PIPERIDINE DERIVATIVES AS CALCIUM CHANNEL ANTAGONISTS

Abstract: Compounds of formula (I): wherein R<1> represents C1-6alkyl, halogen or phenyl; R<2>, represents hydrogen, C1-6alkyl, halogen or phenyl; R<3> represents hydroxyl or a group convertible thereto in vivo; R<4> represents C1-6alkyl; p is zero, 1 or 2; X represents -CH2-, -C = O, O or S; n is an integer from 4 to 10; m is an integer from 3 to 8; and salts thereof are useful as calcium antagonists, e.g. in the treatment of conditions relating to an accumulation of calcium in brain cells.

Description: PIPERIDINE DERIVATIVES AS CALC IUM CHANNEL ANTAGONISTS The present invention relates to heterocyclic compounds, processes for preparing them, their use in therapy and pharmaceutical compositions containing them. EP-A- 190685 describes heterocyclic amides which are said to be anti- inflammatory and anti allergy agents. EP-A-476846 describes known phenols and benzamides for use inter alia in preventing ischaemia-induced cell damage. We have now found that certain heterocyclic derivatives containing a phenol moiety exhibit activity as calcium channel antagonists and radical scavengers. In a first aspect therefore the present invention provides compounds of formula (I) : Formula (I) wherein R! represents Cj.galkyl, halogen or phenyl; R represents hydrogen, Chalky-, halogen or phenyl; R3 represents hydroxyl or a group convertible thereto in vivo ; R4 represents Cj.galkyl; p is zero, 1 or 2; X represents -CH2-, -C=O, O or S; n is an integer from 4 to 10; m is an integer from 3 to 8; and salts thereof. Alkyl groups present in the compounds of formula (I) may be straight or branched. When R* and/or R^ represents C^.^alkyl this may be for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, sec-pentyl, 1,1-dimethylpropyl, or n-hexyl group. R and R^ preferably represent branched alkyl groups, most preferably t-butyl. Groups R which are convertible in vivo to hydroxyl (also referred to as bioprecursors or physiologically functional equivalents) include Cι_4alkoxy; C ] _4alkanoyloxy e.g. acetoxy; aryl C^alkanoyloxy e.g. phenyl Cι_4alkanoyloxy such as benzoyloxy; aryl sulphonyloxy e.g. optionally substituted phenylsulphonyloxy such as toluene sulphonyloxy or Cι_4alkylsulphonyloxy e.g. methylsulphonyloxy. n is preferably 5 to 8. m is preferably 4 to 6. p is preferably zero. 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 the hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, and tartrate salts, and base salts such as alkali metal e.g. sodium or potassium salts. Other non-pharmaceutically acceptable salts e.g. oxalates, may be used for example in the isolation of the final product and are included within the scope of this invention. It will be appreciated that the compounds of formula (I) may contain one 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. Particular compounds according to the invention include : l-f6-oxo-6-(4-hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine, 1 -f 8-oxo-8-(4-hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine, 1 -[ 6-(4-Hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine, 1 - [ 8- (4-Hydroxy- 3 ,5-di-tert-bu tylphenyl)oc ty-]piperidine, 1 - [7-(4-Hydroxy-3,5-di-tert-butyl)thiophenoxy-heptyl]piperidine, 1 - [ 7-(4-Hydroxy-3,5-di-tert-butyl)phenoxyheptyl]piperidine, l-f7-Oxo-7-(4-hydroxy-3,5-di-tert-butylphenyl)heptyl]piperidine, and salts thereof. 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 a compound of formula (I) which comprises: (a) to prepare a compound (I) wherein X is O or S, reaction of a compound of formula (II): Formula (II) in which m, n, R^ and p are as defined in formula (I) and 1-1 is a group displaceable with a nucleophile with a compound of formula (III) : Formula (HI) in which X^ is O or S and R , R^ and R^ are as defined in formula (I); or (b) reaction of a compound of formula (IV) : Formula (IV) in which R , R^, R ? X and n are as defined for formula (I) and L^ is a leaving group with a compound of formula (V) : (CH 2 ) m NH Formula (V) in which m, R^ and p are as defined in formula (I); (c) introduction of the groups R* and/or R^ by reaction of a compound of formula (VI) : Formula (VI) (wherein one of R a and R^ a is hydrogen and the other is selected from hydrogen, halogen, C\ .galkyl or phenyl, and