This invention relates to 1- (arylalkyla inoalkyl) imidazole compounds which are useful in the treatment of neurological damage.

US 5,192,753 describes a method of treating dementia which comprises the administration of a sufficient amount of a non-steroidal anti-inflammatory drug to inhibit prostaglandin synthesis in vivo but insufficient to induce unwanted side-effects in said human. The non-steroidal anti-inflammatory drugs disclosed are characterised by their ability to inhibit prostaglandin synthesis through anti-cyclooxygenase activity and are hereinafter referred to as traditional non-steroidal anti-inflammatory drugs.

WO 93/13075 (incorporated herein by reference) discloses certain 1- (arylalkyl-aminoalkyl) imidazole derivatives which have a novel profile of anti- inflammatory activity. These compounds are not traditional non-steroidal anti-inflammatory drugs in that they do not inhibit cyclooxygenase, nor are they pro-drugs for inhibitors of cyclooxygenase. Consequently these compounds are not expected to display the unwanted side-effects associated with traditional non-steroidal anti-inflammatory drugs.

Traditional non-steroidal anti-inflammatory drugs do not penetrate the brain to any appreciable extent. For example, indomethacin is almost completely protein bound in plasma and consequently, since the protein bound indomethacin cannot cross the blood-brain barrier, only a minute proportion of the administered dose penetrates the brain. Surprisingly we have found in rat

studies that, following administration of a compound described in WO 93/13075 which had been radiolabelled, a significant amount of the radiolabel was rapidly detected in the brain. The present invention has been developed from this observation.

The present invention provides a method of treating neurological damage, in which a the: ^" -^eutically or prophylactically effective amount of c. compound of formula I

including pharmaceutically acceptable salts thereof in which

R-*_, R2 and R3 independently represent hydrogen, halo, a C- _] __g alkyl group, a - _j __g alkoxy group, phenoxy (optionally substituted by a C- _j __^ alkyl group, a C--__4 alkoxy group or halo) , phenyl (optionally substituted by a C- _j __ alkyl group, a C- _j __ ₄ alkoxy group or halo) , a C2_5 alkoxycarbonyl group, an amino group of formula ~N ^R i3R*i4 (in which R-^ and R-<_4 are independently hydrogen or a C- _] __4 alkyl group or R-^ and R^^ together with the nitrogen atom to which they are attached represent a pyrrolidine ring, a morpholine ring or a piperidine ring) , a halogenated C _1-4 alkoxy group, a halogenated C- _] __4 alkyl group, benzyloxy (optionally substituted by a C- _] __4 alkyl group, a C-*__4 alkoxy group or halo) , hydroxy, ^{a c} i-4 hydroxyalkyl group, a (C2_g alkoxycarbonyl)vinyl group; a group of formula -S(0) _n R ₇ (in which R ₇ represents a ^_^ alkyl group and n is 0, 1 or 2) , a

C ₂ _4 carbamoylalkyl group, a C ₂ _ alkoxycarbonyl C- _j __2 alkyl group, a carbamoyl group of formula -C0NR- _] _ι_R- _] _2 (in which R- _] _- _] _ and R-*^ are independently hydrogen or a C-*__g alkyl group) or R-*_ and R2 together with the phenyl ring to which they are attached represent a naphthyl group;

R4 and R5 independently represent hydrogen, a C- _j __^ alkyl group, phenyl (optionally substituted by a C-*__4 alkyl group, halo or a C- _j __ ₄ alkoxy group) or R4 and Rπ- together with the carbon atom to which they are attached represent a C _ cycloalkyl group;

Rg represents hydrogen, a C-*__4 alkyl group or an ω- hydroxy C- _j __4 alkyl group;

A represents a C2_g alkylene group, which may be straight or branched;

Rg represents hydrogen, a C- _j __ alkyl group, halo, a C-*__^ alkoxy group, a - _] __ ₄ hydroxyalkyl group, phenyl (optionally substituted by a C- _| __4 alkyl group, halo or a C- _] __4 alkoxy group) or benzyl (optionally substituted by a C- _j __4 alkyl group, halo or a C-*__4 alkoxy group) ; and

