TRICYCLIC PYRROLIDINE DERIVATIVES AS CALCIUM CHANNEL ANTAGONISTS

Abstract: Compounds of formula (I) wherein A represents (CH2)n in which one -CH2- moiety may be optionally replaced by O, -C(CH3)2 or -OC(CH3)2; and n is 1, 2 or 3; R<1> represents hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylC1-4alkyl, benzyl or 4-methoxybenzyl; R<2> represents a substituent selected from one or more of: a hydrogen or halogen atom, or a hydroxy, C1-4alkyl, C1-4alkoxy, amino, mono-or di-C1-4alkylamino, trifluoromethyl, trifluoromethoxy, cyano, nitro, formyl, C1-4alkynoyl, or C<1-4>alkoxycarbonyl group or a group R<3>R<4>NCO- wherein R<3> and R<4> each independently represents a hydrogen atom or a C1-4alkyl group or R<3>R<4>N forms a 5-7 membered heterocyclic ring; m represents 1, 2, 3, or 4; Ar represents phenyl optionally substituted by 1 to 3 substituents selected from one or more of: halo, C1-4alkyl, C1-4alkoxy, C1-2alkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO2, amino, mono- or di-alkylamino, optionally substitued benzoyl or a group Ph(Alk<1>)rY(Alk<2>)s- wherein Ph is optionally substituted phenyl, Y is oxygen or a bond, Alk<1> and Alk<2> each independenlty represents C1-4 alkyl which may be straight or branched and r and s are independently zero or 1, provided that the length of the chain (Alk<1>)rY(Alk<2>)s does not exceed 5 atoms; or Ar represents an optionally substituted unsaturated monocyclic heteroaryl ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members; and salt thereof are neuronal calcium channel antagonists useful in the treatment of ischaemic conditions e.g. stroke.

Description: TRICYCLIC PYRROLIDINE DERIVATIVES AS CALCIUM CHANNEL ANTAGONISTS The present invention relates to tricyclic heterocyclic 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. In our PCT published applications WO95/04028 and WO95/04027 and unpublished application PCT/EP.5/02695 we describe various compounds as calcium channel antagonists. Included within the scope of these applications are compounds of formulae: (A) (B) (C) wherein: X a represents O, S, NH; X D represents O, S, NH or a bond; and pb and qb independently represent 0-4 such that the sum of pb+qb is at least 1 ; pc and qc independently represent 0-4; and X c represents O, S, NH or, provided that the sum of pc and qc is at least 1, a bond; Ar a and Ar D each represents phenyl optionally substituted by inter alia Ph(CH2) r Y(CH2) s - where Ph is optionally substituted phenyl, Y 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; 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; R l a , R 2a , R l b , R 2b , R lc and R 2c each independently represent hydrogen, C^alkyl. C .gcycloalkyl or Cι_4alkylC3_6cycloalkyl; and n is 1,2 or 3, and salts thereof. We have now discovered novel compounds which exhibit activity as calcium channel antagonists. According to the present invention therefore we provide a compound of formula (I): Formula (I) wherein A represents (CH2)n in which one -CH2- moiety may be optionally replaced by O, -C(CH 3 ) 2 or -OC(CH 3 ) 2 ; n is 1,2 or 3; Rl represents hydrogen, Cj.galkyl, C3_gcycloalkyl, C3_6cycloalkylCμ4alkyl, benzyl or 4-methoxybenzyl; R 2 represents a substituent selected from one or more of a hydrogen or halogen atom (e.g. fluorine, chlorine or bromine), or a hydroxy, Cι_4_lkyl, Cj^alkoxy, amino, ono-or di-Cj.4 alkylamino, trifluoromethyl, trifluoromethoxy, cyano, nitro, formyl, Cι_4_lkanoyl, or C1.4 alkoxycarbonyl group or a group R^R^NCO- wherein and R^ each independently represent a hydrogen atom or a Ci _4alkyl group or R^R^N forms a 5-7 membered heterocyclic ring; m represents 1, 2, 3, or 4; Ar represents phenyl optionally substituted by 1 to 3 substituents selected from one or more of : halo, Cι_4alkyl, C\ .4alkoxy, Cι_2 a lkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO2, amino, mono- or di- alkylamino, optionally substituted benzoyl or a group Ph(Alk^) r Y(Alk ) s - wherein Ph is optionally substituted phenyl, Y is oxygen or a bond, Alk* and Alk 2 each independently represent Cι _4 