CA2128536A1 - Azabicyclo compounds as calcium channel antagonists - Google Patents

Abstract

Compounds of formula (I) in which p, q and r each independently represent an integer from 1 to 4; n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C=C-, oxygen, sulphur or NR1; R1 is hydrogen, C1-8alkyl or phenylC1-4alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted; and salts thereof are useful in medicine, in particular as calcium channel antagonists. Processes for preparing compounds (I) and pharmaceutical compositions containing them are also described.

Description

2128 -~3~

COMPOIJNI~S

5 The present invention relates to novel azabicyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in par~icular as calcium channel antagonists.

Gerrnan OLS 41 16582 describes azabicyclic compounds of the formula:

= (C~t2)n-X-R

A`\N~C

wherein A, B and C independently represent -CH2- or a single bond; n is zero, 1 Qr 2; X is oxygen or sulphur and R is inter ~ phenylalkyl, diphenylallyl, heterocyclicalkyl, phenyl, 15 diphenyl or a heterocycle, each of which may be optionally substituted. These compounds are said to be useful as muscarinic agonists.

Chem Abs. Vol 111, 1989, No. ?32473v reports the attempted synthesis of 3-phenyl-1-azabicyclo[l.l.l.~pentane and 3-phenyl-1-azabicyclo[2.1.1]hexane. Chem Abs. Vol 84, 20 1976, no. 121623y describes~ 4-phenylquimlclidine and Chem Abs. Vol 71, 1969,No. 22026f desc~ibes the synthesis of 4-aminoquinuclidine and its denvatives~ including the ~ben~ylamino deriva~ive. No therapeutic use is ascribed to any of these compounds.

International ~plication WO91/13885 descnbes a class of bridged azabicyclic compounds 25 subs~ituted at the bridgehead carbon atom by a triazinyl group. The compounds are said to act at muscarinic receptors and to be of potential use in the treatment and/or prophyla~cis of dementia.

We have now found novel azabicyclic compounds, substitued at the bridgehead carbon 30 atom, which have activity as calcium channel antagonists.

In a first aspect, the present invention provides, a compound of fonnula (I):

S~EET

P30264 ~ 1 2 8 ~ ;!

/(CH2)n A(CH2)~nAr ,f\
(CH2~p (~H2)q ,~CH2)r \ I /

Formula (I) in which s p, q and r each independently repr~sent an integer from 1 to 4;
A is a bond, -CH=CH-, -C~C-, oxygen, sulphur or NR1; where Rl iS hydrogen, Cl galkyl or phenylCl 4alkyl;
n is 0 to 6, and m is 0 to 6, such that the length o~ the chain (CH~nA(CH2)m is at least 10 two atoms; and Ar is aryl or heteroaryl, each o~ which may be optionally substituted;
with the proviso that when p, q and r each represent 2, n is zero, m is 1 and A i~ then Ar is not unsubstituted phenyl, 5 and s~ts thereo p and r are preferably 2 or 3.
., q is preferably 1 or 2.
llle values of n, m and A should be chosen such that the length of the chain -(CH~nA(CH2~m is at least two atoms. In general ths length of the chain -~CH2)nA(CH2)m is ~rom 2 to 6 e.g. 2 to 5 atorns. Preferred values for n and m depend on the group A. Thus for example, when A is oxygen the sum of n+m is from 1 to 5, for 25 example n may be zero, 1 or 2 and m may be zero or 1 to 5.

A is preferably oxygen or a bond, most preferably oxygen.

When Ar represents aryl~ suitable groups include, for example, unsaturated monocyclic 30 and unsaturated or partially saturated bicyclic or tricyclic ring systems of up to 15 carbon atoms, such as, for exarnple, phenyl, naphthyl, tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and dibenzosuberenone . Preferred are optionally substituted phenyl rings.

~il)E3STlT~TE S~E~, p3()26~ 2 ~

- 2a -An aryl group may be substituted, for example, by a (: 1 2alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cl 4alkoxy, ni~o, SCl 4alkyl, NR2aR2b (in which R2a and R2b can be independently H or Cl 4alkyl), OCF3, Cl 6alkyl, tIifluoromethyl, CN, optionally S substituted phenyl, optionally substituted phenoxy, optionally substituted phenylCl 4allcyl and ophonally substituted phenylCI 4alkoxy.

Suitable op~ionally substituted phenylCl 4alkyl groups include, for example benzyl.
Suitable optionally substituted phenylCl 4alkoxy groups includs, for example benzyloxy 10 groups.

Suitable subst;tuents for said optionally substituted phenyl, phenoxy, phenylCl 4alkyl and phenylCl 4alkoxy groups include for examplehalogen, Cl 4alkyl, Cl 4alkoxy, nitro and tlifluoromethyl groups.

S~ TUTESH ~7-~0 93/15080 ~ pcr/GB93/oo174 Preferably the aryl group Ar is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cl 4)alkyl e.g. benzyl, phenoxy or phenylCl 4alkoxy, e.g.
benzyloxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl s ring.

When Ar represents heteroaryl suitable groups include, for example, unsaturated or par~ially saturated bicyclic and tricyclic ring systems containing at least one heteroatom.
A bicyclic ring systeml preferably contains 8 to 10 nng members, such as quinolinyl, 10 tetrahydroquinolinyl or benzofuranyl. A tricyclic ring system preferably contains from 11 to 15 ring members, and most preferably has the structure:

~Z~

wherein Yl represents Y(CH2)t, Y is O, S or NR3 (wher~ R3 is hydr~gen or Cl:4alkyl), Z
is (C~12)S or -C~=CH-, s is 0, 1 or 2 and t is 0 or 1 or is a corresponding dehydro ring system. Examples of tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine . The heteroaryl ring can be 20 linked to the remainder of formula ~I) via any suitable ring atom.

Suitable substituents for said heteroaryl rings include, for example, 1 to 3 subsdtuents selected from halogen, ~rifluoromethyl, Cl 4allcyl, Cl 4alkoxy, phenyl, phenylCl 4alkyl, andphenylCl 4alkoxy.
ALkyl groups present in the compounds of formula (I), alone or as part of another group, can be s~aight or branched. Thus a C l 4allcyl group may be for exarnple methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.

30 It will be appreciated ~hat for use in medicine a salt of a compound ~l) should be phamlaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobrornide, sulphate, phosphate, acetate, fumarate, maleate, ci~ate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non-35 pharmaceutically acceptable salts may be used for example in the isola~ion of the ~lnalproduct and are included within the scope of this invention.

Wo93/1~08~ ~ 2~ ~ i 4 PCI/GB93tO0174 Particular compounds of the invention include:

4-[2-(3,4-dichlorophenoxy)ethyl]- 1 -azabicyclo~2.2. 1 ]heptane hydrochloride, 4-[2-(4-benzyloxyphenoxy)ethyl]-1-azabicyclol2.2.1]hep~ane hydrochloride, 4-12-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[2.2.1]heptane hydrochloride, (i)5-(4-benzyloxyphenoxymethyl)- l-azabicyclo[3.2. l~octane hydrochloride, (i)5-(4-benzylphenoxymethyl)- 1-azabicyclo[3.2. 1 ]octane hydrochloride, (+)5-~2-dibenzofuranyloxy)methyl- 1 -azaibicyclo[3.2. 130ctane hydrochloride, (~ ) 5-[2-(2-dibenzofuranyloxy~ethyl]- 1 -azabicyclo[3.2. 1 ]octane hydrochloride, 4-[2-(4-phenoxyphenoxy)ethyl]-1-azabicyclo[2.2.1]heptane hydrochloride, 4-[3-(4-benzyloxyphenyl)propyloxyme~hyl]- 1 -azabicylo[2.2. 1 ]heptane hydrochloride, 4-[5-(~phenoxyphenyl)pentyloxy]- 1 -azabicyclo[2.2. 1 ~heptane hydrochloride, 4-~4-benzyloxyphenoxymethyl)- 1 -a~abicyclo[2.2. 1 ~heptane hydrochloride, 15 4-[4-(4-phenoxyphenyl)butyloxy]-1-azabicyclo[2.2.1]heptane hydroehlonde, ~3-(4-benzyloxyphenyl)propyloxy]-1-azabicyclo[2.2.1~hep~ane hydrochlonde, and 4-[5-(4-benzyloxyphenyl)pentyloxy]-1-azabicyclo[2.2.1]heptane hydrochlonde.

lt will be appreciated that certain compounds of formula (I) may contain one or more 20 asymmetric centres, for example where p, q and r all have different vall~es. Such compounds will exist as optical isomers (enan~iomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer~ and unequal mixtures of the two are included within the scope of the invendon. Fur~hert all diastereomeric forrns possible (pure enantiomers and mixtures thereof) are within the scope of the invention. In addition, when 2s A represents -~H=CH- the compounds will exist as geometric isomers, and the invention encompasses all such isomers and mixtures thereof.

