WO1996002494A1

WO1996002494A1 - Benzocycloalkylamine derivatives as calcium channel antagonists

Info

Publication number: WO1996002494A1
Application number: PCT/EP1995/002695
Authority: WO
Inventors: Barry Sidney Orlek; John David Harling
Original assignee: Smithkline Beecham Plc
Priority date: 1994-07-14
Filing date: 1995-07-10
Publication date: 1996-02-01
Also published as: AU2982595A

Abstract

Compounds of formula (I), wherein n is 1, 2 or 3; R?1 and R2¿ each independently represent hydrogen, C¿1-6?alkyl, C3-6cycloalkyl, or C3-6cycloalkylC1-4alkyl; p and q independently represent 0-4; X represents O, S, NH or, provided that the sum of p and q is at least 1, a bond; and Ar represents phenyl substituted by -Y-CR?3R4¿-Ph, where Y is oxygen or a bond, R?3 and R4¿ are indenpendently, H, methyl or ethyl, provided that R?3 and R4¿ are not both H, and Ph is optionally substituted phenyl; and salts thereof are calcium channel antagonists useful in the treatment of ischaemic conditions e.g. stroke.

Description

BENZOCYCLOALKYLAMINE DERIVATIVES AS CALCIUM CHANEL ANTAGONISTS.

The present invention relates to carbocylic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists, e.g. for the treatment of ischaemia, in particular ischaemic stroke.

Stroke is reportedly the third most common cause of death in the developed world. Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.

EPA 303961 describes compounds of the formula

wherein Ri is C1.3 alkylene, n and p are each inter alia zero, R2 and R3 represent inter alia hydrogen or lower alkyl, X is inter alia lower alkyl, lower alkoxy, CF3 or halogen and q is zero, 1 or 2. The compounds are said to be useful as anudepressants and as inhibitors of synapdc norepinephrine and serotonin uptake.

EPA 371508 describes similar compounds and corresponding thiols, which compounds are said to be useful for the treatment of drug-resistant malaria and other drug-resistant protozoal infections.

In our U.K. Patent Applications 9315566.1 and 9315600.8 filed 28 July 1993 (corresponding to PCT applications WO95/04028 and WO/04027) we describe many compounds as calcium channel antagonists. Included within the scope of these applications are compounds of formulae:

(A) (B)

wherein: X^a represents O, S, NH, and X^D represents O, S, NH or a bond, p and q independently represent 0-4 such that the sum of p+q is at least 1; Ar represents phenyl optionally substituted by inter alia Ph(CH2)_rY(CH2)_s- where Ph is optionally substituted phenyl, is oxygen or a bond and r and s each independently represent 0-4 provided that the sum of r+s is not greater than 4;

Rl and R^ each independently represent hydrogen, Cj.galkyl, C3_6cycloalkyl or Cι.4alkylC3.6Cycloalkyl; and n is 1,2 or 3.

We have now discovered novel compounds which have advantageous propertie According to the present invention therefore we provide a compound of formula (I):

Formula (I) wherein n is 1,2 or 3; Rl and R^ each independently represent hydrogen, Cι_6alkyl, C3_6cycloalkyl, or C3_6τycloalkylC \ _4alkyl; p and q independently represent 0-4;

X represents O, S, NH or, provided that the sum of p and q is at least 1, a bond; and AT represents phenyl substituted by -Y-CR^R^-Ph, where Y is oxygen or a bond, R^and R^ are independently, H, methyl or ethyl, provided that R^and R^ are not both H, and Ph is optionally substituted phenyl; or a salt thereof.

Compounds of the invention have improved stability to metabolic degradation, and a favourable duration of action. Preferably Rl is hydrogen, methyl or isopropyl, particularly preferably methyl.

Preferably R^ is hydrogen or methyl, particularly preferably hydrogen. NR1R2 is preferably amino, methylamino or isopropylamino. X is preferably O and p and q are 0, or X is a bond and the sum of p and q is 1. n is preferably 1. Preferably at least one of R^ and R^ is methyl. Particularly preferably R^ and R^ are both methyl; such compounds have good activity and have a minimal number of chiral centres.

Suitable substituents for the group Ph include halogen, especially fluorine, chlorine and bromine; Cj^alkoxy especially methoxy; Ci _4alkyl especially methyl; trifluoromethyl and trifluoromethoxy. Particularly preferred substituents for Ph include 3-chloro, 3-fluoro, 4-chloro, 4-fluoro and 3,4-dichloro. Preferably the substituent is at the 4- position of the phenyl group. Ph may advantageously be unsubstituted.

Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus, a Cj.galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as isopropyl or t-butyl. Preferred meanings of C3_6cycloalkyl are cyclopropyl and cyclohexyl, and preferred meanings of C3_6cycloalkylCι .4alkyl are cyclopropylmethyl and cyclohexylmethyl.

It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non-pharmaceutically acceptable salts may be used for example in the isolation of final products and are included within the scope of this invention. Also included within the scope of this invention are solvates and hydrates of formula (I).

It will be appreciated that the compounds of formula (I) contain two or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. In particular it will be appreciated that the substituents on the carbocyclic (e.g. indane) nucleus may both lie on the same side with respect to the plane of the ring (cw-configuration) or on opposite sides (trαru-configuration). Both forms and all mixtures thereof are included within the scope of this invention. Preferably the compounds of formula (I) are of the cw-configuration.

