Background Neurological disorders, to which the present invention relates, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.

Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5-HT2 receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379-384,1994).

[3H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, <BR> <BR> <BR> <BR> is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148,1993). Moebius et al. have termed this the"anti-ischaemic"binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [3H]-emopamil binding site is localised to the endoplasmic reticulum.

Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [3H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds that interact with either the VSCC or the NMDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations.

Summary of The Invention We have now found a class of compounds that show selective binding at the [3H]-emopamil binding site.

The present invention provides compounds of formula I:

wherein: R is hydrogen, substituted or unsubstituted C1-8alkyl, substituted or unsubstituted C2-8alkenyl or substituted or unsubstituted Cs-galkynyl; wherein said Cl 8alkyl, C28alkenyl and C2-galkynyl, when substituted, are substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkoxycarbonyl,C1-6alkanoyloxy,N-(C1-6alkyl)amino,C1-6al koxy,C1-6alkanoyl, N-(C1-6alkyl)carbamoyl,N,N-(C1-6alkyl)2amino,C1-6alkanoylami no, N, N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkoxy, C1-6alkylS(O)a wherein a is 0 to 2, N-(C1-6alkyl)sulphamoyl or N,N-(C1-6alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3, 2cycloalkyl, and a group of formula IA: G-(CH2)p-X- IA wherein: G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3 2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from-C (O)-,-O-,-OC (O)-,-S-,-S (O)-,-S (O) 2-,-S (O) 2NR4-,-NR4S (O) 2-, -NR4-,-C (O) O-,-C (O) NR4-,-NR4C (O)-,-OC (O) NR4-,-C (O) NR4S02-,-NR4C (0) O-, -C (S) NR4- or-NR4C (S)-, wherein R4 is selected from hydrogen and Cl 4alkyl;

wherein any aryl, heteroaryl, heterocycle or C3, 2cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C, 6alkyl, C26alkenyl, C26alkynyl, C, 6alkoxy, C, 6alkanoyl, Cl 6alkanoyloxy, N-(C1-6alkyl)amino, N-(C1-6alkyl)carbamoyl,C1-6alkanoylamino, N, N- (C1-6alkyl) 2carbamoyl, C, 6alkylSOa where a is an integer selected from the range 0 to 2, N,N-(C1-6alkyl)2sulphamoylorphenylC1-6alkylC1-6alkoxycarbony l,N-(C1-6alkyl)sulphamoyl, and a heterocycle or heteroaryl containing an-NH-group may be unsubstituted or substituted on a ring nitrogen with C, 6alkyl, C26alkenyl, C26alkynyl, C, 6alkanoyl, C, 6alkylsulphonyl or phenylC1-6alkyl; A is a ring selected from phenyl and naphthyl; R2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2-6alkynyl,C1-6alkoxy,C1-6alkanoyl,C1-6alkanoyloxy,C1-6alky l,C2-6alkenyl, C1-6alkanoylamino,N-(C1-6alkyl)carbamoyl,N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, N, N- 6alkyl) 2carbamoyl, Cl 6alkylSOa where a is an integer selected from the range 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, and a group of the formula: W-(CH2)p-B- wherein W is halo, nitro, hydroxy, C, 6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cl 6alkylamino, N, N-(Cl 6alkyl) 2amino, Cl 6alkoxycarbonyl, N-Ct 6alkylcarbamoyl(Cl 6alkyl) 2amino, Cl 6alkoxycarbonyl, N-Ct 6alkylcarbamoyl or N, N-(Cl 6alkyl) 2carbamoyl,(Cl 6alkyl) 2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N- (Cf-6alkyl) imino or-C (O) NH-, with the proviso that p is 2 or more unless B is a bond,-C (O) NH-, or R2 is a group of formula IC: D-E- IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, Cl 6alkylene, Cl 6alkyleneoxy, oxy, imino, N-(C1-6alkyl)imino, C1-6alkyleneimino, -SO2NH-,-NHSO2-,sulphonylC1-6alkylene,N-(C1-6alkyl)-C1-6alky leneimino,-C(O)NH-,

carbonylCs 6alkyleneoxycarbonyl-CI 6alkylene and C26alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cz 6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C, -6alkylamino, N,N-(C1-6alkyl)2amino, C1-6alkoxycarbonyl, N-C l 6alkylcarbamoyl or N, N- (C_6alkyl) 2carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: a) if A and R2 in combination is 4-mesyl then R'is not 2-methoxycarbonylethyl; b) if A and R2 in combination is 4-chloro then R'is not 2-methoxycarbonylethyl, 3-mercaptopropyl, 3-chloropropyl or 3-aminopropyl; c) if m is 0 then R'is not 3-chloropropyl, 2-aminoethyl, 3-aminopropyl, 2-hydroxyethyl, methyl, ethyl, isopropyl or isobutyl; d) if A and R2 in combination is 3-chloro then R'is not 4-acetyl-4-ethoxycarbonylbutyl or 3-chloropropyl; e) if A and R2 in combination is 3,4,5-trimethoxy then R'is not cyanomethyl or 2-aminoethyl; and f) when Rl is a substituted straight chain C, _4alkyl group, the distal carbon atom, that is, the carbon atom of said C1-4alkyl group furthest from the homopiperazine ring, is not substituted with, i) two aryl rings, ii) two heteroaryl rings, or, iii) a heteroaryl and a phenyl ring; and with the further proviso that when Rl is substituted C I-8alkyl, substituted C28alkenyl or substituted C2-8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.

Detailed description of The Invention As used herein the term"alkyl"includes both straight and branched chain alkyl groups but references to individual alkyl groups such as"propyl"are specific for the straight chain version only. A similar convention applies to"alkenyl","alkynyl"and other radicals, for example"phenylC, 6alkyl"includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.

As used herein the term"halo"means fluoro, chloro, bromo and iodo.

As used herein the term"aryl"means an unsaturated carbon ring. Particularly aryl means phenyl, naphthyl or biphenyl. More particularly aryl means phenyl.

As used herein the term"heteroaryl"or"heteroaryl ring"means, unless otherwise further specified, a monocyclic-, bicyclic-or tricyclic-5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a-CH2-group can optionally be replaced by a-C (O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of such heteroaryls include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.

As used herein the term"heterocyclyl"or"heterocyclic ring"means, unless otherwise further specified, a mono-or bicyclic-5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a-CH2-group can optionally be replaced by a-C (O)-. Examples of such heterocyclyls include rnorpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.

As used herein, where optional substituents are selected from"one or more"groups it is to be understood that this encompasses compounds where all substituents are chosen from one of the specified groups and compounds where substituents are chosen from more than one of the specified groups.

In the present invention, examples of Cl galkyl include Cl 6alkyl, Cl 5alkyl Cl 4alkyl, methyl, ethyl, isopropyl and t-butyl; examples of Cl 6alkoxycarbonyl include C, _4alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n-and t-butoxycarbonyl; examples of Cl 6alkoxy include Cl 4alkoxy, methoxy, ethoxy and propoxy; examples of Cl 6alkanoylamino include formamido, acetamido and propionylamino; examples of C, _6alkylS (O) a where a is 0-2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of C, _6alkanoyl include propionyl and acetyl; examples of TV-Cjalkylamino include N-methylamino and N-ethylamino; examples of N, N-(Cl 6alkyl) 2amino(Cl 6alkyl) 2amino include N, N-dimethylamino, N, N-diethylamino and N-ethyl-N-methylamino; examples of C2 galkenyl include C26alkenyl, vinyl, allyl and 1-propenyl; examples of C2-8alkynyl include C2-6alkynyl, ethynyl, 1-propynyl and 2-propynyl; examples of N- (Cl 6alkyl) sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl;

examples of N, N- (C, 6alkyl) 2SUlphamoyl include N, N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; examples of N-(C1-6alkyl) carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C1-6alkyl)2carbamoyl include N, N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl; examples of C, 6alkanoyloxy include propionyloxy, acetyloxy and formyloxy; examples of C 6alkoxyCl 6alkoxy include methoxymethoxy, methoxyethoxy and ethoxymethoxy; examples of C, 6alkylsulphonyl include mesyl and ethylsulphonyl; examples of C3, 2cycloalkyl include cyclopropyl and cyclohexyl.