Rg and R-*_ _Q independently represent hydrogen, a C- _j __ alkyl group, halo, a C -4 alkoxy group, phenyl (optionally substituted by a C-*__^ alkyl group, halo or a C--__4 alkoxy group) , a C^.^ hydroxyalkyl group, a C2_ alkoxycarbonyl group, nitro, an amino group of formula NR3QR3 _ (in which R3 _Q and R3--_ independently represent hydrogen or a C-*__ ₄ alkyl group) , a C-*__g alkanoyloxy C- _j __ ₄ alkyl group, or an aminomethyl group;

is administered in conjunction with a pharmaceutically acceptable diluent or carrier to a mammal in need thereof.

It will be understood that a group containing a chain of 3 or more carbon atoms may be straight or branched, for example propyl includes n-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl .

The compounds of formula I are advantageous in the treatment of neurological damage as they .. e expected to have improved efficacy and reduced side-effects compared to the proposed therapies referred to in US 5,192,753 above. In particular the compounds of formula I are expected to show reduced irritation in the gastro¬ intestinal tract after oral administration.

The term "neurological damage" as used in this specification includes conditions such as brain trauma, cerebral ischaemia, haemorrhage, head injuries and stroke, and neurodegenerative diseases including inter alia Dementia, Alzheimer's Disease, Parkinson's Disease, Huntington's Chorea, Pick's Disease, Post Traumatic Dementia and Creutzfeldt-Jakob' s Disease.

The compounds of formula I are useful in the treatment of dementia, and in particular Alzheimer's disease. In a preferred aspect, the present invention provides a method of treating dementia, and in particular Alzheimer's disease, in which a therapeutically or prophylactically effective amount of a compound of formula I is administered in conjunction with a pharmaceutically acceptable diluent or carrier, to a mammal in need thereof.

In a preferred group of compounds of formula I, R--_, R2 and R3 independently represent hydrogen, halo (for example bromo, chloro or fluoro) , a C- _j __4 alkyl group (for example methyl, ethyl, propyl or butyl), a C-*__4

alkoxy group (for example methoxy, ethoxy, propoxy or butoxy), phenoxy, phenyl, a C2_ alkoxycarbonyl group

(for example methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentoxycarbonyl) , an a ino group of formula -NR-^R- _j ^ in which R-*_3 and R ₁₄ are independently hydrogen or a ^c -2 alkyl group (for example amino, methylamino, dimethylamino, ethylamino or diethylamino) , a polyhalo *-__2 alkoxy group (for example trifluoromethoxy or pentafluoroethoxy) , a polyhalo C-*__2 alkyl group (for example trifluoromethyl or pentafluoroethyl) , benzyloxy, hydroxy, a ( ^c 2-6 alkoxycarbonyl)vinyl group; a C2_g alkoxycarbonyl C- _j __2 alkyl group, or R- _j _ and R2 together with the phenyl ring to which they are attached represent a naphthyl group;

R4 and Re* independently represent hydrogen, a C-*__4 alkyl group (for example methyl, ethyl, propyl or butyl) , phenyl, or R4 and R5 together with the carbon atom to which they are attached represent a 3_g cycloalkyl group (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) ;

Rg represents hydrogen or a C±-4 alkyl group (for example methyl, ethyl, propyl or butyl) ;

A represents a C2_ ₇ alkylene group which may be straight or branched, (for example ethylene, trimethylene, tetramethylene, 1, 1-dimethylethylene, 2 , 2-dimethyl- ethylene or heptamethylene) ;

Rg represents hydrogen, a C-*__4 alkyl group (for example methyl, ethyl, propyl or butyl), phenyl (optionally substituted by a C-*__4 alkyl group, halo or a C-*__4 alkoxy group) or benzyl (optionally substituted by a ^_^ alkyl group, halo or a C-*__4 alkoxy group) ; and

R ₉ and R- _] _ _Q independently represent hydrogen, a C--__4 alkyl group (for example methyl, ethyl, propyl or butyl), halo (for example bromo, chloro or fluoro) , a C*L_ hydroxyalkyl group (for example hydroxymethyl, 2- hydroxyethyl or 3-hydroxypropyl) , a C2_ alkoxycarbonyl group (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl) , nitro or a C-*__g alkanoyloxy C- _j __2 alkyl group (for example formyloxy- ethyl, acetoxymethyl , propanoyloxymethyl , or butanoyloxymethyl) .