The compounds of the present invention can be prepared by p~cesses analogous to ~hose known in the art. The present invention therefore provides in a further aspect, a process 30 ~or the preparation of a compound of formula (1) which comprises:

(a) for compounds of formula (I) in which A is 0, S or NR1, reac~ilon of a compound of formula (II):

WO 93/1~080 5 P~tGB93/00174 .~. .t 2 ~3 i (CH2)nA H
~, (CH2)p (C~2)q ,~CH2).
\ I /

Formula (II) in which p, q, r and n are as described for formula (I) and A 1 is O~ S or NR 1, with a compound of fonnula L(CH2)mAr in which m and Ar are as described for ~ormula (I), and L is a leaving group;

10 (b) for compounds of formula (I) in which A is O, S or NR 1, reaction of a compound of formula (III):

/(CH2)nL
~ .~

(CH2)p (CH2)q ,~;H2), \ 1/
Formula ~III) in which p, q, r and n are as descnbed for forrnula (I) and Ll is a group displaceable by a nucleophile, with a compound of formula HA1~CH2)mAr where m and ~r are as describe~ for formula (I) and A~ is as dcscribed for formula (II); or (c) for compounds of fo~mula ~I) in which A is NR1, reduenon of a compound of formula (IV):

(( H2)p (CH2)q ,~CH2)r \ 1/

Formula ~IV) WO 93/15080 ~ 6 - PCI/GB93/00174 in which R4 represents the group -(cH2)nN(Rl)c(o)(cH2)m lAror-(CH2)n 1C(O)N(R )(CH2)mAr, and p, q, r, n, m, and Ar are as described for formula (I);

(d) for compounds of formula (I) in which A is a bond, reaction of a compound offormula (V):

(CH2)n~mL

~CH2)p (CH2)q ,5ÇH2)r \ I /

Formula (V) ., 15 (wherein Ll, p, q, r, m and n are as hereinbefore defined).

with a compound of formula XlAr in which Ar is as described for formula (I), and Xl is an aLkali metal;

2~ (e) For compounds wherein A is -~I=CH- reaction of a compound of forsnula ~VI):

(CH2 ~n ~HO

(CH2)p ~CH2)q ,~CH2), \ I /

Formula ~VI) (wherein n, p, q and r are as hereinbefore de~lned) with a reagent serving to intrGduce ~he group Ar;

WO 93/15080 - 7 - 2 l 9 j ~ ~ Pcr/GBg3/00174 (f) lnterconversion of one compound of for ~ O a different compound of formula (I) e.g. the reduclion of a compound wherein A is -CH=CH- to a compound wherein A is -CH2CH2-;
and optionally thereafter forming a salt.

In process (a) the reaction between a compound ~; mula (II) and a compound L(CH2)mAr can take place under conditions wh ~ ~end on the nature of the group Land the value of m. For example, when L is ha' ~r a sulphonic acid residue such as a tosylate or mesylate and m is other than zero, the ~ on is carried oul under standard 10 conditions in a solvent, op~ionally in ~e presence i ~ase. When a fluoro-substituted aryl compound F-Ar is employed in process (a), (to prepare cornpounds where m is zero) the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide. Preferably the aryl group is substituted by an activating group such as CE;3 or N02. If necesary, the azabicyclic nitrogen atom ls may be protected during the reaction by methods well known in the art, e.~s. by prior fonnation of a quaternary derivat; t:uch as an N-benzyl derivative. Protection may also be effected by formation of a bor BH3) complex. lt will be appreciated that the N-protecting group should be chose; uch that it can be removed without affectin~ other moieties in ~he molecule. Thus ~or example a benzyl protecting group may not be 20 appropriate when the side chain (CH2~nA(CH2)mAr also contains a benzyl moiety such as a benzyloxy group. ln general, N-protection is prefe~ed when the leaving group Lrepresents halogen, e.g. bromine, but when L is a sulphonic acid residue e.g. a tosylate, N-protection may not be necessary.

2s l~e reaction between a compound of formula (III) and a compound of forrnula HAl(CH2)mAr (process (b)) can take place under conditions which depend on the nature of L1 and A. For example when Ll is hydroxy, m is 0 and Al is oxygen or sulphur the reaction is carried out in the presence of diethyl azodicarboxylate and tnphenyl phosphine.
Such a reaction is 3cnown as the Mitsunobu reaction (as described in Synthesis 198l, 1).
30 Alternatively the leaving group Ll may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy in which case the compound (III) may preferably be protected, e.g. as an acid salt such as a hydrochloride salt.
Reaction may be effected in the presence or absence of solvent, at a temperature in the range 0 to 200C, and may preferably be carried out in the presence of a base.
The reduction of a compound of formula (IV) according to process (c) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride. Conveniently a compound ~ _ula ~ ~/ca bcp--l~a ~ ~fm ~:am~e ~

Wo93tl50X0 ~ t ~ 8 PCI/GB93/00174 described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV) itself.

Ihe reaction between a compound of fonnula (V) and a compound of fonnula XlAr ins process (d) can take place under standa~d conditions known to those skilled in the art for the formation of carbon-carbon bonds.

Process (e) may be effected using a Wadsworth-Emmons reagent for example of the formula Ar(CH2)m+lP(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of 10 the formula Ar(CH2)m+lPPh3X (where X is an anion) which compounds are available commercially or can be prepared by known methods. The reaction may be carried out in a solvent such as tetrahydrofuran, optionally containing a crown ether such as 1 5-crown-5, or l 8-crown-6, and in the presence of a strong base such as sodium hydride, or potassium t-butoxide.
Interconversion reactions according to process (f) may be effected by methods well known in the art. Thus for example conversion of a compound (1~ wherein A represents =CH- into a compound (i) wherein A represents-CH2-CH2- may be effectet by satalytic reduction.
Compounds of formula ~Il) wherein n is l-6 and Al is oxygen can be prepared by reduction of the corresponding ester of formula (VII): -(CH2~n.l C02Alk ~f~ `' (C;H2)p (CH2)q ,~CH2~, \ 1/

Formula (VlI3 wherein p, q and r are as hereinbefore defined and Alk is a Cl 6alkyl group e.g. ethyl.
The reduction may be effected using a reducing agent such as lithium aluminium hydride 30 in a solvent such as diethyl ether or tetrahydrofuran. Esters of formula ~VIl) wherein n is l are described for example in European Patent Applications 287356 and 3928V3 and by Eckhardt ~ al Helv. Chim Acta, 1972, 55, 2432, and B.S. Orlek et al., J. Med. Chem., 1991,34,2726. Esters wherein n is greater than l may be prepared by conversion of an esler wherein n is I to the corresponding N-methyl-N-methoxycarboxamide (e.g. by WO 93/15080 2 :b 2 ~ ~' ` PCI/GB93/00174 hydrolysis of the ester followed by reaction with thionyl chlonde and - N,O-dimethylhydr~xylamine hydrochloride), which is then reduced to the aldehyde using diisobutylaluminium hydride. The aldehyde is further converted to the cyanomethyl deriva~ive for example as described in EPA 363085, followed by acid hydrolysis, and 5 esterification to form an ester wherein n is 2. The sequence may be repeated to form higher homologues.

Alternatively compounds of formula (II) may be prepared by reaction of an aldehyde of formula (VI) with triethylphosphonoacetate or triethylphosphonocrotonate, followed by o catalytic hydrogenation to give an ethoxycarbonylaL~cyl derivative which is further reduced e.g. using lithium aluminium hydride, to the desired hydroxyalkyl compound. It will be appreciated that use of trie~ylphosphonoacetate results in a 2-carbon homologation whilst triethylphosphonocrotonate gives a 4-carbon homologation.