In accordance with convention the (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds. The prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1). Particular compounds of the formula (I) include : (±)cw- 1 -[4-(l -methyl- 1 -phenylethyl)phenoxy]-2-memylaminoindane (±)cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-aminoindane (±)cis- 1 - [4- ( 1 -methyl- 1 -phenylethyl)benzyl]-2-arninoindane (+)«..- 1 -[4-( 1 -methyl- 1 -phenylemyl)benzyl]-2-methylaπιinoindane (±)cύ- 1 -[4-( 1 -methyl- 1 -(4-fluorophenyl)emyl)phenoxy]-2-aπύnoindane (±) s- 1 -[4-( 1 -methyl- 1 -(4-fluorophenyl)ethyl)phenoxy] -2-methylaminoindane (+) cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-memylarninoindane (- )cis- 1 - [4- ( 1 -methyl- 1 -pheny lethyl)phenoxy] -2-meΛylarninoindane (+) cis-l-[4-(l-methyl-l-phenylemyl)phenoxy]-2-dimethylaminoindane and salts thereof.

The compounds of the present invention can be prepared by processes analog to those known in the art. The present invention therefore provides in a further aspect, process for the preparation of compounds of formula (I) which comprises : (a) to prepare a compound of formula (I) wherein R^ is methyl, reduction of a compound of formula (II)

Formula (II)

wherein n, p, q, R , Ar and X are as hereinbefore defined and Alk is a Cι_4alkyl group;

(b) to prepare a compound of formula (I) wherein at least one of R^ and R^ is hydrogen, deprotection of a compound of formula (II);

(c) to prepare a compound of formula (I) wherein R 1 and R^ are both hydrogen and p is 1 to 4, reduction of a compound of formula (HI):

Formula (HI) wherein n, q, X and Ar are as hereinbefore defined and R^ is hydrogen, Cι_4alkyl or phenylCι_4alkyl (e.g. benzyl);

(d) to prepare a compound wherein X is O, S or NH, reaction of a compound of formula (IV)

Formula (IV)

wherein Rl, R^, p and n are as hereinbefore defined and X* is O, S or NH, with a compound of formula L(CH2)qAr wherein L is a leaving group and q and Ar are as hereinbefore defined;

(e) to prepare a compound wherein X is O, S or NH, reaction of a compound formula (V):

Formula (V)

wherein Rl, R^, p and n are as hereinbefore defined and L is a group displaceable by a nucleophile, with a compound HX(CH2) Ar wherein X, q and Ar are as hereinbefore defined;

(f) conversion of a benzoyl group in a compound of formula (VI)

Formula (VI) wherein n, R*, R^, X, p and q are as defined for formula (I) and Ar* is phenyl substituted by optionally substituted benzoyl, to a group -CR^R^.ph

(g) interconversion of a compound of formula (I) to a different compound of formula (D, e.g. (i) where one of R^ and R² is hydrogen and the other is alkyl, conversion to compound of formula (I) wherein R* and R² are both alkyl, or

(ii) where R¹ and R² are both hydrogen, conversion to a compound of formul (I) where at least one of R¹ and R² represent alkyl; and optionally after any of the above processes: separation of enantiomers and/or forming a salt of formula (I).

Reduction according to process (a) may be effected using a suitable reducing agent such as lithium aluminium hydride, preferably in an inert solvent such as tetrahydrofuran or diethyl ether. When Alk in formula (II) represents tert- butoxycarbonyl the process is preferably carried out in tetrahydrofuran at reflux.

Deprotection according to process (b) may be carried out by conventional methods. Thus for example an ethoxycarbonyl group may be removed by hydrolysis under basic conditions. A t -butoxycarbonyl group may be cleaved using trifluoroacetic acid, in a solvent such as dichloromethane.

Reduction of a compound of formula (HI) according to process (c) may be effected using a reducing agent such as lithium aluminium hydride or NaBH3(OCOC in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. Alternatively the process may be carried out using lithium or sodium borohydride in combination w tnmethylsilyl chloride, in tetrahydrofuran. In general this process gives predominantl the άs-form of the product. Preferably in process (c) R^ is Cj^alkyl.

In process (d) the reaction between a compound of formula (IV) and L(CH2)qAr may be effected under conditions which depend on the nature of L and th value of q. For example when q is zero, L is preferably fluoro and the reaction is preferably effected in the presence of a strong base such as sodium hydride, and in a polar organic solvent such as dimethylsulphoxide or dimethylformamide. (This varian of process (d) may advantageously be carried out between a compound of formula (IV and a compound L(CH2) Ar^ where Ar* is phenyl substituted by optionally substitute benzoyl, to give a compound of formula (VI) which may subsequently be transformed into a compound of formula (I) according to the method of process (f).) When q is oth than zero, L may be for example halo or preferably a sulphonic acid residue such as a tosylate or mesylate and the reaction may be carried out using standard conditions, in a solvent and optionally in the presence of a base, which solvent and base may, if desire be selected from those described above. If necessary during process (d) the nitrogen atom may be protected by methods well known in the art, e.g. a carbamate which may be removed for example as described in process (b).

The reaction between a compound of formula (V) and HX(CH2)qAr in process (e) can take place under conditions which depend on the nature of L^ and X. For example when L* is hydroxy, X is oxygen or sulphur and q is 0 the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine. Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1; and J. Org. Chem. 1991, 56, 670-672). Alternatively the leaving group L¹ may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy in which case the reaction may be effected using standard conditions, in the presence or absence of solvent, optionally in the presence of a base. It will be appreciated by the skilled worker that it may be necessary to use a suitable N-protecting group to control the stereochemical outcome of this process.

For process (f) the conversion of the benzoyl group to a group -CR^R^-Ph wherein R^ and R^ are both methyl can be effected by reaction with (CH3)2TiCl2, for example in dichloromethane at -40°C (as generally described by Reetz et al. J.Org.Chem. 48254 (1983)) and analogues can be prepared by variations of this method.