In the linking groups B and E that fall within the definition of R2, examples of Ci-6alkylene include-CH2CH2-and-CH2CH (CH3) CH2-; examples of C, 6alkyleneoxy include C, 4alkyleneoxy,-CH2CH2O-and-CH2CH (CH3) CH2O-; examples of N-(C1-6alkyl) imino include-N (Me)- and-N ('Pr)- ; examples of C1-6alkyleneimino include -CH2CH2NH- and -CH2CH (CH3) CH2NH- ; examples of N-(Cl 6alkyl)-Cl 6alkyleneimino include -CH2CH2N (Me)- and -CH2CH (CH3) CH2N ('Pr)- ; examples ofsulphonylCjaIkyIene include and-SO2CH2CH(CH3)CH2-;examplesofsulphonylC1-4alkylene,-SO2CH 2CH2- -C(O)CH2CH2OC(O)CH2-andcarbonylC1-6alkyleneoxycarbonyl-C1-6a lkyleneinclude -C (O) CH2CH (CH3) CH20C (O) CH2CH2-; examples of kanoylimino include -CH2CH2C (O) NH-and-CH2CH (CH3) CH2C (O) NH-.

In a particular aspect of the invention R'is other than hydrogen. Particularly, Ri is C1-8alkyl substituted with one or more halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C, 6alkoxy, C1-6alkanoyloxy,N-(C1-6alkyl)amino,C1-6alkanoyl,C1-6alkoxyca rbonyl, N-(C1-6alkyl)carbamoyl,N,N-(C1-6alkyl)2amino,C1-6alkanoylami no, N,N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkoxy, C1-6alkylS(O) a wherein a is 0 to 2, N-(C 16alkyl) sulphamoyl or N, N-(C 16alkyl) 2sulphamoyl,(C 16alkyl) sulphamoyl or N, N-(C 16alkyl) 2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3, 2cycloalkyl, or a group of formula IA: G- (CH2) X IA wherein G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3, 2cycloalkyl, p is 0 to 6 and X is a linking group and is selected from-C (O)-,

-0-,-OC (O)-,-S-,-S (O)-,-S (0) 2-,-S (0) 2NR4-,-NR4S (0) 2-,-NR4-,-C (O) O-,-C (O) NR4-, -C(O)NR4SO2-,-NR4C(O)O-,-C(S)NR4-or-NR4C(S)-whereinR4-NR4C(O )-,-OC(O)NR4-, is selected from hydrogen and Cl 4alkyl; wherein in any of the foregoing, any aryl, heteroaryl, heterocycle or C3-12cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C, 6alkyl, C26alkenyl, C26alkynyl, Cs 6alkoxy, C, 6alkanoyl, N,N-(C1-6alkyl)2amino,C1-6alkanoylamino,C1-6alkanoyloxy,N-(C 1-6alkyl)amino, N-(Cl 6alkyl)(Cl 6alkyl) carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, N,N-(C1-6alkyl)2sulphamoylorphenylC1-6alkylC1-6alkoxycarbony l,N-(C1-6alkyl)sulphamoyl, and a heterocycle or heteroaryl containing an-NH-group may be unsubstituted or substituted with C, 6alkyl, C26alkenyl, C26alkynyl, C, 6alkanoyl, C, 6alkylsulphonyl or phenyl -6alkyl and with the proviso that when Rl is substituted CI-8alkyl, substituted C2_$alkenyl or substituted C2-saikynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.

In another aspect of the invention, R is hydrogen or Cx galkyl optionally substituted with fluoro or aryl.

In a particular aspect of the invention Rl is hydrogen or Cx galkyl optionally substituted with fluoro or phenyl.

Particularly Rl is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl.

More particularly R'is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl.

Most particularly R'is methyl.

In one aspect of the invention, Ring A is phenyl.

In another aspect of the invention, Ring A is naphthyl.

In one aspect of the inventions R2 is halo, nitro, trifluoromethyl, trifluoromethoxy, C 6alkyl, Cl 6alkoxy, Cl 6alkoxycarbonyl, or a group of the formula IC as disclosed above, wherein D is phenyl and E is a bond, Cl 6alkyleneoxy or sulphonylCl 6alkylene.

More particularly R2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene.

Particularly R2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond or methyleneoxy.

In one aspect of the invention m is an integer selected from the range 0 to 3.

In a particular aspect of the invention m is an integer selected from the range 0 to 2.

Particular combinations of Ring A and (R2) m are as follows: such combinations are phenyl, naphth-1-yl, biphen-2-yl, 2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2- (phenylsulphonylmethyl) phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-difluorophenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl.

More particular combinations of Ring A and (R2) m are naphth-1-yl, biphen-2-yl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl.

Most particularly combinations of Ring A and (R2) m are 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl.

Therefore, in a particular aspect of the invention, there is provided a compound of formula I as disclosed herein wherein: Rl is hydrogen or CI 8alkyl optionally substituted with fluoro or aryl; Ring A is phenyl or naphthyl; R is halo, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 1-6alkoxy, C, _6alkoxycarbonyl, or a group of the formula IC as disclosed herein, wherein D is phenyl and E is a bond, Cl 6alkyleneoxy or sulphonylCl 6alkylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof;

with the provisos that when A is phenyl: a) if A and R2 in combination is 3-chloro or 4-chloro then R'is not 3-chloropropyl; b) if m is 0 then R'is not 3-chloropropyl, methyl, ethyl, isopropyl or isobutyl; and c) when R'is a substituted straight chain C, 4alkyl group, the distal carbon atom, that is, the carbon atom of said C, 4alkyl group furthest from the homopiperazine ring, is not substituted with two aryl rings.

Therefore, in a more particular aspect of the invention, there is provided a compound of formula I as depicted above wherein: R hydrogen, Chalky I optionally substituted with fluoro or phenyl; Ring A is phenyl or naphthyl; R'is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof; with the proviso that when A is phenyl and a) m is 0 then Rl is not methyl, ethyl, isopropyl or isobutyl b) Rl is a substituted straight chain Cl 4alkyl group, the distal carbon atom, that is, the carbon atom of said C, 4alkyl group furthest from the homopiperazine ring, is not substituted with two phenyl rings.

Therefore, in a further particular aspect of the invention, there is provided a compound of formula I as depicted above wherein: R'is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and Ring A and R2 in combination form phenyl, naphth-1-yl, biphen-2-yl, 2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2- (phenylsulphonylmethyl) phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-difluorophenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl,

3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof; with the proviso that when Ring A and R2 in combination are phenyl then R'is not methyl, isopropyl or isobutyl.

Therefore, in another aspect of the invention, there is provided a compound of formula I as depicted above wherein: R'is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and Ring A and R'in combination form naphth-1-yl, biphen-2-yl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof.

Therefore, in another particular aspect of the invention, there is provided a compound of formula I as depicted above wherein: R'is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and Ring A and R in combination form 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof.

Particular compounds of the invention are those of Examples and include: 1-methyl-4- (4-benzyloxybenzyl)homopiperazine; 1-methyl-4- (2,4-bis (trifluoromethyl) benzyl) homopiperazine; 1-propyl-4- (4-benzyloxybenzyl)homopiperazine; 1-benzyl-4- (4-benzyloxybenzyl)homopiperazine;

1-pentyl-4- (4-benzyloxybenzyl) homopiperazine; 1-methyl-4- (3,5-bis (trifluoromethyl) benzyl) homopiperazine; 1- (2-phenylethyl)-4- (4-benzyloxybenzyl) homopiperazine; 1- (3, 5-difluorobenzyl)-4- (4-benzyloxybenzyl) homopiperazine; 1- (3,4,4-trifluoro-but-3-enyl)-4- (4-benzyloxybenzyl) homopiperazine; 1-butyl-4- (4-benzyloxybenzyl) homopiperazine; 1-isopropyl-4- (4-benzyloxybenzyl) homopiperazine; 1- (2-methylpropyl)-4- (4-benzyloxybenzyl) homopiperazine; 1-ethyl-4- (4-benzyloxybenzyl) homopiperazine; 1-methyl-4- (4-tert-butylbenzyl) homopiperazine, and 1- (2-hydroxypropyl)-4- (4-benzyloxybenzyl) homopiperazine.

