Medicaments

Abstract

The invention relates to the use of compounds of formula (I) ##STR1## wherein Im represents an imidazolyl group of formula: ##STR2## and R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenyl, phenylC.sub.1-3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, --CO.sub.2 R.sup.5, --COR.sup.5, --CONR.sup.5 R.sup.6 or --SO.sub.2 R.sup.5 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, a C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl group, or a phenyl or phenylC.sub.1-4 alkyl group, in which the phenyl group is optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy or hydroxy groups or halogen atoms, with the proviso that R.sup.5 does not represent a hydrogen atom when R.sup.1 represents a group --CO.sub.2 R.sup.5 or --SO.sub.2 R.sup.5);one of the groups represented by R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, phenyl or phenylC.sub.1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-6 alkyl group;and n represents 2 or 3,and physiologically acceptable salts and solvates thereof for the manufacture of a medicament for the treatment of a cognitive disorder.

Description

This invention relates to a further medical use for a group of heterocyclic compounds and pharmaceutical compositions containing them. In particular it relates to the use of certain lactam derivatives in the treatment of cognitive disorders.

Compounds which are antagonists of 5-HT at 5-HT.sub.3 receptors have been described previously for use in the treatment of cognitive disorders in, for example, published European Patent Applications Nos. 190920, 275668, and 279990, U.S. Pat. No. 4,624,961, and in German Offenlegungsschrift No. 3740352.

The present invention relates to the use in this indication of a particular group of compounds which are antagonists of 5-HT at 5-HT.sub.3 receptors, as defined by the general formula (I). ##STR3## In the above formula Im represents an imidazolyl group of formula: ##STR4## and R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenyl, phenylC.sub.1-3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, --CO.sub.2 R.sup.5, --COR.sup.5, --CONR.sup.5 R.sup.6 or --SO.sub.2 R.sup.5 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, a C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl group, or a phenyl or phenylC.sub.1-4 alkyl group, in which the phenyl group is optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy or hydroxy groups or halogen atoms, with the proviso that R.sup.5 does not represent a hydrogen atom when R.sup.1 represents a group --CO.sub.2 R.sup.5 or --SO.sub.2 R.sup.5);

one of the groups represented by R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, phenyl or phenylC.sub.1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-6 alkyl group; and n represents 2 or 3.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleates. The solvates may, for example, be hydrates.

Compounds defined by the general formula (I) are the subject of published European Patent Application No. 306323, which was unpublished at the priority date of the present application.

The compounds of formula (I) are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at `neuronal` 5-HT receptors of the type located on terminals of primary afferent nerves. Receptors of this type are now designated as 5-HT.sub.3 receptors and are also present in the central nervous system. 5-HT occurs widely in the neuronal pathways in the central nervous system and disturbance of these 5-HT containing pathways is known to alter behavioural syndromes such as mood, psychomotor activity, appetite and memory.

The potent and selective antagonism of 5-HT at 5-HT.sub.3 receptors by compounds for use according to the invention has been demonstrated by their ability to inhibit 3-(5-methyl-1H-imidazol-4-yl)-1-[1-(methyl-t.sub.3)-1H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G. Kilpatrick et al. in Nature, 1987, 330, 746), and/or by their ability to inhibit the 5-HT-induced depolarisation of the rat isolated vagus nerve preparation.

Compounds which are antagonists of 5-HT at 5-HT.sub.3 receptors, such as the compounds of formula (I), are of use in the treatment of a human or animal subject suffering from anxiety, a psychotic disorder such as schizophrenia, or nausea and vomiting. The compounds are also useful in the treatment of gastric stasis; symptoms of gastrointestinal dysfunction such as occur with dyspepsia, peptic ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; and pain.

We have now found that the compounds of formula (I) and their physiologically acceptable salts and solvates, may be used in the treatment of cognitive disorders such as attentional and memory deficits and dementia states. These types of condition occur in, for example, senile dementia of the Alzheimers type, ageing, cerebrovascular deficiency and Parkinson's disease.