One group of more preferred compounds of formula I is represented by formula II

and pharmaceutically acceptable salts in which R-γ represents halo, a C--__4 alkyl group, a C ₂ _4 alkoxy group, phenoxy, phenyl, a C2_4 alkoxycarbonyl group, a perhalo C-*__2 alkoxy group, a perhalo C- _j __2 alkyl group, benzyloxy, an amino group of formula NR-^R-^ (in which R- _] _3 and R-*_4 independently represent hydrogen or a ^< ^ - % alkyl group), a (C2_4 alkoxycarbonyl)vinyl group, a C2_g alkoxycarbonyl C- _j __2 alkyl group, or R^ and R ₂ together with the phenyl ring to which they are attached represent a naphthyl group;

R ₂ and R3 independently represent hydrogen, halo, a ^__^ alkyl group, a C- _j __ alkoxy group, a perhalo ^_ ₂ alkyl group, or hydroxy;

R4 and R5 independently represent hydrogen, a C-*__ alkyl group, phenyl or R and R5 together with the carbon atom to which they are attached represent a C3_ cycloalkyl group;

Rg represents hydrogen or a C- _j __3 alkyl group;

A represents ethylene, trimethylene, tetramethylene, 1, 1-dimethylethylene or heptamethylene;

Rg represents hydrogen, a ^_ _^ alkyl group, phenyl or benzyl; and

Rg and R- _j _o independently represent hydrogen, a C--__4 alkyl group, halo, a C-*__4 hydroxyalkyl group, a 2_g alkoxycarbonyl group, nitro, or a C-*__g alkanoyloxy - _j alkyl group.

In a preferred group of compounds of formula II, R- _j _ represents bromo, chloro, methyl, ethyl, t-butyl, butoxy, phenoxy, phenyl, methoxycarbony1 , ethoxycarbonyl , propoxycarbonyl , dimethylamino, trifluoromethoxy, trifluoromethyl, benzyloxy, 2- ethoxycarbonylvinyl or R-*_ and R2 together with the phenyl ring to which they are attached represent a naphthyl group. More preferably R- _j _ represents bromo, chloro, t-butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, propoxycarbonyl, trifluoromethoxy, trifluoromethyl, benzyloxy, 2-ethoxycarbonylvinyl or R-*_ and R ₂ together with the phenyl ring to which they are attached represent a naphthyl group. Most preferably R- _j _ represents bromo or chloro.

In a preferred group of compounds of formula II, R2 represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2- methyl, 3-methyl, 2-methoxy, 2-ethoxy, 2-hydroxy or 3-

trifluoromethyl and R3 represents hydrogen, 2-chloro or 3-chloro. More preferably R2 represents hydrogen, 3- chloro, 2-chloro, 3-fluoro, 2-methyl, 3-methyl, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R represents hydrogen. Most preferably R2 represents hydrogen or 2-chloro and R3 represents hydrogen.

In a preferred group of compounds of formula II, R and R5 independently represent hydrogen, methyl, ethyl or R and R5 together with the carbon atom to which they are attached represent a cyclopropyl group. More preferably R4 and R5 both represent hydrogen or methyl . Most preferably R and R5 both represent methyl.

In a preferred group of compounds of formula II, Rg represents hydrogen or methyl. More preferably Rg represents hydrogen.

In a preferred group of compounds of formula II, A represents ethylene, trimethylene or tetramethylene. More preferably A represents ethylene or trimethylene.

In a preferred group of compounds of formula II, Rg represents hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl . More preferably Rg represents hydrogen or methyl .

In a preferred group of compounds of formula II, Rg and R- _| _o independently represent hydrogen, methyl, chloro, hydroxymethyl, ethoxycarbonyl, n__tro or acetoxymethyl . More preferably Rg and Rη_ _Q independently represent hydrogen, methyl, chloro, acetoxymethyl or ethoxycarbonyl. Most preferably Rg and R-J_Q independently represent hydrogen or methyl.