S Compounds of fo~mula (II) wherein n is zero and p and r are both 2 may be prepared from l-benzyl4-piperidone, by a vanety of methods. For example, a compound (lI) wherein r is 1 may be prepaIed according to the following reaction scheme:

(CH3)3SO+I ~O ~1) HCO2H OHXCH2GH
(2) NaHC03 ~ J

N NaHJDMSO l CH2Ph CH2Ph CH2Ph MeOH-H20 ., (1) tosyl choIide/
py~dine ~ r (2) refluxholuene C)H H2110% Pd-C OH
Ethanol ~

CH2 Ph Alternatively the 1-benzyl-4-piperidone may be converted to the 4-hydroxy-4-hydroxymethyl compound by the method described in EPA 188~55, via coIresponding cyano and ester derivatives WO 93/15080 ~ - 10 PCl/GB93/00174 A compound of formula (II) wherein n is zero, and p, q and r are each 2 may be prepared by the method of C.A. Grob and P. Brenneisen (Helv. Chim. Acta.~ 41, 1184, 1958) in which 1-benzyl-4-piperidone is reacted with zinc and ethylbromoacetate to give the corresponding 1-hydroxy-1-ethoxycarbonylmethyl derivative which is reduced usingS lithium aluminium hydride to the 1 -hydroxy- 1-hydroxyethyl compound and then treated as above to effect cyclisation and deprotection.

Compounds of formula (II) wherein n is zero, p is 3, r is 2 and q is 1, may be prepared as described in EPA 2~73S6.
Compounds of formula (II) wherein A1 is S or NR1 may be prepared from the corresponding hydroxy compound by standard methods, for example via formation of an aL~cyl halide followed by reaction with an appropriate amine or thiol.

15 Compounds of forrnula (III) wherein Ll is OH can be prepared as described forcompounds of formula (Il), and compounds of formula (III) wherein Ll is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner. ~

20 The compounds of formula L(CH2)mAr and HA 1 (CH2)mAr may be prepared by standard methods well known in the art. For example compounds L~CH2)mAr wherein Ar is a substituted phenyl group and L is halo, e.g. bromo, may be prepared by Friedel-Crafts acylation of lhe corresponding substituted benzene derivative, using an appropriate acid chloride and catalysed by aluminium ~ichloride, followed by reduction in situ with 2s ~iethylsilane.

When Ar represents a phenyl group subs~itued by benzyloxy compounds L(CH2)mAr may be prepared according to the following scheme:

OH OCH2Ph OCH2Ph cH2sr ~1~ losylehloride ,~
K2C03 ~ pyridine (CH2)n-OH ~CH2)nOH (CH2)nOTs 3~
The starting materials are available commercially or may be prepared by standardmethods, e.g. by reaction of 4-benzyloxybenzaldehyde with triethylphnsphonocrotonate in a similar manner to that described for the preparation of compounds (II).

WO 93~15080 2 ~ 2 ~3 ~ . PCI /GB93/00174 Compounds of formula (IV) wherein R4 is a group -(CH2)nN(Rl)C(O)(CH2)m 1Ar can be prepared by reacting a compound of folmula (II) wherein Al represents NR1 with an acylating agent corresponding to the group -5 (CH2)mAr, for example an acid chloride ClOC(CH2)m 1 Ar.

Compounds of formula (IV) wherein R4 is a group -(CH2)n lC(O)N(Rl)(CH2)mAr may be prepared for example by reaction of a corresponding compound wherein R4 represents -(CH2)n I C02H or an activated lo derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(Rl)(CH2)m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent. The carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol? ie. a compound of formula (II) wherein A 1 is oxygen.

Compounds of formula (V) may be prepared in analogous manner to compounds of formula (III); where necessary the chain length may be increased using methods well known in the art.

20 Compounds of formula (VI) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherân A 1 is oxygen, or conversion of the corresponding ester, e.g. via the corresponding N-methyl-N-methoxycarboxamide and reduction with diisobutylaluminium hydride, as described hereinabove. Compounds of fonnula ~VI) wherein n is 1 may be prepared from the corresponding compound wherein n 2~ is zero by various methods. For example the aldehyde wherein n is zero may be ~eated with (methoxyrnethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
Altçrnatively the aldehyde may be converted to the corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, convçrsion tO the N-methyl-30 N-methoxycarboxamide and reduction. These procedures may also be used to fo~n higher homologues.

When a compound of formula (1) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving 35 agent, or chromatography. for example using a chiral HPLC column.

The compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neuronal cells. As such the compounds are expected tO be of use in WO 93/15080 ~ 12 pcr/GB93/oo174 therapy in treating conditions and diseases related to an accumulalion of calcium in ~he brain cells of mammals, in panicular humans. For example, the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head inju~y, AIDS-related dementia, neurodegenerative diseases such 5 as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.

In a further aspect of the invention there is therefore provided a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumula~on of 10 calcium in the brain cells of marnmals (e.g. humans) which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceu~ically acceptable salt thereof. Thus for example, the present invention provides a method of trea~ment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative 15 diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. ..

20 In a yet further aspect the invention also provides the use of a compound of fortnula (I) or a phannaceutically acceptable salt thereof in the manufacture of a medicamen~ for the treatment of a condition or a disease related to ~e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of a mammal ~e.g. a human).

2s For use in medicine, the com~ounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharrnaceutical compositions compnsing a compound of formula (1) or a pharmaceutically accep~able salt thereof and a phannaceutically acceptable carrier or excipient.
The compounds of the inven~ion may be administered by any convenient method, forexarnple by oral, parenteral, buccal, rectal or transdennal administration, and the pharmaceutical compositions adapted accordingly.

3~ The compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

WO 93/15080 2 ~ 2 8 ~ X ~ PCl/GB93/00174 A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid calTier(s) for example, ethanol~
glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
s A composition in the fo~n of a tablet can be prepared using any suitablç pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carr~ers include magnesium stearate, starch, lactose, sucrose and cellulose.

10 A composit~on in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using stand~rd carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical can~er(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into lS a soft gelatin capsule.

Compounds of the invention may also be administered parenterally, by bolus injection or continuous in~usion. Typical parenteral compositions consist of a solution or su~pension of the compound or pha~naceutically acceptable salt in a sterile aqueous carrier or 20 parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alterna~ively, the solution can be Iyophilised and then reconstituted with a sui~ble solvent just prior to administration.

Both liquid and solid compositions msy contain other excipients known in the 2~ pharrnaceutical art, such as cyclodex~ins.

Preferably the cvmposition is in unit dose form such as a tablet, capsule Qr ampoule.

Each dosage unit for oral adminis~ation contains preferably from 1 to 25S) mg (and for 30 parenteral administration contains pre~erably from 0.1 to 60 mg) of a compound of the formula (I) or a phannaceutically acceptable salt thereof calculated as the free base.

~e daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an 35 in~ravenous, subcutaneous, or intramuscular dose of between 0.1 mg and l O0 mg, preferably between 0.1 mg and 60 mg, eg. I to 40 mg of the compound of the formula (1) or a phartnaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention wo 93/15080 ~ ~ ?~ ~ - 14 - pcr/GB93/ool74 may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus the total daily dosage by oral administration will be in the range l to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous 5 therapy, for example for a week or more.

BIOLOGICAL DATA

Ca2+ Current Measurement Cell preparations Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), S5-65). Cells were plated out onto glass coverslips and used within 3 days to pennit effective vollage clamp of Ca2+ currents.
Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, l(); EGTA, l0;
MgCL2, 4; ATP, 2; buffered to pH 7.~ with CsOH. Cells were bathed in a normal Tyrodes solution before esta~lishment of whole cell recording when the bathing solution 20 was changed to one allowing isolation of Ca2+ currents. The external solution for recording Ca2+ channel currents contained in mM: EaCL2, l0; TEA-CI, 130; glucose, 10; HEPES, l0; MgCL2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and caIcium dependent inactivation of current is avoided. Compounds were dissolved in DMSO to make a 2Q mM stock 2s solu~ion. At the drug concentra~ion used the vehicle (0. l %) had nv significant effect on Ca2+ currents. All experiments were perfo~med at 2l to 24C. Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for la~er analysis using PC
based software similar to that described previously (Benham & Tsien, Journal of Physiology (l9~8), 404, 767-784).
3~
Ca2~ currents Peak voltage gated Ca2+ channel currents of up to l0 nA from dorsal root ganglion neurons were recorded using 10 mM Ba2+ as charge carrier. Currents were evolced frorn a holding potential of -80 mV to a test potential of 0 or +10 mV every lS seconds. This 3~ test potential was at the peak of the cu~ent voltage relationship and assessing block at this point reduced any elTors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca2+ currents. The rundownrate was measured in control conditions and extrapolated through the time of drug WO 93/15080 ~ ~ 2 3 ~ 3 ~; pcr/GB93/ool74 application to derive a control value to relate the dlug affected current to. Block by 2() ,uM drug was assessed 3 minutes after drug application.

