-3-thiophenecarboxamide:
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)benzo(b)thiophene-2-carboxamide:

2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-3-thiophenecarboxamide;
N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-quinolinecarboxamide;
N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2,3,4-tetrahydro-8-quinolinecarboxarnide;
N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-2.3-dihydro-1H-indole-7-carboxamide;
N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-1H-indole-7-carboxamide;
and physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides thereof.

7. The compounds:

3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-pyridinecarboxamide;
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-thiophenecarboxamide;
N-(4-(4-(1,2,Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide;
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-pyridinecarboxamide;
and physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides thereof.

8. 3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide; and physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides thereof.

9. A process of preparing a compound of formula (I):

(I) wherein Y, V, Z, X, A, B, R, R1, R, R2, R2a, R3, R4, R5, and R6 are as defined in any one of Claims 1 - 9 or a salt, solvate, N-oxide or physiologically functional derivative thereof, comprising the reaction of a compound of formula II.

(II) with a compound of formula (III) (III) wherein L is a leaving group or by reaction of a compound of formula (II) with a compound of formula (IV) (IV) wherein W- is a suitable anion and R12 is -(CH2)4 or -(CH2)5 or by reaction of a compound of formula (V) (V) in which L is a leaving group, with a compound of formula (VI) (VI) or by reaction of a compound of formula VII

(VII) with a compound of formula (VIII) (VIII) in which L is as hereinbefore defined, or by reaction of compounds of formula (IX) or (IXa) (IX) wherein LI is a halogen OMe or OH

(Xa) and wherein Y ? and R2 are as previously described, with a compound of formula (X) (X) or by treatment of a compound of formula (Xa) (Xa) with 1,4-dithiane-2,5-diol or by reduction of a compound of formula (I) in which Z is C2-8alkenylene or C2-8 alkynylene.
or by hydrolysim of the corresponding alkoxycarbonylamino derivative of a compound of formula (I) which is optionally substituted by one or more N(R2)2 orNRN(R2)2.

10. A compound of formula (I) as defined in Claim 1, or a physiologicallv acceptable salt, solvate, N-oxide or physiologically functional derivative thereof, for use in therapy.

11. The use of any of the following compounds, or physiologically acceptable salts, solvates, N-oxides or physiologically functional derivatives thereof, in therapy 3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-pyridinecarboxamide;
3-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl)-2-thiophenecarboxamide;
N-(4-(4-(1,2,Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide;
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-pyridinecarboxamide;
and physiologically acceptable salts, solvates, physiologically functional derivatives and N-oxides thereof.

12. The use of a compound of formula (I) as defined in Claim 1 or a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof for the manufacture of a medicament for the treatment or prophylaxis of a psychotic disorder.

13. Use according to Claim 12 wherein the psychotic disorder is schizophrenia.

14. A pharmaceutical composition comprising a compound of formula (I) as defined in Claim 1, or a physiologically acceptable salt, solvate, N-oxide or physiologically functional derivative thereof.