Interconversion s according to process (g) may be effected by alkylation of a compound (I) wherein one of R* and R² is hydrogen and the other is alkyl or where R* and R² are both hydrogen, using an appropriate alkylating agent such as an alkyl halide e.g. an alkyl bromide or iodide, in the presence of a base, such as potassium carbonate. The reaction may be carried out in a suitable solvent such as acetone. Alternatively said compound of formula (I) may first be acylated, using for example an alkylhaloformate such as ethyl chloroformate, preferably in the presence of a tertiary amine such as triethylamine, or a carbonate such as di-t -butyldicarbonate, in the presence of sodium hydroxide and a solvent such as dioxane, to provide a compound of formula (II) followed by reduction as described above. In a further method a compound of formula (I) may be subjected to reductive alkylation using an appropriate aldehyde (e.g. formaldehyde) or ketone, and a reducing agent such as sodium cyanoborohydride. It will be appreciated that when any of the processes described herein involve a reduction step it will generally be desirable to employ reducing agents and conditions which do not affect or disturb substituents which are intended to be retained in the final product. The choice of appropriate reducing agents and conditions will be readily apparent to the skilled practitioner.

- 1 - Processes (a), (b), (d), (f) and (g) generally proceed with retention of the cis o trans configuration of the starting material. Thus the stereochemistry of the final prod is usually determined by the configuration of formula (II) which in turn is governed by its method of preparation.

Compounds of formula (II) wherein R¹ is hydrogen, X is O, S or NH, p and q are both 0, may be prepared by reaction of a compound of formula (VII) :

Formula (VII) with a compound HXAr where Ar as defined above. In this reaction X is preferably oxygen. This process produces predominantly the cis-isomer.

A compound of formula HXAr may be prepared from a compound HXAr^ (wherein Ar* is phenyl substituted by optionally substituted benzoyl) or a derivative thereof e.g. the corresponding methyl ether, according to the method of process (f) described hereinabove, followed where necessary by cleavage of the ether using trimethylsilyl iodide.

A rrα/is-isomer of formula (II) wherein R is hydrogen and Alk is t -butyl may be prepared by reaction of a compound of formula (V1T) with a Grignard derivativ of formula L²Mg(CH2)pX(CH2)qAr, wherein L² is halo. In this reaction X is preferably a bond. The reaction is conveniently effected in the presence of copper (I) bromide dimethylsulphide complex and in a solvent such as toluene. The Grignard derivative may be prepared using standard procedures from a corresponding compound of formula L²(CH2)pX(CH2)qAr, optionally in situ. Compounds of formula L (CH2)_pX(CH2)qAr are commercially available or may be prepared using standard methods. Cw-isomers of formula (II) may be prepared by acylation of a corresponding compound of formula (I) as described in process (g) above.

Compounds of formula (II) (both cis and trans forms) wherein R* is alkyl may be prepared by alkylation of formula (II) wherein R^ is hydrogen for example using an alkyl halide in the presence of a base such as sodium hydride and in a suitable solvent e.g. dimethylformamide. Alternatively a compound (II) wherein R* is hydrogen may b reduced as described in process (a) above and subsequently acylated as described for process (g) above.

A compound of formula (VII) may be prepared by cyclisation of a compound of formula (Vϋl) :

Formula (VHI) using sodium hydride in a suitable solvent for example an ether such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5; or dimethyl formamide.

Compounds of formula (VIII) may be prepared by addition of N,N-dichloro- alkylcarbamate to an olefϊn of formula (IX):

Formula (IX)

Compounds of formula (IX) are commercially available or can be prepared according to known methods. A compound of formula (Ul) may be prepared by reaction of a compound of formula (X):

Formula (X) with a compound of formula L²(CH2)pX(CH2)qAr in the presence of lithium bis-(trimethylsilyl)amide in a solvent such as tetrahydrofuran. Compounds of formula

(X) may be prepared using methods known in the literature.

TrflrU-isomers of formula (IV) wherein X* is oxygen and p is zero may be prepared as described in the literature e.g. Chem. Pharm. Bull. 1977, 25, 1060.

Corresponding cw-isomers may be obtained by oxidation of the trα/ts-isomer using Jones reagent to give a ketone followed by reduction with lithium tri-O-isobutyl borohydride (L-Selectride®, Aldrich). Reduction of the ketone using sodium borohydride regener the trα/ιs-isomer.

Compounds of formula (IV) wherein X¹ is S or NH may be prepared from th corresponding sulphonyloxy compound e.g. a mesylate and an appropriate amino or th reagent using standard methods. The sulphonyloxy derivative may itself be prepared from the corresponding alcohol in conventional manner.

Cw-isomers of formula (IV) in which p is 0 and X* is oxygen can be prepare according to the following methods:

A compound of formula (XI) can be converted into a compound of formula (XII) for example by heating under reflux in chloroform, and the product can be alkylated e.g. by reaction with an alkyl halide and sodium hydride in a suitable dipolar aprotic solvent. The compound (XI) may be prepared by reaction of the corresponding indene of formula (IX) with N,N-dichloro-terr-butylcarbamate

The compounds of formula (XIII) can be reduced by lithium aluminium hydri to give compounds of formula (IV) in which R² is methyl. Compounds of formula (X or (XIII) can be treated with sodium hydroxide to give compounds of formula (IV) in which R² is hydrogen. Compounds of formula (IV) in which R* is methyl and R² is hydrogen can be prepared by reducing an oxazoline of formula (XV) e.g. with lithium aluminium hydride, which can be prepared from a compound of formula (XIV):

(XIV) (XV) Compounds of formula (XIV) may be prepared by addition of N,N-dichloro- ethylcarbamate to an olefin of formula (IX).