The effectiveness of the compounds of formula (I) for use in the treatment of cognitive disorders may be demonstrated in rats in spontaneous or food reinforced alternation tests, and in marmosets given learning tasks in the Wisconsin General Test Apparatus.

Accordingly the invention provides a method of treatment of a human or animal subject suffering from a cognitive disorder, which comprises administering to a human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof. The treatment of humans is particularly important.

References in this specification to treatment include prophylactic treatment as well as the acute alleviation of symptoms.

The use of all optical isomers of compounds of general formula (I) and their mixtures including the racemic mixtures thereof, and all the geometric isomers of compounds of formula (I), is embraced by the invention.

A particular group of compounds of formula (I) for use according to the invention is that wherein R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkyl, phenyl or phenyl C.sub.1-3 alkyl (n and Im being as defined in formula (I)).

A preferred group of compounds of formula (I) for use according to the invention is that wherein R.sup.1 represents a hydrogen atom or a C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl, C.sub.5-6 cycloalkyl, C.sub.5-6 cycloalkylmethyl, phenyl C.sub.1-2 alkyl, phenylmethoxymethyl, N,N-diC.sub.1-3 alkylcarboxamido or C.sub.1-3 alkylsulphonyl group; R.sup.2 represents a hydrogen atom; and R.sup.3 and R.sup.4 each represent a hydrogen atom or a C.sub.1-3 alkyl group.

A particularly preferred group of compounds of formula (I) for use according to the invention is that wherein R.sup.1 represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N,N-dimethylcarboxamido group; R.sup.2 and R.sup.3 each represent a hydrogen atom; and R.sup.4 represents a methyl group.

Within the above preferred and particularly preferred groups of compounds, an especially important group of compounds is that in which n represents 2.

Preferred compounds for use according to the invention are:

2,3,4,5-tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one; 5-cyclopentyl-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one; 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido[4,3-b]indol-1-one; 5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one; 3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]azepino[4,3-b]indol-1(2H)-one; 2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1-oxo-5H-pyrido[4,3-b]indole-5-carboxamide; 2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propynyl)-1H-pyrido[4,3-b]indol-1-one; and their physiologically acceptable salts and solvates.

A particularly preferred compound for use according to the invention is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one and its physiologically acceptable salts and solvates. Preferred salts of this compound are the hydrochloride and maleate, of which the hydrochloride is particularly preferred.

In a further aspect, the invention provides a pharmaceutical composition which comprises an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate (e.g. hydrate) thereof, for use in human or veterinary medicine, particularly human medicine, for the treatment of a cognitive disorder.

In a yet further aspect, the invention provides for the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a cognitive disorder.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.

Thus the compounds of formula (I) and their physiologically acceptable salts and solvates may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose). Oral administration is particularly important.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, depot preparations constitute a further particularly useful type of composition. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

A proposed dose of a compound of formula (I) for use according to the invention for administration to man (of approximately 70 kg body weight) is 0.001 to 100 mg, for example 0.01 to 50 mg, of the active ingredient per unit dose, expressed as the weight of free base. A preferred dose of active ingredient per unit dose is 0.001 to 10 mg. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated.

Compounds of general formula (I) and physiologically acceptable salts or solvates thereof, may be prepared by the methods described in published European Patent Application No. 306323.

The following examples illustrate the preparation of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one and its hydrochloride salt, covered by formula (I). Temperatures are in .degree. C. Thin layer chromatography (t.l.c.) was carried out on silica. Organic extracts were dried, where indicated, over magnesium sulphate or sodium sulphate.

EXAMPLE 1

2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one

A suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (400 mg) in dry dimethoxyethane (50 ml) was treated with sodium hydride (60% dispersion in oil; 100 mg), and the mixture was stirred at 60.degree. under nitrogen for 6 h. 4-(Chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (474 mg) was added and the reaction mixture was stirred at 60.degree. under nitrogen overnight. 2N Hydrochloric acid (10 ml) and water (10 ml) were then added, and the mixture was heated at reflux for 6 h. After cooling, the mixture was basified with 2N sodium hydroxide and the resulting mixture was extracted with ethyl acetate (2.times.50 ml). The combined, dried organic extracts were concentrated onto flash column chromatography (FCC) silica and purified by FCC eluting with dichloromethane:ethanol:0.88 ammonia (150:8:1) to give the title compound (352 mg) as a solid, t.l.c.