Compounds of the invention gave percentage inhibi~ion of plateau Ca2+ current in the S range 71 to 99%.

WO 93/15080 r s~ r~ ~ 16 - pcr/~B93/oo174 8 ~
~, .
PHARMACEUTICAL ~ORMULATIONS

1. Formulation for intravenous infusion Compound of fonnula (1) 0.1 - 60 mg Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol 0 - 30 ml propyleile glycol 0 - 30 ml alcohol 0 - 10 ml water to lOOml 2. Formulation for bolus injection Compound of fonnula (1) 0.1 - 60 mg sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol 0 ^ 2.~ ml alcohol 0 - 2.5 ml water to S ml 20 A toni~ty adjusting agent eg. sodium chloride, dex~ose or mannitol may also be added.

3. Tablet for oral administration mg/tablet 2s Compound of formula (I) 25 lactose 153 starch 33 crospovidone 12 microcrystalline cellulose 30 magnesium stearate 2 ~ L22~
W093/15080 - 17- PCr/GB93100174 The following non-limiting examples illustrate the preparation of compounds of formul~
(I) Preparation 1 s 4-(Methoxycarbonylmethyl)-l-azabicyclo[2.2.1]heptane A solution of 4-(cyanomethyl)-1-azabicyclo[2.2.1~heptane (EP 363085, Description 25) (1.94g, 14.3mmol) in SN hydrochloric acid (25ml) was heated under reflux for 12h. The reaction mixture was concentrated in vacllo, then coevaporated with toluene to remove the tast ~aces of water. The residue was dissoh~ed in methanol (~Oml), treated with lM
ethereal hydrogen chlolide then heated at reflux for 2h. The solution was concentrated in vacuo, treated with aqueous potassium carbonate (25ml) and extrac~ed into chlorofonn (3x25ml). The combined organic extracts were dried over sodium sulphate, concentrated in vacuo and the oil produced was distilled to afford the title compound as a clear oil (2.1g, 87%) b.p. 125 C, 0.4mm Hg (Kugelrohr).

lH Nmr (CDC13) ~: 1.28-1.42 (2H, m), 1.49-1.64 (2H, m), 2.37 (2H, s), 2.52-2.71 (4H, m), 2.87-3.02 ~2H, m), 3.67 (3H, s).

Preparation 2 4-(2-Hydroxyethyl)-l-azabicyclo[2.2~1]heptane A ~olution of 4-(methoxycarbonylmethyl)-1-azabicyclo[2.2.1]heptane (2.1g, 12.4mmol) in dry diethyl ether (lOml) was added to a stirred suspension of lithium aluminium hydride - 2s (0.94g, 24.9mmol~ in dry diethyl ether (70m1), under nitrogen. The reaction was stirred at room temperature ~or 2.5h and then quenched by careful addition of the minimum amount of water. The reaction was filtered and the precipitate washed thoroughly wi2h 20%
methanol in diethyi ether. The combined ~ ate and washings were concentrated in vacuo and the r~sidue was dis~illed to afford the title compound as a white sQlid (1.49g, 8~%) b.p. 1~5 C, 0.3mm Hg (Kugelrohr).

lH Nmr (CDC13) ~: 1.20-1.35 ~2H, m), 1.42-1.57 (2H, m), 1.94 (2H, t, J=7Hz), 2.29 (2H, m), 2.39-2.80 (3H, m), 2.84-3.00 (2H, m), 3.72 (2H, t, J-7Hz).

wo 93/15080 ~ ? $~ 18 - P~/GB93/00174 jJ
Preparation 3 ~+)~-Hydroxymethyl-l azabicyclo[3.2.1]octane The title compound was prepared in a similar manner to Preparation 2 from (+)ethyl 1-5 azabicyclo[3.2.1~-oct-5-yl carboxylate (EP 287 356, Example 7) (2g, 10.~mmol) and lithium aluminium hydride (0.83g, 21.9mmol). This afforded the title compound as a clear gum (1.24g, 80%) b.p. 150 C, 0.7mm Hg (Kugelrohr).

Preparation 4 ( ~ ) 5-(2-Hydroxyethyl)-l-azabicyclol3.2.1]octane The title compound was prepased in a similar manner to Preparation 2 from (~) 5-methoxycarbonylmethyl-1-azabicyclo[3.2.1]octane (EP 363085, Description 11) (0.74g, 4.0 mmol) and lithium aluminium hydride (0.46g, 12.1 mmol). This afforded the title compound as a clear oil (0.54g, 87%) b.p. 200C, 0.2 mm Hg (Kugelrohr) lH Nrnr (CDC13) ~: 1.37-1.82 (8H, m, overla~ping signals), 2.43-3.05 (6H, m, overlapping signals), 3.68 (2H, t, J=7Hz) Preparation 5 4-Hydroxymethyl~l-azabicyclo[2.2.1]heptane The title compound was prepared in a similar manner to Preparation 2 from methyl 1-azabicyclo[2.2.1]hept-4-yl carboxylate (B.S. Orlek et al., J. Med. Chem., 1991, 34, 2J26) 2~ (3.13g, 20.2 mmol) and lithium aluminium hydride ~1.92g, S0.6 mmol). This afforded ~he title compound as a colourless solid (1.76g, 69%) b.p. 2~0C, 0.3 mrnHg ~Kugelrohr).

lH Nrnr (CD(: 13) ~: 1.27 (2H, m), 1.65 (2H, m), 2.32 (2H, s~, 2.62 (2H, m), 2.94 (2H, m), 3.72 (lH, br s), 3.87 (2H, s) Preparation 6 l-Benzyl-4-hydroxymethyl-4-hvdroxypiperidine To a suspension of sodium hydride (4.76g of an 80% dispersion in mineral oil~ 0.159 mol) 3s in dry dimethyl sulphoxide was added trimethyl sulphoxonium iodide (34.92g, 0.159 mol) over 1.5h. The mixture was stirred for lh, then cooled in ice and treated with a solution of 1-benzyl-4-piperidone (25g, 0.132 mol) in d~y dimethyl sulphoxide (25 ml). The reaction was allowed to warm to room ~emperature and stirred for a further I h. The mixture was wo93/15080 2:12g i ~, Pcr/GBg3/00l74 diluted with wa~cr (500 ml) and extracted into diethyl ether (3x250 ml). The combined organic extracts were washed with bnne, dried over sodium sulphate and concentrated in vacuo. The residue was extracted into pentane and purifled by distillation to give a clear oil (22.48g) b.p. 175C. Ql mm Hg (Kugel~hr). A solution of this cpoxidc in foImic S acid (100 ml) was stirrcd at soom tcmpcraturc ovcrnight, then conce~trated in vacuo. The residuc was dissolved in methanol (200 ml), treatcd with a soludon of sodium bicarbonate (30g) in water (100 ml) and stisred at room tempcrature for 21h. Thc reaction was concent~ed to approximately onc third thc original volumc, saturated with potassium carbonate, and extracted cxhaustivcly with chlo~ofoqm. The combined cxtracts wcre dried 0 ovcr sodium sulphatc and concentratcd in vacuo to givc the title compound (24.5 g).