Suitable pharmaceutically-acceptable salts include acid-addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, phosphate and sulphate. In another aspect suitable salts are base salts such as an alkali metal salt, for example sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine and N, N-dibenzylethylamine, or amino acids, for example lysine. A compound of the invention may have more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is a sodium salt.

Compounds of formula I may possess a chiral centre. It is to be understood that the invention encompasses all optical isomers and diasteroisomers of compounds of formula I that act at the [3H]-emopamil binding site. Further, all tautomeric forms of compounds of formula I are compounds of the present invention.

It is also to be understood that certain compounds of the formula I can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.

In vivo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl.

An in vivo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolyse in the human or animal body to produce the parent acid or alcohol.

Suitable pharmaceutically-acceptable esters for carboxy include C, 6alkoxymethyl esters, for example methoxymethyl; C, 6alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; C3 scycloalkoxy-carbonyloxycl 6alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C, 6alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl. Such esters may be formed at any carboxy group in a compound of this invention.

An in vivo-hydrolysable ester of a compound of the formula I having a hydroxy group includes inorganic esters such as phosphate esters and a-acyloxyalkyl ethers and related compounds which, as a result of the in vivo hydrolysis of the ester, yield the parent hydroxy group. Examples of oc-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo-hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.

Another aspect of the present invention provides a process for preparing a compound <BR> <BR> <BR> <BR> of formula I or a pharmaceutically-acceptable salt or an in vivo-hydrolysable ester, amide or carbamate thereof which process, wherein R', R2, Ring A and m are, unless otherwise specified, as defined for formula I comprises: a) reacting a compound of the formula II: wherein L is a suitable displaceable group, with a compound of the formula III:

wherein, when Rl of a compound of formula I is hydrogen Ra is suitable amino protecting group such as those defined below; or when R'of a compound of formula I is not hydrogen Ra is Rl; or b) for preparing a compound of formula I wherein Rl is not hydrogen, reacting a compound of formula IV:

with a compound of formula V: R'-L V wherein L is a suitable displaceable group and R'is not hydrogen; or c) reacting a compound of the formula VI:

with a compound of the formula III; or d) for preparing compounds of formula I wherein R'is not hydrogen and there is a -CH2-or CH3-moiety attached to the nitrogen of the homopiperazine ring, reacting a compound of formula IV with a compound for formula VII:

wherein Rb is hydrogen or substituted or unsubstituted Cl 7alkyl, substituted or unsubstituted C27alkenyl or substituted or unsubstituted C2-7alkynyl and Rc is hydrogen or hydroxy; and thereafter if necessary: i) converting a compound of the formula I into another compound of the formula I; ii) removing any protecting groups; or iii) forming a pharmaceutically-acceptable salt or ion vivo-hydrolysable ester, amide or carbamate.

As used herein, the L is a displaceable group, and suitable values for L are, for example, a halogeno or sulphonyloxy group, such groups are chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.

Specific reaction conditions for reactions a) and b) are as follows.

Compounds of formula II and III and compounds of formula IV and V are reacted together under standard alkylation conditions. For example in an organic solvent, for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, optionally in the presence of a catalyst, such as an iodide salt for example potassium iodide, and at a temperature in the range of 0-100 °C, preferably 40-80 °C.

Compounds of formula II, III and V are commercially available compounds, are disclosed in the literature, or are prepared by standard processes known in the art.

Compounds of formula IV may be prepared according to the following scheme: N L (.) pg-, L DMF, KI-N Deprotection N \..-.. IV A 0 (R2m A IVA IVB IVC wherein Pg is a suitable amino protecting group such as those described hereinbelow that can be removed by standard deprotection conditions such as those also described hereinbelow.

Specific reaction conditions for reactions c) and d) are as follows.

Amines may be reacted with aldehydes under standard reductive amination conditions.

For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst, for example palladium on carbon, or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.

Compounds of formula VI and VII are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley

and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group; for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.

Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

In order to use a compound of the formula I or a pharmaceutically-acceptable salt or in vivo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The pharmaceutical compositions of compounds of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use such as intravenous, intramuscular or infusion, sterile aqueous or oily solutions or suspensions or sterile emulsions. A preferred route of administration is intravenously in sterile isotonic solution.

In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.

The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.

Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I' :

I' wherein: R is hydrogen, substituted or unsubstituted C salkyl substituted or unsubstituted C2-8alkenyl or substituted or unsubstituted C28alkynyl; wherein said Cl galkyl, C2 galkenyl and C2-8alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkoxycarbonyl,C1-6alkanoyloxy,N-(C1-6alkyl)amino,C1-6al koxy,C1-6alkanoyl, N-(C1-6alkyl)carbamoyl,N,N-(C1-6alkyl)2amino,C1-6alkanoylami no, N, N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkoxy, C1-6alkylS(O) a wherein a is 0 to 2, N-(CI 6alkyl)(CI 6alkyl) sulphamoyl or N,N-(C1-6alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-12cycloalkyl, and a group of formula IA: G- (CH2) X IA wherein: G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3-12cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from-C (O)-,-O-,-OC (O)-,-S-,-S (O)-,-S (O) 2-,-S (O) 2NR4-,-NR4S (O) 2-, -NR4-,-C (O) O-,-C (O) NR4-,-NR4C (O)-,-OC (O) NR4-,-C (O) NR4S02-,-NR4C (0) 0-, -C (S) NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and Cl 4alkyl; wherein any aryl, heteroaryl, heterocycle or C3. ; 2cycloalkyl may be substituted or unsubstituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2-6alkynyl,C1-6alkoxyC1-6alkanoyl,C1-6alkanoyloxy,C2-6alken yl, C1-6alkanoylamino,N-(C1-6alkyl)carbamoyl,N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, N, N- (C, _6alkyl) 2carbamoyl, C, _6alkylSOa where a is an integer selected from the range 0 to 2, N,N-(C1-6alkyl)2sulphamoylorphenylC1-6alkylC1-6alkoxycarbony l,N-(C1-6alkyl)sulphamoyl, and a heterocycle or heteroaryl containing an-NH-group may be substituted or unsubstituted on a ring nitrogen with C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, C1-6alkylsulphonyl or phenylCI 6alkyl;

A is a ring selected from phenyl and naphthyl; R2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2-6alkynyl,C1-6alkoxy,C1-6alkanoyl,C1-6alkanoyloxy,C1-6alky l,C2-6alkenyl, C1-6alkanoylamino,N-(C1-6alkyl)carbamoyl,N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, N, N- (C1-6alkyl) 2carbamoyl, Cl 6alkylSOa where a is an integer selected from the range 0 to 2, C, _6alkoxycarbonyl, N- (C, _6alkyl) sulphamoyl, N, N- (CI 6alkyl) 2sulphamoyl, and a group of the formula: W-(CH2)p-B- wherein W is halo, nitro, hydroxy, C, 6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C1 6alkylamino, N, N- (C 1-6alkyl) 2amino, C I-6alkoxycarbonyl, N-C 1-6alkylcarbamoyl or N, N- (Cs 6alkyl) 2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N- (C1-6alkyl) imino or-C (O) NH-, with the proviso that p is 2 or more unless B is a bond,-C (O) NH-, or R2 is a group of formula IC: D-E- IC wherein D is unsubstituted or substituted phenyl and E is selected from a bond, C1-6alkylene, Cl 6alkyleneoxy, oxy, imino, N- (Cl 6alkyl) imino, Cl 6alkyleneimino, -SO2NH-,-NHSO2-,sulphonylC1-6alkylene,N-(C1-6alkyl)-C1-6alky leneimino,-C(O)NH-, carbonylCI 6alkyleneoxycarbonyl-Cl 6alkylene and C26alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cl 6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-CI 6alkylamino, N, N-(CI 6alkyl) 2amino, Cl 6alkoxycarbonyl, N-C1-6alkylcarbamoyl or N, N-(C X 6alkyl) 2carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof ; with the following provisos:

when A is phenyl: a) if A and R-in combination is 4-chlorophenyl then R'is not 3-mercaptopropyl; b) if A and R2 in combination is 3,4,5-trimethoxyphenyl then Rl is not cyanomethyl or 2-aminoethyl; and c) when Rl is a substituted straight chain Cl 4alkyl group, the distal carbon atom, that is the carbon atom of this Cl 4alkyl group furthest from the homopiperazine ring, is not substituted with i) two aryl rings, ii) two heteroaryl rings or iii) a heteroaryl and a phenyl ring; and with the further proviso that when Rt is substituted Cl salkyl substituted C2 galkenyl or substituted C2_galkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.