R^, R4, X. n , m and p are as defined for formula (I)) with a compound serving to introduce R* and/or R^; (d) to prepare a compound where X is -CH2-, S or O, reduction of an amide of formula (VII) or (VIII) : Formula (VII) Formula (VIII) (e) conversion of a compound of formula (I) to a different compound of formula (I) for example, reduction of a compound (I) wherein X is C=O to a compound wherein X is -CH2-; or reaction of a compound wherein R^ is hydrogen according to process (c) to give a compound wherein R^ is other than hydrogen; followed if desired by salt formation. In process (a) the reaction between a compound of formula (II) and a compound of formula (III) can be carried out under standard conditions. For example when I_l is hydroxy, 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). Alternatively the leaving group L^ may be for example a halogen atom or a sulphonyloxy group e.g. methane-sulphonyloxy or p-toluene sulphonyloxy. In this case the reaction may be effected in the absence or presence of solvent such as dimethylformamide or methylethylketone in the presence of a base such as sodium hydride or potassium carbonate and at a temperature in the range 0 to 200°C. The reaction of a compound of formula (IV) with a compound of formula (V) according to process (b) may be effected in conventional manner, for example using excess amine as solvent or alternatively using an organic solvent, such as dichloromethane or dimethyl formamide. The leaving group 1?- may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy. The reaction may optionally be carried out in the presence of a base such as sodium hydride or potassium t- butoxide. In process (c) the groups R^ and R^ may be introduced by standard methods. Thus for example a halo substituent may be introduced by reaction with the appropriate halogen e.g. Br2 or I2. An alkyl group e.g. t-butyl may be introduced by reaction with isobutylene (CH3)2C=CH2- This method may be used to prepare compounds wherein R and R2 are not identical. Reduction of an amide according to process (d) may be effected using a suitable reducing agent such as lithium aluminium hydride and an inert solvent such as diethyl ether or tetrahydrofuran. Reduction of a compound (I) wherein X represents C=O according to process (e) may be effected similarly. It will be appreciated that when X in formula (VII) or (VIII) represents C=O this will be reduced simultaneously. The compounds of formula (II) can be prepared under standard alkylation conditions by reacting compounds of formula (IX) : lA(CH 2 ) n -Ll Formula (IX) in which L^» 1 and n are as hereinbefore defined, with compounds of formula (V) as hereinbefore defined. The reaction is suitably carried out under analogous conditions to those described above for process (b). It will be appreciated that in compounds of formula (IX) the leaving groups L^ and 1-2, are preferably selected so that the compound of formula (V) reacts selectively with I-A For example, in a compound of formula (IX) L* is suitably hydroxy and \2 is suitably halo. Compounds of formula (III) may be prepared using standard procedures well known in the art. Compounds of formula (IV) where X is O or S can be prepared by reacting a compound of formula (HI) as hereinbefore defined with a compound of formula (IX) as hereinbefore defined. In this reaction both I-, and 1-2 can be identical, for example halo such as bromo. The reaction is suitably carried out in the presence of a weak base such as potassium carbonate. Alternatively the reaction may be carried out under phase transfer conditions, for example using benzyltriethylammonium chloride in the presence of a strong base such as sodium or potassium hydroxide. Compounds of formula (IV) where X is C=O may be prepared by Friedel Craft acylation of the appropriate substituted phenyl derivative with an acylating agent of the formula Hal-C(O)-(CH2) n L^- Preferably Hal represents chloro and U- represents bromo. The reaction may be effected using standard conditions, for example in a solvent such as dichloromethane. The Friedel Craft catalyst may be for example aluminium trichloride or stannic chloride. Compounds of formula (V) are commercially available and may be prepared by standard literature methods. Compounds of formula (VI) may be prepared according to one of the general methods (a), (b) or (d) described herein. Compounds of formula (VII) may also be prepared according to the general processes described herein, e.g. processes (a), (b) or (c). Compounds of formula (VIII) may be prepared by acylation of a compound of formula (V), for example with an appropriate acid chloride or ester, which may itself be prepared from a compound of formula (IN) by standard methods. Alternatively a compound (VIII) may be prepared by a method analogous to process (a). Compounds of formula (IX) are commercially available or may be prepared by standard methods. 