I'reparation 7 l-Benzyl-l-azoniabicyclo[22.1]heptan~d p-toluenesulphonate 5 A solution of l-benzyl~hydroxymcthyl~hydroxypiperidinc (16.8g, 0.076 mol) in pyddine (150 ml) at 0C was treated portionwise ovcr 10 min with ~tolucnesulphonyl chlodde (14.86g, 0.078 mol) and the resulting solution was stored ov~night at 8C. The reaction was concentratcd in vacuo and the residual oil was dissolved in chla¢ofaQm and washcd with sa~uratcd aqueous potassium car'oonate. After drying over sodium sulphate 20 ~hc solution was concentTatcd in vacuo. The sesidual oil was dissoh/ed in dry toluerlc and heated undrcflux for 1.5h. Thc product was isolated by filtration and washed with diethyl ether to give the tille compound as a beige solid (23.3g, 81%) ~:
.
Preparation 8 25 4-Hydroacy-l-azabicyclo[22.1]heptane A solution of l-benzyl-1-azoniabicyclo[2.2.1]heptan~o1 ~tolucnesulphonate (S.0 g, 13.3 mmol) in ethanol (100 ml) was hyd~genated over 10% Pd-C (1.0 g) at atmosphcric pressur~ for 18h. The catalyst was removcd by filtration through kieselguhr, and the 30 filtrate was concentrated in vacuo. The residue was partitioned between saturated aqueous potassium carbonate (20 ml) and chlorofolm (25 ml) and the aqueous layer was extracted cxhaustivdy with chlorof~m The combined organic extracts were dried over sodium sulphate. concentrated in vacuo and dis~lled to give the title compound as a colourless solid (1.2g, 80%), b.p. 17SC (Icugel~hr).
H Nmr C:DC13~ ~: 1.58 (2H, m), 1.78 (2H, m), 2.37 (2H, s), 2.75 (2H, m). 3.17 (2H, m), ~ 3.65 (lH, br s).
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WO 93/15080 ~a5~ - 20 - PC~/GBg3/00174 Preparation 9 3-(4-Benzyloxyphenyl)- 1-propanol A solution of 3-(4-hydroxyphenyl)-1-propanol (2.5g, 16.4 mmol) in acetone (40 ml) S containing po~assium carbonate (5.9g, 42.75 mmol) was treated with benzyl bromide (2.54 ml, 21.35 mmol) and refluxed for 3h. The mixture was concentrated in vacuo and partitioned between water (S0 ml) and chloroform (S0 ml). The aqueous phase was further extracted with chloroform (2xS0 ml) and the combined organic e~tracts were dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica using 0-8% methano! in chloroform as eluant afforded the title compound as a colourless solid (3.g2g, 99%).

1H Nmr (CDC13) ~: 1.36 (lH, s), 1.85 (2H, m), 2.63 (2H, t, J=7Hz), 3.65 (2H, t, J=7Hz), 5.04 (2H, s), 6.91 (2H, d, J=8Hz), 7.11 (2H, d, J=8Hz), 7.27-7.50 (SH, m).
Preparation 10 3-(4-Benzyloxyphenyl)propyl p-toluenesulphonate A solution of 3-(4-benzyloxyphenyl)-1-propanol (4.15g, 17.1 mmol) in absolute chloroform (30 ml) was cooled in ice and treated with pyridine (3.92 ml, 48.5 mmol) followed by p-toluenesulphonyl chloride (6.16g, 32.3 mmol). The mixture was allowed to warm slowly to room temperature and left overnight. After dilution with diethyl ether (90 ml) the solution was washed with lM orthophosphoric acid (S0 ml) followed by saturated aqueous potassium hydrogen carbonate~(S0 ml) and water (S0 ml). The organic pha,se was dried over sodium sulphate and then purified by chromatography on silica using 0-8%
methanol in ~hlorofonn as eluant to give the title compound as a colourless solid (S.lg, 75%)-lH Nmr (CDC13) ~: 1.92 (2H, q, J=7Hz), 2.45 (3H, s), 2.57 (2H, t, J=7Hz), 4.01 (2H, t, J=7Hz), 5.02 (2H, s), 6.83 (2H, d, J=8Hz), 6.97 (2H, d, J=8Hz), 7.30-7.47 (7H, m), 7.78 (2H, d, J=8Hz).

Preparation 11 4-(4-Phenoxyphenyl)butyl bromide To a stirred suspension of aluminium chloride (13.33g, 0.1 mol) in dry dichloromethane (200 ml) was added dropwise over O.Sh 4-bromobutyryl chloride (11.6 ml, 0.1 mol). The resulting mixture was filtered and then added to a solution of diphenyl ether (25.5 g, O.lS

WO93/15080 ~ 8~ PCI/C;;B93/00174 mol) in dry dichloromethane (150 ml) over 0.5 h. The mixture was stirred overnight and then treated with triethylsilane (48 ml, 0.3 mol). After 2 h the reaction was quenched with ice-water. The organic phase was washed with water (200 ml) followed by brine (2x100 ml) then dried over sodium sulphate and concentrated in vacuo. The residue was chromatographed on silica gel using 0-15% diethyl ether in 40-60 petroleum ether as eluant. Subsequent distillation afforded the title compound as a clear oil (22.12g, 73%) b.p. 146-160C at 0.1 mm Hg.

lH Nrnr (CDCI3) ~: 1.68-2.00 (4H, m, overlapping signals), 2.60 (2H, t, J=7Hz), 3.42 (2H, t, J=7Hz), 6.86-7.40 (9H, m).

Preparation 12 ~-(4-Phenoxyphenyl)pentyl bromide 15 The title compound was prepared in a similar manner to Preparation 11 from 5-~romovaleryl chloride (13.39 ml, 0.1 mol), aluminum chloride (13.33g, 0.1 mol), diphenyl ether (25.5g, 0.15mol) and ~iethylsilane (48 ml, 0.3 mol). This afforded the title compound as a clear oil (17.56g, 55%) b.p. 165-180C at 0.2 mm Hg.

lH Nmr (CDC13) ~: 1.36-1.75 (4H, m, overlapping signals), 1.88 (2H, m), 2.60 (2H, t, J=7Hz), 3.40 (2H, t, J=7Hz), 6.8~7.38 (9H, m).

Preparation 13 S-(4-Hydroxyphenyl3-1-pentanol A solution of 4-benzyloxybenzaldehyde (5.0g, 23.56 mmol) and triethyl 4-phosphono-c~otonate (7.07g, 28.25 mmol) in dry tetrahyd~furan (50 ml) was added dropwise to a stirred ice cold slurry of sodium hydride (0.78g of an 80% dispersion in mineral oil, 26.0 mmol) in dry tetrahydrofuran (50 ml) containing 15-crown-5 (0.18g). The mixture was allowed to warrn tO room temperature. After 1 h the reaction was quenched with glacial acetic acid (Sml) and concentrated in vacuo. The residue was partitioned between water (50 ml~ and chloroform (100 ml). The aqueous layer was further extracted with chloroform (2x50 ml) and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Crystallisation from ethyl acetate-pentane afforded a pale yellow solid (5.77g) which was dissolved in ethanol (100 ml) and hydrogenated atatmospheric pressure over 10% Pd-C (lg). After 3 h the reaction mixture was filtered through kieselguhr and then concentrated in vacuo to give ethyl 5-(4-hydroxyphenyl)pentanoate as a clear oil (4.08g). A solution of this ester in dry diethyl wo 93/1~080 2 i 2 ~ i 3 ~J - 22 - PCI/GB93/00174 ether (lOml) was added dropwise to a stined suspension of lithium aluminum hydride (2.08g, 54.8 mmol) in dry diethyl ether (150 ml). After 2.5h the reaction was quenched with wet diethyl ether followed by a minimum amount of water. The reaction was filtered, and the precipitate was washed with methanol. The combined filtrate and washings were 5 concentrated in vacuo. The residue was dissolved in water, acidified with SM
hydrochloric acid. saturated with sodium chloride and extracted exhaustively with chloroform. The combined chloroforrn extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound as a colourless solid. The precipitate was dissolved in SM hydrochloric acid, and the solu~ion was saturated with sodium 0 chloride and filtered through kieselguhr. Exhaustive extraction with chloroform yielded additional product, bringing the to~al recove~y of the title compound tO 3.04g (92%).-lH Nmr (CDC13) ~: 1.25 -1.80 (7H, m, overlapping signals), 2.52 (2H, t, J=7Hz), 3.62 (2H, t, J~7Hz), 4.90 (lH, br s), 6.74 (2H, d, J=8Hz), 7.02 (2H, d, J=8Hz).
Preparation 14 5-(4-Benzyloxyphenyl)-l -pentanol A solution of 5-(4-hydroxyphenyl)-1-pentanol (3.04g, 16.98 mmol) in ethanol (40 ml) 20 containing potassium carbonate (6.1g, 44.2 mmol) was treated with benzyl bromide (2.63ml, 22.07 mmol) and refluxed for lh. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (SO ml) and chloroform (SO ml). The aqueous phase was further extracted with chloroform (2x50 ml) and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Purification by 25 chromatography on silica using 0-8% methanol in chloroform as .oluant afforded the title compound as a colourless solid (4.31g, 94%) lH Nmr (CDC13)~: 1.15-1.70 (7H, m, overlapping signals3, 2.55 (2H, t, J=7Hz), 3.62 (2H, t, J=7Hz), S.O1 (2H, s), 6.87 (2H, d, J=8Hz), 7.07 (2H, d, J=7Hz~, 7.23-7.50 (SH, m).
3û
Preparation 1~

5-~4-Ben~yloxyphenyl)pentyl p-toluenesulphonate 35 The ~itle compound was obtained using the procedure described in Prepara~ion 10 from 5-(4-benzyloxyphenyl)-1-pentanol (3.3g, 12.2 mmol), pyridine (3.0 ml, 37.2 mmol) and p-toluenesulphonyl chloride (4.66g, 24.4 mmol). After a reaction time of 4h at room WO 93/1~080 23 9 l 2~5 3 ~ PCr/GB93/00l74 temperature the mixture was worked up as previously described to give the title compound as a colourless solid (3.64 g, 70~).

