EP0673248A1 - Potassium channel activators for use in therapy - Google Patents

Abstract

A method of treatment and/or prophylaxis of anxiety, mania, depression, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable and/or preventable with anticonvulsive agents, such as epilepsy; and in the treatment or prevention of cerebral ischaemia, disorders resulting from sub-arachnoid haemorrhage, Parkinson's disease, migraine and/or psychosis, comprising administering to the sufferer in need thereof an effective or prophylactic amount of a potassium channel activator.

Description

POTASSIUM CHANNEL ACTIVATORS FOR USE IN THERAPY

This invention relates to a novel method of treatment and to novel compounds for use in such a method. European Published Patent Application No. 0126311 discloses substituted benzopyran compounds having blood pressure lowering activity, including 6-acetyl- trans-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3-ol. Also EP-A-0 376524, EP-A-0 205 292, EP-A-O 250 077, EP-A-0093 535, EP-A-0 150 202, EP-A-0076075 and WO/89/05808 (Beecham Group pic) describe certain benzopyran derivatives which possess anti-hypertensive activity.

EP-A-0 350 805 (Bieredorf), EP-A-0277 611, EP-A-0277612, EP-A-0 337 179, and EP-A-0 355 565 (Hoechst Aktiengesellschaft) EP-A-0415 065 (E.Merck), EP-A-0-450415 (Squibb), EP-A-0-466 131 (Nissan Chemical Industries Ltd), EP-A- 0339562 (Yoshitomi Pharmaceuticals), EP-A-0 360 621 (Ortho Pharmaceuticals), EP-A 0 489 300 (Uriach), DE 3,831,697 (Hoechst), EP-A 0432 893 (Yamanouchi), DE 4,010,488 (Hoechst), EP-A-0482934, EP-A-0296975, JO-2004-791 and WO\S9\11477 and WO\89N07103 also describe certain compounds which are believed to possess anti-hypertensive activity.

EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group pic) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentioned patent applications.

EP-A-0 194 885 (E. Lilly) describes certain amino substituted benzopyran derivatives possessing anti-convulsant activity.

PCT/GB92/01045 (SmithKline Beecham pic; unpublished at the priority date), which describes certain fluorobenzoylamido benzopyrans, pyranopyridines and tetrahydronaphthylenes in which the 3 and 4 position substituents are trans to each other. These compounds are described as possessing inter alia anxiolytic and anti- convulsant activity.

It has now been surprisingly found that certain compounds of formula (I) possess anxiolytic and anti-convulsant activity, and are also believed to have utility in the treatment or prevention of mania, depression and the effects associated with withdrawal from substances of abuse and utility in the treatment or prevention of cerebral ischaemia, disorders resulting from sub-arrachnoid haemorrhage, Parkinson's Disease, migraine and/or psychosis. Accordingly, the present invention provides a method of treatment and/or prophylaxis of anxiety, mania, depression, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy; and in the treatment or prevention of cerebral ischaemia, disorders resulting from sub- arrachnoid haemorrhage, Parkinson's Disease, migraine and/or psychosis, comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I) or pharmaceutically acceptable salt thereof:

R₈NCO-R₇

wherein:

P is a ring system selected from the following: a)

wherein;

and the other variables are as defined below:

b)

in which either a and b together represent a bond or CH2 or a and b together represent a carbonyl uroup, a group C=NOR*\ CHORP or

O

II F

C-OC-R where R*^ is hydrogen or C\. alkyl; or

c)

in which either J is nitrogen and J^a is a lone pair of electrons, M is carbon and M^a is R5; or

J is carbon and M is nitrogen and J^a and M^a are hydrogen; or

in which Z is oxygen or CH2;

and;

where: either one of Rj and R2 is hydrogen and the other is selected from the class of hydrogen, C3_g cycloalkyl, C\. alkyl optionally interrupted by oxygen or substituted by hydroxy, Ci _g alkoxy or substituted aminocarbonyl, C . alkylcarbonyl, Ci .5 alkoxycarbonyl, Cγ. alkylcarbonyloxy, C g alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH, or a group CF2H-A'- where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; tri luoromethoxy, Cμg alkylsulphinyl, perfluoro C2-6 alkylsulphonyl, Cj.g alkylsulphonyl, Cι_6 alkoxysulphinyl, C_j.g alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, heteroarylsulphonyl in which any aromatic moiety is optionally substituted, Cγ. alkylcarbonylamino, Cι_6 alkoxycarbonylamino, Cj.g alkyl-thiocarbonyl, C . alkoxy-thiocarbonyl, C_j.6 alkyl-thiocarbonyloxy, 1-mercapto C2.7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1 _β alkyl groups, or C\. alkylsulphinylamino, C\_ - alkylsulphonylamino,Cι_6 alkoxysulphinylamino or C\. alkoxysulphonylamino, or ethylenyl terminally substituted by C 1.5 alkylcarbonyl, nitro or cyano, or -C(Cj .$ alkyl)NOH or -C(Cι_6 alkyl)NNH2, or one of R\ and R2 is nitro, cyano or C 1.3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two Cj.g alkyl or by C2_7 alkanoyl; or where possible R and R2 together are -(CH2)4- or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring; one of R3 and R4 is hydrogen or C 1.4 alkyl and the other is C 1.4 alkyl, CF3 or CH2 X^a where X^a is fluoro, chloro, bromo, iodo, C1.4 alkoxy, hydroxy, C1.4 alkylcarbonyloxy, -S-Cj.4 alkyl, nitro, amino optionally substituted by one or two Cι_4 alkyl groups; cyano or C 1.4 alkoxycarbonyl or R3 and R4 together are C2-5 polymethylene optionally substituted by C 1.4 alkyl; R5 is C\.(- alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C\_<- alkoxy and Rg and R9 are hydrogen or R5 is hydroxy and R is hydrogen or Cj_2 alkyl and R9 is hydrogen;