(dichloromethane:ethanol:0.88 ammonia 100:8:1) Rf 0.28. .sup.1 H-N.m.r.(DMSO-d.sub.6): .delta.2.2 (3H,s), 3.04 (2H,t), 3.62 (2H,t), 3.72 (3H,s), 4.53 (2H,s), 7.1-7.28 (2H,m), 7.43 (1H,s), 7.47-7.55 (1H,dd), 7.94-8.03 (1H,dd).

EXAMPLE 2

2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one hydrochloride

2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (1.00 g) was suspended in ethanol (40 ml) and concentrated hydrochloric acid (1.00 ml) was added. The mixture was warmed to 40.degree. and charcoal (0.25 g) was added. The resulting suspension was stirred and warmed for 5 min. and then filtered. The filtrate was evaporated in vacuo to ca. 20 ml and was allowed to cool to 20.degree.. Ether (40 ml) was added with stirring over 5 min., and the mixture was stored at 4.degree. overnight. The resulting precipitate was filtered off, washed with ether (2.times.10 ml), dried in vacuo at room temperature for 2 h and then at 70.degree. for 7 h to give the title compound (0.95 g), m.p. 288.degree.-291.degree..

Analysis Found: C,61.4; H,5.8; N,16.7; Cl, 10.7; C.sub.17 H.sub.18 N.sub.4 O.HCl requires C,61.7; H,5.8; N,16.9; Cl, 10.7%

The following examples illustrate pharmaceutical formulations for use according to the invention, containing, as the active ingredient, 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-1-yl)methyl]-1H-pyrido-[4,3-b]indol-1-one (Compound A) in the form of its free base or hydrochloride salt (1.124 g of the hydrochloride is equivalent to l g of the free base). Other physiologically acceptable salts and/or solvates of Compound A, and other compounds of formula (I) and their physiologically acceptable salts and/or solvates may be formulated in a similar manner.

TABLETS FOR ORAL ADMINISTRATION

Tablets may be prepared by the normal methods such as direct compression or wet granulation.

The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Alternatively the tablets may be sugar coated.

Direct Compression

______________________________________(i) Tablet mg/tablet______________________________________Compound A free base 0.50Calcium Hydrogen Phosphate BP* 87.25Croscarmellose Sodium NF 1.80Magnesium Stearate BP 0.45Compression weight 90.00______________________________________ *of a grade suitable for direct compression.

The active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate. The resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 5.5 mm, flat bevelled edge punches.

______________________________________(ii) Tablet mg/tablet______________________________________Compound A hydrochloride 0.562Microcystalline cellulose NF 31.250Lactose (anhydrous) NF 111.303Pregelatinised maize starch BP 6.250Magnesium Stearate 0.625Compression weight 150.0______________________________________ *of a grade suitable for direct compression.

The active ingredient is passed through a 60 mesh sieve, blended with the lactose, microcystalline cellulose, pregelatinised maize starch and magnesium stearate. The resultant mix is compressed into tablets using a suitable tablet machine fitted with 7.0 mm, normal concave punches.

______________________________________Sub-Lingual Tablet mg/tablet______________________________________Compound A hydrochloride 0.562Compressible Sugar NF 63.938Magnesium Stearate BP 0.500Compression Weight 65.0______________________________________

The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using suitable punches.

Tablets of other strengths may be prepared by altering either the ratio of active ingredient to excipients or the compression weight and using punches to suit.

Wet Granulation

______________________________________Conventional Tablet mg/tablet______________________________________Compound A hydrochloride 0.562Lactose BP 152.938Starch BP 30.000Pregelatinised Maize Starch BP 15.000Magnesium Stearate BP 1.500Compression Weight 200.0______________________________________

The active ingredient is sieved through a suitable sieve and blended with lactose, starch and pregelatinised maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 8 mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.

