CA2133984A1 - N-aryloxy(thio)alkyl-azacycloalkanes useful as calcium channel antagonists - Google Patents

Abstract

2133984 9322302 PCTABScor01 Use of compounds of formula (I), in which n is 3 to 8; q is 5 to 11; R1 represents C1-6alkyl or C1-6alkoxy; s is zero, 1 or 2; X represents oxygen or sulphur; and Ar represents phenyl optionally substituted by 1-3 substituents selected from halo, C1-8alkyl, C1-8alkoxy, C1-2alkylenedioxy, trifluoromethyl, trifluoromethyloxy, or a group Ph-(CH2)m-Y-(CH2)p-where Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O, S, or CH=CH, provided that m + p is not greater than 4, or Ar is an optionally substituted tricyclic heteroaryl group (a) in which Y1 is Y(CH2)x where x is 0 or 1 and Y is O, S or NR where R is hydrogen or C1-4alkyl, Z is (CH2)r or -CH=CH-, r is 0, 1 or 2 or Ar is the corresponding tricyclic dehydro ring system, and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of conditions where a calcium channel antagonist is indicated. Novel compounds of formula (I), processes for preparing them and pharmaceutical compositions containing them are also described.

Description

. W O 93/22302 ~13 3 ~ ~ 4 P ~ /GB93/00801 N-ARYLOX~(THIO)ALKYL-AZACYCLOALKANES USEFUL AS CALCIUM CHANNEL ANTAGONISTS

~eFresentLnven~onrela~sto aryl~%yaLkylam ulo and aryl~oa~kyla~no de~va~vcs, prccesses~r~he~ prepala~on,ph~L~eu~e~ cvmposi~onscon~n~ng ~h~m andthe~ use S in ~ho~a~y, ~n par~cular in the b~a~nentof ischae~c s~k~
Stcoke is ~xt~dly the thixd rnos~ ~mmon callse of death h the developed woQ~ld. ~r~nt ~erapies f~ ischae~c s~ke are lirDl~d ~nd hav~ a ~L~ber o~
disadvantages, such as tho sisl~ of exacerb~ hao~age. Th~e is th~fore a need fornew and ~proved trea~ellts ~ is~ha~c s~l~e.
~o EP-A-103252 disclo~s a broad class o~ aryloxy~ylam~no d~a~ves. Th~se compounds arc said t~ h~ve udiir5r as h~Dicides.
French Pa~nt Applica~on ~o. 1601$gl d~scnb~ a class of n~gen~oll~g het~cyclic com~ounds denved ~m phsn~y~l~l al~hols, which arc gald t~ be cholesterol~lower~ng agents.
We have now ~Imdl that ce~ arylo~ya~amino ~d arylthioalkyl~o der~va~ves exhibit acdvi~ as calciu~ cha~el an~g~n~sts.
The present ~nvenGion ther~fare pro~r~des, Ln a ~rst aspect, u~e of a compound of fo~mula (1): ;

"~ ). ;
~ ' (C~2)n N-(CH2k~X A
V

Forr~ula O

in which nis3to 8;
qisSt~ 11;
Rlrepresen~ Cl~6aLkylor Cl.6alkoxy;
siszeno,1 or2;
X ~eprescn~ oxygen orsulphur,and Arrepresents phenyl op~onally subs~tuted by 1-3 subs~nlents selccted ~om halo, C~ ~aLkyl, Cl ~alk~xy,C1 2aLkylenedioxy e.g. me~hylenedioxy,~i~uoIome~hyl, ~iQuorom~thyloxy,oragToup Ph-(C~2)m-Y-(C~I2~p- whele Phisop~ona~ysubc~tuted 2 r~ 2 - P~'/GB~3/00801 phenyl, m and p are ~ndependen~y 0 to 4 and Y is a ~ondf O, S, or ~CH, provided that m ~ p is not ~eater ~an 4, or Ar is all op~ona~ly subs~tu~ed ~icyclic hete~oaryl group:

~z~3 ~n which yl is Y(CH2,)X whore ~c is 0 ~ 1 and ~ is C)~ S or ~ wher~ R is h~dro~en or Cl q,~ll~l, Z is (~2~ or ~ , r ~ 0, 1 or ~ or Ar is ~he correspondin~ tricyclic d~hydro n;la Sj'St~ r a ph~ceu~c~ly a~le s~ A~Of' in ths~ ac~ of medicament fo~ th~ ~ent ~ eonditions rela~ t~ a~umula~ion of calcium ~n ~he b~ain cells of m~ls.
Prçfe~ably n is 4f 5 or 6f most p~erably 5.

Proferably q is 6 to ~, most pr~erably 7.
Wnen s is o~ner ~an ze~ Rl preIe~ablg repre~nts C:1~6alk$ 1, such as m~nyl.

X pT~er~lv represe~s oxyge~
bs~e~ r~p Ph(-~2~ 2~P~ St ,~ p~ably ~x~
o or a ~on~ When ~ is oxyg~n p is pre~erably zero and m is prefe~ably z~ro or 1, When Y
is a bond the sum of m+~ is preferably 1 or 2. ~hen Y re~sents C~, m ~nd p are prefcrably ~th ~ro.
Preferably Ar is phenyl mon~subsdtuted by phenoxy, ben~yl, benzyloxy or halo;
phenyl disubs~tuted by halo; or Ar is 2 dibenzofuranyl. M~st pxef~rably A~ is phcnyl ~s subs~tuted by ben~yl or benzyloxy.
~ .~ampies or ~sicyciic het~aryl ~çroups includ~ aibç~wIuraIlyl~ ai~nwti~icnyi, carba~ole, N-n:lethylcarbazole, ~dine and dibcrl~oxep~ne. The tricyelic moic~ can be linked to the remainder of formula (I) via any suitable r~ng atom.
Suitable subs~t~le~ for Ph, and triic~lic hoteroaryl groups ~ncludol for example, 30 1 to 3 subs~tuents selected f~m halogen, ~uorometbyl, ~fluo~ome~hoxy, C~ 4alkyl and Cl Aalkoxy.
~ 1 ~oups present in the compounds of fo~mula (I), alone or as par~ of anothcr group, can be straight or branched. Thus, a Cl 6aL~ oup may be for example methyl, e~yl, ~-propyl, n-bu~yl, n-pcn~l, n-hexyl or any branched isome~ ~er~f sucb as 35 isop~opyl, t-butyl, ~ C-pCDyl.

Wo 93/22302 ~13 3 9 8 '~ PCr/GB93/00801 ~ 3 -It will be apprecia~ed that for use in medicine a salt of a compoulld (I) should be pharmaceu~ically acceptable. ~amples of phalmaceuticall~ acceptable salts include ~ganic and o~ganic aad a dition salts such a~ h~hl~ide, hydrobromide, sulphate, pllosphate, acetatc~ fuma~ate, maleate, citratc, l~ctate, ~ate, o~alate, methanosulphonate S o~ similarpha~maceutically acceptable in~gan~c or otga~lic acid add~on ~alts. Other non~
pha~ac~utically aecepta~le salts m~g b~ used ~ exa~ple ~ the isolation of th~ final produat and are included w~thin tho sc~po o~ inven~on~
It ~ be appr~cia~l ~1 the cox~po~ds o~ fc rmula ~I) maS~ contain one or more asy~e~ric cen~res. Suah compoh~ds will ~ist as ~pdc~l isom~rs (enan~orr ers). Bo~b the 10 pure ~n~ome~ m~c mix~res ~$0% of ea~h ~n~tiame~ d lmeqllal rnixnL~s af the two arc ~ncluded wi~n~n t~e seope of the in~o~on. F~ ;e~l all diaste~or~:~r.c ~ms possible (pure enanliomels a~d mi~se~ ther~of) a~ within the ~copa ~ the ~nvention.
Ce~ compounds of ~or~ula (I) are ~lieYed to be n~vel. Thus, in a f~er aspect the invention pro~ides a ~ompo~nd of ~ a (~

.

~ 1 (~Ha)n Nu~12)q~X Ar Formllla (IA) in which n, q, Rl, s and X are as defincd for formula (I) and Arl is an op~onally substituted t~icyclic heteroaryl group as d~fin~ for formula (I);
or a sa}t thereof.
^5 ~ ~ y~t ~es ~t t:he L~ve~on ~ provides a comDound of ~ormllla (l~

f~k )~
~N~ 2),X4 F~rmula (IB) 3~
wherein Rl, s, n Md X are as de~ed for farmula (I) and Ar2 repTesents phcnyl op~onally subs~ted by a group Ph-(CH2)mY(CH2)p- o~ a aicyclic heteroaryl ~roup as defined for fo~ula (I)? C~ a salt thereof.

wo 93/22302 ~13 3 9 g ~ pcr/GB93/oo8o~

In the compounds of fDImula (DB) n is preferably ~om 4 to 6~ most preferably 5.
X p~erably re~resents ~xygen. When s is other than z~r~, Rl prefe~ably rcpresents Cl~l. Ar2 prefe~ably re~resents phenyl subs~tuted by a ~oup Ph(~I~)mY(CH2)p-.
Most prefesably Ar2 represents phenyl s~bs~cd by phenoxy, berlzyl or bcnzyloxy. In s gen~al the phenyl subs~cn$ ~rill pre~cxlbly be at the 4-position of the phenyl ring r~la~v~ e group ~C.
~ mpo~ds of f~rmulae ~) and (~B) represent n~vel ~nd advantageo selee~ons on the basis o~ ~heir a~vi~ as calc~um ch~cl an~go~sts.
Pa~cul~r compouD~ ~f tbe inven~on, which are believed to be novel cotnpounds O includc:
7-phenoxy-l~pip¢ridinoheptan~, 7-(~fluvrophenoxy)~l-piper~dinohep~ano, 7~(2,~diehloroph~noxy)~1-pipendinohep~net 7-t~phenox$fphenoxy)~1~pipexidinohep~e, 7-(3-phcnoxyphenvxy~ pipeddinohcp~anc, 7~(2~dibenzo~nyloxy)~1-pipendinohep ~ e, 7-(4~nzyloxyphenoxy)~l~piperidinoheptane, N~ (~benzyloxyphenoxy)hepty~-hexamethylen~im~rle, 20 9-(3,4-dichlornphenoxy)-l-pipcridinononan~, 9-(4-benzyloxyphenoxy)-l-pipe~dinon~nane, 8-(~benzyloxyphenoxy)~l~piper~dinoootane, 8-(4-phenoxyphenoxy)-l-pipe~dinooctarle~
benzyloxyphenoxy)-l-piper~inohe%ane, 2s 7-~4-[2~ hlorophenyl)ethylJphenoxy)~l piperidinohepta~e, srans-7-{4-(2-phenyledlenyl)phonoxy]~l-piper~dinoheptane, 7~(2-phenylethyl)phenoxy]-1-pip~ridinohcptane~
7-(4 benzylpn~noxy)-l~pipendinoheptanc, 7-(2-benzylphenoxy~-l-piperidirlobeptane, 30 7-(~med~oxyphenoxy~-1-pipe~idinoheptane, 7-(~1ert-buylphenoxy)-l-pipendinoheptane, WO 93/22302 ~13 3 ~ ~ ~ PCr/GB93/00801 7-(3,~-methylenedioxyphenoxy) l-pipe~idinohept~ne, 7-[~(3,~dic~ benzyl~xy)phenoxy~-1-pi~dilloheptane, 7-~(~methoxybenzyloxy)phenoxy~ pipcndiIloheptane, 7-~(~fluo~o~nzyloxy)phonox~]~l-pi~L;noh~ptan~, 5 N-p-(~benz~lo~ypheno~y~hep~ 2-meth~rlpi~fidine, N-r7-(4-ben~loxyphenoxy)hep~ 3-methylpip~ridine, N-~7-(4-benzyloxyphcnoxy3h~ 4~methylpip~idirle, N~7-(~benzyloxyphenoxy)h~pt$ l~ thylpiper~dinc, N-~7-(~benzylo~yphelloxy)h~lJ~methoxspip~r~dine, and 0 $-(4-benzyl~yph~noxy)~l~piper~din~pentane, and phar~aceu~ca~y acceptable s~ hereof.
~ he compolmLt.~ of the prese~t lnverl~on aan be prepared by p~cess~s analogous to those ~cnown ~ ~he a~ Th~ present ~nvention the~fsr~ prov~des in a fur~her aspcc~, a process for dle preparadon of a novel ~ompound of fo~mula ~I) in par~culas a compo~md 15 of formula (~A) or (lB) which compnses:

(a) reac~aon of a compound of ~o~ula (II):

~,~(~ )O
N ~CH2~-L

Formula (11) in which n, Rl, s and q a~e as dcfined in fonnula (LA) and L~ is a ~roup displaceable w~th a nucleophile wi~ a compound of fo~nula (XlI):
2~
Ar3-a~H

Fo~mula (m) 30 in ~hich X is as de~incd in fonnula (IA) and Ar3 rcpresents Arl when q is as deined in folmula (IA~ or Ar2 when q is 7;

Wo 93/22302 ~, 13 3 .~ ~ 4 pcr/GB~3/oo8o1 (b) reac~ion of a co~pound of formula Cl~):

Ar3~ L~

Fo~mlla (XV) ~r~ which ~ and q are as defined ~r fo~lu1a (~A), Ar3 is as de~ined Por f~ula (m~ and L~ nng ~oup, ~th ~ compowid of ~aul~ ~):

~1 NH

Formtlla ~V) h which n, Rl and s are as defin~ in f~rmula CLA); or (c) reduc~on of an am~de of f~mllla (~) or (~):

` 1 f~,(R )4 ~C~H2),t.1 /N (C~)qXAr \~0 : ~0 Formula ~1) ~ 2)n N~Cff2)q~1Xa~r Formula (V~) 2~
wherGin Rl, s, D, q, X and Ar3 ue a~ defincd abo~re;
d) Reduc~vo a~n25On of an ~Idehyde of fo~ula (Vm):

wo 93/223n2 2 ~ 3 3 9 ~ ~ PCI/GB93/00801 ~C~(C~2,)q l~3 ~nnula ~m) S whe~ein q, X and ~3 ar~ as herv~nbcfore de~ed, ~n thc prcsen~ of a compouIId of fo~ula (V) as defined above.

e) Ib prepa~e a compo~d where~ Ar3 r~prexents phonyl substitut~d by Ph(~2)mO-~ alkyla~on of a cv~po~d o ~ul (R )~

~N~(CH2)~,X~

~ormul~
where~ Rl, s, n, q and X arv as h~re~nboforo defined; w~th an alkyla~ng agent of formuln (X):
Ph(C~2)~L
Iformul~
where~ Ph, r~ and Ll are as h~befor~ d~iinod.
f) To prepaTe a compound wh~xe n is 5, redu~on of ~ pyridine deri~a~dve of f~lmula (a~

/
~,N~ 2) f~rmul~
whe~ein Rl, s, q, X and ~Ar3 a~e as he~in~for~ defined and A- is a counter anion;

g) L~lterconversion of one compound of formula (I) to a di~ent compound of fo~mula (I) o.g. ~educ~rl of a compound whe~e~ Y represents CH~ ~o a compound 3~ wherei~ Y ~es~ 2~H2-;

WO 93/22302 PCr/GB93/00801 . i~
~ ~ 3 ~ 8 -followed if desired by salt f~a~on.
~ proeess (a) th¢ ~on betwce~l a compound of fom~ula ~Il) and a compound o~ fa~ula (~I) can bo cam~d ou~ a~nder s~andar~ condi1dons. Por example when Ll is S hydroxy, the ~on is carr~ed out o p~esellce of diethyl azodiearboxylatc and ~ .
~iphcnyl phosphine. Such a xcac~on is hlown as ~ ~itsunobu reaction (as descnbedSynthcsis 1981, 1). This r~a~don may op~onally be e~ected ~n the presencc of a solvont such a5 tetrahydrofuran. Al~a~voly tho lea~ng ~up Ll may be f~r examplG a balogen atom o~ a sulphorlyloxy group eg. methanc-su:lphvnyloxy or p-~luene s~lphonyloxy. In lo ~is case the r~on may be e:~ctcd ~ ~he abs~nce ~ ~esence ~ solvcnt such as dimclhyl~G~amide or methyle~hylkc~ne i~ thG presonee sr a base such as sodi~n hyd~ide potassium c~oaate ~d at a temp~a~ ~ the range O to 200~C.
The ~eac~oa of a compound o~ f~ula (~) ~th ~ compound of ~ormula (V) acco~ding to p~cess ~ e ef~ccted in comen~onal manner, for example using excess am~ne as solvent or ~l~rna~voly using an o~an~c sol~en~ such ~s e~hanol or dimethylfo~mam~de. The lea~ing ~Lp L~ rtsay be ~or examplc a halide such as ~romlde or ~hlo~xde, an a~yloxy ~up such ~ acetoxy or chl~raacetaxs~ ~ ~ sulphonylox~ group such as methanesulphonyloxy or p~luenesulphonyloxy. The reaction is prefe~ablSI
Carrled OUt h ~e preserlce of a base suGh as potasshlm carbaxlatc~ sodi~ hydzide or ~eaucnon o~ an amide according t~ p~CSS ~C) may oe errec~ea usmg a sul~able redu~ng agent sueh as li~ium aluminium hydride.
I~ proc~ss ~d) redu~vo am~na~n of a~ aldehyd~ (Vm) may be effeet~d us~ng a reducing agont such as sod~um cyanoba~hydride in the presence of a compound of 2s formula (V), according to pr~cedur~s well ~nown ~n the art.
In process (o) the rcac~don o~ compounds (IX) and (~) may be effected in ar analogous manner tv process ~a) desc~ibed above.
Reductlon o~ a py~dinium dcnva~ve (XI) acc~rding to pr~cess (f) may be ef~ected for example by hyclrogena~on, using a noble metal catalyst such as palladium on charcoal, pla~num or plat~um o~de (Adam's catalyst)~ su~ably ~n a solvent such as an alcohol e.g. ethanol. ~ :
Interconversion reac~ons according to pr~ess (g) may be cani~d aut using standard methods. Thus ~or example conversion of a compound (I) wherein ~ represents into a compound (r) wher~n Y rep~sents -CH2CH2- may be effected by 3s cataly~ hydrogena~on.
A c~mpound of formula (lI) can be prepa~ed und~ standard alkyla~on c~nditions by rea~ting a compound of formula (X~
.

W093/22302 ~ pcr/GB93/oo8ol L~(CH2)q~L

Fo~nula (~

5 in which Ll. L2 and q a~ as heroinbeor~ defined, ~i~ a c~mp~lmd of f~mula (V) as he~einbef~rc def~ned. Th~ reac~on is su~tably ca~r~ed out ~nder analogolls condi~o~s to those de~d a~ove fo~process ~b).
It l1vill ~ apprc~ia~od that ~n ~mpolmds of ~ a ~) thc l~a~g ~roups L~
and L~ arv prçfesably s~ ~ s~ that tho compo~d ~ formula ~) ~eac~s s~lec~vely ~vith 10 L~. For e~camplet in a c~d of ~r~ula ~) L 1 is su~tabl~ h~rdroxy alld L~ is sui~ably halo.
(:~mpounds of ~o~mula ~I) ar~ cammerciall~f ~vailable ~ may b~ prepared u~g stand~d proced~as welI ~no~rn ~n the a~
Compo~nds of f~rmula (rv~ c~ b~ ~pared by ~ea~g a compou~d of f~ul~
lS (IrI) as he~ fore d~f;ned w~th a compoulld c~ mula ~) as hereinbefc ro de~ined.
In tbis rea~hon bo~ Ll and L2 can b~ id~ntical, ~ example halo. Th~ reac~on is sul~ably camcd out in the presence o~ a wca~ bas~ such as ~sium c~nate. Al~natively the reac~on may be ca~Tiçd out unde~ phas~ erans~r condi~ons us~ng a s~ng bas~ such as potassium hy~x~d~.
2~ Compo~ds of ~ula ~V) as~d ~) ase ~^~.. 1211y ~ai~ble c r ~ay be ~epared by stan~ara me~nods.
Compounds of ~ula (V~ y be ~pa~d ac~ding to ger~ral p~esses (a) and (b~ descnbed her~in esnplo~g a~ appr~ de co~s~ g to f~llla ~) ar (~r).
Compounds of fo~ula (Y~) n~y be prepa~ed by acyl~on of a corllpound of fo~ula ('V) for example w~th an appropnate ac~d chl~r~dc or es~, whieh may itself be prepa~cd ~m a compound of formula (m~ by r~ on w~ an appropriate, commere~nlly available bromo~yl ~s~ c r acid, followed if neccssary or dosired by conversion to an a~id chlo~ide. Alterna~ely a compou~d ~ may be pr~pared by a method ~nalogous toprocoss (a).
AI1 aldehy~e of fon~lula ~ may be prepa~d for ex~mple by reduc~on of the coq~esponding ni~ile using a ~du~g agont such as diisobutyl alu~nium hydride, an the prosence of an inert so~vcnt such as toluene. Conven~cntly reduc~ve amina~on o~ the aldehydc is car~ied out ~r ~. i.e. the compound of fo~mula (I) is obtained from the nitsile 3s in a one-potreaction wi~out isola~on of the intesmediate aldehyde. The r~i~rile may itself bc p~pasd by ~eac~ng a compound of fon~ula (IY) whesc~n L2 is halo with potassium cyax~ide. Compounds (Vm) may also be prepared by other standard procedu~es such as redu~on of an estcr or o~idation of an alcohol.

WO 93t22302 PCr/GB93/00801 ~ :
~ ~33~ o~ ` ;

Compounds of f~mula (I:;~) may be p~epared by me~hods analogous to any of p~cesses (a) ~ (d) desc~ d he~ein. Altema~vely a compou~d (IX) may be obtained by catal~c hydrogena~on of a corresponding compolmd of formula (I) where~n Ar represents a benzyloxyphenyl group. This theref~re p~ov~des a furthor method of convs~ng a s compound of formula a) t~ a different compo~d of ~rmula (I).
Compounds of fa~mula (~ nay also ~e prepared ~ a similar manner to p~esses (a) to (d) described above.
When a compound o~ formula (~A) or (~) is ob~d as a m~xr~ of en~n~om~s, these may be s~p~d by conv~n~onal meth~ds su~h as cr~stallis~on Ln the 0 pz~sence ~ a ~sol~Lng ag~ntt or chr~r~at~raphy, ~or cxample us~ a chiral ~PLC
colu~nn.
It ~All be apprecia~ ~hat w~t the u~ mcdiatos of ~ormulao (~) to (~ e d~ined w~th rc~ésencç to formulae ~) and (~3), the abovo p~cesses can ~e used toprepare any othcr n~vel compoun e scope of ~mula ~ and the prescnt 15 inv0ndon extends to the p~eparati~n of such compo~ds.
Thc ~nventi~n also encompass~s any n~el lnt~cdiates des~bed he~ein, la par~cular thosG of ~ormulae ~), (~), (VI), ~, (~X) and (~.
Com~ounds of ~e invcnti~n havc b~en found ~ cxhibi~ high cal~u~ influx blocl~lg a~rity, f~ example in neu~ons. As such the comp~unds arc oxpectcd to be of 20 use ;~ thc~ ;~ ;r~r.g ~nd~ d dlsc~sGs r~at~d t~ a~ acc~ lætion ~f c~!cillm ~nthe b~ain cells of mamma~s. m p~cuiar n~an~. ~or exampio, ~ile c~mpolmds ~re expected to be of use Ln the ~eatmeslt of anox~a, ischaem~a ~cluding for ex~mple s~ke, mi~e, viseeral paLn, cpilcpsy, ~ c head or sp~:naI ~njury, AIl)S~sela~d demen~, neurodegcnera~ve dis~os such as Alzheimer's discase and age rcla~cd memor~ disardels, ~S mood diso~dcrs and drug addiction w~thdrawa~ such as e :hanol addic~on w~thdrawal.
Par~eu1arly prefe~ed compounds ac~ording to the present invention a~e 7-t4-benzylphenoxy)~l-pi~dinoheptane and 7-t~bcnzylox~phenoxy)-l^pi~dinQhcp~e (which may also be named as l~p~ ben~rlphcnoxy)hoptyI~piperidine and l-p-(~
bcnzyloxyphenoxy)heptyl]pipcridine) and pharmaceutically acceptable salts thereo~.
30 These compounds poten~ly inhibit Ca2~ c~ent par~cularly ~n neur~nal cba~nels. The comp~unds also demons~te neu~oprotectivc effects ~n ~arious animal models of ischa~mia, when adminis~red post-ischacmi~
The in~fcn~on also pro~r~des a me~od of treatment of condi~ons or diseases rela~d to (e.g. causcd or exac~bated by) the accumula~on of calcilL~ in ~c brain cells of 35 mammals which comprises administenng to a subjecs in need thercof a~l e~fec~ve amowlt of a compound of formula (I) as her~inbefore defi~ed or a pha~maceu~cally acceptable salt d~eof.