R7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by Cj_4 alkyl, cyano, azido, C1.4 alkyl, Cι_4 alkoxy, trifluoromethoxy and trifluoromethyl;

Rg is hydrogen; C\. alkyl, OR9 or NHCORJO wherein R9 is hydrogen, Cι_6 alkyl, formyl, C\. alkanoyl, aroyl or aryl-Cμ6 alkyl and Rio is hydrogen, Cι_6 alkyl, C\. alkoxy, mono or di C\. alkyl amino, amino, amino-C^*ι_6 alkyl, hydroxy- C 6 alkyl, halo-Cι_6 alkyl, Ci.g acyloxy-C^.g alkyl, Cι_6 alkoxycarbonyl-C g- alkyl, aryl or heteroaryl; and the Rg-N-CO-R7 group is cis or trans to the R5 group;

All Cj.g alkyl or C 1.4 alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n - and iso -propyl, n -, iso -, sec - and tert-butyl. Suitable C3_g cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Suitable halo substituents include fluoro, chloro and bromo. Aryl whenever mentioned herein includes but is not limited to phenyl and naphthyl. Heteroaryl whenever mentioned herein includes a 5- or 6- membered monocyclic or 9- or 10- membered bicyclic of which 5- or 6- membered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different. Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl. Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl. Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazolyl. Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.

Suitable examples of groups or atoms for optional substitution especially of aryl and heteroaryl include one, two or three substituents independently selected from Cμ4 alkyl, C1.4 alkoxy, halo (such as fluoro, chloro, bromo), hydroxy, nitro amino optionally substituted once or twice by C1.4 alkyl, cyano and SO_nH, where n=0 to 2.

Preferred variables are as those mentioned in the atom mentioned patents which are incorporated herein by reference.

For compounds of formula (I) in which P is selected from a); the thienophene moiety is preferably i). R, and R^ are preferable both hydrogen or R, is nitro and R« is hydrogen.

R- and R. are preferably both methyl. Preferably R- is hydroxy, R_fi is hydrogen and R_Q is hydrogen. Preferably R~ is hydrogen. Preferably the R_j,NCOR₇ group is trans to the Re group. For compounds of formula (I) in which P is selected from d) R*. is preferably cyano or nitro. R- and R . are preferably both hydrogen or both methyl. Preferably R_<- is hydroxy, R_fi is hydrogen and R_Q is hydrogen.

Preferably R^ is hydrogen. Preferably the RoNCOR- group is trans to the R_e¬ group. It should be appreciated that for all compounds of formula (I) when R7 is phenyl optionally independently substituted; this includes substitution by 1,2,3,4 or 5 groups or atoms attached to the phenyl ring. Preferably there are 1 or 2 groups or atoms attached to the phenyl ring. The groups or atoms may be in any position around the phenyl ring. Likewise, it should be appreciated that when R7 is heteroaryl optionally independently substituted; this includes substituents at any vacant positions around the heteroaryl moiety. Preferably there are 1 or 2 groups or atoms around the heteroaryl moiety, most preferably there is one group or atom around the heteroaryl moiety. Preferably R7 is fluorophenyl. More preferably R7 is mono-fluorophenyl and even more preferably R7 is 2-, 3 or 4-fluorophenyl. Most preferably R7 is 4- fluorophenyl.

It should be appreciated that the compounds of formula (I) may have chiral carbon atoms at positions around the saturated portion of ring system P especially at the atoms attached to R5 and the moiety Rg NCOR7 and therefore may exist as enantiomers. The present invention extends to each enantiomer and to mixtures thereof including racemates.

It should also be appreciated that certain R substituents also have chiral centres and therefore may exist as enantiomers. The present invention extends to each enantiomer and to mixtures thereof including racemates It should be appreciated that the compound of formula (I) or a pharmaceutically acceptable salt thereof also includes solvates of such compounds, such as for example the hydrate.

The administration to the mammal may be by way of oral or parenteral administration. An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg day, more usually 0.1 to 6 mg kg/day, for example 1 to 6 mg kg/day. It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, rectal, topical or parenteral (especially intravenous) composition.

Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl /. -hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention. As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

The present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage, neural shock, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a further aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression and/or disorders associated with a subarachnoid haemorrhage, neural shock the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia.

Such compositions may be prepared in the manner as hereinbefore described.

The invention also extends to novel compounds of formula (I) and pharmaceutically acceptable salts thereof.

Examples of such novel compounds are: rrα i_'-3-cyano-5-(4-fluorobenzamido)-6,7,8,9-tetrahydro-5H-benzocycloheptan-6-ol and rrα/w-7-cyano-5-(4-fluoroben__ami__o)-4-hydroxy-2,2-dimethyl-2,3,4,5-tetrahydro-l- benzoxepine.