alkyl which may be straight or branched and r and s are independently zero or 1 , provided that the length of the chain (Alkl) r Y(Alk ) s does not exceed 5 atoms; or Ar represents an optionally substituted unsaturated monocyclic heteroaryl ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members; and salts thereof. In the compounds of formula (I) R^ is preferably hydrogen or methyl. R 2 is suitably hydrogen. The group A is preferably (CH2) n . Suitably n is 1. When Ar represents phenyl substituted by a group Ph(Alkl) r Y(Alk 2 ) s - the groups Alk^ and Alk 2 preferably each independently represent -(CH2K -C(H)(CH3>- or -C(CH3) _-• When Y is oxygen, s preferably represents zero and r represents zero or 1. When Y is a bond, the sum of r and s is preferably 1 or 2. When Alk* represents -C(CH3>2 and r is 1, s is preferably zero. In a particular embodiment Alk* and Alk 2 each represent -(CH2)-, such that the group Ph(Alk 1 ) r Y(Alk 2 ) s - can be represented as Ph(CH2) v Y(CH2) w - wherein v and w each represent 0-4 such that the sum of v+w is not greater than 4 and preferably not greater than 1. In a further embodiment Alk* represents -CRSR -, where R^ is hydrogen, methyl or ethyl and R > is methyl or ethyl; r represents 1 and s represents zero. At least one, preferably both, of R^ and R^ represent methyl. Particularly preferred substituents of the formula Ph(Alk^) r Y(Alk 2 ) s - include optionally substituted benzyloxy, benzyl, phenoxy, benzoyl or Ph(CH3)2C-. Suitable substituents for the group Ph include halogen, Cι _4alkoxy; C1.4a_.yl; trifluoromethyl; and trifluoromethoxy. When Ar represents a bicyclic aryl suitable groups include naphthyl. When Ar represents unsaturated monocyclic heteroaryl suitable groups include optionally substituted pyridyl, thienyl and furyl. When Ar represents bicyclic heteroaryl, suitable groups include benzofuranyl e.g. 5-benzo[b]furanyl. Suitable substituents for bicyclic aryl and monocyclic and bicyclic heteroaryl groups include halogen; Cj^alkyl; Cι _4alkoxy; trifluoromethyl; trifluoromethoxy; phenyl; phenylCj^alkyl; and phenyl Cj^alkoxy. Ar preferably represents phenyl, most preferably substituted by halogen, e.g. 3,4-dichloro. Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus, a Ci .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 C3.6cycloa_.ylC1 _4_lkyl are cyclopropylmethyl and cyclohexylmethyl. When m in formula (I) represents from 2-4 it will be appreciated that the values of the substituents R 2 may be the same or different. Thus for example, when m is 2 the values of the two substituents R 2 may be selected independently from the above list. 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, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non- pharmaceutically acceptable salts e.g. oxalates 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 three 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. For example, it will be appreciated that when A is (CH2) n and n is 1, ie compounds having the structure: the substituents at the 3/3a and 3a/8a positions may lie on the same side with respect to the plane of the ring (ris-configuration) or on opposite sides (trans-configuration). All forms and mixtures thereof are included within the scope of this invention. Preferably when n is 1 the hydrogen atoms at the 3a/8a positions are in the cis-configuration; the 3/3a hydrogen atoms may be in either the cis- or trans -configuration. Particular compounds of the formula (I) include : (3RS, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3SR, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3RS, 3aRS, 8aSR) and (3SR, 3aRS, 8aSR)-l-(4-methoxybenzyl)-3-(3,4- dichlorophenyl)- 1 ,2,3,3a,8,8a-hexahydro- 1 -azacyclopenta[a]indene; (3RS, 3aRS, 8aSR) -3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3SR, 3aRS, 8aSR)-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; and salts thereof. In this specification the compounds have been named as azacyclopenta-indenes; alternatively they can be named as indenopyrroles, in which case the first