1H Nrnr (CDC13) ~: 1.20-1.76 (6H, m, overlapping signals), 2.33-2.60 (5H, m, s overlapping signals), 4.0 (2H, t, J=6Hz), 5.0 (2H, s), 6.83 (2H, d, J=8Hz,), 7.02 (2H, d, J=8Hz), 7.23-7.50 (7H, m), 7.77 (2H, d, J=8Hz).

wO 93/15080 ~ 24 - pcr~GB93too174 9 ~
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Example 1 ~ ~

4-[2-(3,4-Dichlorophenoxy)ethyll-l-azabicyclo[2.2.1]heptane hydrochloride (El) A solution of 4-(2-hydroxyethyl)-1-azabicyclo[2.2.1]heptane (O.Sg, 3.55mmol) in dry te~ahydrofuran (40ml), under nitrogen, was ~eated with 3,4-dichlorophenol (0.87g, 5.32mmol) in dry tetrahydrofuran (2ml), followed by ~phenylphosphine (1.21g, 4.61mmol) in tetrahydrofuran (2ml). Diethyl azodicarboxylate (0.80g, 4.61mmol) was added to the r~action over O.Sh and the mixture was stilTed ovemight at room temperature~
The reac~on was concentrated in vacuo, treated with saturated aqueous potassium carbonate (25ml) then extracted into chloroform (3x25 ml). The combined organic extracts were dried over sodium sulphate, concentrated in vacuo and the residue chromatographed on neutral alumina in a gradient of 0-2% methanol in chloroform. The gum produced was converted into ~e HCl salt, which was washed thoroughly with diethyl ether then crystallised to afford the title compound as a white solid (0.65g), m.p. 188-190 C (methanol-diethyl ether).

1H Nmr (DMSO-d6) ~: 1.70-2.09 (4H, m), 2.18 (2H, t, J=7Hz), 3.12 (2H, s), 3.23-3.56 (4H, m), 4.20 ~2H, t, J=7Hz), 7.06 (lH, dd, J=3, 10Hz), 7.35 (lH, d, J=3Hz3. 7.62 (lH, d, 20 J=lOHz).

Example 2 4-[2-(4-Benzyloxyphenoxy)ethyl]-l-azabicyclo~2.2.1]heptane hydrochloride (E2) The ~tle compound was prepared in a similar manner to Example 1 from 4-(2-hydroxyethyl)-l-azabicyclo~2.2.1~heptane ~O.Sg, 3.55mmol), 4-benzyloxyphenol (1.06g, 5.32mmol), ~iphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (0.24g~, m.p. 209-212 C
30 (from rnethanol-diethyl ether.

H Nmr (DMSO-d63 ~: 1.70-2.09 (4H, m), 2.16 (2H, t,(J=6Hz~, 3.13 (2Ht s), 323-3.66 ~4H, m), 4.10 (2H, t, J=6Hz), 5.12 (2H, s), 6.89-7.08 (4H, m), 7.36-7.S7 (SH, m3.

35 Example 3 4-12-(2-Dibenzofuranyloxy3ethyl]-1-azabicyclol2.2.1]heptane hydrochloride (E3) WO 93/15080 - 25 - PCl /GB93/00174 ~ 2 ~;..' The title compound was prepared in a similar manner to Example 1 from 4-(2-hydroxyethyl)-1-azabicyclo~2.2.1]heptane (0.39g, 2.77mmol), 2-hydroxydibenzofuran (0.76g, 4.1~mmol), triphenylphosphine (0.94g, 3.60mmol) and diethyl azodicarboxylate (0.63g, 3.60mmol). The crude product was chromatographed on silica in a gradient of 5-5 20% methanol in chlorofrom. Pooling of ~ractions containing the major slower runningcomponent afforded an oil which was treated with ethereal hydrogen chloride tO give the title compound as a white solid (0.12g), m.p 206-209 C (from methanol/acetonetdiethyl ether).

lH Nmr (DMSO-d~ 1.75-2.13 (4H~ m), ~.26 (2H, t, J=6Hz), 3.20 (2H, s), 3.26-3.~7 (4H, m), 4.30 (2H, d, J=6Hz), 7.19 tlH, dd, J=2, 7Hz), 7.40-7.79 (SH, m), 8.22 (lH, d, J=7Hz).

Example 4 (+)S-(4-Benzyloxyphenoxymethyl)-l-azabicyclo[3.2.11octane hydrochloride (E4) The ~itle compound was prepared in a similar manner to Example 1 from ~+)5-hydroxymethyl-l-azabicyclo[3.2.1]octane (O.Sg, 3.55mmol~, 4-benzyloxyphenol (1.065g, 5.32mmol), mphenylphosphine (1.21g, 4.61mmol) diethyl azodicarboxylate (0.80g, 4.61mmol). l~his afforded the title compound as a white solid (0.1 lg), m.p. 188-191 C
(from methanol-acetone-diethyl ether).

1H Nmr (DMSO-d6) ~: 1.48-1.55 (lH, m), 1.60-1.97 (SH, m), 3.02-3.16 (4H, m), 3.25-3.37 (2H, m), 3.80 (2H9 s~, 4.95 (2H, s), 6.74 6.98 (4H, m), 7.18-7.35 (SH, m).

Example 5 ~ 35-(4-l~en~ylphenoxymethyl)-1-azabicyclo(3.2.1]octarle hydrochloride (E~) The title compound was prepared in a similar manner to Example 1 from (*)~-hydroxymethyl-l-azabicyclo~3.2.1]octane (O.~g, 3.55mmol), 4-hydroxydiphenylmethane (0.98g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol~ and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (O.lSg), m.p.
35 168 C (dec) (~;rom methanol-ether).

wo 93/15080 c~ S~ 26 - pcr/GBs3/oo174 lH Nmr (DMSO-d6) ~: 1.62-1.70 (lH, m), 1.7~2.11 (5H, m), 3.16-3.30 (4H, m), 3.38-3.51 (2H, m), 3.92 (2H, s), 3.97 (2H, s) 6.88-6.93 (2H, m), 7.14-7.25 (SH, m), 7.27-7.34 (2H, m).

E~cample 6 ~i)5~(2-Dibenzofuranyloxy)methyl-l-azabicyclol3.2.11octane bydrochloride (E6) The dde compound was prepared n a similar manner to Example 1 f~m (i)5-o hydroxymethyl-1-azabicyclo[3.2.1]octane (Q53g, 3.76mmol), 2-hydroxydibenzofuran (1.04g, 5.64mmol) triphenylphosphine (1.28g, 4.89mmol) and diethyl azodicarboxylate (0.8~g, 4.89mmol). The crude product was chromatographed on neut~al alumina in agradicnt of 0.5-2% methanol in toluene. Pooling of fractions containing the faster running component and conversion of the res~ting gum into the hydrochlo~ide salt afforded the title compound as a white solid (Q98g), m.p. 22~225 C (from methanol-acetone-diethyl ether).

lH Nmr (I)MSO~ 1.62-2.22 (6H, m), 3.15-3.59 (6H, m), 4.10 (2H, s), 7,08-7.17 (lH, m), 7.33-7.87 (SH, m), 8.09-8.18 (lH, m).
E~ample 7 ( t ) 5-[2-(2-Dibenzofuranyloxy)ethyl]-l-azabicyclo[3.2.1~oc~ne hydrochloride ~E7) 2~ The ~de compound was pr~par~ in a similar manner to Example 1 ~m ( ~ ) S-(2-hydroxyethyl~l-axabicyclo[3.2.1]oc~ne (0.53g, 3.42 mmol), 2-hydroxydibenzofu~an (09Sg, 5.13 mmol~, triphenylphosphine (1.17g, 4.45 mmol) and di~dlyl awdi~arboxylate (0.54ml, 3.42 mmol3 emplo~g a reac~on ~me of 2h. The crude p~odua was purified by chromatography on neutral al~na using 0.5-2% methanol in toluene as eluan~ and conveTted into the hydrochlonde salt to give the title compound as a coulourless solid (0.7g), m.p. 137-138C (from methanol-acetone-die~yl ether).