Generally, compounds of formula (I) which have trans isomerisation between the groups attached to the atom attached to the group Rg NCOR7 and the group attached to the atom adjacent, on the right-hand side of the diagram as shown herein may be prepared by procedures generally described or analogous to those described in EP-0126311, EP-0376524, EP-205292, EP-0250077, EP-0093535, EP-0150202, EP-0076075, WO/89/05808, EP-0350805, EP-0277611, EP-0277612, EP-0337179, EP-0355565, EP-A-0482934, EP-A-0296975, JO-2004- 791 WO\89\l 1477and WO\89\07103 EP-0466131, EP-A-0489300, DE 3,831,697, EP-A-0432893 and DE 4,010,488. Generally, compounds of formula (I) which have cjs isomeration between the groups attached to the atom attached to the group RgNCOR7 and the group attached to the atom adjacent on the right-hand side of the diafrom as shown herein may be prepared according to the procedures generally described on or analogous to those described in EP-A-0139992. Cis compound of formula (I) may also be prepared according to the procedures described by G. Burrell et al, Tet. Letters, 21, 3649-3652 (1996) or by the procedures described by U. Quast and E. Villhauer, Eur. J. Pharmacol, Molecular Pharmacology Section 245, 165-171 (1993). It should be appreciated that racemates for formula (I) may be resolved or enantiomerically purified compounds of formula (I) may be prepared using procedures conventional in the art and in particular using the procedures outlined in EP-0430631 and EP-0355584.

Where appropriate it should also be appreciated that it is preferred that the compounds of formula (I) may be prepared in the required enantiomeric form by forming a chirally pure epoxide using catalysts and conditions generally outlined in WO91M4694 or WO 93M7026 and thereafter converted to the required compound of formula (I) using procedures outlined herein.

Compounds of formula (I) may be prepared from readily available starting materials using the procedures outlined or analogous to those described in the above- mentioned patents.

Compounds of formula (I) in which R5 is hydroxy, Rg is C^*μ2 alkyl and R9 is hydrogen may be prepared according to the procedures outlined in R. Gericke etal. J. Med. Chem. Vol.34, p3074(1991). The invention also provides a pharmaceutical composition comprising novel compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides the use of novel compounds of formula (I), or a pharmaceutically acceptable salt thereof as a therapeutic agent, in particular in the treatment and/or prophylaxis of anxiety, mania, depression, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy; cerebral ischaemia disorders resulting from subarachnoid haemorrhage, Parkinson's disease, migraine and/or psychosis. The following compounds were prepared by methods analgous to those described in the abovementioned patents publications.

The following examples and pharmacological test results illustrate the present invention:

Example 1

Trans-7-(4-fluoroben__amido)-5,6-Dihydro-6-hydroxy-5,5-dimethyI-7-H- thieno[3,2-b]pyran

To a stirred solution of 7-amino-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H- thieno[3,2-b]pyran (1 g, 5 mmol, described in European patent application 360 621) in dichloromethane (10 mL), was added 4-fluorobenzoyl chloride (0.8 g, 5 mmol) in dichloromethane (1 mL) dropwise, followed by diisopropylethylamine (0.65 g, 5 mmol) in dichloromethane (1 mL). The resulting mixture was allowed to stir at room temperature for 2 hours and evaporated to dryness. The residue was purified by silica gel chromatography eluted with ethyl acetate/hexane (1:4) to furnish the product as a colourless solid (1.68 g). This was further purified by recrystallisation from ethyl acetate-hexane, mp. 166-167 °C [lit. - EPA 360 621 - 162-164 oq. ms.(C.I.) M++l=322 nmr (270 MHz) (dmso-α^) d ppm 7.20 (m, 2H), 7.15 (m, 4H), 6.63 (d, 1H), 6.46 (d, 1H), 5.13 (t, 1H), 4.73 (s, 1H), 3.77 (d, 1H), 1.50 (s, 3H), 1.35 (s, 3H)

Example 2

Trans-7-(4-fluorobenzamido)-5,6-dihydro-6-hydroxy-2-nitro-5^-dimethyI-7H- thieno[3,2-b]pyran To a stirred solution of the thienopyran of example 1 (1 g, 3 mmol) in glacial acetic acid (10 mL) at 0 °C, was added cone, nitric acid (2 mL) dropwise. The resulting mixture was stirred with cooling for a further 30 minutes. It was then poured into cold water/ethyl acetate. The aqueous phase was washed with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution and then brine, and dried over anhydrous sodium sulphate. The solvent was evaporated to dryness and the residue was chromatographed on a silica gel column eluted with ethyl acetate in hexane (20% to 30%). The product was obtained as a yellow solid (0.79 g, 72%) and was recrystallised from ethyl acetate-hexane, mp. 189 °C (decomp.) [lit. - EPA 360 621 - 198-202 °C] . ms. (C.I.) M++l=367 nmr (270 MHz) (dmso-α^) d ppm 9.10 (d, 1H), 8.00 (m, 2H), 7.74 (s, 1H), 7.35 (t, 2H), 5.98 (d, 1H), 4.95 (t, 1H), 3.90 (m, 1H), 1.44 (s, 3H), 11.23 (s, 3H).

Example 3 _Tr Λ_^;-3-cyano-5-(4-fluorobenzomido)-6,7,8-.9-tetrahydro-5H-benocycloheptan-6- ol. a) 5-(4-Bromophenyl)-5-oxo-pentanoic acid

Bromobenzene (90 ml) and γ-carbomethoxybutyroyl chloride (28g) were mixed together under N2 and AICI3 (47 g) was added in small portions maintaining the temperature between 5- 10°C.

The reaction mixture was allowed to reach room temperature and then heated at 100°C for 2 hours, then poured into a mixture of ice and 37% HC1 (55ml) and extracted with EtOAc three times. The combined organic phases were washed with water, brine, dried and concentrated to give a crude product as an oil (42g).