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. The compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neurons. 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 anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal. The compounds also have antioxidant properties and are therefore expected to be useful in the treatment of conditions in which free radicals are implicated, for example prevention of ischemic cell damage. The invention also provides a method of treatment of conditions or diseases 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) as hereinbefore defined or a pharmaceutically acceptable salt thereof. Thus for example, the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age- related memory 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. In a further aspect the invention also provides the use of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition in which free radicals are implicated and/or in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal. For use in medicine, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The compounds of the invention 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, 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 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. 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 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. Alternatively 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. BIOLOGICAL DATA Ca 2+ Current Measurement Cell preparations Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca 2+ currents. Solutions The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL 2 , 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 external solution for recording Ca 2+ channel currents contained in mM: BaCL 2 , 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCL 2 , 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 20 mM stock solution. At the 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, Journal of Physiology (1988), 404, 767-784). RESULTS Ca 2+ currents Peak voltage gated Ca + channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba + as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV 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 control value to relate the drug affected current to. Block by 20 μM drug was assessed 3 minutes after drug application. Compounds of the invention gave percentage inhibition of plateau Ca 2+ current of greater than 60%. Preparation 1 1 -[6-oxo-6-(4-hydroxy-3,5-di-tert-butylphenyl)hexyI]bromide 2,6-Di-tert-butylphenol (5.15g) and 6-bromohexanoyl chloride (4.2ml) were stirred together in anhydrous dichloromethane (40ml). The reaction mixture was cooled to -70°C and stannic chloride (5.9ml) in anhydrous dichloromethane (75ml) was added dropwise. The reaction mixture was stirred for lh. Water was added and the mixture extracted with ether. The organic phase was washed with water and dried with anhydrous sodium sulphate. The solvent was removed in vacua and the product purified by silica chromatography using hexane/ether mixtures as elutant. The title compound was obtained (8.47g 89%) M.P. 78-82°C Preparation 2 l-[8-oxo-8-(4-hydroxy-33-di-tertbutylphenyl)octyl]bromide Substituting 8-bromooctanoylchloride (0.65g) for 6-bromohexanoylchloride in Preparation 1 above and using appropriate molar quantities of the other reagents gave the title compound (1. lOg quantitative yield) M.P. 115-118°C. Preparation 3 7-(4-Hydroxy)-3,5-di-tert-butyI)thiophenoxy-l-bromoheptane A mixture of water (240ml) and dichloromethane (21ml) were stirred together under argon. Sodium hydroxide (0.4g, 10 mmol) was added and stirred until dissolved. Benzyltriethyl-ammonium chloride (11.78g, 51.7 mmol), dibromoheptane (4.32g 16.7 mmol) and 2,6-di-te-ι-butyl-4-mercaptothiophenol (2g, 8.4 mmol; EPA 190682) were added and the reaction mixture heated until the internal temperature reached 60°C. The temperature was maintained until the reaction was complete. The mixture was allowed to cool and dichloromethane (80ml) was added. The organic phase was separated, washed with brine and dried over sodium sulphate. Solvent was removed in vacua. The resulting oil was purified by silica chromatography using hexane as elutant to give the title compound (3.90g) in quantitative yield. Mass spectroscopy gave a mass ion m /z:416 (M + ) Preparation 4 2,6-Di-tert-butyl-l,4-benzohydroquinone 2,6-Di-tert-butyl-l,4-benzoquinone (5g, 22.7 mmol) was stirred in hexane (250ml) and acetic acid (90ml) under argon. Zinc powder (lOg) was added over 30min. The reaction mixture was left to stir for lh. The reaction mixture was filtered and the filtrate washed with a dilute solution of sodium hydrosulphite. The hexane solution was extracted with 5% sodium hydroxide solution containing a trace of sodium hydrosulphite. Acidification of the basic extract with hydrochloric acid gave a solid which was collected by filtration. Recrystallisation of this solid from hexane gave the title compound (2.724g, 54%) m.p. 103-105°C. Preparation 5 7-(4-Hydroxy-3,5-di-tert-butyl)phenoxy-l-bromo-heptane A mixture of water (240ml) and dichloromethane (25ml) were stirred under argon. Sodium hydroxide (0.54g, 13.5 mmol) was added and stirred until dissolved. Benzyltriethylammonium chloride (16.05g, 70.5 mmol), dibromoheptane (5.94g, 23.0 mmol) and 2,6-di-tert-butyl-l,4-benzohydroquinone (2.724g, 12.3 mmol) were added. The reaction mixture was heated until an internal temperature of 60°C had been achieved. The mixture was then refluxed for 16h. Dichloromethane (80ml) was added and the mixture stirred for lOmin. The organic phase was separated, washed with brine and dried over sodium sulphate. The solvent was removed in vacua and the residue purified by silica chromatography using dichloromethane as elutant. The title compound (6.24g) was obtained as an oil. Preparation 6 7-Bromoheptanoyl chloride ω-Bromoheptanoic acid (9.0g, 43.0 mmol) was stirred and heated with thionyl chloride (5ml) at 100°C for 96h. The mixture was allowed to cool and toluene (50ml) was added. The solvent was removed in vacua. Kugelrohr distillation of the residue gave the title compound (8.79g) b.p. 145° at 0.03mbar. Preparation 7 l-[7-Oxo-7-(4-hydroxy-3,5-di-tert-butylphenyl)heptyl]bromide 2,6-Di-tert-butylphenol (7.06g, 34.2 mmol) was stirred under argon in dichloromethane at -70°C. 7-Bromoheptanoyl chloride (7.79g, 34.2 mmol) in dichloromethane (40ml) was added. Stannic chloride (8ml) in dichloromethane (50ml) was added over approx. 30min. The reaction mixture was stirred at -70°C for 4h. Ice cold water (50ml) was added and the mixture extracted with ether. The ether solution was washed with brine, dried over sodium sulphate and the solvent removed in vacuo. The residue, an oil, was purified by silica chromatography using hexane: ether (9:1) as elutant. This gave the title compound (12.19g) as an oil. Example 1 l-[6-oxo-6-(4-hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine hydrochloride Piperidine (1ml) was added to l-[6-oxo-6-(4-hydroxy-3, 5-di-tert- butylphenyl)hexyl]bromide (0.7 lg) in anhydrous dichloromethane and stirred under nitrogen at room temperature for four days. The reaction mixture was washed successively with dilute hydrochloric acid, aqueous sodium hydroxide and water. After drying with sodium sulphate the solvent was removed in vacuo. The product was dissolved in anhydrous ether and treated with a slight excess of 1M hydrogen chloride in ether. The resulting solid was collected by filtration and recrystallised from ethylacetate/methanol mixture to give the title compound (0.40g 54.1%). M.P. 161- 166°C. Found : C, 69.13%; H, 9.55%; N, 3.29%; CI, 8.22% (C 2 5H 41 NO 2 .HCl. 0.5 H 2 O) requires C, 69.33%; H, 10.00%; N, 3.23%; CI, 8.19%. Example 2 l-[8-oxo-8-(4-hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine hydrochloride Piperidine (1.30ml) was added to l-[8-oxo-8-(4-hydroxy-3,5-di-tert- butylphenyl)octyl] bromide (1.05g) in anhydrous dichloromethane (20ml). The mixture