. .

Wo 93/22302 ~ l ~ 3 ~ PCr/GB93/00801 Thus for exan~le, the present invention pro vides a meth~ of ~eatment of anoxia"scha~a includirlg for exaDIple stroke, mi~e, visceral pain, epilepsy, ~auma~c h~ ~ sp~nal injurSr, A~S-~elated demen~a, ncurodegcnera~e diseases such as Alzheime~s diSeasG and age~related m&m~y disorde~s, mood disorders and drug ::
s addietion withdraw~l such as etha~ol addic~on w~thdrawal, which compr~ses admin~t~g to a subject ~n need tbe~eoft an e~eeti~!e, amount ~ a compound of ~on~ula (I) or a pharma~etl~cally ~ceep~ablc salt ~ereof.
Pot use in medi~ne, tho c~mpolmds af the presen~ L vention are usually a~mirlistered in a stasldard ph~rmaceutical camposi~on. The p~s~nt ~llwn~on therefore 0 provides in a furth~ asp~bt pharmac6udcal eompos~tiatls c~mp~sing a novcl compaund of fosmula (I) as he~inberore de~cd o~ a ph~ceudca~ly accep~blo s~lt th~ and a phannaceu~cally acceptable ca~r~es or exclpient.
The compo~ads o the in~en~on may be ~inistered ~y any co~venient method :~
for example by oral, parenteral, buccal, reet~ or ~ansdermal administration and the pharmaceu~cal composi~ons adapted accordingly. Parenteral admiDis~ation is generally preferred.
The compounds of formula (I~ and their ph~rmaceu~cally accepta~le salts which are acdve when g~en orally can be formlllat~ as liquids or solids9 ~r exa~ple syrups, -suspensions or ~mulsions, table~, capsul~s a~d lozenges.
A li4uid f~a~on ~ ~ly ~ns~ss of s~s~on or salu~n of ~be cornp~und ~r phan~e~cally acceptaole salt ~ a suita~ie ii~d cameT~s; ~ar ~la, e~anol, glycenne, non-aque~us solven~, for cxample polycthylene glycol, oils, or water with a suspending ag~t, proserva~e, ~ ~o~g or colou~g agen~ :
A composi~on ~n thc form of a tablet can b~ prepared using any slL~table 2s pharmaceu~cal ca~mes(s) rou~nely used for preparing solid formul~ons. Examples of such ca~ie~s ~nclude magnesium stea~ato, starch, lac~se, sucroso and cellulosc.
A composition in the form of a capsule can be pr~pa~d us~ng rou~nc encapsula~on p~ocedures. ~or cxample, ~llets containing the ac~ve in~ient can beprepared using stan~ ca~riers and thon filled into a hard gelatin capsule; alternatively, a dispersion or suspensic~n can be prepared us~g any suitable phaTmaceutical ca~rier(s), ~or example aqueous gums, celluloses, silicates or oils and the dispcrsion or suspcnsion then f;lled into a soft gelatin capsule.
Compounds o the invention may also be ~istered parentesally, ~y bolus injec~on or co~l~nuous in~us~. Typical pa~onte~al composi~ons consist of a solu~on o~
suspension of the com~und or ph~maceutically acceptabl~ salt in a stesile aqueous carrier o~ p~enterally acceptablc oiL fo~ exasnple polyetbylene glycol, poly vinyl pyrrolidone, lecithin, aIachis oil OI` sesame oil. Alterna~vely, the soludon ca~ be lyophilised and then recons~nlt~d with a suitable solvent just prior to administration.

WO 93/22302 ~13 3 5 ~ ~ PCr/GR93/V0801 Bo~ uid and solid composi~ons m~y contain other excipients known in thc ph~eu~dc~l ~, such as cyclodex~ins~
Preferably the co~posi~on is ~rl un~t dose form such as a tablet, capsule or ampoule.
s Bach dosage un~t f~ ~1 ad~nistra~on cantains preferably *om 1 to 250 mg (and for par~ntczal adminis~a~;on cont~ins pre~bly ~m 0.1 to 60 mg) of a comp~ d~R ~he fo~u~ a~ or a ph~eu~cally acceptable ~t the~eof calculat~d as the frec base.
Ibe daily dosage neg~men for an ad~t p~ont may bo, f~ cxample, an oral ~se of between 1 m~ and ~00 m~ ferably b~t~een 1 mg and ~50 rn~, e~. S ~o ~00 ~g or an 0 i~travenous, subcutaneous, or in~amuscular doss of ~tween 0.1 ~g and 100 mg, ~rably betwe~n 0.1 mg and 60 mgl e~. 1 to 40 mg Ot ~e compo~d of ~he form~a (X~
ar a pha~ceu~cally a~c~table salt th~f aa~culatad ~ thc ~ec base, thc compound bc~ng adminis~d 1 to 4 ~mos pe~ day. Alt~ vely the co~npounds of thc in~ention ~y ~ adminis~ by corltinuous ~nt~ensus infusion, p~e~erably at a dose of up t~
~ mg per day. Thus d~o to~l daily dosage by ora~ administra~oll c~d be ~n ~he ~ge 1 to 2000 mg and the total daily dosage by pa~enteral ad~nis~ation cotlld be in the r~nge 0.1 to 400 mg. The compound~ may bo ~ru~t~red for a peAod of con~nuous therap~, for example for a we~k or m~re.
desi~ed a compound of ~smula a) or a ph~rmacou~ally acceptable ~alt th~f ~y ~c a~rl~s~ sbi~on o~ c3n~ ntly w~th on~ ~ m~ ath~ ~e~c agents, f~ example a tns~m~iyi~c ag~n~ sucn as anistrcplase, s~rGptoK~ase o~ a ~ssuo ~: plasm~nogen a~ator, an excitatory am~no acid ant3gon~t su~h as an ~A an~gon~sts;
a ~ree radlcal ~hibi~or, or a calpah~ ~hibitor.

WO 93/22302 ~ 1 3 3 ~ ~ ~1. PCI /GB93/008Q1 ~ 13-BIOLOG~CAL l)ATA

l~ Vitro S Ca2~ Curr~nt M~rement Cell pFepar~tia~s SensoIy neurons f~m d~al root gall~lia we~ di~ ~ated f~m 1 day old ~at pups (Forda et al, l:~cvelopme~ Bra~n E~sea~h, ~2 ~l985~, SS-65). (:~lls w~ plat~d out onto glass c~v~rslips and used withi~ 3 days to ~t e~foe :iv~ voltag~ alamp o~ Ca~ currents, Solu~ons The pipettc (inte~nal s~lu~on) ~n~ined ~n n~[: CsCl, 130; E~ES, la; EGT~, la;
Mg~, 4; ATP, ~; bufercd t~pH 7.2 v~ CsOEI. ~ells wc~e bathed in a normal Ty~des solu~an bef~e establishment of whola c~l reaording when the bathing s~ution was changcd ~ onc allow~g isolation of ~a~ curren~s. The çxtemal s~lu~on for r~cc1rding Ca~ channcl c~rents cantai~cd ~n mM: : 3aCL2, 10; TEA~C1, 130; glucose, 10; HEP13S, 10; MgCL2, 1; buifer~d to pH 7.3 w~th l~;A~OH. Ban~n was used as the ~;
chargo ca~r~er as this assists ~n current isola~n and calc~uxn depondant ~nac~va~ion of Cl~eM iS aYoided. C~mpoU;ldS W^._ ~ssol~ d in D~ o m~ ~ ~ mM s~ck ss: lu~on. At thc drug concenmltlon us~ ~no venicie ~0.i~/oj i~aa no ~.,~ ~ n Ca2~ c~Tell~s. All e~ents wem pc;f~ed at ~ ~ ~o 24C. Whole eell currents were reco~ded us~ng List ~ 7 ar~lifiers and stored, d~gi~sed f~ lat~r a~lys~s us3ng PC
based sof~wa~ similar to dlat descr~bed prg~iousl~ ~Benham & Tsien, Jo~nal of 2s Physiology (1~88j~ 404, 767~784).

~Ca~ currents Peak voltage gated Ca2~ chaMel cu~ents of up to 10 nA ~m d~sal ~o~ ganglion ~eurons were recorded us~ng 10 ~ Ba2~ as charge c~er. ~rents we~ evoked from 30 a holding poten~al of -80 mV to a test poten~al of 0 or ~10 mV e~ery 15 seconds. This test pot~dal was at the ~ of the current ~oltage relationship and assessing block at this poht ~uced any e~rors due tO d~if'ting hol~g potential. Some cells showed 51OW
rundown of c~scnt as is commonly se~n when recording Ca2~ currents. The $undown ~ate was measured in control condi~ons and ext:rapola~d through the ~me of drug 3s applica~on to denve a con~ol value to :rclate the drug affected current to. Block by 20 ~1 drug was assessed 3 minutes a~es drug applica~on.

.

~,~33g~
WO 93/2~302 pcr/cB93/oo8 Compounds of the inYen~on gave perc~n~age ~hibition of plateau Ca2~ cur~ent Ln the range 35~100%

~ o s Test ~ompound A - 7 (4~B0n~yloxgpheno~y)~1~ pi,wridinoh~ptan~ hydrwbloride Test c~mpound B _ 7~(4~Be~ylphealo~y)~l~p~p0ridilloh~pt~sle hydr~hloride Gerbil B(:AO Model M~le Mong~liaD g~rbils wG~gh~na betwecn ~80 g w~e anaesth~ised with h~lothane, 10 placed on a hea~l mat and the ~arodd ~cs ~cluded. Aft~ repe~fusion, the alli~al5 wcre su~red and pla~ed in an ~ncubator malllt~ed at ~dy ~empera~e until r~cry.
Thc animals we~ then caged sepa~tely and on the 4tb day a~t~r the day of surgery, thcy wcr~ assesscd for loGomot~ a~ty using an autoxr ated locomotor acti~y mon~tonng system. The dosLng p~otocol ~ th~se ex~ents was 3û :ninutes post~ischaemia then lS b.i.d. f~r 3 days, Lnjections be~ng g~vcn ~ ho i.p. xoute. Two sets of experiraerlts we~
c~ied out. In the ffrst thG duration of occlusian was 8 minutcs and test compound A was gi~en 10 mg.kg-~ or 3 mg.kg-l using the abovo dosing regime. Ln tho second exporimontl :
10 minutes of occlusion was used alld 30 mg.kg~l of tcst comp~unds A and B
admil~LiSte~ed 30 ~utes post-ischaemia ~l~wcd by 10 mg.K~l b.i.d. ror 3 days.

Ln the 8 minu~ iod of ischaerc~a expe~imont test compound A at 10 mg.kg-l pr~duced ~ Si~iflCa~lt mtersal of the histolog.ical impalrmcnt in the t: Al reg.ion of dle hippocamplls seen ~n the ischae~c vehicle~ated animals. This dose also p~duccci a slight, though s~a8stically non-significant, revcrsal of the ischa~m~a-induccd hypeslocomotion. Iho 25 highe~ dose of tcst compouulds A and B used in the second ox~ent pr~duced a si~ihcant reversal of the lo~oD:~otvr dehcit hlduced by the 10 m~slute period of ischaem~a, but did not pr~duce a stads~ically significant effect on his~ology.