According to a further aspect of the present invention there is provided a compound of the formula I'or a pharmaceutically-acceptable salt or an in vivo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.

A further feature of the present invention is a compound of formula I'and pharmaceutically-acceptable salts or an in vivo-hydrolysable ester, amide or carbamate thereof, for use as a medicament.

Conveniently, such a compound of formula I'is a compound of formula (I"): wherein: Rl is hydrogen, substituted or unsubstituted Cl 8alkyl, substituted or unsubstituted C28alkenyl or substituted or unsubstituted C28alkynyl; wherein said Cl 8alkyl, C28alkenyl and C2-8alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkoxycarbonyl,C1-6alkanoyloxy,N-(C1-6alkyl)amino,C1-6al koxy,C1-6alkanoyl, N,N-(CI 6alkyl) 2amino, Cl 6alkanoylamino, N-(CI 6alkyl) carbamoyl,

N, N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkoxy, C1-6alkylS(O)a wherein a is 0 to 2, N-(Cx 6alkyl) sulphamoyl or N, N-(CI 6alkyl) 2sulphamoyl,(Cx 6alkyl) sulphamoyl or N, N-(CI 6alkyl) 2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-12cycloalkyl, and a group of formula IA: G- (CH2) X IA wherein: G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3, 2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from-C (O)-,-O-,-OC (O)-,-S-,-S (O)-,-S (O) 2-,-S (O) 2NR4-,-NR4S (O) 2-, -NR4-,-C (O) O-,-C (O) NR4-,-NR4C (O)-,-OC (O) NR4-,-C (O) NR4S02-,-NR4C (O) O-, -C (S) NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and C1-4alkyl ; wherein any aryl, heteroaryl, heterocycle or C3-12cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2-6alkynyl,C1-6alkoxy,C1-6alkanoyl,C1-6alkanoyloxy,C2-6alke nyl, C1-6alkanoylamino,N-(C1-6alkyl)carbamoyl,N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, N, N- (C, 6alkyl) 2carbamoyl, Ct 6alkylSOa where a is an integer selected from the range 0 to 2, N,N-(C1-6alkyl)2sulphamoylorphenylC1-6alkylC1-6alkoxycarbony l,N-(C1-6alkyl)sulphamoyl, and a heterocycle or heteroaryl containing an-NH-group may be unsubstituted or substituted on a ring nitrogen with C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkanoyl, C1-6alkylsulphonyl or phenylC1-6alkyl; A is a ring selected from phenyl and naphthyl; R2at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C2-6alkynyl,C1-6alkoxy,C1-6alkanoyl,C1-6alkanoyloxy,C1-6alky l,C2-6alkenyl, N-(C1-6alkyl)amino, N-(C1-6alkyl)carbamoyl,C1-6alkanoylamino, N, N- (C-6alkyl) 2carbamoyl, C, _6alkylSOa where a is an integer selected from the range 0 to 2, Cl 6alkoxycarbonyl, N-(CI 6alkyl) sulphamoyl, N, N-(CI 6alkyl) 2sulphamoyl,(CI 6alkyl) sulphamoyl, N, N-(CI 6alkyl) 2sulphamoyl, and a group of the formula: W- (CH2) p B

wherein W is halo, nitro, hydroxy, CI-6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C1-6alkylamino, N-C1-6alkylcarbamoylorN,N-(C1-6alkyl)2amino,C1-6alkoxycarbon yl, N, N- (CI 6alkyl) 2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N- (C1-6alkyl) imino or-C (O) NH-, with the proviso that p is 2 or more unless B is a bond,-C (O) NH-, or R2 is a group of formula IC: D-E- IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, C, 6alkylene, Cl 6alkyleneoxy, oxy, imino, N-(Cj 6alkyl) imino, Cl 6alkyleneimino, N-(CI 6alkyl)-Cl 6alkyleneimino,-C (O) NH-,-SO2NH-,-NHSO2-, sulphonylCI 6alkylene, carbonylCl 6alkyleneoxycarbonyl-Cl 6alkylene and C2_balkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cl 6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, C1-6alkoxycarbonyl,N,N-(C1-6alkyl)2amino, N,N-(C1-6alkyl)2carbamoyl;N-C1-6alkylcarbamoylor m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof; with the following proviso: when R'is substituted C1-8alkyl, substituted C2-sa ! kenyl or substituted C2-8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro; for use as a medicament to inhibit the [3H]-emopamil binding site in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided the use of a compound of the formula I", or a pharmaceutically-acceptable salt or an in vivo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the

inhibition of the [3 H]-emopamil binding site in a warm-blooded animal such as a human being.

According to a further feature of the invention there is provided a method of inhibiting of the [3H]-emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I"or a pharmaceutically-acceptable salt or an in vivo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.

The following Biological Test Methods, Data and Examples serve to illustrate the present invention.

The following Biological Test Methods, Results and Examples serve to illustrate the present invention.

Biological Test Methods 3H-Emopamil binding to guinea pig liver membranes Binding at the ['H]-emopamil binding site was determined by a modification of the method described by Zech, C., Staudinger R., Muhlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-3H- emopamil. Eur. J. Pharm. 208: 119-130,1991.

Guinea-pig liver membrane preparation: Male guinea pigs were sacrificed by C02 asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 mL were stored at-70 °C.

Assay Reaction Mixture: Assay buffer: 10 mM Tris-HCI, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C.

Radioligand: 0.96 nM (-)-3H-emopamil (Amersham).

Guinea pig liver membranes: 40mg/mL original wet weight.

Compounds: 1-300 nM.

Total volume: 500 RL.

This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 10 mM Tris-HCI, 10 mM MgC12,0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 LtM emopamil. In general compounds of the present invention bound to the [3H]-emopamil binding site with an IC ; o below 200 nM in this test.

Results: The following results were obtained in the 3H-Emopamil binding to guinea pig liver membranes test: Example IC50 (nM) 3 111 17 72 32 13 3H-D-888 binding to rat brain cortical membranes 3H-D-888 binding was determined by a modification of Reynolds, I. J., Snowman, A. M. and Synder, S. H. (-)-[3H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no. 3,731-738,1986.

Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice.

The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/mL.

Assay Reaction Mixture:

Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 Radioligand: lM 3H-D888 (Amersham) Rat cortical membranes: 6 mg/mL original wet weight Compounds: 0.3-100, uM Total volume: 1000 u. L This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl2, pH 7.4. Specific binding was measured with 10 RM methoxyverapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i. e. high affinity for the 3H-D888 binding site would show a lack of selectivity. The Icso of compounds of the invention at the 'H-D888 binding site was between 542 nM and 4098 nM.

Gerbil Global Model of Cerebral Ischaemia Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water <BR> <BR> <BR> <BR> available ad libitum. The animal room is maintained at 23 2 °C, and is on an automatic 12 hour light cycle.

The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen.

The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils

removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia. When they have regained the righting reflex and are beginning to walk around, they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery.

Twenty-four hours post ischaemia gerbils are tested for spontaneous locomotor activity, using a Photobeam Activity System from San Diego Instruments. They are individually placed in Plexiglas chambers measuring 27.5 cm x 27.5 cm x 15 cm deep. The chambers are surrounded by photocells, and every time a beam is broken one count is recorded. Each gerbil is tested for two hours, and cumulative counts are recorded at 30,60, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour.