Some individual enantiomers of formula (IV) are known, e.g. the compound in which X* is oxygen, p is zero, n is 1 and R* and R² are both hydrogen (E.J.Corey et al., Tet. Lett. 34, 8399 (1993), G. DeSimoni et al. Gazz. Chim. Ital. 122, 269 (1992), and analogues can be made by appropriate modifications, or by asymmetric synthesis (e.g. see D.E. McClure et al., J.Org.Chem. 48, 2675 (1983)). The use of a resolved enantiomer of formula (IV) should give rise to a resolved enantiomer of formula (I). Compounds of formula (V) wherein L is OH and p is zero may be prepared as described for the compounds of formula (IV). When L is halogen or a sulphonyloxy group such compounds may be prepared from the corresponding alcohol in conventional manner.

Compounds of formula (VI) may be prepared using processes analagous to (a) to (g) described above, advantageously by reaction of a compound of formula (IV) with a compound L(CH2)qAr^ where Ar^ is phenyl substituted by optionally substituted benzoyl according to process (d).

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

Preferably the compounds of formula (I) are resolved by conversion to a mixture of diastereomeric amides, which are separated by conventional methods and then reconverted into resolved compounds of formula (I). Preferably the amides are formed with S(+)-α-methoxyphenylacetic acid, and the separated amides can be converted into the resolved amines by treatment with an excess of methyllithium, or by treatment with an excess of potassium t-butoxide in wet tetrahydrofuran as generally described in U.S. 5,149,714.

An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen and glucose. A cascade of biochemical reactions ensues, a consequence of which is to permit the influx of calcium ions into the brain cells (neurons) via so-called Voltage Operated Calcium Channels (VOCCs) causing cell death. It is believed that agents which inhibit such calcium influx will minimise cell death and hence increase the potential for recovery. Compounds of formula (I) have been found to exhibit high calcium influx blocking activity, for example in neurons. The compounds may thus be referred to as neuronal calcium antagonists. As such the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans. For example, the compounds are expected to be of use in the treatment of ischaemia, including for example stroke; anoxia, due to causes including cardiac arrest, and cardiac surgery; and traumatic head injury. They may also be of use in the treatment of migraine; pain; epilepsy; ATDS-related dementia; neuro- degenerative diseases, such as Alzheimer's disease and age-related memory disorders; mood disorders; and drug addiction withdrawal such as ethanol addiction withdrawal.

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

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal.

Compounds of the present invention will preferably be of use in the treatment of ischaemic stroke.

A preferred compound for use according to the invention is (+) cis-l-[4- (1 -methyl- 1 -phenylethyl)phenoxy]-2-methylaminoindane and salts thereof. For use in medicine, the compounds of formula (I) are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

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

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carriers), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as cyclodextrins.

Preferably the composition is in unit dose form such as a tablet, capsule or ampoule. Each dosage unit for oral administration contains preferably from 1 to 250 m (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compou of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The daily dosage regimen for an adult patient may be, for example, an oral do of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of t invention may be administered by continuous intravenous infusion, preferably at a dos of up to 400 mg per day. Thus, the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be i the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

If desired a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination or concurrently with one or more other therapeutic agents, for example a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator; an excitatory amino acid antagonist such as an NMD A antagonists; a free radical inhibitor; or a calpain inhibitor.

BIOLOGICAL DATA

Ca²⁺ Current Measurement Cell preparations

Superior cervical ganglion neurons were isolated and cultured following a meth modified from Marrion et al, Neurosci. Lett., 77, 55-60 (1987). Cells were plated on laminin coated plastic tissue culture dishes and incubated at 37°C until just prior recording. Electrophysiological recordings were performed from 2 to 9 days aft dissociation.

Solutions

The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 1 MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH. Cells were bathed in a norm Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca²⁺ currents. The external solution for recording Ca²⁺channel currents contained in mM: BaCl2, 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided. Compounds were dissolved in DMSO to make a 20mM stock solution. At the highest drug concentration used the vehicle (0.1%) had no significant effect on Ca²⁺ currents. All experiments were performed at 21 to 24°C. Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784).

Results Ca²⁺ currents Peak voltage gated Ca²⁺ channel currents of up to 10 nA were recorded using lOmM Ba²⁺ as charge carrier. Currents were evoked from a holding potential of -80mV to a test potential of 0 or +10mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca²⁺ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a rundown corrected control value.

Once a constant calcium current had been recorded for 4 successive pulses (1 minute) 10 μM Nimodipine, a dihydropyridine, was applied to the cell to block L type calcium current. After three minutes 5μM drug was coapplied with lOμM Nimodipine for three minutes. Such drug application tested the block of the remaining, predominantly N type, calcium current.

Compounds of Examples 1-6 gave percentage inhibition of plateau Ca²⁺ current in the range 85-98% at 5μM. In Vivo

Test compound:

(+) cis- 1 -[4-( 1 -Methyl- 1 -phenylethyl)phenoxy]-2-methylaminoindane hydrochloride Gerbil BCAO Model

Male Mongolian gerbils weighing between 60-80 g were anaesthetised with halothane, placed on a heated mat and the carotid arteries occluded for 6 min. After reperfusion, the animals were sutured and placed in an incubator for 2 hours to maintain body temperature during the acute recovery phase. The animals were then caged separately and on the 5th day after the day of surgery, they were assessed for locomotor activity using an automated locomotor activity monitoring system and were then euthanased and the brains removed for histological analysis. The dosing protocol in these experiments was lOmg.kg"¹ 30 minutes post-ischaemia then 3 mg.kg"¹ b.i.d. for 3 days. Injections were given via the i.p. route, the vehicle was distilled water.

The test compound produced a significant reversal of the histological damage in the CA1 region of the hippocampus compared with that seen in the ischaemic vehicle-treated animals, and produced a significant reversal of the ischaemia- induced hyperlocomotion.