A second group of more preferred compounds of formula I is represented by formula II in which R-*_, R2 and R3 represent hydrogen, R and Re- represent ethyl, Rg represents hydrogen, A represents ethylene, Rg represents hydrogen or C-*__4 alkyl and Rg and R-*_ _Q independently represent hydrogen, methyl, hydroxymethyl or acetoxymethyl .

A third group of more preferred compounds of formula I is represented by formula II in which R^_ represents chloro; R2 represents hydrogen or 3-chloro; R3 represents hydrogen; R , R ₅ , and Rg each represent hydrogen; A represents ethylene; Rg represents hydrogen or methyl and Rg and R-*_Q independently represent hydrogen or methyl .

Specific compounds of formula I are:

N- [ 1- (4-Chlorophenyl ) ethyl ] -3- (imidazol-1-yl ) propyl- amine;

N- [1- (2 , 4-Dichlorophenyl) ethyl] -3- ( imidazol-1-y1 ) - propylamine; N- [1- (3 , 4-Dichlorophenyl) ethyl] -3- ( imidazol-1-y1 ) - propylamine;

N- [1- (4-Fluorophenyl ) ethyl] -3- (imidazol-1-yl )propyl¬ amine;

N- [1- (4-Benzyloxyphenyl) ethyl] -3- (imidazol-1-y1)propyl- amine;

N- [1- (4-Dimethylaminophenyl ) ethyl] -3- (imidazol-1-y1) - propylamine;

N- [ 1- (3-Chlorophenyl ) ethyl] -3- (imidazol-1-yl ) propyl¬ amine; N- [1- (2-Chlorophenyl) ethyl] -3- (imidazol-1-y1 ) propyl- amine;

N - [ 1 - ( 4 - Chl o ro - 3 - t r i f l uo r ome t hy 1 pheny l ) e t hy l ] - 3 - ( imidazol-1-yl ) propylamine ;

N- [1- (4-Chloro-3-fluorophenyl ) ethyl] -3- ( imidazol-1- yl)propylamine;

3- ( Imidazol-1 -yl ) -N- [1- ( 4-t ifluoromethylpheny1 ) - ethyl]propylamine; N- [1- (4-Chloro-3-methylpheny1 ) ethyl ] -3- ( imidazol-1- yl)propylamine;

N- [1- (2 , 3 , 4-Trichlorophenyl) ethyl] -3- (imidazol-1-y1 ) - propylamine;

N- [1- (4-Bromophenyl) ethyl] -3- (imidazol-1-yl)propylamine; N- [1- (2 , 5-Dichlorophenyl) ethyl] -3- ( imidazol-1-yl ) - propylamine;

3- (Imidazol-1-yl) -N- [1- (4-phenoxyphenyl ) ethyl] propyl¬ amine;

N- [ 1- (4-Chloro-2-methoxyphenyl ) ethyl ] -3- (imidazol-1- yl)propylamine;

N- [l-(4-Chloro-2-ethoxyphenyl) ethyl] -3- (imidazol-1-yl) - propylamine;

N- [1- ( 4-Tert-butylpheny1) ethyl] -3- ( imidazol-1-yl ) - propylamine; Ethyl . ,1- [3- (imidazol-1-yl)propylamino] ethyl}benzoate;

N- [1- (4-Ethylpheny1) ethyl]-3-(imidazol-l-yl ) propyl¬ amine;

N- [ 1- (4-Butoxyphenyl ) ethyl ] -3- (imidazol-1-y1 ) propyl¬ amine; 3- (Imidazol-1-yl) -N- [1- (4-trifluoromethoxyphenyl) ethyl] - propylamine;

N- [1- (4-Chlorophenyl) ethyl] -3- (4, 5-dimethylimidazol-l- yl)propylamine;

J- [1- (4-Chlorophenyl)ethyl] -3- (2-phenylimidazol-1-yl ) - propylamine;

N- [1- (4-Chlorophenyl) ethyl] -4- ( imidazol-1-yl ) butyl- amine;