was stirred under nitrogen at room temperature until the reaction was complete. The reaction mixture was washed succesively with dilute hydrochloric acid, aqueous sodium hydroxide and water. After drying with anhydrous sodium sulphate, the solvent was removed in vacuo. The product was dissolved in anhydrous ether and treated with a slight molar excess of ethereal hydrogen chloride. The resulting solid was collected by filtration and recrystallised from ethyl acetate/methanol mixtures to give the title compound (0.4 lg 36%) M.P. 160-162°C Found: C, 71.54%; H, 9.89%; N, 2.93%; CI, 8.34% (C27H 45 NO HCl) requires C, 71.73%; H, 10.26%; N, 3.10%; CI, 7.84% Example 3 l-[6-(4-Hydroxy-3,5-di-tert-butyIphenyl)hexyl]piperidine hydrochloride Lithium aluminium hydride (9.7 lg) suspended in anhydrous diethyl ether (100ml) and a solution of l-[6-oxo-6-(4-hydroxy-3,5-bis-tert-butylphenyl)hexyl] piperidine (2.0g) in anhydrous diethyl ether (20ml) was added dropwise. The reaction was left to stir at room temperature for two days. The reaction mixture was treated with brine. The ether layer was separated, dried with anhydrous sodium sulphate and the solvent removed in vacuo. The product was dissolved in anhydrous ether and treated with a slight molar excess of hydrogen chloride in ether. The resulting solid was collected by filtration and recrystallised from ethyl acetate to give the title compound (0.37g, 17%) M.P. 152- 153°C Found: C, 72.81%; H, 10.37%; N, 3.38%; CI, 8.28% (C25H43NO.HCI) requires C, 73.22%; H, 10.81; N, 3.42%; CI, 8.65% Example 4 1 -[8-(4-Hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine hydrochloride Lithium aluminium hydride (0.20g) was suspended in anhydrous diethyl ether (70ml) and a solution of l-[8-oxo-8-(4-hydroxy-3,5-di-tert-butyl-phenyl)octyl]piperidine (0.43g) in anhydrous diethyl ether (5ml) was added dropwise. The reaction was left to stir at room temperature for two days. The reaction mixture was treated with brine. The organic phase was dried with anhydrous sodium sulphate and the solvent removed in vacuo. The product was dissolved in anhydrous ether and treated with a slight molar excess of hydrogen chloride in diethyl ether. The resulting solid was collected by filtration and recrystallised from ethyl acetate/methanol to give the title compound (0.40g 89%) M.P. 145-146°C Found: C, 73.68%; H, 10.59%; N; 3.20%; CI, 8.68% (C27H47NO.HCI) requires C, 74.02%; H, 11.04%; N, 3.20%; CI, 8.09% Example 5 l-[7-(4-Hydroxy-3 -di-tert-butyl)thiophenoxyheptyl]piperidine hydrochloride 7-(4-Hydroxy-3,5-di-tert-butyl) thiophenoxy-1-bromoheptane (3.41g, 8.2 mmol) was stirred under argon with an 80% oil dispension of sodium hydride (0.26g, 10.8 mmol) in anhydrous dimethylformamide. Piperidine (0.8ml) was added over lOmin and the reaction mixture heated at 60°C for 16h. The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The organic phase was evaporated. The residue was dissolved in dichloromethane and agitated with an excess of 50% V/V hydrochloric acid. The organic phase was washed with brine, dried over sodium sulphate and evaporated in vacuo. The resulting oil was purified by silica chromatography using dichloromethane/methanol mixtures as elutant. The product was recrystallised from ethyl acetate to give the title compound (0.334g, 10% yield), M.Pt. 122-123°C Found: C, 68.14; H, 9.79; N, 3.09; CI, 7.65% (C26H45NOS. HC1) requires C, 68.46; H, 10.16; N, 3.07; CI, 7.77% Example 6 l-[7-(4-Hydroxy-3,5-di-tert-butyI)phenoxyheptyl]piperidine hydrochloride 7-(4-Hydroxy-3,5-di-tert-butyl)phenoxy-l-bromoheptane (6.24g, 15.6 mmol) was stirred with piperidine (45ml) in dichloromethane (70ml) under argon for 48h. The reaction mixture was washed with 5% aqueous sodium hydroxide and brine and dried over sodium sulphate. The solvent and excess piperidine were removed in vacuo. The resulting oil was purified by silica chromatography using dichloromethane (90): methanol (10): aqueous ammonia (1), as elutant. The product was dissolved in dichloromethane and washed with 50% V/V hydrochloric acid . The organic phase was separated and dried over sodium sulphate. The solvent was removed in vacuo and the resulting oil crystallised from isopropyl acetate to give the title compound (0.769g) m.p. 166-167°C. Found: C, 70.96; H, 10.54; N, 3.18; CI, 