For the next two days no specific testing is performed, but the gerbils are observed two to three times per day for any unusual behaviours or obvious neurological symptoms (i. e. ataxia, convulsions, stereotypic behaviour). Four days post ischaemia the gerbils are sacrificed by decapitation and their brains removed and preserved in 10% buffered formalin. Brains were removed, fixed and stained with hematoxylin and eosin. Under a light microscope, hippocampal fields were observed and graded for damage to the CA 1 subfield: 0 to 4 scale, with 0 representing no damage and 4 representing extensive damage.

Transient focal ischaemia in rats The method was performed substantially as described by Lin, T-N., He, Y. Y., Wu, G., Khan, M. And Hsu, C. Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24: 117-121,1993. This model is generally considered to be relevant to the clinical situation. Male Long-Evans rats 250-350 g were used. Surgery to establish a focal ischaemia was conducted under anaesthesia induced with 100 mg/kg ketamine and 5 mg/kg i. m. xylazine. Rectal temperature was monitored and maintained at 37.0 0.5 °C. The right middle cerebral artery (MCA) was exposed using microsurgical techniques. The MCA trunk was ligated immediately above the rhinal fissure with 10-0 suture. Complete interruption of blood flow was confirmed under an operating microscope.

Both common carotid arteries were then occluded using nontraumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries.

Twenty-four hours post occlusion, rats were killed under ketamine anesthesia by intracardiac

perfusion with 200 mL of 0.9% NaCI. The brain was removed and processed with 2% triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours.

Examples: The Examples which follow are intended to illustrate but not limit the invention. In the Examples, unless otherwise stated:- (i) concentrations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere; (iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385); (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the formula I were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in DMSO-d6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (6 scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, dt, double of triplets, m, multiplet; bm, broad multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected, in this application, (M+H) + is quoted; (vi) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations (also used hereinabove) may be used :- DMF is N, N-dimethylformamide DMSO is dimethylsulphoxide CDC13 is deuterated chloroform m/s is mass spectroscopy THF is tetrahydrofuran DCM is dichloromethane

NMP is N-methylpyrrolidone.

Example 1: 1-Methyl-4- (2,4-bis (trifluoromethyl) benzyl) homopiperazine A 1 litre 3-necked flask equipped with a condenser was charged with a solution of 1-methylhomopiperazine (4.05 mL; 3.7 g, 32.6 mmol) in THF (250 mL). Triethylamine (4.54 mL, 3.3 g, 32.6 mmol) and then 3,5-bistrifluoromethylbenzyl bromide (5.97 mL, 10.0 g, 32.6 mmol) were added. The solution was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography ethyl acetate: hexane: methanol (4: 5: 1) to obtain the title compound as a yellow oil (7.0 g). NMR 8 8.08 (d, 1H), 7.86 (s, 1H), 7.79 (d, 1H). 3.85 (s, 2H), 2.80-2.61 (m, 8H), 2.38 (s, 3H), 1.89 -1.81 (m, 2H); m/s: M+H+ 341.

Example 2: 1-Methvl-4-(4-benzeloxvbenzvl) homopiperazine A 1 litre 3-necked flask equipped with a condenser was charged with a solution of 1-methylhomopiperazine (10.89 mL; 10 g, 88 mmol) in THF (600 mL). Triethylamine (12. 24 mL, 8.8 g, 88 mmol) and then 4-benxyloxybenzyl chloride (20.5 g, 88 mmol) were added. The flask was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed.

The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography using dichloromethane: methanol (90: 10) as the solvent to obtain the title compound as a yellow oil (11.1 g).'H NMR 8 1.92 (m, 2H), 2.46 (s, 3H), 2.70-2.93 (m, 8H), 3.48 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.25 (d, 2H), 7. 31-7.45 (m, 5H); m/s: M+H+ 311.

Examples 3-30: Using an analogous procedure to that described in Example 1 and 2, the appropriate benzyl bromide (or benzyl chloride) was reacted with the appropriate homopiperazine to give the compounds described in the following table. Ex R'R2 NMR M/s M+H+ No 1 3 Me I (CDCl3) 1 80 (m, 2H), 2.38 (s, 3H), 283,285 2.2. 60-2.72 (m, 8H), 3.58 (s, 2H), 7. 22 (d, 2H), 7.43 (d, 2H) Br 4 Me 1.81 (m, 2H), 2.36 (s, 3H), 2.58-2.73 241 (m, 8H), 3.63 (s, 2H), 6.98-7.15 (m, 2H). 7.21 (m, 1 H) V F F 5'Me 1.81 (m, 2H), 2.37 (s, 3H), 331 (m, 8H), 3.57 (s, 2H), 7.04 (t, 1H), 7. 30 (d, 1H), 7.57 (d, 1H), 7.71 (s, in) I 6 Me 1. (m, 2H), 2H), 38 (s, 3H), 3H), 60-2.60-2.250 (m, SH), 3.73 (s, 2H), 7.48 (t, 1H), 7. 69 (d, 1H), 8.10 (d, IH), 8.23 (s, in) Nô 2 7 Me 1. (m, 2H), 2H), 33 (s, 3H), 3H), 43 (s, 219 3H), 2.68-2.81 (m, 8H), 3.61 (s, 2H), 7.11 (d, 2H), 7.21 (d, 2H) Me 8 Me 1.77 (m, 2H), 2.37 (s, 3H), 2.49 (m, 281 2H), 2.60 (m, 6H), 3.65 (S, 2H), 7.42-7.21 (m, 8H), 7.59 (d, J H) v839 Me 1. (m, 2H), 2.38 (s, 3H), 2.60-2.75 273 (m, 8H), 3.68 (s, 2H), 7.39-7.55 (m, 3H), 7. 61 (s, 1H) F F F F F 10 Me (CDC13) 1.85 (m, 2H), 2.30 (s, 3H), 273 2. 60-2.84 I (m, 8H) 3.62 (s, 2H), 7.44 (d, 2H), 7.7. 66 (d, 2H) F F 112 Me (CDC13) 1.86 (m, 2H), 2.37 (s, 3H), 239,241 2. 60-2.72 (m, 8H), 3.60 (s, 2H), 7.21 (m, 3H), 7.41 (s, 1H) Ci 12 Me OMe 1.89 (m, 2H), 2.42 (s, 3H), 2.68-2.81 280 (m, 8H), 3.69 (s, 2H), 3.92 (s, 3H), 6. 8 9 (d, I H), 8.14 (dd, 1 H), 8.36 (d, I H) Nos 13 Me l (CDCl3) 2.05 (m, 2H) 2.57 (s, 3H), 263 2.2. 70 (m, 2H), 2.85 (m, 4H), 3.00 (m, 2H), 3.64 (s, 2H), 3.92 (s, 3H), 7.55 (t, 1H), 7.64 (d, 1H), 7.95 (d, 1H), 8.18 (s, 1H) O OMe 143 Me (CDCI3) 1.84 (m, 2H), 2.37 (s, 3H), 255 2.60 (m, 2H), 2.67 (m, 2H), 2.76 (m, 4H), 3.79 (s, 2H), 7.42 (m, 2H), 7.47 (d, 1H), 7.80 (m, 4H) 15 Me 1. 93 (m, 2H), 2H), 45 (s, 3H), 3H), 71-2.71-2.263 (m, 8H), 3.69 (s, 2H), 3.91 (s, 3H), OMe 7.41 (d, 2H), 7.99 (d, 2H) o, 16 Me 1.96 (m, 2H), 2.49 (s, 3H), 2.72-223 2.90 (m, 8H), 3.64 (s, 2H), 7.07 (m, 3H), 7.25 (m, 1H) F F 17 Me 1. (m, 2H), 2H), 38 (s, 3H), 3H), 60-2.60-2.289 \< (m, 8H), 3.63 (s, 2H), 7.14 (d, 2H), 7. 36 (d, 2H) vOCF3 ULJr, 18 Me orme 1. 88 (m, 2H), 2.41 (s, 3H), 2.64-2.77 310 (m, 8H), 3.93 (s, 3H), 3.96 (s, 2H), 0 JJL3. 98 (s, 3H), 7.27 (s, 1H), 7.52 (s, 2 e IH) 19 Me Me 233 1 Me 20 Me CF3 (CDC13) 1.85 (m, 2H), 2.37 (s, 3H), 291 2.60-2.69 (m, 8H), 3.74 (s, 2H), 7.21 (m, 1 H), 7.33 (m, 1H), 7.83 (m, 1 H) F F 21 Me Br 1.84 (m, 2H), 2.37 (s, 3H), 2.60-2.82 283,285 (m, 8H), 3.67 (s, 2H), 7.09 (m, 1H), 7.28 (m, 1H), 7.52 (m, 2H) \ I 22 Me F 1.81 (m, 2H), 2.36 (s, 3H), 2.56-2.75 241 (m, 8H), 3.65 (s, 2H), 6.73-6.87 (m, 2H), 7.40 (m, 1H) F F 23 Me 1. 81 (m, 2H), 2H), 37 (s, 3H), 3H), 59-2.59-2.223 \< (m, 8H), 3.59 (s, 2H), 6.99 (m, 2H), 7.30 (m, 2H) F F 24 Me N02 1.80 (m, 2H), 2. 35 (s, 3H), 2.53 (m, 250 2H), 2.60-2.75 (m, 6H), 3.90 (s, 2H), 7.38 (m, 1H), 7.54 (m, 2H), 7.77 (m, IH) 25 Me CF3 1.85 (m, 2H), 2.37 (s, 3H), 2.60-2.76 273 (m, 8H), 3.79 (s, 2H), 7.31 (t, 1H), 7. 51 (t, 1H), 7.61 (d, 1H), 7.86 (d, 1H) 26 Me l 1. (m, 2H), 2H), 45 (s, 3H), 3H), 75 (m, 341 3 8H), 3. 73 (s, 2H), 7.60 (s, 1H), 7.93 (s, 2H) CF '-"3 27 Me 1. (m, 2H), 2H), 40 (s, 3H), 3H), 60-2.60-2.359 (m, 8H), 3.49 (s, 2H), 4.87 (s, 2H), 6.99 (m, 1H), 7.15 (m, 2H), 7.24 (m, f/%/1H), 7.48 (m, 2H), 7.60-7.69 (m, 3H) ors / 0 J 28 Me 1. 82 (m, 2H), 2H), 37 (s, 3H), 3H), 56-235 2.2.74 (m, 8H), 3. 62 (s, 2H), 3. 81 (s, 3H), 6.79 (m, 1H), 6.92 (m, 2H), 7.22 (m, 1H) 29 Me 1.85 (m, 2H), 2.39 (s, 3H), 2.62-2.78 250 (m, 8H), 3.73 (s, 2H), 7.53 (d, 2H), 8.18 (d, 2H) NO') 30 Me Me 233 mye Me 'This reaction was carried out at 60 °C for 2 hours and then at room temperature for 16 hours.