N- [1- (4-Chlorophenyl ) ethyl] -3- (2-methylimidazol-1-yl ) - propylamine; N- [α- (4-chlorophenyl) benzyl] -3- (imidazol-1-yl)propyl¬ amine;

5-Chloro-2-{l- [3- ( imidazol-1-yl ) propylamino] ethyl } - phenol

N- [1- (4-Chlorophenyl ) propyl] -3- (imidazol-1-yl ) propyl¬ amine; N- [1- (4-Chlorophenyl ) ethyl] -3- (2 , 4-dimethylimidazol-l- yl)propylamine;

3- (2-Benzyl-4-methylimidazol-l-yl) -N- [1- (4-chloro- phenyl) ethyl]propylamine;

3- ( 2 -Benzyl-5-methylimidazol-l-yl ) -N- [1- (4-chloro- phenyl) ethyl]propylamine;

N_- [1- (4-Chlorophenyl ) ethyl] -3- ( 4-methyl-2 -phenyl- imidazol-1-yl)propylamine;

N_- [1- (4-Chlorophenyl) ethyl] -3- (5-methyl-2-phenyl- imidazol-1-yl)propylamine; N-Benzhydryl-3- (imidazol-1-yl)propylamine;

N- (3 , 4-Dichlorobenzyl) -3- (imidazol-1-yl) ropylamine;

N- (4-Bromobenzyl) -3- (imidazol-1-yl)propylamine;

3- (Imidazol-1-yl) -N- (4-trifluoromethylbenzyl)propyl¬ amine; 3- (Imidazol-1-yl) -N- (4-phenoxybenzyl)propylamine;

N- ( 4-Chloro-2-methylbenzyl ) -3- (imidazol-1-yl ) propyl¬ amine;

N- (2 , 4-Dichlorobenzyl) -3- (imidazol-1-yl)propylamine;

N- (4-Chlorobenzyl) -3- (2-methylimidazol-1-yl)propylamine; N- (4-Chlorobenzyl) -3- (4-methylimidazol-1-yl)propylamine;

N- (4-Chlorobenzyl) -3- (5-methy1imidazol-1-y1)propylamine;

N- (4-Chlorobenzyl) -3- (4, 5-dimethylimidazol-1-y1)propyl¬ amine;

N- (4-Chlorobenzyl) -4- (imidazol-1-yl)butylamine; N- (4-Chlorobenzyl) -3- (5-methyl-2-phenylimidazol-l-yl) - propylamine;

N- (4-Chlorobenzyl) -3- (4-methyl-2-phenylimidazol-l-yl) - propylamine;

Methyl 4- [3- ( 2 -methyl imi dazol - 1 -y 1 ) propylaminome thy 1] ^■ benzoate;

3- (Imidazol-1-yl) -N_- (4-methoxy-2, β-dimethyl- benzy 1 ) propylamine ; Ethyl 4- [3- (2-methylimidazol-l-yl ) ropylaminomethyl] • cinnamate;

(-)N- [1- (4-Chlorophenyl) ethyl] -3- (imi dazol -1-yl ) ropyl¬ amine;

N- [1- (4-Chlorophenyl) ethyl] -3- ( 2-ethylimidazol-l-yl ) - propylamine;

N- [1- (4-Chlorophenyl) ethyl] -3- (4-methylimidazol-l-yl ) * propylamine;

N- [1- (4-Chlorophenyl) ethyl] -3- ( 5-methylimidazol-l-yl ) - propylamine; N- [1- (4-Chlorophenyl) ethyl] -5- ( imi dazol -1-yl ) pen tyl - amine ;

( + )N- [1- (4-Chlorophenyl) ethyl] -3- ( imi da zol - 1 -y 1 ) propyl¬ amine ;

N- [1- (4-Chlorophenyl) ethyl] -3- ( imidazol -1-yl ) -2,2- dimethylpropylamine;

N- [1- (4-Chlorophenyl) -1-methylethyl] -3- (imidazol-1-yl ) - propylamine;

N- [ 1- (4-Chlorophenyl ) -1-methylethyl] -3- ( 2- me thy 1- imidazol-1-yl ) ropylamine; N- (4-Chlorobenzyl ) -3- (imidazol -1-yl ) -2 , 2 -dimethylpropyl¬ amine ;