compound listed above would be named: (3RS, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)- l,2,3,3a,8,8a-hexahydroindeno[2,l-b]pyτrole The compounds of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides in a further aspect, a process for the preparation of compounds of formula (I) which comprises : reaction of a compound of formula (II): Formula (II) (wherein Ar, A, R 2 and are as defined for formula (I)) with a compound of formula (IH): Formula (III) (wherein R^ is as defined for formula (I)); followed, where necessary or desired by one or more of the following steps: i) conversion of a compound (I) wherein R is benzyl or 4-methoxybenzyl to a compound wherein R * is hydrogen; ii) conversion of a benzoyl substitutent in the group Ar to benzyl or to a group -C(CH 3 ) 2 Ph; iii) separation of diastereoisomers; iv) salt formation. Reaction of a compound (II) with a compound (HI) may be carried out in an inert solvent such as toluene, under reflux conditions. It will be appreciated that a compound of formula (II) may be employed as a mixtue of geometric (E and Z) isomers or altematively the isomers may be separated prior to reaction with a compound of formula (III). A single E or Z isomer of formula (II) will cyclise with a compound (III) in a stereospecific manner to give a single diastereoisomer of formula (I) An aldehyde of formula (II) may be prepared by oxidation of the corresponding alcohol, with for example sulphur rrioxide-pyridine complex in a solvent such as dimethylsulphoxide. For compounds where A is (CH2) n "d n is 1, the alcohol may be prepared by reaction of an optionally substituted isochroman-1-ol of formula (IV): Formula (IV) wherein R 2 and are as hereinbefore defined; with a compound of formula (V): ArCH PPh3Hal Q Formula (V) (wherein Ar is as defined for formula (I) and Hal is a halide ion e.g. a chloride ion). To prepare compounds of formula (II) wherein n is 2 or 3, die alkylene chain may be lengthened by methods well known in the art. To prepare compounds of formula (II) wherein A is (CH2)n in which one -CH2- moiety is replaced by -C(CH3)2, 0 or -OC(CH3)2 an appropriately substituted isochroman-1-ol or an appropriately functionalised benzoxepine derivative may be employed in the above process in place of a compound of formula (V). A mixture of E and Z isomers of formula (II) may be separated by standard methods, e.g. by HPLC. Compounds of formula (III) are commercially available or may be prepared by methods well known in the art. Compounds of formula (IV) and (V) may also be prepared by standard procedures. Conversion of a compound of formula(I) wherein Rl is 4- methoxybenzyl, into a compound (I) wherein R is hydrogen may be effected by treatment with a haloformate such as 1-chloroethylchloroformate. Reduction of a benzoyl substitutent to benzyl may be effected using e.g. sodium borohydride in trifluoracetic acid. The conversion of a benzoyl group to a group -C(CH3)2Ph can be effected by reaction with (CH3)2TiC-2, 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. When a compound of formula (I) is obtained as a mixture of diastereoisomers, these may be separated for example by chromatography. A mixture of enantiomers of a compound of formula (I) 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. 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; AIDS-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. 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; altematively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), 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. Altematively, 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 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound 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 dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or 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. Altematively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose 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 in 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 NMDA antagonists; a free radical inhibitor; or a calpain inhibitor. BIOLOGICAL DATA Ca 2+ Current Measurement Cell preparations Superior cervical ganglion neurons were isolated and cultured following a method modified from Marrion et al, Neurosci. Lett., 77, 55-60 (1987). Cells were plated onto laminin coated plastic tissue culture dishes and incubated at 37°C until just prior to recording. Electrophysiological recordings were performed from 2 to 9 days after dissociation. Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH. Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents. The extemal solution for recording Ca 2+ channel currents contained in mM: BaCl2, 10; TEA-C1, 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 Ca 2+ 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, Joumal of Physiology (1988), 404, 767-784). Results Ca 2+ currents Peak voltage gated Ca 2+ channel currents of up to 10 nA were recorded using lOmM Ba + 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 Ca 2+ 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 the invention gave percentage inhibition of plateau Ca + current in the range 33-81% at 5μM. 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 glycollate, 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 - O mg Buffer to pH ca 5 - 8 Co- solvent 0 - 40 mg Flavour 0.01 - O 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 E-2-[2-(2-(3,4-dichlorophenyl)vinyl)phenyl]ethanol and Z-2-[2-(2-(3,4-dichlorophenyl)vinyl)phenyl]ethanol To a suspension of of 3,4-dichlorobenzyltriphenylphosphonium chloride (28.36g, 62mmol) in dry THF (300ml) at O°C was added n-butyllithium (39ml of a 1.6M solution in hexanes, 62mmol) dropwise. After 10 minutes a solution of isochroman- 1 -ol (4.71 g, 31.4mmol) in dry THF (30ml) was added in one portion and the orange mixture was allowed to stir ovemight at room temperature. The reaction mixture was then poured into water (IL) and extracted with diethyl ether (3x150ml). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue subjected to column chromatography on silica gel eluting with 30% diethyl ether in 60-80 petrol to afford E and Z-2-[2-(2-(3,4- dichlorophenyl)vinyl)phenyl]ethanol (8.92g, 97%) as a colourless oil. The geometric isomers were separated by preparative HPLC on a Dynamax60-A silica column eluting with 2% isopropanol in hexanes. H Nmr (CDCl3)(E isomer) δ : 1.43 (IH, t, J=7Hz), 3.07 (2H, t, J=7Hz), 3.88 (2H, q, J=7Hz), 6.90 (IH, d, J=17Hz), 7.23-7.46 (6H, m), 7.60 (2H, m). !H Nmr (CDCI3) (Z isomer) δ : 1.48 (IH, br. s), 2.89 (2H, t, J=7Hz), 3.83 (2H, m), 6.51 (IH, d, J=12Hz), 6.85 (2H, m), 7.20 (6H, m) Preparation 2 E-2-[2-(2-(3,4-dich.orophenyl)vinyl)phenyl]acetaldeyde To a solution of E-2-[2-(2-(3,4-dichlorophenyl)vinyl)phenyl]ethanol (950mg, 3.2mmol) and triethylamine (4.45ml, 32mmol) in dry dimethyl sulfoxide (15ml) under argon was added a solution of sulfur trioxide-pyridine complex in DMSO (15ml). After 45 minutes the reaction mixture was acidified with IN HCl then poured into water (250ml) and extracted with diethyl ether (3x50ml). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the residue subjected to column chromatography on silica gel eluting with 20% diethyl ether in 60-80 petrol to afford the title compound (598mg, 63%) as an off white solid. ! H Nmr (CDCI3) δ : 3.86 (2H, d, J=3Hz), 6.85 (IH, d, J=17Hz), 7.12-7.68 (8H, m), 9.73 (lH, t, J=3Hz). Preparation 3 Z-2-[2-(2-(3,4-dichlorophenyI)vinyl)phenyl]acetaldeyde To a solution of Z-2-[2-(2-(3,4-dichlorophenyl)-vinyl)-phenyl]-ethanol (890mg, 3 mmol) and triethylamine (4.2ml, 30mmol) in dry dimethyl sulfoxide (15ml) under argon was added a solution of sulfur trioxide-pyridine complex (1.43g, 9mmol) in DMSO (15ml). After 45 minutes the reaction mixture was acidified with IN HCl then poured into water (250ml) and extracted with diethyl ether (3 50ml). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the residue subjected to column chromatography on silica gel eluting with 20% diethyl ether in 60-80 petrol to afford the title compound (445mg, 50%) as a yellow oil *H Nmr (CDCI3) δ : 3.68 (2H, d, J=3Hz), 6.48 (IH, d, J=12Hz), 6.68 (IH, d, 12Hz), 6.90 (IH, dd, J=8,3Hz), 7.21 (6H, m), 9.67 (IH, t, J=3Hz). Preparation 4 E and Z-2-[2-(2-(3,4-d.chIorophenyl)vinyI)phenyl]acetaIdeyde The title compounds were prepared from E and Z-2-[2-(2-(3,4-dichlorophenyl)- vinyl)phenyl]ethanol as described in Preparations 3 and 4 for the individual isomers. Example 1 (3RS, 3aRS, 8aSR)-l-Methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a- hexahydro-l-azacyclopenta[a]indene Hydrochloride (El) A mixture of E-2-[2-(2-(3,4-dichlorophenyl)-vinyl)-phenyl]-acetaldehyde (600mg, 2mmol) and sarcosine (356mg, 4mmol) in toluene (25ml) was heated at reflux ovemight under argon using a Dean-Stark trap. On cooling, the toluene was removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 4% ethanol in chloroform to afford a white solid (530mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid m.p.246-249 "C dec. (from methanol-diethyl ether) *H Nmr (CDC1 3 ) (free base) δ : 2.44 (3H, s), 2.45 (IH, m), 3.03 (2H, m), 3.30 (3H, m), 3.76 (IH, m), 7.07-7.27 (5H, m), 7.45 (2H, m). Example 2 (3SR, 3aRS, 8aSR)-l-Methyl-3-(3,4-dichlorophenyI)-l,2,3,3a,8,8a- hexahydro-l-azacyclopenta[a]indene Hydrochloride (E2) A mixture of Z-2-[2-(2-(3,4-dichlorophenyl)-vinyl)-phenyl]-acetaldeyde (420mg, 1.4mmol) and sarcosine (256mg, 2.8mmol) in toluene (25ml) was heated at reflux ovemight under argon using a Dean-Stark trap. On cooling, the toluene was removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 4% ethanol in chloroform to afford a white solid (335mg) which was converted to the HCl salt and crystallised to afford the title compound as a white solid m.p.>225 ^C dec. (from methanol-diethyl ether). 1H Nmr (CDCI3) (free base) δ : 2.43 (3H, s), 2.86 (2H, m), 3.01 (2H, m), 3.30 (IH, m), 3.66 (IH, m), 4.12 (IH, dd, J=7,7Hz), 6.17 (IH, d, J=7Hz), 6.82 (6.82 (2H, m), 7.09 (4H, m). Example 3 (3RS, 3aRS, 8aSR) and (3SR, 3aRS, 8aSR)-l-(4-Methoxybenzyl)-3-(3,4- dichlorophenyl)-l,2 r 3,3_.8,8a-hexahydro-l-azacyclopenta[a]indene (E3) A mixture of E and Z-2-[2-(2-(3,4-dichlorophenyl)-vinyl)-phenyl]-acetaldehyde (1.46g, 5 mmol) and 4-methoxybenzylglycine (1.5g, 8.3mmol) in toluene (50ml) was heated at reflux for 6 h under argon using a Dean-Stark trap. On cooling, the toluene was removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 1 % ethanol in chloroform to afford the title compound as a yellow oil (l.Og). Mass spectmm (AP+) M + 424 Examples 4 and 5 (3RS, 3aRS, 8aSR) -(3,4-dichlorophenyl)-l^^a . Ja-he_ahydro-_- azacyclopenta[a]indene Hydrochloride (E4) (3SR, 3aRS, 8aSR)-3-(3,4-dichlorophenyl)-l^,3a,8,8a-hexa_ydro-l- azacyclopenta[a]indene Hydrochloride (E5) To a solution of (3RS,3aRS, 8aSR) and (3SR, 3aRS, 8aSR)-l-(4- methoxybenzyl)-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene (809mg, 1.9mmol) in dichloromethane at O^C under argon was added proton sponge (413mg, 1.9mmol) followed by 1-chloroethyl chloroformate (0.405ml, 3.9mmol). After 30 minutes, volatiles were removed in vacuo. The residue was taken up in methanol (50ml) and heated at reflux for 30 minutes. On cooling, the methanol was removed in vacuo to afford a mixture of the two diastereomers which were readily separated by column chromatography on silica gel eluting with a gradient of 5-7% ethanol in chloroform. The faster eluting diastereomer was converted to the HCl salt and crystallised to afford (3RS, 3aRS, 8aSR) -3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-_exahydro-_- azacyclopenta[a]indene Hydrochloride as a white crystalline solid m.p. 222- 224 0c (from methanol ether). H Nmr (CDCI3) (free base) δ : 2.04 (IH, br. s), 2.93 (2H, m), 3.30 (3H, m), 3.73 (IH, m), 4.24 (IH, t, J=7Hz), 7.18 (5H, m), 7.44 (2H, m). Similarly the slower eluting diastereomer afforded (3SR, 3aRS, 8aSR)-3-(3,4- dichlorophenyI)-l,2-3,3a,8,8a-hexahydro-l-az_cyclopenta[a]indene Hydrochloride m.p. 201-202°C. ] H Nmr (CDCI3) (free base) δ : 2.82-3.63 (6H, m), 3.97 (IH, t, J=7Hz), 4.44 (IH, m), 6.08 (IH, d, J=7Hz), 6.80 (2H, m), 7.16 (4H, m).