lH Nmr (DMSad6) ~: 1.60-2.08 (8H, m), 3.10-3.50 (6H~ m), 4.14 ~, t, J=5Hz), 7.12, (lH, dd, J=8Hz and 2Hz), 7.40 ~lH, t, J=8Hz), 7.52 (lH, t, J=8Hz), 7.63 (lH, d, J=8Hz), 3s 7.67 (lH, d, J=8Hz), 7.77 (lH, d, J=2Hz), 8.14 (lH, d, J=8Hz), 10.93 ~lH, br s).

wo 93/1~080 2t~ ~ 2 ~ ? pcr/GB93/ool74 Example 8 4-[2-(4-Phenoxypheno~y)ethyl]-l-azabicyclo[2.2.1]heptane hydrochloride (E8) s The dde compound was prepared in a similar manner to Example 1 from 4-(2-hydroxyethyl)-l-azabicyclo~2.2.1]heptane (0.62g, 4.4 mmol), ~phenoxyphenol (1.23g, 6.61 mmol), triphenylphosphine (1.5g, 5.72 mmol) and diethyl azodicarboxylate ~û.9 ml, 5.72 mmol). The reacdon mixture was concentrated in vacu~, and the residue was convcrted into the hydrochloride salt with éthereal hydrogen chloride. Aftcr tritu~ation 0 with cther, the salt was treated with sa~urated aqueous potassium carbonate (20 nil) and extracted into chlorofonn (3x25 ml). The combined cxt~acts were d~ied over sodium sulpbate, concentrated ~n vacuo and then purified on neutral alumina using ~2% methanol in cbloroform as eluant. i~fter pooling pure fracdons the product was treated with ethereal hydrogen chlolide to give the title compound as a colourless solid (0.85g), m p. 209-5 211C (methanol - acetone - diethyl edler) lH Nmr a)MSO-d6) ~: 1.73 (2H, m), 1.93 (2H, m), 2.12 (2~I, t, J~lz), 3.07 (2H, s), 3.25 (4Hr m), 4.12 (2H, t, J=6Hz), 6.88-7.13 (7H, m), 7.38 (2H, t, J=7Hz).

20 E~mple 9 4-[3-(4-Benzyloxyphenyl)propylo~cymethyl]~ zabicylol2.2.1]heptane hydrochloride ~E9) A solution of ~hydroxymethyl-l-azabicyclo[2.2.1]he~ e (0.2g, 1.57 mmol) in ~ N,N-dimed~ylformamide (Snil) wa~ treated ~i~ sodium hydride (SOmg ~f an 80% di~ersion in nnn~al Qil, 1.66 mmol) and the mix~ure was s~d at 50C unde~ nitrogen u~l hydrogen evolution had ceased. Por~on~nse add~non of 3-(4-benzyloxyphenyl)I~ropyl toluenesulphonate (û.58g, 1.57 ~1) was casried out over lh, and d~e mixt~Me was st~
for a further lh. The reac~on was concen~ated in vacuo and dle residue was co evapo~a~ed wi~h successive ~ons of toluene. The residue was treated w~th samrated aqueous postassium carbonate (lOml) and extIacted into chlorofo~m (3x15 ml). Thecombined extracts were dried over sodium sulphate and dlen concentrated in vacuo. The crude product was pusified by flash chromatography on neu~al alumina using ~15%
3s methanol in chloroform as eluant. Pooled ~ac~ons containing dle fastellunningcomponent were converted into the hydrogen chloride salt to give the title oompound as a colourless solid (0.1 lg), m.p. 16~168C (f~om methanol-diethyl edler).

wO93/15080 ~ 9 ~5 ~J ~ 28 - pcr/Gss3/ool74 lH Nmr (DMSO-d6) ~: 1.72 (2H, m), 1.87(2H, m), 2.03 (2H, m), 2.65 (2H, t, J=8Hz), 3.12 (2H, s), 3.2~-3.55 (6H, m, overlapping signals), 3.68 (2H, s), ~.16 (2H, s), 7.01 (2H, d, J=9Hz), 7.20 (2H, d, J=9Hz), 7.37-7.63 (SH, m).

Example 10 4-15-(4-Phenoxyphenyl)pentyloxy~ azabicyclol2.2.1]heptane hydrochloride (13:10) A solution of l-benzyl-l-azoniabicyclol2.2.13heptan~ol ~toluenesulphonate (0.5g, 1.33 lo mmol) in dry N,N-dimethylforma~de ~7ml) was treated with sodium hydride (80 mg of an 80% dispersion in mineral oil, 2.66 mmol) and then stirred under nitrogen at room te~perature f~r lh. A soludon of 5-(~phenoxyphenyl)pentyl bromide (0.85g, 2.66 mmol) in dry N, N-dimethylformamide (2ml) was added, and dle mi~cture was sdrred for 3h. The rcaction was quenched with glacial acetic acid (O.Sml) and then concen~rated in vacuo.
After c~evaporadon with successive pordons of tolllene, the residue was disolved in - ~ ~ ethanol (lO ml) and hydrogenated at atmospheric pressure over 10% Pd-C (O.lg) for 2h.
The reaction n~ix~re was filtered through a pad of kieKlguhr and the filtrate was conclu~ed in vacuo. The residue was treated with saturated aqueous potassiym carl~nr~ (~0 ml) and ex~d into chlorof~m (3x20ml). The combined extracts were dried~over sodium sulphate and conc~ntratcd in vacuo. The crudc p~duct was purified by flash chn~tography on neu~al alumina using 0-15% mcthanol in cblo~ofo~m as eluant.
Afte~ pooling pure fractions the product was ~eated with ethereal hydrogen chlo~ide to give ~e title oompound as a col~less solid ~0.14g), m.p. 129-131C (~om acetone--~ diedlyl edler).
: 25 lH Nmr (DMS~d6) ~: 1.33 (2P~ m), 155 (4H, m), 1.8~2.10 (4H, m), 2.53 (~, t, J=7Hz), 3.18 ~2H, s), 3.3~3.58 (~iH, m, overlapping signals), 6.93 (4H, m~, 7.11(1H, t, J=8Hz), 7.22 (lH, d, J-8H~, 7.38 (2~ t, J=8~1z).

30 Example 11 , 4~ Benzylo~ypheno~methyl)-l-azabicyclol2.2.1]heptane hydrochloride (Ell) The title compound was prepared in a similar manner to Example 1 from 4 3s hydroxymethyl-1-azabicyclo[2.2.1]heptane (0.5g, 3.94 mmol), ~benzyloxyphenol (1.18g, ~; 5.91 mmol), tnphenylphosphine (1.55g, 5.91 mmol) and diethyl azodicarboxylate (0.93ml, 5.91 mmol). After a re~cd(m period of Sh the mixture was worked up as pre~riously described for E~xample 1. Purification on neut~al alumina using 5% ethanol in chlorofo~m ~' WO 93/150X0 - 29 2 ~ ? ~ Pcr/GB93/00l74 as eluant afforded a pale yellow oil which was treated with ethereal hydrogen chloride to give the title compound as a colourless solid (0.09g), m.p. 20~208C (~om methanol-ace~ne-diethyl ether).

s lH Nmr (DMS~d6) ~: 1.73 (2H, m), 2.02 (2H, m), 3.12 (2H, s~, 3.20-3.50 ~4H, m, overlapping signals), 4.17 (2H, s), 5.03 (2H, s), 6.93 (4H, m), 7.2~7.48 (SH, m).

E~ample 12 'I l4-(4-Phenoxyphenyl)butyloxy]-l-azabicyclo[2æ.1]heptane hydrochloride (E12) The title compound was prepared in a similar manner to Example 10 from l-benzyl-l-azoniabicyclo[2.2.1]heptan-~ol p-toluenesuphonate ~0.5g, 1.33 mmol), sodium hyd~ide (80 mg of an 80% dispersion in mineral oil, 2.66 mmol) and ~(~phenoxyphenyl)butyl b~omide (0.89g, ~.91 mmol). The crude product was purified by chromatography on silica using 5-10% edlanol in chloroform as duant, and ~eated with ethe~eal hydrogen chloride to givc the title compound as a ~olouriess solid nLp. 115-117.5C (~om acetonc-died yl e~h~).

lH Nmr (DMS~d6) ~: 1.46-1.67 (4H, m), 1.85-2.06 (4H, m~, 2.57 (2H, t, J--7Hz), 3.17 (2~I, s), 3.3~3.60 (6H, m, ove~ ping signals), 6.93 (4H, m, overlapping signals), 7.11 (lH, t, J=7Hz), 7.21 (2H, d, J=8Hz), 7.38 (2H, t, J=8Hz).