This crude compound was saponified with 10% NaOH solution (140ml) in EtOH (140ml) by refluxing for half an hour. The EtOH was removed under vacuum and the aqueous solution was washed with Et2θ, acidified with 37% HC1 and extracted with EtOAc. After drying and evaporating under vacuum the solid residue obtained was triturated with E_2θ and filtered giving 26.4g of the title compound as a solid. m.p. = 123-124°C Yield = 57.4%

b) 4-BromophenyIpentanoic acid

KOH (19.8g) was dissolved in ethylene glycol (132ml) and then 5-(4- bromophenyl)-5-oxo-pentanoic acid (26.4g) and hydrazine hydrate (2ml) were introduced. The solution was kept at 100°C for 2 hours. Hydrazine hydrate was distilled off by raising the temperature of 190°C. This temperature was maintained for 5 hours. The solution was poured into ice, acidified with 37% HC1 and extracted twice with E_2θ. The organic layer was dried and evaporated at reduced pressure to give 23g. of the title compound as a solid. m.p. = 85°C. Yield = 89.8%

c) 8-Bromo-benzocycloheptan-l-one

Polyphosphoric acid (80ml) wa warmed at 100 °C and then 4- bromophenylpentanoic acid (14.6g) was introduced in small portions. The reaction was kept at this temperature for 2 hours. Then it was poured into ice and extracted with E_2θ. The combined organic phases were washed with 10% NaOH and with water. After drying and evaporating, a crude compound (1 lg) was obtained that was chromatographed on silica gel eluting with Et2θ/hexane 10:90 to give 3.5g of the title compound as a light yellow oil. Yield = 25.7%

d) 8-Cyano-l,2-benzocycIoheptene

8-Bromo-benzocycloheptan-l-one (3.5g) dissolved in EtOH (30ml) and CH2CI2 (5ml) was treated with NaBH4 (0.5g) in small portions. The mixture was stirred two hours at room temperature. Evaporation and partition of the residue between EtOAc and water and drying and evaporation of the organic layer gave 3.5g of the desired alchol. It was dissolved in toluene (40ml) and p-toluensulfonic acid (0-15g) and refluxed for two hours using a Dean-Stark H2O separator. The solution was cooled, evaporated and partitioned between E_2θ and water. The organic layer was washed with NaHCO3 solution, water, brine and dried. Evaporation gave 3.5g of 8-bromo- 1 ,2-benzocycloheptene as an oil.

A solution of this crude compound and CuCN (1.8g) in DMF (25ml) was refluxed for four hours. The reaction was cooled and poured into 10% aqueous ethylenediamine and extracted with EtOAc. The organic layer was washed twice with brine, dried and evaporated under vacuum. The crude compound (2.5g) was chromatographed on silica gel using 10:90 EtOAc-hexane as eluent, to give 1.5g of the title compound as a solid. Yield = 60%

e) trans- 1 - Amino-2- hydroxy-8-cyano- benzocyclohepten e NBS (1.5g) was added to a vigorously stirred solution of cyano-1,2- benzocycloheptene (2.5g) in DMSO (14ml)/H2θ (1.4ml) maintaining the temperature below 10°C. The mixture was stirred at room temperature for one hour, diluted with water and extracted with EtOAc. The organic layer was washed with water, brine and dired. Evaporation under vacuum gave the bromohydrin as an oil. The mixture of the bromohydrin was stirred at room temperature with 7%

NaOH (6ml) Dioxane (10ml) for three hours. After partition with EtOAc and water, the organic layer was washed with brine, dried and evaporated under vacuum giving 1.5g of the epoxide as an oil.

This epoxide was dissolved in EtOH (20ml) and NH4OH (16ml) and kept for five hours at 60°C in a sealed tube. After evaporating the solvent, the residue was dissolved in 10% HC1, washed with E_2θ, made basic with Na2CO3 and extracted with EtOAc. The organic extract was washed with brine and dried. Evaporation of the solven under vacuum gave 0.6g of the title compound as a white sold. m.p. = 160°C. Yield = 20%

f) _^rran_^;-3-cyano-5-(4-fluorobenzamino)-6,7,8,9-tetrahydro-5H- benzocycloheptan-6-oI.

A solution of the aminoalcohol (0.25g) in CH2CI2 (10ml) and Et3N (0.45ml) was cooled to 0°C and a solution p-fluorobenzoyl chloride (0.2ml) in CH2CI2 (1ml) was added dropwise. After one hour at room temperature water was added. After stirring for half an hour the solid was filtered under vacuum obtaining 0.2g of the desired compound m.p. = 230°C Anal. (Ci₉H₁₇FNO2)C,H,F,N. Yield = 50%

Example 4 rrfl/i5-5-(4-fluorobenzamino)-4-hydroxy-7-nitro-2,3,4^-tetrahydro-l- benzoxepine.

This compound was prepared as described in Example 2 of PCT\GB89\00588.

Example 5 rrα/i5-7-cyano-5-(4-fluorobenzamino)-4-hydroxy-2,2-dimethyl-2 _>4,5- tetrahydro-1-benzoxepine.

This compound was prepared from the corresponding epoxide which was prepared as described by Buckle et al, J. Chem. Soc. Perkin I (1991) 2763-2771, and thereafter forming the 5-amino, 4-alcohol and coupling with 4-fluorobenzoyl chloride using conventional procedures. p 199-201°C.

PHARMACOLOGICAL DATA

1. Rat Social Interaction Test The compounds of formula (I) or pharmaceutically acceptable salts thereof are tested for therapeutic utility using the procedure outlined as follows:

Potential anxiolytic properties are evaluated using the rat social interaction procedure based on that originally described by File (1980, J. Neurosci. Methods, 2, 219 - 238). In this model anxiolytic agents selectively increase social interaction independently of any effect on locomotor activity.