Mouse MCAO Model

Male CD1 mice weighing 25-29g were anaesthetised with tribromoethanol, placed on a heat-pad and the mid-cerebral artery cauterised and divided via the intra-cranial route. On completion of surgery the mice were placed in an incubator for 2 hours to maintain body temperature during the acute recovery phase. On the 4th day the mice were euthanased and the brains removed for histological analysis. The dosing protocol in these experiments was lOmg.kg^*1 30 minutes post-ischaemia then lOmg.kg"¹ b.i.d. for 3 days. Injections were given via the i.p. route, and the vehicle was 10% HPCD (hydroxypropyl-β- cyclodextrin).

The test compound produced a significant reversal of the histological damage in the cerebral cortex as seen in the ischaemic vehicle-treated animals. Cardiovascular Screen

Male Lister Hooded rats were anaesthetised with sodium pentobarbitone (60 mg.kg"¹ i.p.). The effects on diastolic blood pressure and heart rate were measured over the drug infusion. Test compound (10 mg.kg^-1 dissolved in 10% HPCD) was infused over 30 minutes. Minor pressor effects, similar to those seen in vehicle treated animals, were observed, together with minor reductions in heart rate. These results indicate that the compound was without significant cardiovascular effects at the dose tested.

PHARMACEUTICAL FORMULATIONS

The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.

IV Infusion

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Solvent/complexing agent to 100 ml

Bolus Injection

Compound of formula (I) 1-40 mg

Buffer to pH ca 7

Co-Solvent to 5 ml

Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.

Solvent : Typically water but may also include cyclodextrins, e.g. hydroxypropyl-β- cyclodextrin (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol. Tablet

Compound 1 - 40 mg

Diluent/Filler * 50 - 250 mg

Binder 5 - 25 mg

Disentegrant * 5 - 50 mg

Lubricant 1 - 5 mg

Cyclodextrin 1 - 100 mg

* may also include cyclodextrins

Diluent : e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose

Disintegrant : e.g. Sodium starch glycoUate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.

Oral Suspension

Compound 1 - 40 mg

Suspending Agent 0.1 - 10 mg

Diluent 20 - 60 mg Preservative 0.01 - 1.0 mg

Buffer to pH ca 5 - 8

Co-solvent 0 - 40 mg

Flavour 0.01 - 1.0 mg

Colourant 0.001 - 0.1 mg

Suspending agent :e.g. Xanthan gum, microcrystalline cellulose

Diluent : e.g. sorbitol solution, typically water

Preservative : e.g. sodium benzoate

Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin The invention is further illustrated by the following non-limiting Preparations and Examples:

Preparation 1 (±)trαns-l-Chloro-2-tert-butoxycarbonylaminoindane

To a solution of indene (32.58g, 0.28 mol) in toluene (350 ml) under nitrogen was added dropwise a solution of N,N-dichloro-rert-butylcarbamate (60g, 0.323 mol) in toluene (200 ml). The solution was then stirred at 50°C for 5 h. Saturated aqueous sodium metabisulfite (500 ml) was then added with cooling from an external ice/water bath. The two phase mixture was then vigorously stirred at room temperature for 3 h. The phases were then separated and the aqueous phase extracted with diethyl ether (3 x 100 ml). The organic phases were then combined and washed successively with saturated aqueous sodium bicarbonate, water and brine. After drying over Na2SO4, solvents were removed in vacuo to afford the title compound as a white solid (71.60g).

*H N r (CDC1₃) δ : 1.47 (9H, s), 2.80 (1H, dd, J=7,15Hz), 3.52 (1H, dd, J=7,15Hz), 4.47 (1H, m), 4.78 (1H, m), 5.19 (1H, br. s), 7.27 (3H, m),7.42 (1H, m).

Preparation 2

(±)cw-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-t<?rt-butoxycarbonylamino- indane

To a suspension of NaH (80% disp. in oil, 2.016g, 67.2 mmol) in dry tetrahydrofuran (300 ml) was added (±) tr- s- l-chloro-2-tert- butoxycarbonylaminoindane (15g, 56 mmol) and 15-crown-5 (50μl). The mixture was then warmed at 50°C under nitrogen for 18 h after which it was poured into water (700ml) and extracted with diethyl ether (3x150ml). The combined organic extracts were dried (Na2SO4) and solvents were removed in vacuo to afford (+) N-t -butoxycarbonyl-l,2-iminoindane as a brown solid (12.67g). A solution of (+) N-tert-butoxycarbonyl-l,2-iminoindane (5g, 22 mmol), 4-cumylphenol ( 4.68g, 22 mmol) and pyridinium p-toluenesulfonate (113mg) in chloroform (150ml) was heated at reflux for 2.5h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (3.7 lg). *H Nmr (CDC1₃) δ : 1.40 (9H, s), 1.67 (6H, s), 3.04 (1H, dd, J=7,15Hz), 3.25 (1H, dd, J=7,15Hz), 4.66 (1H, m), 5.21 (1H, d, J=9Hz), 5.56 (1H, d, J=7Hz), 6.93 (2H, d, J=9Hz), 7.14-7.34 (HH, m).

Preparation 3

(i) N-Ethoxycarbonylamino-l,2-iminoindane

To a slurry of sodium hydride (0.9g of an 80% dispersion in oil, 30mmol) in dry tetrahydrofuran (60ml) was added a solution of (+) trans l-chloro-2- ethoxycarbonylaminoindane (B.J. Walker and P.J. Wrobel, J. Chem. Soc. Chem. Commun., 1980, 462) (6.0g, 25mmol) in tetrahydrofuran (50ml) and 15-crown-5 (56μl). The mixture was stirred under argon at 55°C for 18h, then cooled and quenched with water (5ml). The reaction was poured into ice cold water (150ml) and the aqueous phase extracted with diethyl ether (3x30ml). The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated in vacuo to afford the title compound as a brown oil which solidified on cooling. ^lU Nmr (CDCI3) δ: 0.90 (3H, t, J=7Hz), 3.07 (1H, dd, J=5,18Hz), 3.48 (1H, d, J=18Hz), 3.55 (1H, t, J=5Hz), 3.90 (3H, m), 7.20 (3H, m), 7.49 (1H, m).