2 This reaction was carried out at room temperature for 2 days.

3 This reaction was carried out at 60 °C for 3 hours and then at room temperature for 16 hours.

Example 31: 1- (Isopropyl)-4- (4-benzyloxvbenzvl) homopiperazine A solution of 1- (4-benzyloxybenzyl) homopiperazine (400 mg, 1.35 mmol) in THF (20 mL) was placed in a 50 mL flask equipped with a condenser. Triethylamine (1.87 mL, 13.5 mmol) and then 2-bromopropane (1.66 g, 13.5 mmol) were added. The flask was immersed in a 60 °C oil bath for 2 days. Additional Triethylamine (0.374 mL, 2.7 mmol) and

2-bromopropane (1.66 g, 13.5 mmol) were added. The mixture was heated for an additional 2 days. The resulting mixture was filtered. The filtrate was poured into diethyl ether (50 mL) and washed with water and saturated sodium chloride. The diethyl ether layer was dried over anhydrous magnesium sulphate, filtered, and concentrated to give a crude product. This crude product was purified by column chromatography using dichloromethane: methanol (95: 5) as the solvent to obtain the title compound as a yellow oil (240 mg). lH NMR 1.00 (d, 6H), 6H), 76 (m, 2H), 2.62-2.74 (m, 8H), 2.88 (m, 1H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.25 (d, 2H), 7.30-7.46 (m, 5H); m/s: M+H+ 339.

Example 32: 1- (3-Phenylpropyl)-4- (4-benzyloxybenzyl) homopiperazine A solution of 1- (4-benzyloxybenzyl) homopiperazine (500 mg, 1.7 mmol) in THF (40 mL) was placed in a 100 mL flask equipped with a condenser. Triethylamine (0.24 mL, 1.7 mmol) and l-bromo-3-phenylpropane (338 mg, 1.7 mmol) were added. The flask was immersed in a 60 °C oil bath for 16 hours. Additional Triethylamine (0.24 mL, 1.7 mmol) and 2-bromopropane (338 mg, 1.7 mmol) were added. The mixture was heated for an additional 24 hours. The resulting mixture was filtered. The filtrate was poured into diethyl ether (50 mL) and washed with water and saturated sodium chloride. The diethyl ether layer was dried over anhydrous magnesium sulphate, filtered, and concentrated to give a crude product. This crude product was purified by column chromatography using dichloromethane: methanol (95: 5) as the solvent to obtain the title compound as a yellow oil (510 mg). lH NMR: 1.87 (m, 4H), 2.55-2.83 (m, 12H), 3.59 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.16-7.45 (m, 12H); m/s: M+H+ 415.

Examples 33-36: Using an analogous procedure to that described in Example 32, the appropriate benzyl bromide (or benzyl chloride) was reacted with the appropriate homopiperazine to give the compounds described in the following table. Ex Ri NMR M/s No M+H+ 33-n-Pr 0.88 (t, 3H), 1.48 (m, 2H), 1.79 (m, 2H), 2.43 (m, 2H), 339 2.65-2.75 (m, 8H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.25 (d, 2H), 7.30-7.46 (m, SH) 341 \/0.88 (t, 3H), 1.36 (m, 2H), 1.54 (m, 1H), 1.79 (m, 2H), 367 2.48 (m, 2H), (m, 8H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.31-7.48 (m, 5H) 35/F 1.75-1.94 (m, 4H), 2.59-2.75 (m, 10H), 3.57 (s, 2H), 357 4.50 (dt, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.25 (d, 2H), 7.30-7.45 (m, 5H) 36/Ph 1.92 (m, 2H), 2.72-2.88 (m, 8 H), 3.69 (bs, 4H), 5.05 (s, 387 I 2H), 6.94 (d, 2H), 7.26-7.42 (m, 12H) 'The reaction was carried out at for 2 days with 1 equivalent of base and the appropriate bromo compound.

Example 37: 1- (4-Benzyloxybenzyl) homopiperazine A solution of homopiperazine (43.0 g, 431 mmol) in DMAC (200 mL) was placed in a 1 litre flask. Potassium iodide (4.4 g, 27 mmol) was added. A solution of 4-benxyloxybenzyl chloride (25.0 g, 108 mmol) in DMAC (50 mL) was added and a precipitate began to form.

The mixture was stirred at room temperature for 2 hours. The mixture was filtered. The filtrate was concentrated by distilling away the DMAC. The resulting residue was poured into diethyl ether and washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The diethyl ether layer was concentrated to give 11.4 g crude product. This crude product was purified in portions as needed. A 1.0 g portion of the crude product was purified by column chromatography using a gradient from 0 to 5% methanol in diethyl ether: hexane (1: 1) to obtain the title compound as a yellow oil (0.48 g).'H NMR 5 1.66 (bs, 1H), 1.74 (m,

2H), 2.65 (m, 4H), 2.88-2.98 (m, 4H), 3.60 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.25 (d, 2H), 7.30-7.46 (m, 5H); m/s: M+H+ 297.