Rat Rose Bengal Mbdel ~fale Listes Hooded rats (250-280 g) anaesthe~sed with halothane were posi~oned in a st~reo~c fs~me. Rectal tempesature was ma~ntaLned at 39t~ skull was exposed ;~
and a bif~ated fibre op~c light g ~ide (3.0 mm diameter3 ~om a 300 w xenon arc lamp was posi~on~ to the sl~ull at Bregma in the antcr~or-pos~es~or plane in a holder desi~ed 35 to cont:re the heads o~ the Ught guides 2.5 mm to the left and r~ght of the m~dline. Rose .

Wo s3~22302 ~ PCr/GB93/00801 bengal (20 mg.kg~l) was Lnje~ted into a latc~al tail ~ein~ The skull was iLl~ated for S minutes, aftcr which the wound was sutured and anaes~hesia discon~nued.

Test eompounds were administer~ i.p. at 30 r~g.kg~l 10 ~x~nut0s po~t-opera~vely,S foll~wed by a ~urthes dose of 10 mg,~g~ l onç hour pc st surgery and then tw~ce d~ily f~r three days. A 75% I~dUGtiC~n 1~ lesion volumo was ~bserved ~ mpound A.

At th~ aboYe ~oses of Comp~unds A ~d ~ ~s~ed, no ad~e~se ~o~colog~Gal effects were obscr~
Cardiovassular S~r~ll Male Lister ~I~dGd ~ats we~ znaosth~tised w~th sodium pentobaJrbitone (~ mg.kg-l i.p.).
The effec~s on diastolic blood p~ssur~ a~d hcart rat~ w~re rn~sured OVG~ the dsug in~usîon. Test compound A ~10 mg.kg~l dissolvcd ~n 10% ~ l)), was i~used ove~ 3015 minutes. Minor press~r effe~tsf 8imilaI to thOBe æon in v~h~cle ~eated nnimals, wese observed, tc)g~ther w~th min~ ~u~ons i~ h~art rate. These results indica~e ~hat the compound was w~thout signi~cant cardiovascular ef~c~ at the dose tested.

C~mpounds of formula (I) have been fo~nd tv exhibig ~d brairl-ponetrant prope~os.

W~ 93t22302 .~ 1~ 3 9 ~ ~ pC~ 93/OO~Ol l--PHAIRMAC~E~JTIC~ FORMULATXC)N8 1. Fo~mllation Sor inh a~now in~u~ion ~mpound of ~oImula (I) 0.1 ~ 60 mg ~odium hydrox~de/hy~hlcn~a acid ~n pH ca 7 po1yethy1ene g1yco1 0 - 30 ml ~pylene dycol O ~ 30 ml alcohol 0 ~ 10 m~
watcI to 10a ml 2., Formul~tion for b~lus in,~ection Compound ~f f~ la ~I) 0.1 ~ 60 mg sodium hydro%ide ~ hy~chlc~c ~ to p~ c~ 7 polye~yl~ne glycol 0 ~ 2.5 ml alcohol O ~ 2.5 ml waler tO 5 ml ~, ~
A tonici~ a~ent e~ di~ chlQ~dc, d~x~se ~ ~nas~1 may a~so bc ~ , 3. Tablet t~r oral admi~istratio .

m~ltablet Compound of fo~mula (I) 25 lac~se 1~3 starch 3~
crospovidone 12 ; ~ 30 mi~crystalline cellulose 30 magrlesium stearate ::

Wo 93/22302 PCr/GB~3/0080l ~133~ 17-~xamples Lntermediate prep~rs~on~

5 1) 7~PiperidiYIohep~nol 7-Bromohep~ol (S.ûg) was added ov~ 30 mirlu~es to pipe~ (20ml) s~rred at ro~m temperature. The resul~ng mi~ w~ fc to s~nd ~or 60 hau~ and dl~ disso1ved Ln chl~ofo~. This solu~on was washed ~nth dllu~ s~dium hyd~ox~de s~u~on, ~rino 0 c~ntaining a few dr~p~ of dilute sodium hy~d~ solu~n alld dried ov~r magnesiumsulphate. The solv~nt was ~emovcd and ~c r~sidue was ~ugeirohr dis~ll~ tO ~e ~e ~tle compollnd as a solid ~4.53g) m.p. 37~3gC

Bromo~7 (~ Dibenzofi~ lo~y)hep :ane A m~xture of 1,7-dibromoheptane t8.5g), 2-hydroxydibenzofuran ~4.66g), potassiumcar~nate (6.91g) and butan-2 one (lOOml) was he~ted at reflux temperature for 18 hours.
The m~xture was filtered and tbe filtrate was evap~ted. ~e r~sidue was pax~nonedbe~vee~ ehlo~fo~m and dilute s~um h~rdroxide. The cb~a~m laycr was separated, 20 wasned wi~ D~ine, drie~ aver mag;nesi~ s~ph~ d ~ ~lve3~ vas ~m~ e ~sidue was suspos~d~ ~n boiling hexano ~l~)t and filterea, an~ ate was a~iow~a tO cool. The precipi~ate was ~llcc~d by ~ on to g~ve tho title, compound ~1.89g) m.p.
65-70~C which was us d wnhout ~cr puri~ca~ion. The ~l~ate was e~apo~ated tO giVCa secon~ c~op of ~e ti~e compourld (5.82g).
2s 3) 7~(4 Benz~lo~ypheno~ bro~heptane 1,7-Dibr~moheptano (12.9g) was ~ed dropw~se tO a stirrcd soluion ~f ~
be~loxyphenol (lOg), sodiurn hydroxide (2.5g~, benzy}~ethylammonium chlo~de 30 (0.4g) and water (30ml)~ The mixture was s~ at SO~ for 18 hours, water (50ml) added and the solu~on extrac~d w~th dichloromethane (2 x lOOml). The combined dichloro~ethane ex~wts wcre dried over magnesium sulphate~ solvent was removed and the residue was cbrom~tographed on silica gel eluted w~th hexane/~ichloromethane to giYe the ~tle compouIId (4.25g) as a soli~ m.p. 56 - 59C.
: ~ 35 :

WO 93/22302 ;~L33 ~ ~ PCr/GB93/00801 4) 6- Piper~dinoh0xanol The ~tle com~ound wa~s pTepared ir. a similar manner to ~nte~ediate 1 star~ng ~m 6~
bromohGxanol tlO.Og). Kugd~hr dis~llation (ovpn temperature 150~ @ 0.1 mmHg) gave S ~ tle compound as a clear oil, (~.a7g).

S) 8 Piper~di~ooct~nol The ~tle comp~und was ~epared ~n a s~nilar ~er to ~te~mediato 1 st~ng fr~m 8 10 ~omo~tanol (lO.Og). Kug~ la~on (o~en ternpe~ture 1~ ~ 0.1 mmHg) gave the ~tle cornpound as a whi~e solid, (9.~) m.p. ~5-r7~C.

6) 9~Piperidinonanol 5 The dtle compc)und wa~ prcpared ~n a similar rnanncr to Intermcdiate 1 stardng ~rom 9-bromononanol (S.Og). Eugclrohr dis~lIad~n (oven temperature 180~ ~ O.OS mmHg) gave thc titlc compound as a white solid, (4.632g) n:Lp. 53~55C.

7) 7~(4~Hydro~phen~xy)~l piper~dinoh~ptan~

~i ~ure OI 7-~Dcnzyiox~ cnoxy) i~pîp~ainoncp~ane (i3.Z~g)l ~o pa~aaium or c~on (0.5g), astd ethanol (250ml) was shaken ~der an atr~osphe~e of hydrogen a~ 50 p.s.i. for 16 hours. The catalyst was remored by fll~a~on a~d the ~ was evapora~ed.
The residue was recrystallis~ om aceton~trile, to g~re thc titlc eompound as a white 2S ~stalline solid (8.-38g), m.p. 106-106.5~C

Found: C, 74.03; ~I, 9.81; N, 4.93%
(ClgH2~N02~ICl) ~qu~es: C, 74.18; F~, 10~03; N, 4.81%

30 8) 1~[7-(4~Benzyloxypbenoxy)heptyl]~4~methoxypyr~dinumbrvmide .A solu~on of ~methoxypyndine (3.21g) and 7-~benzyloxyph~noxy)-1-b~moheptane (1 l.O9g) ir ethanol (lOOml) was heated at reflux fol 55 hours. The so1vent was removed, the residue was treated with ether and the ~esul~}g solid was collec~ed and ~ecrystallised 3s ~om acetonitrile to give the ~tle cou~ md (5.23g~ which was used WithOUI fu~
purifica~on.

WO 93/22302 ; - 19 - PCr/GB93/00801 9~ 5~(4-Beslzyloxyphenoxy) l bron~pentane , Substi~uting 1,5~dibromop~ ane (12.~g) ~r 1,7-dib~moheptane ~n lnte~mediate pr~para~orl 3 and using c~csponding molar p~p~ions of the o~her Teag nts gave the 5 titl~ c~mpound~ (11.60g) m.p. 45~C, which wa~ use~ without furth~s pu~calion.
10) 6 (4~Benzylvxypheno~r) l~lbromohe~ e .

A mixtD of 4-benzyl~x~honol (17.47~), l,~b~omohexa~e (26.9ml), 10 ~en~yltrimethylarrmonium chlos~de (1~03g~, s~iu~ h~drox~de, water (OOml) and dichloromethane (~5ml~ was s~sed and heatcd to 60~C and then reiluxed ~r 6 hours. The cooled m~xt~ was ex~act~d w~th dlchl~m~t~ane. The dlchl~mothano cxt~s were wæhcd w~th watcr, dried over s~iu}xl sulphate and ~c ~lvent was rorr oved. ~e residue was recrystallised ~vice ~rom hexane to g~ve the ~e eompound, (17.83g), IlLp. 74-76C.
S
Found: C~ 63.07; H, 6.25; Br, ~1.68%
(C15H23~ reql~res: (:, 6~.8~; .H, 6.38; B~, 22.00~o 11) 7~(4~Benzyloxyphelloxy)heptanellitrile ~o A m~xtur~ of 6~ ben~yloxyphcnoxy)~l~bramohexane ~lO.O~g), potassium cyan~de (1.79g) and dimethyl sulphox~d0 was ~ and heatcd at 6~C ~or 16 hours. Ih~ c~oledmixnlre wa~ poured ~nto water (lL). ThG ~pi~a~e was collected, washed with water and recrystal~ised f~m tolueno/hexane ~o ~e c~d~ compound (7.82g) -~
~5 Example 1 ' 7 Phenoxy~l~pipe~dinoheptane hydrocbloride 30 A s~ution OI 7-pipendinohept~nol (l.Og), phenol (0.48g), ~iphenylphos~hine (1.31g) in tetrahydrofuran (SOml) was treated wi~h died~yl awdicarboxylate (0.87g). ~le resul~ng solu~oll was stirred at r~om temperature f~ 18 hours, the solvent removed and the residue chr~matographed on silica gel eluted ~nth mothanoVdichloromethane. The sesul~g oil was dis ved i~ ethyl acetate (5~) and trcated ~ith ethereal hydrogen cblor~de. The 35 ~ecipi~ate was collected by filtra~on and r~c~yst;~llised (methanol/e~hyl acetate) to g~ve the dde compound (0.645g) as white needles, m.p. 154 - 155C.

wo 93/22302 ~, 13 3 ~ ~ ~ PC~/GB93/00801 .