Preparation 4

4>[l-(4-FIuorophenyl)-l-methylethyI]phenyl methyl ether.

To a solution of titanium tetrachloride (40ml of a 1M solution in dichloromethane, 40mmol) cooled to -40°C under argon was added dimethylzinc (20ml of a 2M solution in toluene, 40mmol), and the mixture was stirred for 10 minutes. A solution of 4-fluoro-4'-methoxybenzophenone (4.18g, 18.2mmol) in dichloromethane (20ml) was added whilst maintaining the temperature between - 30°C and -40°C. The mixture was then allowed to warm to room temperature and stirred for 72h. The reaction was poured into ice cold water (100ml) and the aqueous phase extracted with diethyl ether (3x30ml). The combined organic phases were washed with sodium hydrogen carbonate followed by brine, then dried over Na2SO After concentration in vacuo the residue was subjected to column chromatography on silica gel eluting with 5% diethyl ether in 40-60 petroleum ether to afford the title compound as an oil (3.34g). !H Nmr (CDCI3) δ: 1.64 (6H, s), 3.78 (3H, s), 6.80 (2H, d, J=9Hz), 6.92 (2H, t, J=9Hz), 7.10-7.22 (4H, m).

Preparation 5

4-[l-(4-Fluorophenyl)-l-rnethylethyl]phenol

To a solution of 4-[l-(4-fluorophenyl)-l-methylethyl]phenyl methyl ether (3.34g, 13.67mmol) in chloroform (40ml) was added trimethylsilyl iodide (4.10g, 20.51 mmol). The solution was stirred under argon at 40°C for 18h, then cooled and poured into ice cold water (50ml). The aqueous phase was extracted with chloroform (6x20ml), and the combined organic layers were washed with sodium metabisulfite then brine, and dried over Na2SO.j. After concentration in vacuo the residue was subjected to column chromatography on silica gel eluting with 10- 40% diethyl ether in 40-60 petroleum ether to afford the title compound as an oil (2.4g).

*H Nmr (CDCI3) δ:1.64 (6H, s), 4.81 (1H, s), 6.74 (2H, d, J=9Hz), 6.93 (2H, t, J=9Hz), 7.08 (2H, d, J=9Hz), 7.18 (2H, m).

Preparation 6

(±) cis and trans l-[4-(l-(4-Fluorophenyl)-l-methylethyl)phenoxy]-2- ethoxycarbonylaminoindane

A solution of (+) N-ethoxycarbonyl-l,2-iminoindane (1.33g, 6.5mmol), 4-[l-(4- fluorophenyl)-l-methylethyl]phenol (1.5g, 6.5mmol) and pyridinium tosylate ( 18mg) in chloroform (35ml) was stirred at reflux under argon for 9.5h. During this period a further portion of pyridinium tosylate (lOmg) was added. The solvent was removed in vacuo, and the residue was subjected to column chromatography on silica gel eluting with 20% diethyl ether in 6O80 petroleum ether to afford an 85: 15 mixture of the cis and trans isomers of the title compounds as an oil (0.44g) which was used in the next stage. Example 1

(i)cw-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-methylaminoindane Hydrochloride (El)

To a solution of LiAlH4 (1.65g, 43mmol) in dry tetrahydrofuran (50 ml) under argo was added dropwise a solution of (±)cύ - 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-t butoxycarbonylaminoindane (3.7 lg, 8.4mmol) in dry tetrahydrofuran (150ml). The reaction was heated at reflux for 3h then cooled with an ice/water bath and quenched with the minimum of water. The reaction was filtered and dried over MgSO4. Solve were removed in vacuo and the residue subjected to column chromatography on silic eluting with 5% ethanol in chloroform to afford a colourless oil (1.51g) which was converted to the HC1 salt and crystallised to afford the title compound as a white sol m.p. >235°C dec. (from methanol-diethyl ether). ^lH Nmr (DMSO-d₆) δ : 1.73 (6H, s), 2.74 (3H, s), 3.30-3.42 (2H, m), 4.19 (1H, q, J=7Hz), 5.98 (1H, d, J=7Hz), 7.19-7.40 (10H, m), 7.44-7.51 (3H, m), 9.47 (2H, br.s)

Example 2

(±)cis-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-aminoindane Hydrochloride (E To a solution of (±)ris-l-[4-(l -methyl- l-phenylethyl)phenoxy]-2-N-tert- butoxycarbonylaminoindane (1.45g, 3.3mmol) in dichloromethane (25ml) at 0°C wa added trifluoroacetic acid (5ml) dropwise. The solution was stirred at room temperat for 3 h, then poured into saturated aqueous NaHCO3 (150ml) and extracted with dichloromethane (3x30ml). The combined organic phases were dried over Na2SO4, concentrated in vacuo. The residue was subjected to column chromatography on silic eluting with 5% ethanol in chloroform. The product was extracted into diethyl ether insoluble impurities were removed by filtration. Treatment with ethereal hydrogen chloride afforded the HC1 salt which was crystallised to give the title compound as a white solid m.p. > 190°C (dec.) (from methanol/ether).