8.06% (C2.5H45NO2.HCI.O.25H2O) requires C, 70.50; H, 10.24; N, 3.32; CI, 8.08% Example 7 l-[7-Oxo-7-(4-hydroxy-3,5-di-tert-butylphenyl)heptyl]piperidine hydrochloride l-f7-Oxo-7-(4-hydroxy-3,5-di-tert-butylphenyl)heptyl]bromide (12.10g, 30.4 mmol) was stirred in dichloromethane (100ml). Piperidine (15.5ml) was added and the mixture stirred at room temperature for 48h. The reaction mixture was washed with water and dried over sodium sulphate. Solvent was removed in vacuo to give an oil which crystallised on trituration with ether. The product was purified by recrystallisation from ethyl acetate/methanol to give the title compound (6.371g) m.p. 165-167°C. Found: C, 70.88; H, 9.89; N, 3.30; CI, 7.76% (C26H45NO.HCI.) requires C, 71.28; H, 10.12; N, 3.20; CI, 8.09%

Claims: Claims 1. A compound of formula (I) : 5 Formula (I) wherein R! represents C^.g-tlkyl, halogen or phenyl; R 2 represents hydrogen, Ci.galkyl, halogen or phenyl; R^ represents hydroxyl or a group convertible thereto in vivo ; 10 R4 represents C \ _6-Ukyl ; p is zero, 1 or 2; X represents -CH2-, -C=O, O or S; n is an integer from 4 to 10; m is an integer from 3 to 8; 15 or a salt thereof. 2. A compound according to claim 1 wherein one or both of R! and R 2 represents a branched Ci.galkyl group. 20 3. A compound according to either claim 1 or claim 2 wherein p represents zero. 4. A compound according to any of claims 1 to 3 wherein n is an integer from 5 to 8. 25 5. A compound according to any of claims 1 to 4 wherein m is an integer from 4 to 6. 6. A compound of formula (I) selected from: ' 30 l-[6-oxo-6-(4-hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine, l-[8-oxo-8-(4-hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine, l-[6-(4-Hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine, l-[8-(4-Hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine, l-[7-(4-Hydroxy-3,5-di-tert-butyl)thiophenoxy-heptyl]piperidine, l-[7-(4-Hydroxy-3,5-di-tert-butyl)phenoxyheptyl]piperidine, l-[7-Oxo-7-(4-hydroxy-3,5-di-tert-butylphenyl)heptyl]piperidine, or a salt thereof. 7. A process for the preparation of a compound of formula (I) as hereinbefore defined, which process comprises: (a) to prepare a compound (I) wherein X is O or S, reaction of a compound of formula (II): (CH 2 ) m N-(CH 2 ) n -L Formula (II) in which m, n, R^ and p are as defined in formula (I) and L^ is a group displaceable with a nucleophile with a compound of formula (III) : Formula (III) in which X* is O or S and R*, R 2 and R^ are as defined in formula (I); or (b) reaction of a compound of formula (IV) : Formula (IV) in which R , R 2 , R^, X and n are as defined for formula (I) and L 2 is a leaving group with a compound of formula (V) : (CH 2 ) m NH Formula (V) in which m, R^ and p are as defined in formula (I); (c) introduction of the groups R* and/or R 2 by reaction of a compound of formula (VI) : Formula (VI) (wherein one of R a and R 2a is hydrogen and the other is selected from hydrogen, halogen, Cj.galkyl or phenyl, and R^, R 4 , χ t n, m and p are as defined for formula (I)) with a compound serving to introduce R and/or R 2 ; (d) to prepare a compound where X is -CH2-, S or O, reduction of an amide of formula (VII) or (VIII) : Formula (VII) Formula (VHI) (e) conversion of a compound of formula (I) to a different compound of formula (I); followed if desired by salt formation. 8. A method of treatment of a condition in which free radicals are implicated, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof. 9. A method of treatment of a condition or disease caused or exacerbated by 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 formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof. 10. Use of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition in which free radicals are implicated. 11. Use of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal. 12. A pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Inventors: BROWN THOMAS HENRY, COOPER DAVID GWYN, KING RONALD JOSEPH, BROWN, THOMAS, HENRY, COOPER, DAVID, GWYN, KING, RONALD, JOSEPH
Applicants: BROWN THOMAS HENRY, COOPER DAVID GWYN, KING RONALD JOSEPH, SMITHKLINE BEECHAM PLC, BROWN, THOMAS, HENRY, COOPER, DAVID, GWYN, KING, RONALD, JOSEPH
Application year: 1993
Main classification: C07D295
IPC codes: A61K31, A61P3, A61P9, A61P25, C07D295