Method

Male Sprague - Dawley rats (Charles River, U.K., 250 - 300g) are singly housed for 3 days prior to testing. On the test day, the animals are then randomly assigned to groups of 8 - 16 and dosed orally at a dose volume of 1 ml/kg with various doses of compound (1 - 300 mg/kg) or vehicle. At 60 min post dose the rats are placed with a weight - and treatment - matched pair male (encountered for the first time) in the social interaction box under high - light, unfamiliar conditions. The box is made of white perspex 54 x 37 x 26 cm with a transparent perspex front side. The floor is divided into 24 equal squares and is brightly lit (115 lux). Time spent (sees) in active social interaction (sniffing, grooming, following, mounting, climbing over or under, boxing, biting) is scored "blind" by remote monitoring as is the number of squares crossed (as an index of locomotion). The mean and standard error for time spent in social interaction and number of squares crossed are then calculated for each particular treatment group and drug - induced changes are expressed as a percentage increase or decrease from control values. Statistical comparisons are made between vehicle - and drug - treated groups using Dunnett's multiple comparisons procedure following significant one way analysis of varience.

Drugs are suspended in 1% methyl cellulose. 2. MES TEST

The maximal electroshock seizure (MES) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties¹. In this model, anticonvulsant agents elevate the threshold to electrically - induced seizures whilst proconvulsants lower the seizure threshold.

Method

Mice (male, Charles River, U.K. CD - 1 strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml kg with various doses of compound (0.3 - 300 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC50) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948)². Stastical comparisons between vehicle - and drug - treated groups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested. The percentage increase or decrease in CC50 for each group compared to the control is calculated. Studies are carried out using a Hugo Sachs Electronik Constant Current Shock

Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used.

Drugs are suspended in 1% methyl cellulose.

References

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145 - 181

2. Dixon, WJ. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43, 109 - 126

3. Litchfield, J.T. and Wilcoxon, F.(1949). J. Pharmacol, exp. Ther., 96, 99 113 Results

The compound of example 2 enhanced the threshold of shock by 95% at 30 mg kg p.o.

3. X-Maze

The compounds of formula (I) or pharmaceutically acceptable salts thereof are tested for therapeutic utility using the procedures outlined as follows:

Introduction

The X-maze test of anxiety (Handley and Mithani, 1984) examines the exploratory response of naive rats in an environment which offers both anxiogenic (open arms) and relatively non-anxiogenic (closed arms) areas. A selective increase in exploration of the open arms following drug pretreatment is therefore postulated to indicate anxiolytic effects.

Method

The X-maze was raised 70cm above the floor and consisted of two enclosed arms 45cm (long) x 15cm (wide) x 10cm (high) and two open arms 45 x 10 x 1cm arranged such that the two arms of each type were opposite each other. Both arm types were marked into two equal sections. Rats were placed onto the centre of the X-maze and observed for a period of 10 minutes during which time the following parameters were recorded: 1) the number of entries onto, and the time spent on, (a) open arms, (b) closed arms, (c) end of open arms and (d) end of closed arms. 2) the number of sections crossed. The fear-drive evoked in the open arms exceeds that in the enclosed arms and rats typically show a clear preference for the enclosed arms. Anxiolytic drugs increase the number of entries made onto, and the time spent on, the outer half of the open arms, and also the percentage of entries made onto, and the time spent on, the whole of the open arms. These four measures of anxiety, and also the total number of sections traversed, were calculated for each animal. Drugs are administered intraperitoneally or orally to groups of 6 to 12 rats 30 to 60 mins before testing. Statistical comparisons between vehicle- and drug-treated groups were made using a Mann- Whitney 'U' test (two tailed).

S.L. Handley and S. Mithani, Arch. Pharmacol, 1984327 1-5 4. Mongrel Dog Delayed Cerebral Vasospasm

The compounds of formula (I) or pharmaceutically acceptable salts thereof are tested for therapeutic utility using the procedures outlined as follows:

Twenty-five male mongrel dogs, weighing 9-12 kg, are used in these studies. The animals are housed and cared for in accordance with the Guide for the Care and Use of Laboratory Animals [DHEW (DHHS) publication No. (NIH) 85-23, revised 1985]. All procedures using laboratory animals are approved by the Institutional Animal Care and Use Committee of SmithKline Beecham Pharmaceutical. Each animal is anaesthetized with pentobarbital (35 mg/kg, iv) and placed on a heated operating table in the supine position. All animals are then tracheotomized, paralyzed (tubocurarine; 0.1 mg/kg, i.v.) and artificially ventilated with room air. End-tidal CO2 (et CO2) is monitored continuously and arterial blood gas analysis was performed periodically to assure stable and adequate ventilation throughout each experiment. Polyethylene cannulae are placed in the left external jugular vein and the right femoral artery and vein for drug administration, monitoring arterial blood pressure, and blood sampling, respectively. Transfemoral catheterization of the left vertebral artery is then performed via the left femoral artery using a 5 french Lehman dacron catheter ( Bard, Tewksbury MA). Anaesthesia is supplemented as needed with pentobarbital (5 mg/kg, i.v.) prior to the experimental period.