N- [1- (4-Chlorophenyl) -1-methylethyl] -8- ( imidazol-1-yl ) - octylamine;

N- (4-Chlorobenzyl) -3- (4, 5-dichloroimidazol-l-yl ) propyl - amine ;

N- [1- (4-Chlorophenyl ) ethyl] -3- (2-isopropylimidazol-l- y1)propylamine;

N- [1- (4-Chlorophenyl) ethyl] -3- (2,4, 5-trimethylimidazol- 1-yl)propylamine; N- [1- (4-Chlorophenyl) ethyl] -3- (4, 5-dichloroimidazol-l- y1)propylamine;

N- [1- (4-Chlorophenyl ) -1-methylethyl] -3- (4-methyl- imi dazol - 1 -yl ) propylamine ;

N- [ 1- (4-Chlorophenyl ) -1-methylethyl] -3- ( 5 -methyl - imidazol -1-yl ) propylamine; N- [1- (4-Chlorophenyl) -1-methylethyl] -3- (4, 5-dimethyl- imidazol-1-yl) propylamine;

N- (4-Chlorobenzyl ) -3- (2-isopropylimidazol-l-yl ) propyl¬ amine ;

N- (4-Chlorobenzyl) -3- ( 2 -ethyl imi dazol - 1 -yl ) propylamine; 3- (2-Methylimidazol-l-yl) -N- [1-methyl-l- (p-tolyl ) ethyl] - propylamine ; - [1- (4-Chlorophenyl) -1-methylethyl] -3- (4-nitroimidazol- 1 -yl ) propylamine ;

3- (Imidazol-1-yl) -N_- [ 1-methyl-l- (p-tolyl) ethyl] propylamine;

1 - ( 4 -Chloropheny 1 ) - 1 -ethyl -3 ' - (imidazol-1-yl) di - propylamine;

1- {3 - [ 1- ( 4-Chlorophenyl ) -1-methylethyl ami no] propyl } - imidazol -4 -ylmethanol ; N- (1 -Ethyl -1-phenylpropyl) -3- ( imidazol -1-yl) ropylamine ;

E t hy 1 4 - { 1 - [3- (imidazol-l-yl)propylamino] - 1 - methy lethy 1 } benzoate ; _. - [1- (4-Biphenylyl) -1-methylethyl] -3- (imidazol-1- yl ) propylamine ; N_- [ 1- ( 4-Chlorophenyl ) cycloprop-1-yl ] -3 - ( imidazol -1- yl ) propylamine ;

Ethyl 1- {3- [1- ( 4- chloropheny 1 ) -1-methylethylamino] - propyl} -4-methylimidazole-5-carboxylate; _. - [1- (2 -Naphthyl) -1-methylethyl] -3- ( imidazol -1-yl ) - propylamine;

1 - { 3 - [ 1 - ( 3 , 4-Dichlorophenyl ) -1 -methy lethy 1 ami no ] - propyl} imidazol -5 -ylmethanol ;

1 - { 3 - [1- (4-Chlorophenyl) -1-methyl ethyl amino ] - propyl} imidazol-5-ylmethanol ; 1- { 3 - [ 1 - ( 4-Biphenylyl ) - 1 -methy lethy lami no] propyl } - imidazol -4 -ylmethanol ;

1- [ 3 - ( 1-Ethyl-l-phenylpropylamino) propyl ] imidazol-4- ylmethanol ;

N- [1- (4-Benzyloxyphenyl) -1-methylethyl] -3- ( imidazol -1- yl ) propylamine ; N- [1- (4-Chlorophenyl) -1-methylethyl] -4- (imidazol-1-yl ) - butylamine;

N- [1- (4-Chlorophenyl) ethyl] -3- ( imidazol-1-yl ) -N-methyl- propylamine ;

N- [1- (4-Chlorophenyl)propyl] -3- (imidazol-1-yl) -N- methy lpropylamine;

N- (4-Chlorobenzyl) -3- (2 , 4-dimethy1imidazol-1-y1)propyl¬ amine;