!H Nmr (DMSO-d₆) 1.54 (6H, s), 3.23 (1H, dd, J=7,15Hz), 3.34 (1H, dd, J=7,15Hz) 3.95 (1H, m), 5.58 (1H, d, J=6Hz), 7.03-7.30 (13H, m), 8.78 (3H, br.s). Examples 3 and 4

(+) cw-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-methylaminoindane Hydrochloride (E3)

(-)cκ-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-methylaminoindane Hydrochloride (E4)

To a solution of S-(+)-α-methoxyphenylacetic acid (1.71g, 10.3mmol) in dichloromethane (70ml) was added thionyl chloride (12.5ml) and d e mixture heated at reflux for 90 minutes. On cooling, the mixture was concentrated in vacuo. The residue was then dissolved in dichloromethane (40ml) and added to a mixture of (±)cis- 1 -[4-(l -methyl-1 -phenylethyl)phenoxy]-2-methylaminoindane (3.7g, 10.3mmol), dichloromethane (40ml) and 1M aq. sodium hydroxide (80ml). The two phase mixture was then stirred vigorously for lh. The layers were then separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over Na2SO₄ and concentrated in vacuo to afford a 50:50 mixture of two diastereomers which were readily separated by column chromatography on silica gel, eluting with 50% diethyl ether in 60-80 petroleum ether.

The faster eluting diastereomer (1.97g, 3.9mmol) was dissolved in dry tetrahydrofuran (120ml) and treated with potassium r -butoxide (19.7g), and water (0.330ml). The mixture was then stirred vigorously for 90 minutes. . After filtering off the solid material, the mixture was poured into water (400ml) and extracted with diethyl ether (3 x 100ml). The combined organic extracts were dried over Na2SO₄ and concentrated in vacuo to afford a yellow oil which was converted to the HC1 salt and crystallised to afford (+)ro-l-[4-(l-methyl-l- phenylethyl)phenoxy]-2-methy.aminoindane hydrochloride (920mg) as a white solid, m.p. 239-242 °C dec. (from methanol-diethyl ether). Specific optical rotation = +212° (methanol, c=l, 30°C) The slower eluting diastereomer (1.65g, 3.3mmol) was then dissolved in dry tetrahydrofuran (120ml) and treated with potassium t -butoxide (16.5g), and water (0.300ml). The mixture was then stirred vigorously for 90 minutes. After filtering off the solid material, the mixture was poured into water (400ml) and extracted with diethyl ether(3 x 100ml). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo to afford a yellow oil which was converted to the HC1 salt and crystallised to afford (-)ct$-l-[4-(l-methyl-l- phenylethyl)phenoxy]-2-methylaminoindane hydrochloride (785mg) as a white solid, m.p.240-242 °C dec. (from methanol-diethyl ether). Specific optical rotation = -207° (methanol, c=l, 30°C)

Example 5

(±) cis-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-dimethylaminoindane Hydrochloride (E5)

To a solution of (±) cύ-l-[4-(l -methyl- l-phenylethyl)phenoxy]-2- methylaminoindane (0.52g) in acetonitrile (19ml) was added formaldehyde (0.95ml of a 37% aqueous solution) and sodium cyanoborohydride (O.lδlg). The solution was maintained at a pH of 6 by addition of glacial acetic acid, and stirred at room temperature for 18h. The reaction was diluted with diethyl ether (50ml), and washed with 1M sodium hydroxide (50ml) followed by water(50ml). The aqueous layer was back extracted with diethyl ether (3x30ml), and the combined organic phases were washed with brine, dried over Na2SO₄, and concentrated in vacuo. The residue was subjected to column chromatography on silica eluting with 5% ethanol in diethyl ether. The product was treated with ethereal hydrogen chloride to afford the HC1 salt which was crystallised to give d e title compound as an off- white solid m.p. 133°C (dec.) (from ethyl acetate/diethyl edier). *H Nmr (DMSO-ds) δ: 1.62 (6H, s), 2.9 (6H, s), 3.38 (2H, m), 4.17 (1H, m), 5.97 (1H, d, J=5Hz), 7.10-7.30 (10H, m), 7.35-7.44 (3H, m), 10.44 (1H, s)

Example 6

(±) cw-l-[4-(l-(4-Fluorophenyl)-l-methylethyl)phenoxy]-2- methylaminoindane Hydrochloride (E6)

To a solution of L.AIH₄ (0.12g, 3.2mmol) in dry tetrahydrofuran (5ml) was added (+) cis and trans- 1 -[4-( 1 -(4-fluorophenyl)- 1 -methylethyl)phenoxy]-2- ethoxycarbonylaminoindane (85:15 mixture) (0.437g, l.Olmmol) in dry tetrahydrofuran (lOml). The solution was stirred at reflux, under argon for 3h then quenched with wet diethyl ether followed by a minimum amount of water. The resulting precipitate was filtered off and washed with diethyl ether. The combined filtrate and washings were concentrated in vacuo, and the residue subjected to column chromatography on silica gel eluting with 5% methanol in dichloromethane. Pooling of fractions containing the major slower eluting product afforded an oil. Treatment with ethereal hydrogen chloride afforded the HC1 salt which was crystallised to give the title compound as an off-white crystalline solid (0.15g) m.p. 218°C (dec.) (from methanol/diethyl etner). *H Nmr (Free base)(CDCl3) δ: 1.60 (6H, s), 2.50 (3H, s), 2.97 (1H, dd,

J=7,14Hz), 3.12 (1H, dd, J=7,14Hz), 3.59 (1H, q, J=7Hz), 5.59 (1H, d, J=7Hz), 6.94 (4H, m), 7.08-7.35 (8H, )

Example 7 (±)trans-l-[4-(l-Methyl-l-phenylethyl)phenoxy]-2-methylamino indane hydrochloride

In a similar manner to Example 1, column residues from a preparation according to the method of Preparation 2, which contained a small quantity of (±)-trans-l- [4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-tert-butoxycarbonylanιino indane and much 4-cumylphenol (3.5g crude mixture) were reduced with lithium aluminium hydride (1.5g, 39mmol) in dry tetrahydrofuran (total 150ml) to afford a very impure brown oil (1.7g). This was subjected to column chromatography on silica gel, using dichloromethane as initial eluent when 4-cumylphenol was cleanly eluted. Changing eluting solvent to dichloromethane 2% methanol (methanol contains 10% NH₄OH) gave further impure fractions containing one main product by t.l.c. These were combined and evaporated to give a light-brown oil (0.44g). This was dissolved in ethyl acetate and treated with ethereal HC1 to give a brown solution. Evaporation to dryness and scratching gave a crystalline solid. This material was treated with ethyl acetate/Et₂O (1/1), filtered, washed with ether and dried to give a pale-buff solid (0.3g). This material was finally crystallised from methanol/ether to give the title product (0.14g) as a pale-buff solid, m.p. = 182- 183°C. (Mass Spec (MH⁺)=358)