The effects of the compounds of this invention on acute cerebral vasospasm are evaluated in 15 dogs. In all animals a control digital subtraction angiogram of the anterior spinal artery and basilar artery is obtained following the intravertebral injection of radiocontrast material (Omnipaque 300). In each dog, 4 mis of cerebrospinal fluid is then removed from the dorsal cistern via needle puncture of the atlantooccipital membrane and 4 mis of autologous venous blood was injected. An angiogram is then repeated in each dog 30 minutes following the intracisternal administration of blood and an acute vasospasm of the basilar and anterior spinal arteries is identified and quantitated. The infusion of vehicle (10% polyethylene glycol 200) for 30 minutes has no effect on the acute vasospasm. The effect of a 30 minute infusion of test compounds on the reversal of acute vasospasm is observed in the basilar and anterior spinal arteries.

The effects of the compounds of this invention are also examined in the chronic canine model of delayed cerebral vasospasm (two haemorrhage model of cerebral vasospasm). In this model, a control vertebral angiogram is obtained and autologous blood is administered intracisternally on day 1 (as above). On day 3 the intracisternal administration of blood is repeated and the severe delayed vasospasm is quantitated angiographically on day 7 in all animals. The infusion of vehicle (10% polyethylene glycol 200) for 60 minutes has no effect on the delayed vasospasm observed in the basilar and anterior spinal arteries (n=5). The effect of an infusion of test compounds on the reversal of significantly delayed cerebral vasospasm is observed.

5. The compounds of formula (I) or pharmaceutically acceptable salts thereof are tested for therapeutic utility using the procedures outlined as follows:

1) Anti-Parkinsonian Activity 6- Hydroxydopa ine-lesioned rat model

The above test as described by Ungerstedt, U, 1971, Acta Physiol. Scand 367, 49 - 68, and/or

Ungerstedt, U, 1971, Acta Physiol Scand. 367. 69-93, may be used to determine the anti-Parkinsonian activity of compounds of formula(I) or pharmaceutically acceptable salts thereof.

2) Anti-Psychotic Activity Amphetamine-induced rat hyperlocomotion model

The above test as described by Kokkindis L, and Anisman, M, 1980, Psychological Bulletin, 88, 551-579, may be used to determine the anti-psychotic activity of compounds of formula (I) or pharmaceutically acceptable salts thereof.

3) Anti-Migraine Activity

Cortical Spreading Depression and Migraine

The above test as described by Wahl et al, 1987, Brain Research, 411,

72-80 may be used to determine the anti-migraine activity of compounds of formula (I) or pharmaceutically acceptable salts thereof.

4) Cerebral ischaemia a) Mongolian Gerbil Test

The in vivo experiments are carried out on adult Mongolian gerbils (Tumblebrook Farm (MA), weighing 60-80 g. Transient forebrain ischemia is produced by bilateral carotid artery ligation under 2.5% isoflourane in 100% O2 anesthesia, the animals being placed onto a heating pad to maintain body temperature at 37° C. The common carotid arteries are exposed and aneurism clips are placed on both arteries for a certain period of time indicated in the figure legends. 5 PBN dissolved in saline was administered intraperitoneally as a bolus

30 min before occlusion (pretreatments) or immediately after and again at 6 h of reperfusion, followed by the same dose b.i.d. for 2 days (post-treatment). For quantification of CAl neurons, animals are sacrificed at 7 days postischemia and perfused with buffered formalin. 10 Brains were removed, stored in formalin for 3 days, embedded in paraffin, cut at 7-μm-thick coronal sections (1.5-1.9 mm posterior to bregma^) and stained with thionin. The number of intact neurons over a 750-μm length of the CAl layer on both hippocampal sides of 3 sections is counted for each animal.

15 b) MCAO Method

Three strains of mature male rats (SHR) are obtained from commercial vendors (Taconic Farms, Germantown, NY; Charles River, Danvers,

20 MA; and Charles River, respectively) at 18 wk of age (250-300 g in weight) and are housed for 2 to 4 weeks prior to utilization in these studies. In order to verify that the strains of animals studied are indeed hypertensive and normotensive, groups of animals from each strain are anesthetized with 2% isoflourane (Anaquest, Madison, Wl) and

25 chronically prepared under aseptic conditions for recording of blood pressure. The femoral artery is cannulated with polyethylene tubing (PE60; Clay Adams. Parsippany, NJ) extending just into the descending aorta. The tubing is lead subdermally from the artery and exteriorized between the scapula just below the back of the neck and

30 cleared/filled with sterile isotonic saline. Incisions are closed using 2-

0 silk suture and treated with 5% lidocaine ointment (Astra Pharmaceuticals, Westborough, M.A.) Animals recover from surgery/anesthesia within 5 min. Mean arterial blook pressures are recorded 4 to 5 h after surgery for 5 min/rat by connecting the

35 exteriorized tubing in each rat to a Statham pressure transducer

(P2.3Db; Statham Medical Instruments. Los Angeles, CA) with output to a polygraph (Model R711 : Beckman Instruments, Inc., Fullerton.CA). Focal Stroke Procedure

MCAOO or sham surgery is carried out in the SHR, SD rats under sodium pentobarbital (65 mg/kg, i.p. and supplemented as needed) anesthesia. All animals are allowed free access to food and water prior 5 to and after surgery. Body temperature is maintained at 37°C using a heating pad throughout the surgical procedure. Surgery is conducted similar to that described previously (2.4). The right dorsal surface to the head and shaved and propped with providone-iodine, and the rat placed in a stereotaxic device (David Kopf Instruments, Tujunga, CA)

10 with the surgery (right) side of the head superior. A 1-2 cm incision was made between the orbit and the external auditory canal. The temporal muscle is dissected from the skull and retracted without damaging the zygomatic bond or maηdibular nerve. Under an operating microscope and with saline irrigation, a 2-3 mm craniotomy

15 is made just rostral to the zygomatic-squamosal skull suture. The dura is opened over the artery using the modified tip of a 30-gauge needle. For permanent right MCAO, using electrocoagulation (Force 2 Electrosurgical Generator, Valley Lab Inc., Boulder, CO), the artery was stimultaneously occluded and cut dorsal to the lateral olfactory

20 tract at the level of the inferior cerebral vain. A small piece of sterile saline-soaked Gelfoam (Upjohn, Kalamazoo, Ml) is then positioned over the craniotomy and the temporails muscle and skin are closed in two layers. Animals are allowed to recover from anesthesia under a heating lamp and then are returned to their cages. The animals are

25 sacrificed 24 hours following MCAO and the brains are prepared from reactive histologic examination.