3- (2-Benzyl-4-methylimidazol-1-yl) -N- (4-chlorobenzyl) - propylamine; 3- (2-Benzyl-5-methy1imidazol-1-yl) -N- (4-chlorobenzyl) - propylamine;

N- [1- (4-Chloropheny1) -1-methylethyl] -5- (imidazol-1-yl) - pentylamine;

Propyl 4- [3- (2-methylimidazol-1-yl)propylaminomethyl] - benzoate;

N- (4-Chlorobenzyl) -5- (2-methylimidazol-1-yl)pentylamine;

N- [1- (4-Chlorophenyl) -1-methylethyl] -3- (imidazol-1-yl) - N-methylpropylamine;

N- (4-Chlorobenzyl) -N-methyl-3- (2-methylimidazol-l-yl) - propylamine;

__- [1- (4-Chlorophenyl ) -1-methylethyl] -3 - ( 2- isopropylimidazol-1-yl)propylamine;

Propyl 4-{ [1- (3-imidazol-1-yl)propylamino] -1-methyl¬ ethyl}phenylacetate; 1- {3- [1- (4-Chlorophenyl) -1-methylethy1amino]propyl} -5- methylimidazol-4-ylmethyl acetate; and

2- (4-{l- [3- (Imidazol-1-yl) propylamino] -1-methylethyl} - phenyl) ethanol

or pharmaceutically acceptable salts thereof in the form of individual enantiomers, race ates or other mixtures of enantiomers.

An especially preferred compound is N-[l-(4* chlorophenyl) -1 -methylethyl ] -3- (imidazol-1-yl) ^• propylamine.

The compounds of formula I may form organic or inorganic salts, for example, the compounds of formula I may form acid addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulphuric acid, hydriodic acid, phosphoric acid, maleic acid, acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecanoic acid and acidic amino acids such as glutamic acid. Some compounds of formula I may form base addition salts, for example, with alkali metals for example sodium hydroxide, or with aminoacids for example, lysine or arginine. It will be appreciated that such salts, provided they are pharmaceutically acceptable may be used in therapy in place of the corresponding compounds of formula I. Such salts are prepared by reacting the compound of formula I with a suitable acid or base in a conventional manner. Such salts may also exist in form of solvates (for example, hydrates) .

It will be appreciated by those skilled in the art that certain compounds of formula I contain one or more chiral centres. Thus, compounds of formula I in which R4 and R5 are not identical contain a chiral centre. Certain of the substituents R- _] _, R ₂ , R3, R4, R5, Rg, Rg, Rg and R-*_Q may also contain at least one chiral centre, for example when R--_, R ₂ , R3 , R4, R5, Rg, Rg, Rg or R-J_Q is sec-butyl .

When a compound of formula I contains a single chiral centre it may exist in two enantiomeric forms. The present invention includes individual enantiomers

and mixtures of those enantiomers. The enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include resolution via formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation processes described above, a further step will subsequently be required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral centre it may exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of compounds of formula I or II and mixtures thereof .

Certain compounds of formula I may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof . Certain compounds of formula I may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

As used hereinafter, the term "active compound" denotes a 1- (arylalkylaminoalkyl) imidazole derivative of formula I. In the treatment of neurological damage the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a systemic effect. The active compounds may be administered in a prophylactic manner. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention suitably contain 0.1-90% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form.

Compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacists' art.

Tablets may be prepared from a mixture of the active compound with fillers, for example, lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethyl- cellulose phthalate.

The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may if desired be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.

Similarly capsules, for example hard or soft gelatin capsules containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods to give sustained release of the active compound. Enteric coated compositions of the invention may be advantageous, depending on the nature of the active compound. The tablets and capsules may conveniently each contain 1-1000 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg) of the a ^c tive compound. Other compositions for oral administration include, for example, aqueous suspensions containing the compound of formula I in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present

invention in a suitable vegetable oil, for example sunflower oil.

The active compound may be formulated into granules with or without additional excipients . The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.

Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such adminstration, for example suppositories with hard fat, semi-synthetic glycerides or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.