1H Nmr (DMSO-dβ): 1.65 (6H, s), 2.63 (3H, s), 3.12 - 3.19 (1H, m), 3.35 - 3.45 (1H, m), 4.02 (1H, m), 6.27 (1H, d), 7.04 - 7.36 (13H, m)

Claims

1. A compound of formula (I):

Formula (I) wherein n is 1,2 or 3;

R¹ and R² each independendy represent hydrogen, Chalky!, C3_6cycloalkyl, or C3.6cycloalkylC j .4alkyl; p and q independently represent 0-4;

X represents O, S, NH or, provided that the sum of p and q is at least 1, a bond; and Ar represents phenyl substituted by -Y-CR^R^-Ph, where Y is oxygen or a bond,

R^and R^ are independently, H, methyl or ethyl, provided that R^and R^ are not both H, and Ph is optionally substituted phenyl; or a salt thereof.

2. A compound of claim 1 in which R is methyl, isopropyl or hydrogen.

A compound of claim 1 or claim 2 in which R² is hydrogen or methyl.

4. A compound of any of claims 1 to 3 in which -NR R² is amino, methylamino or isopropylamino.

A compound of claim 4 in which -NRIR² is methylamino.

6. A compound of any of claims 1 to 5 in which X is O and p and q are 0, or X is a bond and the sum of p and q is 1.

7. A compound of claim 6 in which X is O and p and q are 0.

8. A compound of any of claims 1 to 7 in which R^ and R^ are both methyl.

9. A compound of any of claims 1 to 8 in which Ph is 3-chlorophenyl, 3- fluorophenyl, 4-chlorophenyl, 4-fluorophenyl or 3,4-dichlorophenyl.

10. A compound of any of claims 1 to 8 in which Ph is unsubstituted phenyl.

11. A compound of formula (I) selected from :

(±)cis-l -[4- (1 -methyl- 1 -phenylethyl)phenoxy]-2-methylaminoindane (+)cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-aminoindane (±) s- 1 -[4-( 1 -methyl- l-phenylethyl)benzyl]-2-aminoindane (±)cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)benzyl]-2-methylaminoindane ±)cis- 1 -[4-( 1 -methyl- 1 -(4-fluorophenyl)ethyl)phenoxy]-2-aminoindane

(±) s- 1 -[4-( 1 -methyl- 1 -(4- fluorophenyl )ethyl)phenoxy] -2-methylaminoindane (+) cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy] -2-dimethylaminoindane or a salt solvate or hydrate thereof.

12. A compound of any one of claims 1 to 11 in the form of a resolved enantiomer, substantially free from the other enantiomer.

13. A compound of formula (I) which is :

(+) OΪ-1-[4-(1 -methyl- l-phenylethyl)phenoxy]-2-methylaminoindane or a salt solvate or hydrate thereof.

14. A compound of formula (I) which is :

(-)cw-l-[4-(l -methyl- l-phenylethyl)phenoxy]-2-methylaminoindane or a salt solvate or hydrate thereof.

15. A process for the preparation of a compound according to any one of Claims 1 to 14 which comprises :

(a) to prepare a compound of formula (I) wherein R² is methyl, reduction of a compound of formula (II)

Formula (II)

wherein n, p, q, R , Ar and X are as hereinbefore defined and Alk is a Cι_4alkyl group; (b) to prepare a compound of formula (I) wherein at least one of R 1 and R² is hydrogen, deprotection of a compound of formula (II);

(c_{) t}o prepare a compound of formula (I) wherein R* and R² are both hydrogen and p is 1 to 4, reduction of a compound of formula (HI⁾:

Formula (ul)

wherein n, q, X and Ar are as hereinbefore defined and R^ is hydrogen, C galley! or phenylCι_4alkyl (e.g. benzyl);

(d₎ to prepare a compound wherein X is O, S or NH, reaction of a compound of formula (IV)

Formula (IV)

wherein Rl, R², p and n are as hereinbefore defined and X* is O, S or NH, with a compound of formula L(CH2)q Ar wherein L is a leaving group and q and Ar are as hereinbefore defined;

Formula (V)

wherein R¹, R², p and n are as hereinbefore defined and L is a group displaceable by a nucleophile, with a compound HX(CH2)qAr wherein X, q and Ar are as hereinbefore defined;

(f) conversion of a benzoyl group in a compound of formula (VI)

Formula (VI) wherein n, R , R², X, p and q are as defined for formula (I) and Ar* is phenyl substituted by optionally substituted benzoyl, to a group -CR^R^-Ph

(g) interconversion of a compound of formula (I) to a different compound of formula (I);

and optionally after any of the above processes, if necessary or desired, separating a mixture of enantiomers and/or forming a salt of formula (I).

16. A pharmaceutical composition comprising a compound of any of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

17. The use of a compound of any of claims 1 to 14 in the manufacture of a medicament for the treatment of a disorder wherein a calcium channel antagonist is indicated.

18. Use according to claim 17 wherein the disorder is a condition or disease related to an accumulation of calcium in the brain cells of a mammal.

19. Use according to claim 18 wherein the condition or disease is ischaemia, anoxia or traumatic head injury.

20. Method of treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need thereof an effective amount of a compound of any of claims 1 to 14.

21. A novel intermediate selected from a compound of formula (II), (III) and (VI).