Found: C, 6g.37; H, 9.62; N, 4.28; Cl, 11.11%.
(C1gH~gNO.HC1) requires: C, 69.32; ~I, 9.70; N, 4.49; Cl, 11.37%

E~mple 2 7 ~4~1Fluoropheno%y)~1~pip#riditloheptane ~drochloride The ~ compolmd was prep~ ~n a ~imilaI ~n~ to ~xample 1 ~ ng ~m 7 pipcr~diDohept~ol (l.Sg), ~lu~ph~nol (0.84g), ~phenylphosphin~ (1.97g) and diethyl 0 a~dicarboxylate (1.30g,); Cl~n~togr~hy on s~llca ~el 01uted ~rlth me~oUdichlor~me~ane asld ~ea~ent ~ e~hereal hy~gen chl~de ~ltowe~ by res~stallisi~n ~m e~hyl aceta~o~etharlol gav~ a whi~e solid,(l.~7g), m.p. 126~127~C.

Found: C, 6S.ll; ~I, 8.49; N, 4~19; Cl, 10!83~o 5 (C18~28F~C) HCl) ~equires: C, 65.54; ~, 8.86; N, 4.~!5; Cl, 10.75~o Exa~nple 3 7~(2941~1~ichlorophenoxy)~piperidi~aoheptane tl~drochlor~de lne nu~ compouna was propar~ in a sim~ar ~ncr tC) ~Xa~lpiC: i S~g Ir~m 7~
pipesidinohcpt~ol (l.Og), 2,~dichlorophenol (0.81g), tr;phenylphosphine (1.31g) and diethyl a~odicarboxyla~ (O.B7g). Chr~mato~aphy on s~lica g51 eluted wlth methanol/dichlorom~thane and ~eatment w~th ethe~eal hydkogen chlor~de gave a white 25 soli~ which was r~crystallised f~m acoton~ile, n:~.p. 17~178~C.

Found: C, 56.54; H, 7.03; N, 4.00; Cl, 28 3~qo (C18~7~2NQ-~ es: C~ $6.78; H, 7.41; N, 3.6B; Cl, Z7.93%

30 Example 4 7-(3,4~Dichlorophelloxy) l~piperidinoheptane hydr~chloride The ~le compound was prepa~ed in a simila~ manner to Examplc 1 star~ng f~om 7~
35 piperidinoheptanol (l.Og), 3,~dichlorophenol (0.81g), tnphellylphosphirle (1.31g) and diethyl azodicar~xylate (0.87g). Ch~mato~aph~ on silica gel eluted with me~hanolldichlorome~atle and trea~ment w~th eth~real hydrogen chloride gave a white solid which was recrysta~lised frorn medlaDoVethyl acetate, (1.27g)9 m.p. 139~141C.

WO g3~22302 PCI /Gs93/00801 ~1~393A 21 FoLuld: C, 56.G2; EI~ 7.06; N, 3.57; Cl, 27.64%
(ClgH27C12NC).~Cl)~uiKs: C, 56.78; H, 7.41; N, 3.68; Cl, 27.93%

S E~ample S
,.
7~(q Phen~yphello~ piperidinoh~p~e hydrochlorids Tho ~:itle c~mpound w~s prcpar~ in a similar ~ne~ t~ ~mplc 1 ~ ng fi~m 7 0 pip~r~din~heptanol ~l.Og), 4~phe~ p&onol ~0.93~), ~phenylphosphino (1.31g) a~d dicthyl azodicarboxylate (0.87g). C~graphy on siiica gel clut~d with methan~l/dichlc~aeth~ne ~d ~a~nt wi~ ethereal hydrogen chloride gav~ a whi~e sobd which wa~ r~rystallised ~ methan~V~ cctatet ~1.238), ~p. 176~178~C.

Found: C. 71.13; H, 8.20; N, 3.4~; Cl, 8~8()~o ~C~33N02~HCl) reql~ros: C, 71.35; ~, 8.48, N, 3.~; Cl, 8.77Yo .
E~ample 6 ~: ~Q 7~(3 Pheno~ypheno~)-l~piper~dinoheptane hydr~ch30ride l~e ude compound was ~ared ~n a similar ma~cr tO Example 1 s~ar~ng ~om 7~ ;
pipendirloheptanol ~1.Og), 3~phc~o~cyphenol (0.93g), ~phenylphos~ e tl-31g) and diedlyl a20dicarboxylate (0.87g). C~matography on s~lica gel 01utcd wlth 2s methanoUdichloromctb~ne and trea~ent w~th e~crcal hydrogen chlo~de gave a white solid which was re~ystallised f rom metha~ol/ethy~ acetate9 (0.8g4g)l m.p. 100~101C.
~: :
~ound: C, 71.23; H, 8.31; ~, 3.~; (::1, 8.94%
(C2~H33NO~-HCl~ ~lu~es: C, 71.35; H, 8.48; N, 3.47; Cl, 8.77Yo E~cample 7 7-(2~Dibenzofuranyl~y)~l pîpeFidirloheptane l~ydrochloride C~rude 1-b~omo~7-(2~ zo~yloxy)heptane (5.8g) was added ove~ 20 minutes to piperi~e (lSml) s~rred a~ ~m temp~eran~re. The resul~ng mixture was left to stand ~r . 18 hours and ~n dissolved Ln ehlorofoqm. This soludon was washed with dilute sa~ium hydroxide solu~on, ~ine contahling a fow drops of dilute sodium hydroxide soludon arld W0 93/2Z302 2, ~ 3 3 9 ~ 4 Pcr/cB93/no80 1 d~ied over magnesium sulphate~ The solrent was rernoved and ~e residue was ueated with ctherea1 bydrogen chloride and rec~ystallised f~m acetonitrile to g~ve the title compound as white nccdles. (l.9~Sg), m.p. 1~7 ~ 129C.

s Found: C:, 70.70; H, 7.77; N, 3.37; ~l, 9.03%
tC24H31NC)~C1Ø25 ~()) reqlL~res: Cl 70.91; ~, 7.81; N, 3.~; Cl, 8.7~%

Ex~mple 8 7al4aBenzyloxypherloxy~ pip~ Inoh~ptasle hydr~hloride A m~xture 7~ cnzy1oxypheno~y)~1~b~mohep~e (S.Og), pipçri~tne (~.18g~, potassitLmcarbonau: (2.73g) ~nd ~thanol (S~) was s~Ted a~ reflwc f~r 18 h~urs. The rr~x~c was filtered and the residue was washed witb ~l:hanol. The ~ t~s were comb~ned, the sclvent was rem~ved and the residue was par~tioned l~twe~n dichloromc~ane and dilute s~
hydroxide solu~on. The dichlorornGthane layer was s~para~, ~ied o~er m~esium sulphate and the solvent was remo~ed ~ g~ve an oil wbich was ~eated wi~ etherealhydrogon chl~de. Recr,Ystallisa~on ~m othyl as:0tate gavo tbe titlo compound, (1.9;~) m.p. 171- 173C.

Founa~ i.25; *~ 7; ~ i; C, r)~ J4/o (C2sE~3sNo~cl.o~s H20) seqt~r~s: C, 71.07; H, 8.70; N, 3.30; Cl, 8.30~0 Ex~mple 9 2s :
7 (4-Benzylo%yphenoxy) l~pyrrolidinobeptane hydrochloride The dtle comp~und waæ prepared in a simi}ar maM~r to E~ample 8 s~ng from 7-(~
benzyloxyphenoxy)-1-bromoheptane (1.Og), pyrroli~ine (1.13g), potassium c~bonate30 (1~62g) and ethanol (~Sm~). Chrom~tography on sîlica gel elu~ with methanoVdichlarom~thane and treatme~lt w~th ethereal hydrogen chloride gave a white solid which was rec~ystallised from acetone, (0.45g), m.p. 132 - 134C.

Fuund: C, 70.89; H, 8.17; N, 3.45; Cl, 8.49~
(C2~33~ Q25H20) requlles: C, 7056i H, 8.26; N, 3.42; Cl, 8.69%

213~3~
WO 93/22302 PCrtGB93/00801 - 23 - i Example 10 N~p~(4~Benzylo%~pbenoxy)heptyl]~he~amethylenelmine hydrochloride S A mixture 7-(4~benzylaxyphcnoxy)~ om~ (1.8~g~, and 80% sodium hydride ~0.17g) and dimcthylf~de was s~d under n~gen ~r hve minutes.
Hexam¢thyleneimine (O.S63~nl) was addcd by s~in~ and the snix~e was ~sred a~ 60C
for 4 hours. The soludon was ~ted w~ wate~ ~3~1) and ex~ted ~vith tichl~romcthane. The dichl~om~thanc layor wa~ washed consccu~vely with water and0 dilute hydrachlos~c acid and ~en dA~d over ma~os~u~n sulphste7 tho solvent was removed and the rcsiduo was chr~maw~phed on silica gcl olu~ w~th dichl~ome~ rnetha~ol and r~stalliscd l~om a~oton~ilc to ~e tho ~tle compound, (0.738g) m.p. 162 - 163~C.

Fou~sd: C, 71.92; H, 8.66; ~, 3.25; Cl, 8.1S~a lS ~C26H37NO~Cl) rcquiros: C, 72.2~; ~, 8.87; N, 3.~; Cl, 8.~1%

Example 11 6~(3,4~Dichlorophenox~ piperidirlob~an0 h~drochlor~de The ~ c~mpound was psepar~d m a s~mi~ar manner ~o i~;c; ~
pipc~idinohcxanol ~ g), 3~chl~phenol (1.32g~ riphenylphosphislc ~".12g~ and die~yl azodicar~oxy1ate ~1.40g). C~ ato~raph5r on s~lica gel olu~ed ~th : methanoVdichlorome~ane followed by ~eatment with c~ hyt~ogen chl~ride and 2S rccrystallisation f rom DthanoVothyl acetate, gave the ~tle comp~und as white needles, (1.17g), m.p. 138-139C.
:` ~ ` : ~ :
Found: C,~55.60; H, 6.83; N, 3.90; C1~, 9.68%
(C17H2sCl~NO.HCI) rcqu~res: C, 55.67; H, 7.14; N, 3.81; Cl~, 9.66%
Examplel2 ~ ~

9~(3,4.Dichlorophenoxy) l~pi~dinonane hydrochloride 3S The ~dc com~ound wa~ p~epared ~n a similar manner to ~xample 1 star~ng ~om 9-pipaidinonanol (1.2g), 3,~dichl~ophenol (0.84g), triphenylphosphine (1.38g) and diethyl azodicarboxylate (0.92g). Chsomatography on silica gel eluted with me~anoUdicbloromedlane follo~ved by trea~nent w~th ethereal hydsogen chl~de and ~J~33~

recrys~allis~tion ~rom acetoni~ile, gav~ the ~tle compound a~ white nee~les, (1.25g), m.p.
127-1~8C. .

Found: C, 58.65; H, 7.73; ~, 3.47; Gl, 26.21%
~C~5~31C12NO.I~C1) requ~s: C7 58.76; H, 7.89; N, 3.43; C17 ~6.01~ ) E~ample 13 9~(4~Be~zylo~pbenoxy)~1~piperidino~ h~drac~larid~
~e 7~de compou~d was p~cp~ in a ~imil~ ~ner to :E:xample 1 s~g f~m ~-piperidinonanol ~1.2g), 4~$enzylox~phenol (l.OSg), triphenylph~sp~e (1.38g) and dieth~rl a~dicarboxylate (O.9~g). C~m~o~aphy orl silica gel eluted with rne~anoUdlchloromethane followecl by ~eatIn~nt vvith ethereal h~drog~n ~hloride and recrystallisa~on f~ra a~etoni~rile7 g~vc the ~tle c~mpound as whi~e needles, (0.834g~, ~
m.p. 144 -145C. ; ;

Found: C, 72.39; H, 8l86; N, 3.16; Cl, 7.88~
(C27H3gN02~ICl) re~s: C, 72.70; ~ .04; N, 3.14; Cl, 7.95~a E~ample l~

~4~Benzylo~ypheno~)-l-pîperi~inooct~e h~drochloride The title compound was prepared in a simil~r manner to Example 1 star8ng ~om 8- :
piperidinooc~ol (1 3g)? ~benzyloxyphenol (1.22g), ~iphenylphosphine (1.60g) and diethyl azodicar~xyla~e (1.06g). Chrornatography on silica gel eluted with methanoVdichlorome~ane followed by ~ ment with ethereal hydrogen chl~ide and re xystalLisation from ethyl acetate, gave the ~tlc compound as whit~ needles, tO.793g), m.p. 141 -143~.