Measurements of Ischemic Damage

30 Following the neurologic evaluation (24 hours after surgery) rats are euthanized with an overdose of sodium pentobarbital. Within 2-3 min, brains are removed and six coronal forebrain slices (2 mm thick) are made from the level of the olfactory bulbs to the cortical-cerebellar junction using a rat brain slicer [(59); Zivic-Miller Laboratories Inc.,

35 Allison Park, PA]. These forebrain slices then are immersed immediately in a 1% solution of triphenyltetrazolium chloride (TTC) in phosphate buffer at 37°C for 20-30 min (6.78). Strained tissues then are fixed by filtration in 10% phosphate buffered formalin. The two sides of each TTC-strained section are photographed in colour using a polaroid camera. These photographs are analyzed for the quantification of ischemic damage using an image analysis system (Amersham RAS 3000; Loats Associates, Inc.). Morphological changes following surgery are evaluated in the entire forebrain (total 5 of 11 planar surfaces) for each animal. The 11 planar images are planar surfaces) for each animal. The 11 planar images were obtained from each side of the six 2 mm thick sections and correspond approximately to 1 mm section surfaces from + 5mm to -5 mm from bregma (97) and include the complete forebrain. These planar image

10 surfaces (from the photographs) are digitized and used in the Image

Analysis System for planimetry determination of infarct size and swelling. Two parameters of ischemic damage due to MCAO are determined for each slice as described previously (2,4,98,122). "Hemispheric swelling" is expressed as the percent increase in size of

15 the ipsilateral (i.e., surgery side) hemisphere over the contralateral

(normal) hemisphere and is calculated as:

Ipsilateral Contralateral Hemisphere - Hemisphere Area Area

Percent

Hemispheric = x 100

Contralateral

Swelling

Hemisphere Area

20 "Infarct size" which was expressed as the percent infarcted tissue in reference to the contralateral (normal) hemisphere and is calculated as:

Percent ^{ln,arct area}

Hemispheric = x 100

Infarct Size Contralateral

Hemisphere Area

25

The swelling and infarct size are expressed in reference to the contralateral hemisphere (i.e., ipsilateral ischemic damage is normalized to the normal contralateral hemisphere). These parameters are determined for each slice to evaluate the profile of damage 30 throughout the forebrain (i.e., "fore-brain profile") and for "total" forebrain changes by using the sum of all individual slice data in these formulas.

The occurrence of brain edema asociated with hemispheric swelling following MCAO was determined by comparison of wet/dry weight as 5 described previously (45,118). Rats were sacrificed by an overdose of sodium pentobarbital 24 hours after sham or MCAO surgery. The brains are quickly removed, the forebrain isolated at the cerebellar cortical junction and cut into two hemispheres, and each forebrain hemisphere measured on a Mettler Types H5 chemical balance 10 (Metder Instruments Corp, Hightstown, NJ) within 2 min after decapitation. The dry weight was measured on the same scale after drying the hemisphere in an over at 80°C for 48-72 hours. The water content of each hemisphere was calculated as the difference between the wet and dry weight as a percent fraction from the wet weight:

15

Percent

Wet Weight - Dry Weight

Water Content = * 100

Wet Weight

Claims

Claims

1. A method of treatment and/or prophylaxis of anxiety, mania, depression, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable and/or preventable with anticonvulsive agents, such as epilepsy; and in the treatment or prevention of cerebral ischaemia, disorders resulting from sub-arrachnoid haemorrhage, Parkinson's Disease, migraine and/or psychosis, comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I) or

pharmaceutically acceptable salt thereof:

R₈NCO-R₇

|

P

wherein: P is a ring system selected from the following:

and the other variables are as defined below: b)

in which either a and b together represent a bond or CH₂ or a and b together represent a carbonyl group, a group C=NOR^F, CHOR^F or

O

II

CO-C-R^F

where R^F is hydrogen or C_1-6 alkyl; or c)

in which either J is nitrogen and J^a is a lone pair of electrons, M is carbon and