______________________________________Sub-Lingual Tablet mg/tablet______________________________________Compound A hydrochloride 0.562Mannitol BP 58.438Hydroxypropylmethylcellulose 5.000Magnesium Stearate BP 1.000Compression Weight 65.0______________________________________

The active ingredient is sieved through a suitable sieve and blended with the mannitol and hydroxypropylmethylcellulose. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended into tablets using suitable punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to mannitol or the compression weight and punches to suit.

CAPSULES

______________________________________ mg/capsule______________________________________Compound A hydrochloride 0.562*Starch 1500 98.438Magnesium Stearate BP 1.000Fill Weight 100.0______________________________________ *a form of directly compressible starch.

The active ingredient is sieved and blended with the excipients. The mix is filled into size No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight an if necessary changing the capsule size to suit.

SYRUP

This may be either a sucrose or sucrose free presentation.

______________________________________A. Sucrose Syrup mg/5 ml dose______________________________________Compound A hydrochloride 0.562Sucrose BP 2750.0Glycerine BP 500.0BufferFlavourColour as requiredPreservativePurified Water BP to 5.0 ml______________________________________

The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.

______________________________________B. Sucrose-Free mg/5 ml dose______________________________________Compound A hydrochloride 0.562Hydroxypropylmethylcellulose USP 22.5(viscosity type 4000)BufferFlavourColour as requiredPreservativeSweetenerPurified Water BP to 5.0 ml______________________________________

The hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant solution is adjusted to volume and mixed. The syrup is clarified by filtration.

INJECTION FOR INTRAVENOUS ADMINISTRATION

______________________________________ mg/ml______________________________________(i)Compound A free base 0.05 0.5Sodium Chloride BP as required as requiredWater for Injection 1.0 ml 1.0 ml(ii)Compound A hydrochloride 0.0562 0.562Sodium Chloride BP as required as requiredWater for Injection BP to 1.0 ml 1.0 ml______________________________________

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas.

SUPPOSITORY

______________________________________(i) Compound A free base 0.5 mg *Witepsol H15 to 1.0 g(ii) Compound A hydrochloride 0.562 mg *Witepsol H15 to 1.0 g______________________________________ *Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur.

A suspension of the active ingredient is prepared in the molten Witepsol and filled, using suitable machinery, into 1 g size suppository moulds.

The efficacy of the compounds of formula (I) in the treatment of cognitive disorders has been demonstrated in rats in a spatial memory task, more particularly in an alternation task using an elevated T-maze.

Test Compound

2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one hydrochloride.

Introduction and Test Procedure

Scopolamine has been used to produce experimental cognitive deficits in performance of a task in which a rodent is required to retain spatial information.

Male Lister Hooded rats were trained on a food reinforced alternation task using an elevated T-maze in a modification of the protocol described by J. D. Salamone et al., Behav. Brain Res., 1982, 13, 63-70. Food was withdrawn 2 days prior to testing and throughout testing animals were deprived of food for 23 h/day, but with water available ad libitum (85% normal body weight maintained). Training consisted of paired trials, the first being "forced" in that one arm of the T-maze was blocked whilst the other was baited. The second was a choice trial in which reward pellets were placed in the arm opposite to that reinforced in the first trial of the pair. A correct choice (i.e. alternation) was when the rat entered the arm containing the food on the choice trial.

Results

Scopolamine (0.25 mg/kg i.p. b.d.) produced a reduction in correct responses (compared to control) over the 9 day test period. Administration of the test compound (10 ng/kg i.p. b.d.) to rats also treated with scopolamine (0.25 mg/kg i.p. b.d.) inhibited this impaired performance. Thus, for example, for control rats, scopolamine-treated, and scopolamine+test compound-treated rats, the percentage of correct responses on day 5 were 74.1, 41.2, and 66.7 respectively (p<0.05 Dunnett's t-test).

Conclusion

The test compound reduces the cognitive deficits produced by scopolomine in rats.