Example 13 4.~3-(4-Benzyloxyphenyl)pr~pyloY~y]-l~azabicyclo[2.2.1~heptane hydrochloride (E13) A solu~on of ~hydroxy-l-azabicylo~2.2.13heptane (0.38g, 3.36 mmol) in dry N, N-dimedlylfoImamide (l~ml) was treated under ni¢ogen with sodium hydride ~120 mg of an ~0% dispersion in ~eral oil, 4.0 mmol). The mixture was warmed to 4~50C and sti~red for 2h. The temperature was raised to 60C and a solu~ion of 3-(4-benzyloxyphenyl)pr~pyl tosylate (0.9Og, 2.69 mmol) in dry N, N-dimethylfo~de (8ml) was added dropwise over 2h. After a further lh at 60C ~e reac~ion was cooled and quenched with glacial acetic acid (0.23 ml). The reaction was concentratecl in vacuo and ~en paltitioned between cbloroform (20 ml) and satarated a~ueous potassium carbonate (20 ml). The aqueous phase was extracted with chlorofoIm (2x20 ml) and the combined organic layers were dried oYer sodium sulphate and concen~ated in vacuo. Purification on neutral alumina using 1-2% ethanol in chloroform as eluant afforded a colourless wo 93/1~080 ~" ~ 30 - PCI`/GB93/00174 crystalline solid which was treated with ethereal nydrogen chloride to give the title compound as a colourless solid (0.30g) m.p. 180-181 C (from methanol-acetone-diethyl ether).

s lH Nmr (DMSO-d6) ~: 1.78 (2H, m); 1.92 (2H, m); 2.02 (2H, m); 2.56 (2H, t, J= 7Hz);
3.18 (2H, s); 3.25-3.60 (6H, m); 5.07 (2H, s~, 6.92 (2H, d, J=8Hz); 7.12 (2H, d, J=8Hz);

7.28-7.50 (SH, m).
Example 14 4-15-(4-Benzyloxyphenyl)pentyloxy~ azabicyclol2.2.1~heptane hydrochloride (E14) A solution of 4-hydroxy-1-a~abicyclo 12.2.1] hep~ane (0.38g, 3.36 mmol) in dry N, N-dimethylformamide (lSml) was treated under nitrogen with sodium hydride (120mg of an 80% dispersion in mineral oil, 4.0 mmol). The mixture was warmed tO SOC and stilTed for 2h. The temperature was raised to 60C and a solution of 5-(4-benzyloxyphenyl) pentyl p-toluenesulphonate (1.07g, 2.52 mmol) an dry N, N-dimethylfonnamide (9ml) was added dropwise over a period of 3h. After a further 45min at 60C the mixtur~ was cooled and quenched with glacial ace~ic acid (0.23ml). The reaction was concenlrated in vacuo then par~tioned between chloroform (75ml) and satura~ed aqueous potassium carbonate (75ml). The aqueous pha~e was exhaustively extracted with chlorofonn. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Purification on neu~ral alumina using 1% ethanol in chloroform as eluanl followed by treatment with ethereal hydrogen chloride afforded Ihe title compound as a colourless so~id (0.30g) m.p.
15~151.5C (acetone-diethyl ether).

lH Nmr (DMSO-d6) ~: 1.32 (2H, m); 1.53 (4H, m~; 1.82-2.08 (4H, m), 2.S0 (2H, t, J=7Hz), 3.17 (2H, s); 3.25-3.60 (6H, m); 5.06 (2H, s); 6.92 (2H, d, J=8Hz), 7.10 (2H, d, J=8Hz); 7.28-7.50 (5H, m).

Claims (11)

Claims:

1. A compound of formula (I):
Formula (I) in which p, q and r each independently represent an integer from 1 to 4;
A is a bond, -CH=CH-, -C?C-, oxygen, sulphur or NR1; where R1 is hydrogen, C1-8alkyl or phenylC1-4alkyl;
n is 0 to 6, and m is 0 to 6, such that the length of the chain (CH2)nA(CH2)m is at least two atoms; and Ar is aryl or heteroaryl, each of which may be optionally substituted;
with the proviso that when p, q and r each represent 2, n is zero, m is 1 and A is NR1 then Ar is not unsubstituted phenyl, or a salt thereof.

2. A compound according to claim 1 wherein p and r are independently 2 or 3.

3. A compound according to claim 1 or claim 2 wherein q is 1 or 2.

4. A compound according to any of claims 1 to 3 wherein A is oxygen or a bond.

5. A compound according to any of claims 1 to 4 wherein the length of the chain -(CH2)nA(CH2)m is from 2 to 6 atoms.

6. A compound according to any of claims 1 to 5 wherein m is 0 to 3.

7. A compound according to claim 1, selected from:

4-[2-(3,4-dichlorophenoxy)ethyl]-1-azabicyclo[2.2.1]heptane, 4-[2-(4-benzyloxyphenoxy)ethyl-1-azabicyclo[2.2.1]heptane, 4-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[2.2.1]heptane, (?)5-(4-benzyloxyphenoxymethyl)-1-azabicyclo[3.2.1]octane, (?)5-(4-benzylphenoxymethyl)-1-azabicyclo[3.2.1]octane, (?)5-(2-dibenzofuranyloxy)methyl-1-azabicyclo[3.2.1]octane;
(?) 5-[2-(2-dibenzofuranyloxy)ethyl]-1-azabicyclo[3.2.1]octane, 4-[2-(4-phenoxyphenoxy)ethyl]-1-azabicyclo[2.2.1]heptane, 4-[3-(4-benzyloxyphenyl)propyloxymethyl]-1-azabicylo[2.2.1]heptane, 4-[5-(4-phenoxyphenyl)pentyloxy]-1-azabicyclo[2.2.1]heptane, 4-(4-benzyloxyphenoxymethyl)-1-azabicyclo[2.2.1]heptane, 4-[4-(4-phenoxyphenyl)butyloxy]-1-azabicyclo[2.2.1]heptane, 4-[3-(4-benzyloxyphenyl)propyloxy]-1-azabicyclo[2.2.1]heptane, and 4-[5-(4-benzyloxyphenyl)pentyloxy]-1-azabicyclo[2.2.1]heptane, or a pharmaceutically acceptable salt thereof.

8. A process for the preparation of a compound of formula (I) as defined in any of claims 1 to 7 which comprises:

(a) for compounds of formula (I) in which A is O, S or NR1, reaction of a compound of formula (II):
Formula (II) in which p, q, r and n are as described for formula (I) and A1 is O, S or NR1, with a compound of formula L(CH2)mAr in which m and Ar are as described for formula (I), and L is a leaving group;

(b) for compounds of formula (I) in which A is O, S or NR1, reaction of a compound of formula (III):

Formula (III) in which p, q, r and n are as described for formula (I) and L1 is a group displaceable by a nucleophile, with a compound of formula HA1(CH2)mAr where m and Ar are as described for formula (I) and A1 is as described for formula (II); or (c) for compounds of formula (I) in which A is NR1, reduction of a compound of formula (IV):
Formula (IV) in which R4 represents the group -(CH2)nN(R1)C(O)(CH2)m-1Ar or -(CH2)n-1C(O)N(R1)(CH2)mAr, and p, q, r, n, m, and Ar are as described for formula (I);

(d) for compounds of formula (I) in which A is a bond, reaction of a compound offormula (V):

Formula (V) (wherein L1, p, q, r, m and n are as hereinbefore defined).

with a compound of formula X1Ar in which Ar is as described for formula (I), and X1 is an alkali metal;
(e) For compounds wherein A is -CH=CH- reaction of a compound of formula (VI):

Formula (VI) (wherein n, p, q and r are as hereinbefore defined) with a reagent serving to introduce the group Ar, (f) Interconversion of one compound of formula (I) to a different compound of formula (I) e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2CH2-;
and optionally thereafter forming a salt.

9. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

10. A compound of formula (I) as defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in therapy.

11. A method of treatment of a condition or disease related to the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.