Four~ C, 71.63; H, 8.50; N, 3.16; ~1, 8.47~o (~2~H[37N2~ 2) re~ulres: C, 71.54; H9 8.65; Nt 3.20; Cl~ 8.12%

~133~
Wo g3/2~302 PCr/G~93/0080l E~ample lS

~(4~PhenoxypheD~y) l~piperidinoo~e hydrocbloride 5 l~e ~e comE~und was prepared ~n a similar manne~ to ~ixample 1 stardng ~m 8-piperidinooctanol ~1.3g), ~phen~ phenol (1~12g)~ phenylphos~hine (1.60g) and diethsll azodicarbox~ylate (1.06g). Chromat~aphy o~l silica gel ~lute~ with methanol/diehloromethane followed ~ nt ~th ethereal hydT~g~ll chloridc and re~st~lli~tion ~rn othyl acetate, ~a~ e ~tle eompound as d white solld, (0.98g), ~p.
10 75 ~ 76 Foulld: C, 71.57 H, 8.41, N, 3.46; Cl, 8.11~
~C~H3sNO2~Cl) r~u~res: C, 71.83; H, 8.68; ~, 3.35; Cl, 8.~8~o 5 Example 16 6^(4 ~enzylox~pheno~y) l-piperidinohe%ane hydr~hlorid~

The ~tle compound was p~epared ~n a s~ar mann~r to E~L~ple 1 star~g ~m 6 ~o piporiainohe~anol (1~5g), ~bo~loxypheI~ol (1.6"g~ h~ylphcsph~e (1.1 g) a~d diethyl azodicasboxyla~ (1.40g~. C~ornatograp~y on s~ica gei ~iuted w~
methanol/L~hloromc~ane followed by trea~eIlt wi~ ~thesG71 hydrogen cblc~de and recrysta~lisa~n f:~m ethyl aceta~, ga~e the ~e compound as a whit~ (1.33g), m.p.174- 17~C.
2s FouIId: C, 71.16; lI, 8.~4; N, 3.67; Cl, 9.2%
(C24~33NO2 H~) ~equ~s: C, 71.35; H, 8.43; N, 3.46; C1, 8.80~a .:
E~ample 17 3~
7~{4-12 (4Chlorophenyl)egbyl]pheno~y~ piperidinoheptane hydr~h1Oride .

l~e ~tle com~ound was prepared ~n a similar mann~r to ~xample 1 sta~ng from 7-pipesidinoheptanQl (1.Og), 4-~2~(4-chlo~ophenyl)sthyl]phenol (1.19g), tripheIlylph~ ine 35 (1.31g) and dietlhyl a~odicarboxylate (0.87g). (X~omasography on silica gcl eluted with mcthanoVdichlorome~ane ~ollowed by treatmc~t w~th ethercal hydrogen chloride andrecrystallisa~on ~m acetonitrile, gave the title compound as white needles, (0.853g), m.p. 167- 169C

:

WO 93/22302 ;!, - 26 - PCI`/GB93/00801 Found: C, 69.87; H, &.09; N, 3.10; Cl~ 15.43~o (C~6H3~GINO~ICl) re~s: C, 69.32; H, 8.28; N, 3.11; CI9 15.74%
s E~x~mple 18 t~7~ Z~Phenyle~hengl)phenoxy]~1dpiper~d;nohept~n~ hydr~hloride The ~ compound was prc pared in a ~imilar manner t~ l~arnpl~ 1 sta~ f~am 7-pi~ noheptanol (3.0g), ~ans-4 hy~xys~lbene (3.01g), ~iphonylphosphine t3.93~g) and dîe~yl a~dicar~oxylat~ (2.61g). Chr~mato~aphy Oll silica ~ol loluted ~dl me~hanoVdichl~romethane gavo a white solid (4.0$6g~. A sample of this ~torial (1.75g) W s ~eated with ethereal hydr~gen chlo~do to g~v~ a white solid which wa~ r~ystall!ised i~om ethanoll to g~ve the title compound, (1.145g), m.p. ~19~20C.
Found: C, 7S.0; H, 8.47; N, 3~37, Cl, ~.S6%
(C26H3sNO.HCl) requ~res: C, 75.43; ~, 8.76;.N, 3.38; Cl, 8.S7%
E~mple 19 7~ Pnenyie~yljpheno~y]~i~piperînînon~p~an~ nyd~cnloria~

Amix~reof ~ s7^[4 ('~-phenylethonyl)phencxy~ pipcr~ ohep~c (~ g), 10~
palladium on carbon (0.35g), me~anol (50ml) and ethan~l ~S0ml) was shaken ~mder an 2s atmosph~e of hydrogen at S0 p.s.i. for 2 hours. The catalyst w~s removed by fil~uon and the i~lltrate was evaporated. The residue was dissoIved ~n e~hyl acetate and treated w~th e~hereal hydro~en chlonde to g~ve a white solid wh~ch was re~ystalliscd from acetonitrile~ to give the titlo compound, (1.253g), m.p. 165-166~C

30 Fousld: C, 74.77; H, 9.05; N, 3.32, Cl, 8.27%
(C26H37N(:).H(: 1) reqli~res: Cl 7~.06; H, 9.21; N, 3.37; (: l, 8.52%

E~ample 20 , 35 7~ Benzylo~yphellQ~y)~lupiperidinoheptalle hydroclbloride The ti~le compound was prepared in a similar manner to Example 1 star8ng from 7-pip~idinoheptanol (l.Og), ~benzylo%yphenol (1.14~ iphenylpho~hine (1.31g) ~d - WO 93/22302 ~ }~ 3 ~ ~ ~ PCT/GB~3/00801 - ~7 -diethyl azodicar~oxylat~ (0.87g). Ch~ma~gr~phy on silica g~l cluted with m9~hallOVC~ ~ and treatment w~th ethe~eal h~drogen chl~r~dc followed by secrystallision from a~etonil:rilc gave ~e ~e compound as white n~edles,(1.94g), m.p.
173-174C.
S
~;ound: C, 71.70; H, 8.S0; N, 3.38; C: 1, 8.26~o (C2~3sNC)z~Cl) requ~es: C, 71.83; ~, 8.68; N, 3.35; C1, 8.48%

10 Exanrlple 21 7~Benz~lpheno~ piperidinoh~pt~n~ hydrochlo~id~

The title compound wa~ prcp~ ~ a sirrlilar ~nanner to Exarnple I star~ng f~om 7~15 pipaidinoheptanol (l.Og), 4-benzylphenol (0.93~ iphenylphasphine (1.31g) and diethyl azodicarboxylate (~.87g). Chromato~aphy an sili~a ~cl elute~ w~th methanoVdichlor~methanc and ~e~lme~t with ethe~eal h$~dragen chlor~de followed by recrystall~sion f~m ethyl ace~t~/methanol gaYe the ~tle compound a~ a whi~e solid,(1.94g), m~p. 95-96C.
2~
Found: C, 74.31; H, 8.7~; N, 3.42; Cl, 8.79% ~:
(C2sH3sNO.~Cl) requ~s: C, 7J,.69; H, 9.03; ~i, 3.48; Cl, 8.82~a Example 22 7-(2~Ben~lpheno%y)~lapiperid~noheptane hydrochlQride The ~tle compolmd was prep~ in a similar ma~ner to ~ample 1 stamng frorn 7 pip~idinoheptanol (2.0g), 2-benzylphenol (1.84g), triphenylphosp~aine (2.62g) and 30 diethyl azodicarboxylate (1.74g). Chro~tography on silica gel eluted with metha~loUdichloromcthane a~d ~reatment with ethereal hydrogen chloride followed by recrystallision ~rom e~yl ac~te/methanol gave the ~le compound as a whi~
solid,(1.17g), m.p. 11$-120C

35 ~ound: C, 73.96; H" 8.80, N, 3.71 Cl, 8.74%
(C2s~3sN(3.HClØ~2O) reql~lres: C, 74.02; ~ 9.Q4; N, 3.45; Cl, 8.74%

W0 93/Z2302 ~3~9~, ~ 28 - pcr/GB93/oo8ol E~mple 23 7-~4 ~1eth~xyphenoxy) 1~pipefidinolbepta~e hydrochloride S Tho ~dde ~ompoulld was p~pared in a ~imilar ~annGr to ~ample 1 s~ng i rom 7-pi~dinoheptanol (1.Og), ~methox~h~nol tO.~2g), ~iphenylpbosphi~e (1.31g) and diethyl azodicarbo~ylate (0.87g). Cbr~mata~aph~r a~ ~ilica gel oluted with me~ oVdichlo~r~e~an~ and ~atrnent ~h e~aeal hyd~gen chl~de followed b~
rstallision fr~m ethyl acetate/methanol gaYe th~ ~tle eo~auIld as white lo needles,(1.143g~ Lp. 128~130C.

Pound: C, 66.71; H, 9.30; ~, 4.1S; ~ .37~b :
(C1~31N02~C~ rss: C, ~6.74; ~ 9.43; N, 4.10; ~, 10.37~o 5 Example ~4 7 (4~ Butylpheno~y).l~p;p~ridinoheptaneb~drochloride The ~tlc compound was prvpared in a similar ma~er to :Example 1 st~r~ng fr~m 7-inohep~ol (1 Og), 4 ~ers~ he;~cl ~0.7Sg), ~ he~y~phos~hine (1.31~ d diethyl a~odicar~oxylate ~0.87g). ~ ma~aphy on silica gd eluted with methanolldichlorome~ane arld treat:ment wi~ cth~eal hydrogc~ chlonde ~ollowed by~crystallision ~m ~c~anoVe~yl ace~te gave the ~o c~polm~ as a white sclid, (0.779g~, m.p, 17~171C.
~s Found: C, 71.69; H, 1O.OO; N, 3.88; Cl, 9.57%
(C22H37NO.HCI) reqlLires: C, 71.80; H, 10.41; N, 3.81; C1, 9.63%

E~ample 25 7~(3,4 Meth~lelledio~:yphen~cg) l~piperidinoheptane hydrochloride The ~tle c~mpolmd was prepa~ed in a s~ manncr to Examplc 1 star~ng f rom 7-pipcridinoheptanol (l.Og~, sesamol (0.69g), ~iphenylphos~hine (1.31g) and dic~hyl 3s a~odicarboxylate (0.87g). Chromat~graphy on s;lica gol eluted with methanoVchloroform and ~ea~nent with ethcreal hydrogen chlondc ~o)lowcd by ~ecrystallision ~m mo~hanoVethyl ace~ate gave the ~tle compouDd as a white solid, (1.16g), m.p. 141-142C.

wo 93~22302 ,~ ~ 3 3 ~ ~ 4 Pcr/GBg3/00801 ~ 29 -Fo~ndi: C, 63.9~; H, 8,18; N, 3.g9; Cl, 10.38%
(C1~I2gNO3.HCI) requ~es: C, 64.11; Hl 8.4g; N, 3.93; C1, 9.965'o 5 Exampie 26 7 t4~(3,4~1)ichloro~enz~1Oxy)phen~x~ pip~;dinoheptane hydr~hlaride The ti~lG compound was prep~red ~ a similar manne~ t~ Example 1 s~ng frorn 7~
hYdk~XYPhCnXY)~1-PiPO~ ~ePtan~ ~1.45g), 3~ Oh1~b~nZY1 a1COhOI (1.885g), l:nphCnyiphosphine ~1.31g) and di~yl a~dic~Xyla~e (0.87~). The SOI~rent W~5 I'emOYed and th~ residUe W~S diss~lYed ~ ~Ch1~eth~e~ ThiS SO1Ut;~n WaS WaSh~d thOr~Ugh]Y With dilUte h~r~Ch1~iC acid, driCd OV~ SO~itlln SU1Phate and ~aP~ated.
Chromatography on silica gel eluted w~th me~ oVdichlorometh~n~ and r~ystallis~onlS from ethanol, gave the ~le c~mpo~d as a white solid, (0.827g~, m.p. 184-186C.