Example 38: 1- (2-hydroxypropyl)-4- (4-benzyloxybenzyl) homopiperazine A solution of 1- (4-benzyloxybenzyl) homopiperazine (300 mg, 1.0 mmol) in t-butanol (5 mL) and toluene (5 mL) was placed in a flask equipped with a condenser. Propylene oxide (0.176 mL, 2.5 mmol) was added and then the flask was immersed in a 30 °C oil bath for 16 hours. Additional propylene oxide (0.176 mL, 2.5 mmol) was added and the mixture was heated for an additional 24 hours. The resulting mixture was concentrated. The resulting residue was purified by column chromatography using dichloromethane: methanol (95: 5) as the solvent to obtain the title compound (220 mg).'H NMR 8 (CDC13) 1.11 (d, 3H), 1.79 (m, 2H), 2.20 (dd, 1H), 2.55-2.90 (m, 9H), 3.57 (s, 2H), 3.72 (m, 1H), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.32-7.43 (m, 5H); m/s: M+H+ 355.

Example 39: 1- (2-hydroxybutyl)-4- (4-benzvloxybenzyl) homopiperazine A solution of 1- (4-benzyloxybenzyl) homopiperazine (300 mg, 1.0 mmol) in t-butanol (5 mL) and toluene (5 mL) was placed in a flask equipped with a condenser. 1,2-epoxybutane (0.215 mL, 2.5 mmol) was added and then the flask was immersed in a 30 °C oil bath for 16 hours. Additional 1,2-epoxybutane (0.215 mL, 2.5 mmol) was added and the mixture was heated for an additional 24 hours. The resulting mixture was concentrated. The resulting residue was purified by column chromatography using dichloromethane: methanol (95: 5) as the solvent to obtain the title compound (170 mg).'H NMR 8 0.97 (t, 3H), 1.36-1.64 (m, 3H), 1.80 (m, 2H), 2.23 (dd, 1H), 2.58-2.91 (m, 9H), 3.47-3.57 (m, 3H), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.32-7.45 (m, 5H); m/s: M+H+ 369.

Example 40: 1- (3- (4-chlorophenoxv)-2-hydroxypropyl)-4- (4-benzyloxybenzyl) homopiperazine A 4-dram vial was charged with 1- (4-benzyloxybenzyl) homopiperazine (250 mg, 0.84 mmol) and 4-chlorophenyl 2,3-epoxypropyl ether (0.20 mL, 310 mg, 1.68 mmol). A loose cover was placed over the vial and the vial was irradiated with microwaves for 1.50 minutes at

hi power. The resulting light yellow product was purified by column chromatography using 5% methanol in methylene chloride to obtain the title compound as a light orange oil (370 mg). NMR (CDC13) 1.81 (m, 2H), 2.52-2.94 (m, 11 H), 3.58 (s, 2H), 3.90-4.02 (m, 3H), 5.05 (s, 2H), 6.84-6.94 (m, 4H), 7.20-7.25 (m, 4H), 7.31-7.45 (m, 5H); m/s: M+H+ 481,483.

Examples 41-49: Using an analogous procedure to that described in Example 40, the appropriate substituted epoxide was reacted with 1- (4-benzyloxybenzyl) homopiperazine to give the compounds described in the following table.

Ex No Rl NMR m/s M+H+ 41 OH (CDC13) 1.81 (m, 2H), (m, l lH), 3.58 (s, 477 0 2H), 3. 76 (s, 3H), 3. 91-4.01 (m, 3H), 5.05 (s, 2H), ll l 6.79-6. (m, 6H), 6H), 24 (d, 2H), 2H), 32-7.32-7. (m, 7H) OMe 42 OH (CDC13) 1.60 (bs, 1H), 1.81 (m, 2H), 2.54-2.94 (m, 447 1 O 10H), 3.57 (s, 2H), 3.95-4.06 (m, 3H), 5.05 (s, 2H), 6.91-6.97 (m, 4H), 7.24 (d, 2H), 7.23-7.46 (m, 10H) 43 OH (CDC13) 1.62 (bs, 1H), 1.83 (m, 2H), 2.54-2.95 (m, 465 wl, O 10H), 3.59 (s, 2H), 3.93-4.02 (m, 3H), 5.05 (s, 2H), 6. 84-6 : 99 (m, 6H), 7.25 (d, 2H), 7.32-7.45 (m, 5H) F 44 OH (CDC13) 1.54 (bs, 1H), 1.83 (m, 2H), 2.44 (dd, 1H), 417 2.59-3.00 (m, 9H), 3.58 (s, 2H), 4.63 (dd, 1H), 5.06 (s, 2H), 6.93 (m, 2H), 7.24-7.45 (m, 12H) 45 OH (CDC13) 1.60 (bs, 1H), 1.77 (m, 2H), 2.31 (dd, 1H), 431 I 2. 55-2.87 (m, 11H), 3.54 (s, 2H), 3.81 (m, 1H), 5.05 (s, 2H), 6.91 (d, 2H), 7.18-7.45 (m, 12H) 46 OH (CDC13) 1.82 (m, 2H), 2.49 (dd, 1H), 2.62-2.90 (m, 461 9H), 3.46-3.49 (m, 2H), 3.57 (s, 2H), 3.80-3.87 (m, IH), 4. 57 (s, 2H), 5. 05 (s, 2H), 6. 92 (d, 2H), 22-7.22-7. (m, 12H) 47 OH (CDC13) 1.54 (bs, 1H), 1.77 (m, 2H), 2.44 (dd, 1H), 451 2.59-2.86 (m, 9H), 3.48 (m, 2H), 3.56 (s, 2H), 3.77 (m, 1H), 4.51 (s, 2H), 5.05 (s, 2H), 6.33 (m, 2H), 6.92 (d, 2H), 7.22 (d, 2H), 7.29-7.44 (bm, 6H) 48 OH (CDC13) 1.16 (d, 6H), 1.84 (m, 2H), 2.54 (dd, 1H), 413 2.62-2.97 (bm, 11H), 3.42 (d, 2H), 3.51-3.61 (m, 3H), 3.83 (m, 1H), 5.05 (s, 2H), 6.93 (m, 2H), 7.21 (m, 2H), 7.30-7.48 (bm, 5H) 49 OH (CDC13) 1. 59 (bs, 1H), 1.79 (m, 2H), 2.47 (dd, 1H), 411 it 62-2. 91 (m, 9H), 3.46 (m, 2H), 3.57 (s, 2H), 3.79 (m, 1H), lu), 4.03 (d, 2H), 5.05 (s, 2H), 5.17-5.30 (m, 2H), 5.85- 5.98 (m, 1H), 6.93 (d, 2H), 7.24 (d, 2H), 7.30-7.45 (m, SH)

Example 50: 1-methyl-4- (2 5-bistrifluorometh lybenzxl) homopiperazine A solution of 1-methyl-homopiperazine (456 mg, 4.0 mmol), 2,5-difluorobenzyl bromide (1.23 g, 4.0 mmol) and triethylamine (400 mg, 4.0 mmol) in 40 mL THF was prepared and stirred at ambient temperature for two days. The resulting mixture was filtered.

The filtrate was concentrated, dissolved in diethyl ether, washed with water and then concentrated. The resulting oil was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound (1.0 g).'H NMR 8 (CDC13) 1.90 (m, 2H), 2.43 (s, 3H), 2.68-2.78 (bm, 8H), 3.85 (s, 2H), 7.58 (d, 1H), 7.75 (d, 1H), 8.19 (s, 1H); <BR> <BR> <BR> m/s: M+H+ 341.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>Examples 51-52: Using an analogous procedure to that described in Example 50, the appropriate benzyl bromide was reacted with 1-methyl-homopiperazine to give the compounds described in the following table. Ex No R1 NMR m/s M+H+ 51 X F (CDC13) 1.83 (m, 2H), 2.37 (s, 3H), 2.59-2.77 (m, 241 8H), 3.67 (s, 2H), 6.82-6.98 (m, 2H), 7.20 (m, 1H) i F 52 (CDC13) 1. 32 (s, 9H), 1.75-1.83 (m, 2H), 2.36 (s, 3H), 261 1 2. 59-2.76 (m, 8H), 3.61 (s, 2H), 7.25 (d, 2H), 7.36 (d, cl3 2H) CH3 CHg

Example 53: 1-ethvl-4-(4-benzyloxvbenzvl) homopiperazine A solution of 1- (4-benzyloxybenzyl)-homopiperazine (500 mg, 1.7 mmol), bromoethane (370 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) in 40 mL THF was prepared and stirred at 60 °C for 16 hours. The resulting mixture was filtered and concentrated. The concentrate was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give an orange-brown oil. This product was purified by column chromatography using 5% methanol in methylene chloride to <BR> <BR> <BR> provided the title compound as a light brown oil (480 mg).'H NMR 8 (CDC13) 1.07 (t, 3H), 1.81 (m, 2H), 2.56 (q, 2H), 2.68-2.75 (bm, 8H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.21 (d, 2H), 7.30-7.46 (bm, 5H); m/s: M+H+ 325.