Claims

1. A method for the treatment of a cognitive disorder which comprises administering to a human or animal subject suffering from a cognitive disorder an effective amount for the treatment of said cognitive disorder of a compound of formula (I) ##STR5## wherein Im represents an imidazolyl group of formula: ##STR6## and R.sup.1 represents a hydrogen atom or a group selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, C.sub.3-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenyl, phenylC.sub.1-3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, --CO.sub.2 R.sup.5, --COR.sup.5, --CONR.sup.5 R.sup.6 or --SO.sub.2 R.sup.5 (wherein R.sup.5 and R.sup.6, which may be the same or different, each represents a hydrogen atom, a C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl group, or a phenyl or phenylC.sub.1-4 alkyl group, in which the phenyl group is optionally substituted by one or more C.sub.1-4 alkyl, C.sub.1-4 alkoxy or hydroxy groups or halogen atoms, with the proviso that R.sup.5 does not represent a hydrogen atom when R.sup.1 represents a group --CO.sub.2 R.sup.5 or --SO.sub.2 R.sup.5);

one of the groups represented by R.sup.2, R.sup.3 and R4 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-6 alkenyl, phenyl or phenylC.sub.1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C.sub.1-6 alkyl group;

and n represents 2 or 3,

or a physiologically acceptable salt or solvate thereof.

2. A method according to claim 1 in which in the compound of formula (I) R.sup.1 represents a hydrogen atom or a C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl, C.sub.5-6 cycloalkyl, C.sub.5-6 cycloalkylmethyl, phenylC.sub.1-2 alkyl, phenylmethoxymethyl, N,N-diC.sub.1-3 alkylcarboxamido or C.sub.1-3 alkylsulphonyl group; R.sup.2 represents a hydrogen atom; and R.sup.3 and R.sup.4 each represent a hydrogen atom or a C.sub.1-3 alkyl group.

3. A method according to claim 1 in which in the compound of formula (I) R.sup.1 represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N,N-dimethylcarboxamido group; R.sup.2 and R.sup.3 each represent a hydrogen atom; and R.sup.4 represents a methyl group.

4. A method according to claim 1 in which in the compound of formula (I), n is 2.

5. A method according to claim 1 in which said compound of formula (I) is selected from

2,3,4,5-tetrahydro-5-(phenylmethyl)-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one;

5-cyclopentyl-2,3,4,5-tetrahydro-2-[5-methyl-1H-imidazol-4-yl)-methyl]-1H-pyrido[4,3-b]indol-1-one;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-propyl-1H-pyrido[4,3-b]indol-1-one;

5-(cyclopentylmethyl)-2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one;

3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-azepino[4,3-b]indol-1(2H)-one;

2,3,4,5-tetrahydro-N,N-dimethyl-2-[(5-methyl-1H-imidazol-4-yl)-methyl]-1-oxo-5H-pyrido[4,3-b]indole-5-carboxamide;

2,3,4,5-tetrahydro-2-[(5-methyl-1H-imidazol-4-yl)methyl]-5-(2-propynyl)-1H-pyrido[4,3-b]indol-1-one;

and physiologically acceptable salts and solvates thereof.

6. A method according to claim 1 in which said compound of formula (I) is administered in the form of a medicament in a form adapted for oral administration or as a depot preparation.

7. A method according to claim 1 in which said compound of formula (I) is administered in a unit dose of from 0.001 to 100 mg of the active ingredient.

8. A method according to claim 1 in which said compound of formula (I) is administered in a unit dose of from 0.001 to 10 mg of the active ingredient.

9. A method for the treatment of a cognitive disorder which comprises administering to a human or animal subject suffering from a cognitive disorder an effective amount for the treatment of said cognitive disorder of a compound which is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

10. A method according to claim 9 in which said compound is used in the form of its hydrochloride salt.

11. A method according to claim 9 in which the compound is administered in the form of a medicament in a form adapted for oral administration or as a depot preparation.

12. A method according to claim 9 in which the compound is administered in a unit dose of from 0.001 to 100 mg of the active ingredient.

13. A method according to claim 9 in which the compound is administered in a unit dose from 0.001 to 10 mg of the active ingredient.

14. A method according to claim 2 wherein n is 2.

15. A method according to claim 3 wherein n is 2.

16. A method according to claim 2 wherein R.sup.1 is C.sub.1-4 alkyl.

17. A method according to claim 16 wherein n is 2.