;: ~ Found: C, 61.62; H, 6.87; ~, 2.98: Cl, ~1,759~
~: (C25~33~2N~ ) rcquireg: C~ 61.67; H, 7.04; N7 ~.88; Cl, :~1.84qo : ~xample 27 7-~4 (4~Metho~ben~loxy)pbenoxy~ l-piperldin~heptane hydl~chloride 2s The ~tle compound was prepared ~n a similar ma~ner to Example 26 star~ng i~ :n 7-(~
hydroxyphenoxy)-l-pi~l~di.loheptane (1.45g), 4-methoxybenzyl alcohol (0.69g), tdphenylphosph~ne (1.31~) and diethyl azodicar~xylate ~0.87g). Recrystal~ on from acet~nitrilQ gave the d~ compound as a white crystalline solid, (0.519g~, m.p. 17Z-176C.
~ ' ! . , . .
Found: (:, 69.20; H, 8.21; N, 3.23; C 1, 7.73%
(C26H37NO2~c~ 2o) zcq~ es: C, 69.40; EI, 8.51; N, 3.11: Cl, 7.88qo W093/22302 ~$ P~/GB93/01)8UI,--Example 28 7 l4 (4 ~luorobenzyloxy~phenoxy~ piperid;noheptanehydrochloride s The dtle compound was pr~pared in a s~ilar manner to ~xample ~6 sta~ng from 7-~hydroxyphenoxy)- 1-piperidirloh~pta~e (1.45g), ~flu~benzyl alcohol (0.63g), ~iphenylphosphin~ (1.31g) and di~thyl a~ca~x~lat~ (0.87g). ~ecrystallisa~on fromacetonitrilc gave the ~tic compound as a white c~s~e solid, (0.782g), m~p. 167-168C.
Found: C, 68.37; ~I, 7.6~, N, 3.~, Cl, 8.09~
(C~sH34FNO2.~ClØ1H2C)) r~qu~es: Ct 6~.S8; H, 8.07; N, 3.~; Cl, 8.10%

Exalmple 2g lS
N~ (4 Be~ylo%ypheno~)heptyl~ mekh~lpip~ridine hydr~chloride A mixture 7-(4-~enzyloxyphonoxy) l~bromoheptane ~1.8&g), 80q~ sodium nydAde (0.17g) and dimethyl~rmamde (lOml) was s~ed undes ni~gen. 2~m~thylpiper~dine ~0 (0.6ml) was added ~y syr~g~ a~ ~ ~ ~as s~d 3~ 60C ~or 16 houss. ~he soiurion was ~rea~ea wiul wa~r asld ~c soiid wa~ co~l~ ~nd od ~ ~. ~e eth~ was ev~porate~, the residuo dissolved in dichloromethane, washed cons4cu~vely vnth wat4r and dilute hyd20chlor~c acid and then dried over sodiurn sulphate. The solvent was removed and the ~esidue was chrDmatographed cn silica g~l eluted with 25 dichloromethane-methanol and r~stallised ~rom acetotutrile to g~e the ~tle compound, (0.66g) m.p. 128-129C.

Found: C, 72.OB; H, 8.h3; N, 3.~5, ~, B.O~qo (C26H37NO~.HC~l) requires: C~ 72.28; Ht, 8.87; N, 3.:24; (:1, 8.21~o , 30 Example 30 N~7~(4-Benzylo~ypheno~y)heptyl]-3-methylpiperidine hydrochloride 35 Subs~ ng 3-methylpiperidine for 2-methylpipendine ~n Example 29 and recIys~allis~ng the product ~m acetonitrile gave title compound (0.989g) as a whi~e crystalline solid.
m.p.161-163C.

WO 93/22302 ~ 3 3 ~ PCr/GB93/00801 Found: C, 72.20; H, 8.S8; N, 3.20; Cl, 8.30'ro (C2~H37N02~Cl) rcqu1reis; C, 72.28; H, 8.87; N, 3.~; Cl, 8.21'ro E~ample 31 S
N~7~(4~Benzglo~gpheno%~)heptyll~ methglp3pei~ e hydr~hlo~de Substitu$ing ~methylpip~ridine f~ ~methylpi~dins In l~xamp~e ~ a~d ~y~tallis~ng ~e pr~duct ~r~m aceton~trilo gave ~ ~mpound (O.~g8g~ as a whit~i ~rystall1na solid.
m.p.1~8-170C. ~;

Found: C~ 7~.~0; H~ 8.6l; N, 3.32; Cl, 8.12~o (~ 2~37~ es: C, 7~.~8; H, 8.87 N, 3.24; Clt 8.21~o i S E%~mple 32 N [7~4~BenzyIoxgphenoxg)beptyl]~2~6~dimethyIpiperidine hydrochIoride Subsdt~ng 2,~dimethy1pip~ ~ 2~meshy1pipesidine ~n ~xa~ple 29 and 20 rc~ys~aIlismg ~ne ~c~ ~m o~hy1 acetate~othar~o1 g~o ~le c~mpou~d (0,1 6g~
white cr~stallil~e solid. sn.p.127~128C.

Folmd: C, 71.13; H, 8,63; N, '3.~qo (c~7H3gNc)2~Hcl~o~5H2oj rcquirgs: C, 71.26; H, 9.08; N, 3.~7%
E~ample 33 N~17~(4~Belozyloxyphenoxy~heptyI]~4meth~ypiperidine hydrobrom~de ; "
30 A mix~e of 1-~7-(A-BenzyIoxyphenoxy)hepty1~4~methoxypyndinum bro~de t2.0g) and Adams catalyst (O.lg) in etharlol (SOml~ wa~ shaken under an atmosphcr~ of hydrogen at S0 p.s,i. for 24 hours. The ~xNro was fil~ered, the r~sidue suspended in dichlo~omethane, filte;~ and the filtrate evap~ated. The residue was chxornatographed on silica eluted w~th ethyl ac~tate/mcthanol ~d ~crystallised fr~m ethanol to gi~e the ~tle 35 comp~und as a white ~rstalline solid (0.242g), m~p. 14~14~C

:E;au~d: C, 63.21; H, 7.56; N, 3.18, Br, lS.95%
(C26H37NO3~Br) ~equires: C, 63.41; H, 7.78; N, 2.84; Br, 16.22%

WO 93/22302 PCr/GB93/00801 ;~333~ - 32 - .

Example 34 5-(4~Benzyloxypheno~ pip~r~dinop~lltane h3~drochloride .
A mixtu~ 5~ bo~zy1Ox$phenoxy)-1-brc~m~n~ (Z.Og), pi~r~din~ (0.43g), potassium carbona~e (0.8g) and ~anol (SOn~ll) was sti~redl at r~ or 18 hours. I~e r:~ixt~ was fil~e~ed and ~e residuo was wash~ with ~than~. Tho ~ s ~ve~ combi~dt the s~lven~was removed and the residue wa~ p~tiancd be~voen oth~ and dllute s~d~um hydraxlds 10 solu~on. Thc e~e~ layer was s~p~ated7 d~ied tSV~ ~agnÇsSillm sulphate and the solYent was removed ~o give an oil wh~ch was ~ated wi~h edn eal hyd~gen chl~nde. The solid was colleGted and re~s~sed fr~m ethyl acc~ate to g~vo a s~lid whlch wals fu~
~rstallised f~om watel to gi~rc tho titl~ c~m~d a~; a white solid, (0.265g) l:n.p. 202 2~4or~
Found: C, 68.23; H, 8.00; N, 3.72; Cl, 8.32%
(C23H31N02~I~1Ø75 H~,O) req~ res: C, 6~.46; ~, 8.36; N, 3.46; Cl, 8.78%

Example 35 ', O
4-Benzy~oxyph~noxg)~l plpor~dirtonep~ e ~y~rocniori~e solu~on of 7-~benzyloxyphenoxy)heptarlen~trile (O.lg) i~ toluene (5ml) under ~îtrogen was treated Y~nth diisobu~l aluminium hyd~ide i~ toluene (0.7ml, l.5mola~ solutio~l). The ~: 25 m~xnlre was s~rred ~r 16 ~ours and then pi~di~e (lral) was added. The mixture was s~d for 1 hour, when methanol was added ~nd tho m~xture was stirred for a further 1 hour. Water (lml) and sodium cyano~ohydride tl.Og) was added and the mixture wass~red for 3 hours and then pourcd into water and extracte~ w~th dichloromethane. The dichl~romethane layer was washed with dilute hyd~echloric ac~d, dried over sodium 30 sulphatc and the s~lvent was removed to givç a white solid (0.109g) which wasrecrystallised to give the dtle compound as a white solid, (0.03g). Product idendcal to the p~oduct ~om Ex~mple 8 (~IPLC, TLC~) W093/22302 ~? ~ $~ Pcr/GBg3/00801 , Example 36 . . .
7 (4-~enzyl~xyphen~%y3~1~piperidinohept~ne me~ylate S The produc~ of Example 8 ~1.Og) wa~ equilibrated between e~hyl acetatc and O.SN NaOH.
The aqueous ~ o~ was re-e3~ t~ with ethyl acota~e and ~ comblned orga~c ex~ts washed (H20, b~ine), dried (anhy~us Na~S04) and waparated ~o dryness ~o ~î~e a colourlcss ~il. This ail was dissolved ~ mothanollc~hyl ace~ a~d methane sutphot~ic acid (0.23g, 1 ~quivalent) in methan~ ~ ~as c~wen~ated ;0 and stood o~e~ight in the fridge ta produce the ~e compound ~0~86~) as white crystals, m.p. 1~148'C.

Folmd: C, 6S.3j; H, 7.92; ~, 3.01%
tC23E131N02~CH3S03H) ~ es: C, 65.38; Hl 8.23; N~ 2.~3%
Example 37 7 ~4 Benzyloxyphenoxy)~l pipel~dinoheptane t~rtrat~

~ne pr~d~ of ~le 8 (1.0~) was e~ dichlorome~ane and N NaC~L
The aqueous ~c~on was ~o~x~c~ wi~n a~ciuaromem~c (~ d ~ 4V~
o~ga~ia cxtracts washed (H~,0, brlne),, d~ied (~IgSt:)4) a~d e~ra~ted to ness to ~iv¢ a colouslcss oil. This oil was dissolved in boiling methanol a~d ~ t~c acid (0.36g? 1 equivalent) in rnoehanol added. Tho ~e was concent:rat~, hot ethyl acctate add~d and urther concentrated to g~ve a white crys~e solid (l.lSg). This matcrial was crystallised filrst from methanol/eth~l acetate and ~nally from methanoVwater to g~ve the title compound (0.52g) as a white ~rystallline solid, m.p. 83-84C.

Example 3 7~(4-Benzyl~ypheno~y)~ l~pipe~dinoheptalle o~calate A mixnlre 7~ benzylo~;yphenoxy)-1-~mohcptane (l.Og), piperidine (0.25g), potassium carbonate (2.00g) and ethanol (25ml) was s~red at ~eflux for 48 hours. The m~x~ure was 35 filte~ d the rcsidue was wa~hed w~th etha~ol. The filtrates were comb~ned, thc solvent was remo~ed and the ~sidue was par~doned between dichloromethanc and dilutc sodium hyd~oxide solu~on. The dichloromethane laye~ was scparated, dried over magnesillm sulphate and the solvent was rem~ved to give an: oil ~hich was t~atcd widl oxalic acid ~n WO 93JZ2302 PCr/GB93/0080l 39Qv~ 34~ '~

mEthanol/ethyl acetate. The r~sul~dng .solid was re~rys~Jised frorn ethyl acetate/methanol to give the title compoun~, (0.49g) m.p. 161~163C.