Example 54: 1- (2-phenylethyl)-4- (4-benzyloxybenzyl) homopiperazine A solution of 1- (4-benzyloxybenzyl) homopiperazine (500 mg, 1.7 mmol), 2- bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) in 40 mL THF was prepared and stirred at 60 °C for 16 hours. Additional 2-bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) were then added to the solution and stirring at 60 °C was continued for another 16 hours. The resulting mixture was filtered and

concentrated. The concentrate was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give an orange-brown oil. This product was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound as a light brown oil (680 mg).'H NMR 8 (CDC13) 1.85 (m, 2H), 2.70-2.87 (m, 8H), 3.16 (t, 2H), 3.57 (t, 2H), 3.59 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.19- 7.45 (m, 12H); m/s: M+H+ 401.

Examples 55-XX Using an analogous procedure to that described in Example 53 (Method A), or Example 54 (Method B), the appropriate benzyl bromide (or benzyl chloride) was reacted with 1- (4-benzyloxybenzyl) homopiperazine to give the compounds described in the following table. Ex Method R'NMR M/s No M+H+ 55 B CH3 (CDC13) 0.89 (d, 6H), (m, 3H), 2.25 353 (d, 2H), 2.64-2.76 (m, 8H), 3.61 (s, 2H), 5.05 CH3 (s, 2H), 6.92 (d, 2H), 7.27 (d, 2H), 7.31-7.45 (m, SH) 56 A 0 (CDC13) 1.89 (m, 2H), 2.01 (m, 2H), 2.67-2.87 431 (bm, lOH), 3. 61 (s, 2H), 4. 01 (t, 2H), 5.05 (s, 9 2H), 6.88-6.96 (bm, 5H), 7.24-7.46 (bm, 9H) 57 B ~CH3 (CDC13) 0.91 (t, 3H), 1.24-1.36 (m, 2H), 1.43- 353 1.53 (m, 2H), 1.78-1.86 (m, 2H), 2.51 (t, 2H), 2.63-2.79 (m, 8H), 3.57 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.25 (d, 2H), 7.32-7.46 (m, 5H) 58 A /\CH (CDCI3) 0.89 (t, 3H), 1.20-1.36 (m, 4H), 1.56 367 1 (m, 2H), 1.90 (m, 2H), 2.58 (m, 2H), 2.70-2.90 (m, 8H), 3.59 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.30-7.46 (m, 5H) 59 A (CDC13) 1.90 (m, 2H), 2.70-2.89 (m, 8H), 432 3.68-3.79 (m, 4H), 5.06 (s, 2H), 6.95 (d, 2H), 7.7. 31-7.50 (m, 8H), 7.67 (d, 1H), 8.09 (m, 1H), _ 2 8.21 (bs, 1H) 60 A F (CDC13) 1.97 (bs, 2H), 2.70-3.05 (m, 8H), 3.62 423 (s, 2H), 3.84 (bs, 2H), 5.07 (s, 2H), 6.69 (m, 1H) 6.86 (d, 2H), 6.97 (d, 2H), 7.31-7.45 (m, 7H) F 61 A CF3 (CDCI3) 1.92 (bs, 2H), 2.73-2.94 (m, 8H), 3.73 523 (bs, 2H), 3.86 (s, 2H), 5.06 (s, 2H), 6.95 (d, 2H) 7. 32-7.45 (m, 7H), 7.77 (d, 1H), 7.87 (s, 1H), CF 3 8. 01 (d, 1H) 3 62 A H3C wCH3 365 1 63 CF3 (CDC13) 1.78 (m, 2H), 2.34-2.48 (m, 2H), 405 2.64-2.77 (m, 10H), 3.57 (s, 2H), 5.05 (s, 2H), 4\/CF 6.93 (d, 2H) 7.24 (d, 2H), 7.31-7.46 (m, 5H) 64 BCF _ 393 3

1The reaction was carried out at for 2 days with 1 equivalent of base and the appropriate bromo compound.

Reference Example 1 Using an analogous procedure to that described in Example 1 and 2, benzyl chloride was reacted with 1-methylhomopiperazine to give the compound described in the following table. Ref Rl R2 NMR M/s M+H+ Ex No 1-Me 1.75 (m, 2H), 2.29 (s, 3H), 2.51-2.67 205 (m, 8H), 3.56 (s, 2H), 7.11-7.31 (m, su) \

The following examples are intended to illustrate, but not limit, methods of preparing salts of compounds of formula I.

Example 65: l-Methyl-4-(2,4-bis (trifluoromethyl) benzyl) homopiperazine dihydrochloride A solution of Example 1 (7.0 g) in ethanol (25 mL) was treated with saturated ethanolic HCI. Diethyl ether was added while stirring until precipitation began. The solution was placed in a 0 °C refrigerator for 16 hours during which time a precipitate formed. The mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (8.1 g). Mp 200-202 °C ;'H NMR (CD30D) 8 2.31 (m, 2H), 2.98 (s, 3H), 3.55 (m, 8H), 4.53 (bs, 2H), 8.12-8.10 (m, 2H), 8.31 (d, 1H) ; Anal; Calcd. for Cl5Hl8N2F6 2HC1 0. 7H2O 0. 2ethanol: C, 42.51; H, 5.24; N, 6.44. Found: C, 42.45; H, 5.17; N, 6.18. m/s: M+H+ 341.

Example66: l-Methyl-4-(4-benzvloxybenzel)(4-benzvloxybenzel) homopiperazine dimaleate salt A solution of Example 2 (11.1 g) in ethanol (35 mL) was prepared in a 250 mL erlenmeyer flask. A solution of maleic acid (9 g) in ethanol (50 mL) was added and a precipitate began to form. Diethyl ether (30 mL) was then added and the mixture was stirred.

The mixture was placed in a 0 °C refrigerator for 16 hours during which time a precipitate continued to form. The mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (15.86 g). Mp 174-177 °C ;'H NMR (DMSO-D6) # 1. 99 (m, 2H), 2.78 (s, 3H), 2.93 (m, 2H), 3.12 (m, 2H), 3.28 (m, 2H), 3.37 (m, 2H), 3.92 (m, 2H), 5.11 (s, 2H), 6.12 (s, 4H (CH=CH, maleic acid)), 7.03 (d, 2H), 7.39 (m, 7H); Anal; Calcd. for C2oH26N2Ol. 2C4H402 0. 5H2O: C, 60.97; H, 6.40; N, 5.08. Found: C, 61.00; H, 6.25; N, 5.03. m/s: M+H+ 311.

Example 40:

Following conventional procedures well known in the pharmaceutical art the following exemplary pharmaceutical dosage forms containing compounds of formula I, I'or I" can be prepared: (a) Tablet mg/tablet Compound of Formula I, I'or I" 50.0 Mannitol, USP 223.75 Croscarmellose sodium 60 Maize starch 15.0 Hydroxypropylmethylcellulose (HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule mg/capsule Compound of Formula I, I'or I"10.0 Mannitol, USP 488.5 Croscarmellose sodium 15.0 Magnesium stearate 1.5 (c) Injectable solution For intravenous administration, a compound of Formula I, I'or I"is dissolved in an isotonic sterile solution at a concentration of 5 mg/mL