M^a is R₅; or

J is carbon and M is nitrogen and J^a and M^a are hydrogen; or d)

in which Z is oxygen or CH₂; and; where:

either one of R₁ and R₂ is hydrogen and the other is selected from the class of hydrogen, C_3-8 cycloalkyl, C_1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C_1-6 alkoxy or substituted aminocarbonyl, C_1-6 alkylcarbonyl, C_1-6 alkoxycarbonyl, C_1-6 alkylcarbonyloxy, C_1-6 alkoxy, nitro, cyano, halo,

trifluoromethyl, CF₃S, or a group CF₃-A-, where A is -CF₂-, -CO-, -CH₂-, CH(OH), SO₂, SO, CH₂-O, or CONH, or a group CF₂H-A'- where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; trifluoromethoxy, C_1-6 alkylsulphinyl, perfluoro C2-6

alkylsulphonyl, C_1-6 alkylsulphonyl, C_1-6 alkoxysulphinyl, C_1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl,

heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C_1-6 alkylcarbonylamino, C_1-6 alkoxycarbonylamino, C_1-6 alkyl-thiocarbonyl, C_1-6 alkoxy-thiocarbonyl, C_1-6 alkyl-thiocarbonyloxy, 1-mercapto C_2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C_{1 -6} alkyl groups, or C_1-6 alkylsulphinylamino, C_1-6 alkylsulphonylamino,C_1-6 alkoxysulphinylamino or C_1-6

alkoxysulphonylamino, or ethylenyl terminally substituted by C_1-6 alkylcarbonyl, nitro or cyano, or -C(C_1-6 alkyl)NOH or -C(C_1-6 alkyl)NNH₂, or one of R₁ and R₂ is nitro, cyano or C_1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C_1-6 alkyl or by C_2-7 alkanoyl; or where possible R₁ and R₂ together are -(CH ₂)₄- or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring;

one of R₃ and R₄ is hydrogen or C_{1 -4} alkyl and the other is C_{1 -4} alkyl, CF₃ or CH₂ X^a where X^a is fluoro, chloro, bromo, iodo, C_{1 -4} alkoxy, hydroxy, C_1-4

alkylcarbonyloxy, -S-C_{1 -4} alkyl, nitro, amino optionally substituted by one or two C_{1 -4} alkyl groups; cyano or C_{1 -4} alkoxycarbonyl or R₃ and R₄ together are C_2-5 polymethylene optionally substituted by C_{1 -4} alkyl;

R₅ is C_1-6 alkylcarbonyloxy, benzoyloxy, ONO₂, benzyloxy, phenyloxy or C_1-6 alkoxy and R₆ and R₉ are hydrogen or R₅ is hydroxy and R₆ is hydrogen or C_1-2 alkyl and R₉ is hydrogen;

R₇ is heteroaryl or phenyl; both of which are optionally substituted one or more times independendy with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C_{1 -4} alkyl, cyano, azido, C_{1 -4} alkyl, C_1-4 alkoxy, trifluoromethoxy and trifluoromethyl;

R₈ is hydrogen; C_1-6 alkyl, OR₉ or NHCOR₁₀ wherein R₉ is hydrogen, C_1-6 alkyl, formyl, C_1-6 alkanoyl, aroyl or aryl-C_1-6 alkyl and R₁₀ is hydrogen, C_1-6 alkyl, C_1-6 alkoxy, mono or di C-μg alkyl amino, amino, amino-C_1-6 alkyl, hydroxy- C_1-6 alkyl, halo-C_1-6 alkyl, C_1-6 acyloxy-C_1-6 alkyl, C_1-6 alkoxycarbonyl-C_1-6- alkyl, aryl or heteroaryl; and

the R₈-N-CO-R₇ group is cis or trans to the R₅ group.

2. A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage, neural shock, the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia, which comprises a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable carrier.

3. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression and/or disorders associated witii a subarachnoid haemorrhage, neural shock the effects associated with withdrawal from substances of abuse such as ***e, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia.

4. A method, a pharmaceutical composition or a use according to claims 1 to 3 respectively in which the compound of formula (I) has a ring P which is selected from a).

5. A method, a pharmaceutical composition or a use according to claim 4 in which the thiophene moiety is selected from i).

6. A method, a pharmaceutical composition or a use according to claims 4 or 5 in which R₁ and R₂ are either both hydrogen or R₁ is nitro and R₂ is hydrogen.

7. A method, a pharmaceutical composition or a use according to claims 4 to 6 in which R₃ and R₄ are both methyl.

8. A method, a pharmaceutical composition or a use according to claims 4 to 7 in which R₅ is hydroxy and R₆ and R₉ are hydrogen.

9. A method, a pharmaceutical composition or a use according to claims 4 to 8 in which R₈ is hydrogen.

10. A method, a pharmaceutical composition or a use according to claims 4 to 9 in which the R₈NCOR₇ group is trans to the R₅ group.

11. A method, a pharmaceutical composition or a use according to claims 1 to 3 respectively in which the compound of formula (I) has a ring P selected from d).

12. A method, a pharmaceutical composition or a use according to claim 11 in which R₁ is cyano or nitro.

13. A method, a pharmaceutical composition or a use according to claims 11 or 12 in which R₃ and R₄ are both methyl.

14. A method, a pharmaceutical composition or a use according to claims 11 to 13 in which R₅ is hydroxy and R₆ and R₉ are both hydrogen.

15. A method, a pharmaceutical composition or a use according to claims 11 to 14 in which R₈ is hydrogen.

16. A memod, a pharmaceutical composition or a use according to claims 11 to 15 in which the R₈NCOR₇ group is trans to the R₅ group.

17. A method, a pharmaceutical composition or a use according to claims 1 to 15 in which R₇ is fluorophenyl.

18. A method, a pharmaceutical composition or a use according to claim 17 in which R7 is 4-fluorophenyl.

19. A compound selected from Trans-3-cyano-5-(4-fluorobenzamido)-6,7,8,9- tetrahydro-5H-benzocycloheptan-6-ol and Tra ns-7-cyano-5-(4-fluorobenzamino)-4- hydroxy-2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepine.

20. The use of a compound of claim 19 as a therapeutic agent.

21. A pharmaceutical composition comprising a compound of claim 19 and a pharmaceutically acceptable carrier.