Fouuld: C, 67.67; H, 7.73; N, 3.~%
S (C~ 35NC)~ ~2H2C)4 0-5 ~2Q) ~qu~s: C, 67.47; ~, 7~97; M, 2.~1%

W093/22302 ~13 3 9 S 135 pc~r/GB93/oo8 Pharmaceut;cal Formula~oll~

The following rcprosent typical pharmaceu~cal f~mulations according to the present inven~on, which ~ay bc p~par~ us~ng st~ rd methods.
S
IV Infusion Compound ~ ~ula (1) 1~4~ mg Buf~er tc) p~ ca 7 Sovent/c~mplexing t~ ~00 ml Bolus Inje~tion Compound of fo~ula (I) 1~0 mg Buf~r t~ pH ca 7 Co-Solvent tO 5 ml Bu~fer: Suitable bu:~fcrs include citIa~, phosphate, sodilim hydroxide/hyd~chlonc acid.

.
Sol~rent: Typieally wat~r but may also inclllde aycl~dox~s (1~1~ mg) and c~solvcslts such as ~ylos~e glyc~l, paly~hylene gly~l a!ld alcahal.

Tablet Co~pound 1 - 40 mg Dilu~nt/F;ller * 50 ~ 250 mg Binder 5 ~25 mg Disente~rant ~ S - 50 mg l.ubricant 1 -Smg Cyclodex~rin 1 ~ 100 mg 30 * may also Lnclude cyclodex~rins ., Diluent: e.g. Mi~stalline cellulose, lactose, starch Binder: e.g Pol~ylp~solidone, hydroxypropymethylcellulose Disinte~arlt: e.g. Sodium starch glycollate, crospovidone : ~ ~ 3s Lubricant: e.g. Magnesium stearate9 sodium stearyl fu~rate.

wo 93/~2302 ~ 39~o 4 36 - PCr/GB93/Oo~o1 Oral suspension Compound 1 - 40 mg SuspendingAgen~ 0.1- 10mg Diluellt ~0~60mg s ~eserva~vc 0.01 ~ 1.0 ~g Buf~ to p~ ca 5 ~ 8 C~solveslt O ~ 40 mg Flavou;r 0.01 ~ 1.0 mg C~lo~rant 0.0~1 ~ 0.1 Suspending ag~ent :e.g. ~anthan gum, m~yrst~e cellulose l:~iluent: c.g. sor~itol solu~on, typicaLly water Prese~va~ve: G.g. sodium benzoate Buffer: e.g. ~ :rate Co solvent: e.a. alcohol, pr~pylene glycol1 polyethylene glycol, cycl~ex :rin ;

Claims (18)

Claims:

1. Use of a compound of formula (I):
Formula (I) in which n is 3 to 8; q is 5 to 11; R1 represents C1-6alkyl or C1-6alkoxy; s is zero, 1 or 2;
X represents oxygen or sulphur; and Ar represents phenyl optionally substituted by 1-3 substituents selected from halo, C1-8alkyl, C1-8alkoxy, C1-2alkylenedioxy, trifluoromethyl, trifluoromethyloxy, or a group Ph-(CH2)m-Y-(CH2)p- where Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O,S, or CH=CH, provided that m + p is not greater than 4, or Ar is an optionally substituted tricyclic heteroaryl group:
in which Y1 is Y(CH2)x where x is 0 or 1 and Y is O, S or NR where R is hydrogen or C1-4alkyl, Z is (CH2)r or -CH=CH-, r is 0, 1 or 2 or Ar is the corresponding tricyclic dehydro ring system, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions related to an accumulation of calcium in the brain cells of a mammal.

2. Use of a compound according to claim 1 in which n is 4 to 6.

3. Use of a compound according to claim 1 or 2 in which q is 6 to 9,

4. Use of a compound according to any of claims 1 to 3 wherein s is zero.

5. Use of a compound according to any of claims 1 to 4 wherein X
represents oxygen.

6. Use of a compound according to any one of claims 1 to 5 in which Ar is phenyl mono-substituted by phenoxy, benzyl, benzyloxy, or halo; phenyl disubstituted by halo, or Ar is 2-dibenzofuranyl.

7. Use of a compound according to claim 1 wherein n is 3 to 8; q is 5 to 11;
X is oxygen or sulphur, s is zero, and Ar is phenyl optionally substituted by 1-3 substituents selected from halo, C1-8alkyl, trifluoromethyl, trifluoromethyloxy, or a group Ph-(CH2)m-Y-(CH2)p- where Ph is optionally substituted phenyl, m and p are independently 0 to 4 and Y is a bond, O or S provided that m + p is not greater than 4, or Ar is an optionally substituted tricyclic heteroaryl group:
in which Y1 is Y(CH2)x where x is 0 or 1 and Y is O, S or NR where R is hydrogen or C1-4alkyl, Z is (CH2)r or -CH=CH-, r is 0, 1 or 2 or Ar is the corresponding tricyclic dehydro ring system, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions related to an accumulation of calcium in the

8. Use according to claim 1 of a compound selected from:
7-phenoxy-1-piperidinoheptane, 7-(4-fluorophenoxy)-1-piperidinoheptane, 7-(2,4-dichlorophenoxy)-1-piperidinoheptane, 7-(3,4-dichlorophenoxy)-1-piperidinoheptane, 7-(4-phenoxyphenoxy)-1-piperidinoheptane, 7-(3-phenoxyphenoxy)-1-piperidinoheptane, 7-(2-dibenzofuranyloxy)-1-piperidinoheptane, 7-(4-benzyloxyphenoxy)-1-piperidinoheptane, 7-(4-benzyloxyphenoxy)-1-pyrrolidinoheptane, N-[7-(4-benzyloxyphenoxy)heptyl]-hexamethyleneimine, 6-(3,4-dichlorophenoxy)-1-piperidinohexane, 9-(3,4-dichlorophenoxy)-1-piperidinononane, 9-(4-benzyloxyphenoxy)-1-piperidinononane, 8-(4-benzyloxyphenoxy)-1-piperidinooctane, 8-(4-phenoxyphenoxy)-1-piperidinooctane 6-(4-benzyloxyphenoxy)-1-piperidinohexane, 7-[4-[2-(4-chlorophenyl)ethyl]phenoxy]-1-piperidinoheptane, trans-7-[4-(2-phenylethenyl)phenoxy]-1-piperidinoheptane, 7-[4-(2-phenylethyl)phenoxy]-1-piperidinoheptane, 7-(4-benzylphenoxy)-1-piperidinoheptane, 7-(2-benzylphenoxy)-1-piperidinoheptane, 7-(4-methoxyphenoxy)-1-piperidinoheptane, 7-(4-tert-butylphenoxy)-1-piperidinoheptane, 7-(3,4-methylenedioxyphenoxy)-1-piperidinoheptane, 7-[4-(3,4-dichlorobenzyloxy)phenoxy]-1-piperidinoheptane, 7-[4-(4-methoxybenzyloxy)phenoxy]-1-piperidinoheptane, 7-[4-(4-fluorobenzyloxy)phenoxy]-1-piperidinoheptane, N-[7-(4-benzyloxyphenoxy)heptyl]-2-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl-3-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl-4-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-2,6-dimethylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-4-methoxypiperidine, or 5-(4-benzyloxyphenoxy)-1-piperidinopentane, or a pharmaceutically acceptable salt thereof.

9. A method of treatment of a condition or disease related to an accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. A compound of formula (IA) Formula (IA) in which n, q, R1, s and X are as defined for formula (I) and Ar1 is an optionally substituted tricyclic heteroaryl group as defined for formula (I);
or a salt thereof.

11. A compound of formula (IB):
Formula (IB) wherein R1, s, n and X are as defined for formula (I) and Ar2 represents phenyl optionally substituted by a group Ph-(CH2)mY(CH2)p- or a tricyclic heteroaryl group as defined for formula (I), or a salt thereof.

12. A compound of formula (IB) according to claim 11 wherein Ar2 represents phenyl optionally substituted by a group Ph-(CH2)m-Y(CH2)p- as defined in formula (I).

13. A compound of formula (IB) according to claim 11 or claim 12 wherein s is zero.

14. A compound selected from:
7-phenoxy-1-piperidinoheptane, 7-(4-fluorophenoxy)-1-piperidinoheptane, 7-(2,4-dichlorophenoxy)-1-piperidinoheptane, 7 (4-phenoxyphenoxy)-1-pipendinoheptane, 7-(3-phenoxyphenoxy)-1-piperidinoheptane, 7-(2-dibenzofuranyloxy)-1-piperidinoheptane, 7-(4-benzyloxyphenoxy)-1-piperidinoheptane, 7-(4-benzyloxyphenoxy)-1-pyrrolidinoheptane, N-[7-(4-benzyloxyphenoxy)heptyl]-hexamethyleneimine, 9-(3,4-dichlorophenoxy)-1-piperidinonane, 9-(4-benzyloxyphenoxy)-1-piperidnonane, 8-(4-benzyloxyphenoxy)-1-piperidinooctane, 8-(4-phenoxyphenoxy)-1-piperidinooctane, 6-(4-benzyloxyphenoxy)-1-piperidinohexane, 7-{4-[2-(4-chlorophenyl)ethyl]phenoxy}-1-piperidinoheptane, trans-7-[4-(2-phenylethenyl)phenoxy]-1-piperidinoheptane, 7-[4(2-phenylethyl)phenoxy]-1-piperidirnoheptane, 7-(4-benzylphenoxy)-1-piperidinoheptane, 7-(2-benzylphenoxy)-1-piperidinoheptane, 7-(4-methoxyphenoxy)-1-piperidinoheptane, 7-(4-tert-butylphenoxy)-1-piperidinoheptane, 7-(3,4-methylenedioxyphenoxy)-1-piperdinoheptane, 7-[4-(3,4-dichlorobenzyloxy)phenoxy]-1-piperidnoheptane, 7-[4-(4-methoxybenzyloxy)phenoxy]-1-piperidinoheptane, 7-[4-(4-fluorobenzyloxy)phenoxy]-1-piperidinoheptane, N-[7-(4-benzyloxyphenoxy)heptyl]-2-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-3-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-4-methylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-2,6-dimethylpiperidine, N-[7-(4-benzyloxyphenoxy)heptyl]-4-methoxypiperidine, or 5-(4-benzyloxyphenoxy)-1-piperidinopentane, or a salt thereof.

15. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 10 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

16. A pharmaceutical composition for use in the treatment of conditions related to the accumulation of calcium in the brain cells of a mammal comprising a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

17. A process for the preparation of a compound of formula (I) as defined in any of claims 10 to 14 which comprises:
(a) reaction of a compound of formula (II):
Formula (II) in which n, R1, s and q are defined in formula (IA) and L1 is a group displaceable with a nucleophile with a compound of formula (III):
Ar3-XH
Formula (III) in which X is as defined in formula (IA) and Ar3 represents Ar1 when q is as defined in formula (IA) or Ar2 when q is 7;
(b) reaction of a compound of formula (IV):
Ar3-X-(CH2)q-L2 Formula (IV) in which X and q are as defined for formula (IA), Ar3 is defined for formula (III) and L2 is a leaving group, with a compound of formula (V):
Formula (V) in which n, R1 and s are as defined in formula (IA); or (c) reduction of an amide of formula (VI) or (VII):
Formula (VI) Formula (VII) wherein R1, s, n, q, X and Ar3 are as defined above;
d) Reductive amination of an aldehyde of formula (VIII):
OHC-(CH2)q-1xAR3 formula (VIII) wherein q, X and Ar3 are as hereinbefore defined, in the presence of a compound of formula (V) as defined above.

e) To prepare a compound wherein Ar3 represents phenyl substituted by Ph(CH2)mO-, alkylation of a compound of formula (IX):
formula (IX) wherein R1, s, n, q and X are as hereinbefore defined; with an alkylating agent of formula (X):
Ph(CH2)mL1 formula (X) wherein Ph, m and L1 are as hereinbefore defined;
f) To prepare a compound where n is 5, reduction of a pyridine derivative of formula (XI):
formula (XI) wherein R1, s, q, X and Ar3 are as hereinbefore defined and A- is a counter anion;
g) Interconversion of one compound of formula (I) to a different compound of formula (I) e.g. reduction of a compound wherein Y represents CH=CH to a compound wherein Y represents -CH2-CH2-;
followed if desired by salt formation.

18. A novel intermediate of formula (II), (IV), (VI), (IX) or (XI).