Claims: Claims 1. A compound of formula (I) : wherein A represents (CH2)n in which one -CH2- moiety may be optionally replaced by O, -C(CH3 2 or -OC(CH3)2; and n is 1,2 or 3; R 1 represents hydrogen, Cj.galkyl, C3.6cycloa_.yl, C3_6cycloalkylCι_4alkyl, benzyl or 4-methoxybenzyl; R 2 represents a substituent selected from one or more of: a hydrogen or halogen atom; a hydroxy, Cι_4_lkyl, Cj.4alkoxy, amino, mono-or di-Cj.4 alkylamino, trifluoromethyl, trifluoromethoxy, cyano, nitro, formyl, C j ^alkanoyl, or Cι_4alkoxycarbonyl group; or a group R^R^NCO- wherein R^ and R^ each independently represent a hydrogen atom or a Ci^alkyl group or R^R^N forms a 5-7 membered heterocyclic ring; m represents 1, 2, 3, or 4; Ar represents phenyl optionally substituted by 1 to 3 substituents selected from one or more of: halo, C1.4ah.yl, Cj.4alkoxy, Cj^alkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO2, amino, mono- or di- alkylamino, optionally substituted benzoyl or a group Ph(Alkl) r Y(Alk 2 ) s - wherein Ph is optionally substituted phenyl, Y is oxygen or a bond, Alk^ and Alk 2 each independently represent Cj_4 alkyl which may be straight or branched and r and s are independently zero or 1, provided that the length of the chain (Alkl) r Y(Alk 2 ) s does not exceed 5 atoms; or Ar represents an optionally substituted unsaturated monocyclic heteroaryl ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members; or a salt thereof. 2. A compound according to claim 1 wherein R 2 is hydrogen. 3. A compound according to claim 1 or claim 2 wherein the group A is (CH2) n - 4. A compound according to claim 3 wherein n is 1. A compound of formula (IA): Formula (IA) wherein n is 1,2 or 3; Rl represents hydrogen, Cj.fialkyl, C3_6cycloalkyl, _3_6-cycloal_ylCι_4alkyl;, benzyl or 4-methoxybenzyl and Ar represents phenyl optionally substituted by 1 to 3 substituents selected from : halo, Cj^alkyl, Cj^alkoxy, Cj^alkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO2, amino, mono- or di- alkylamino, optionally substituted benzoyl, Ph(CH 2 ) v Y(CH2)v . - and PhCR 5 R 6 Y; or Ar represents an optionally substituted unsaturated monocyclic heteroaryl ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members; Ph is optionally substituted phenyl; Y is oxygen or a bond; v and w each independently represent 0-4 such that the sum of v+w is not greater than 4; R5 is hydrogen, methyl or ethyl; R6 is methyl or ethyl; or a salt thereof. 6. A compound according to any of claims 1 to 5 in which R s hydrogen or methyl. 7. A compound according to any of claims 1 to 6 wherein Ar represents optionally substituted phenyl. 8. A compound according to claim 7 wherein Ar represents halophenyl. 9. A compound of formula (I) selected from : (3RS, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3SR, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3RS, 3aRS, 8aSR) and (3SR, 3aRS, 8aSR)-l-(4-methoxybenzyl)-3-(3,4- dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l-azacyclopenta[a]indene; (3RS, 3aRS, 8aSR) -3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; (3SR, 3aRS, 8aSR)-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene; or a salt, solvate or hydrate thereof. 10. A process for the preparation of a compound according to any one of claims 1 to 9 which comprises : reaction of a compound of formula (II): Formula (II) (wherein Ar, A, R 2 and m are as defined for formula (I)) with a compound of formula (III): Formula (ni) (wherein R* is as defined for formula (I)); followed, where necessary or desired by one or more of the following steps: i) conversion of a compound (I) wherein R* is benzyl or 4-methoxybenzyl to a compound wherein R is hydrogen; ii) conversion of a benzoyl substitutent in the group Ar to benzyl or to a group -C(CH 3 ) 2 Ph; iii) separation of diastereoisomers; iv) salt formation. 11. A pharmaceutical composition comprising a compound of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. 12. The use of a compound of any of claims 1 to 9 in the manufacture of a medicament for the treatment of a disorder wherein a calcium channel antagonist is indicated. 13. Use according to claim 12 wherein the disorder is a condition or disease related to an accumulation of calcium in the brain cells of a mammal. 14. 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 9.

Inventors: HARLING JOHN DAVID, ORLEK BARRY SIDNEY, HARLING, JOHN, DAVID, ORLEK, BARRY, SIDNEY
Applicants: HARLING JOHN DAVID, ORLEK BARRY SIDNEY, SMITHKLINE BEECHAM PLC, HARLING, JOHN, DAVID, ORLEK, BARRY, SIDNEY
Application year: 1996
Main classification: C07D209
IPC codes: A61K31, A61P9, A61P25, A61P43, C07D209