Compositions for topical administration may comprise a matrix in which the active compound is dispersed so that it is held in contact with the skin in order to administer the compound of formula I transdermally. Alternatively the active compound may be dispersed in a cream, gel or ointment base or applied in the form of a spray.

Compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for

example aerosols, nebulised solutions or powders. Metered dose systems, known to those skilled in the art, may be used.

Compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwaεn*=s or rinses.

The compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may b' a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a r- - ry sparingly water-soluble derivative such as a d decanoate salt or b) solid in the form of an implanted support for example a synthetic resin or waxy material for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.

In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.

The pharmaceutical compositions containing a therapeutically effective amount of a compound of

formula I may ^■ be used to treat neurological damage in human beings . In such treatment the amount of the compound of formula I administered per day is in the range 0.1 to 3000 mg. Specific compounds which may be incorporated into the compositions of this invention are the compounds disclosed above.

The therapeutic activity of the compounds according to the present invention may be demonstrated by tests on standard laboratory animals . These include techniques such as transvascular occlusion of the middle cerebral artery in rats and the rat bilateral carotid occlusion global model .

The therapeutic activity of the compounds according to the present invention may also be demonstrated by their ability to inhibit superoxide production in purified mouse microglial cells which have been exposed to aluminosilicate as described by Evans et al in Free Radicals and Aging, pages 178-189, edited by I. Emerit & B. Chance, published by Birkhauser Verlag, 1992, and references cited therein.

Electroconvulsive shock treatment (ECST) to rats has been shown to inhibit the acquisition and retention of memory in a passive avoidance model ( eher, B. et al, 1986, Physiology & Behaviour, 36; 471-475) . The therapeutic activity of the compounds of the present invention may be determined, using this model, by their efficacy to prevent this inhibition. Following the administration of test compound or vehicle, anaesthetised rats receive ECST sufficient to cause a tonic-clonic seizure (or sham-seizure where electrodes are attached, but no current passed) , on five occasions over ten days. Passive avoidance training and testing

are conducted in a two-chamber shuttle-box, with one chamber brightly lit, and the other dark.

In acquisition tests, animals are allowed to explore the light chamber, prior to a door to a dark chamber being opened. The time taken to enter the dark chamber is measured. Upon entry the rats receive an aversive, inescapable footshock.

In retention tests the same procedure is used, except that no footshock is applied if, and when, the animal (which has previously experienced the acquisition test) crosses to the dark side. ECST administered prior to the acquisition trial, impairs the ability of the rats to acquire the knowledge that the dark-side is associated with an aversive footshock. When ECST is administered after the acquisition trial, the ability of the rats to retain this knowledge is impaired. The efficacy of drugs to prevent these impairments can be demonstrated by increased latency to enter the dark chamber, compared with vehicle treated animals.

Whilst the precise amount of active compound administered will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history and always lies within the sound discretion of the administering physician, a suitable dose for enteral administration to mammals, including humans, is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses. For parenteral administration, a suitable dose is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses or by continuous infusion. Oral administration is preferred.

Accordingly, in another aspect, the present invention provides the use of a compound of formula I in the manufacture of a medicament for use in the therapeutic or prophylactic treatment of neurological damage.

In a preferred aspect, the present invention provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of dementia and in particular Alzheimer's disease.

The compounds of the present invention may be prepared as described in WO 93/13075.

PHARMACEUTICAL EXAMPLES

Example U

In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 10 mg active compound.

Example V

Tablets are prepared from the following ingredients .

Parts by Weight

Active compound 10

Lactose 190 Maize starch 22

Polyvinylpyrrolidone 10

Magnesium stearate 3

The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol . The dry granulate is blended with magnesium stearate an he rest of the starch. The mixture is then compressed in a tableti... machine to give tablets containing 10 mg of active compound.

Example W

Tablets are prepared by the method of the previous Example. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol -dichloromethane (1:

Example X

In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of semi-synthetic glycerides as the suppository base and the mixture formed into suppositories each containing 100 mg of active ingredient.

Example Y

In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containix _. 50 mg of active ingredient .

Example Z

The active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed. The ointment is packed into 10 g amber jars with screw-capped lined lids.

Active compound 0.1 g White soft paraffin to 10 g