4-AMINOPIPERIDINE DERIVATIVES OF TETRAHYDRONAPHTHALENE, CHROMANS AND THIOCHROMANS

Abstract: 1,2,3,4-tetrahydronaphthalenes, chromans and thiochromans, of formula (I), wherein r, s and X are as defined in the specifications, R<1>, R<2>, R<3> and R<4> are various substituents, also as defined in the specification, pharmaceutical compositions containing them and uses of them for the therapeutic treatment of neurological disorders.

Description: 4-AMINOPIPERIDINE DERIVATIVES OF TETRAHYDRONAPHTALENE, CHROMANS AND THIOCHROMANS The present invention relates to chemical compounds, in particular 1 ,2,3,4- tetrahydronaphthalenes, chromans and thiochromans, to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to 1,2,3,4-tetrahydronaphthalenes, chromans and thiochromans, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders. Neurological disorders, for which the present compounds are useful, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and ATDS-related dementia. The compounds useful in the present invention are believed to act by binding with the [ 3 H]-emopamil binding site. Background Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5-HT 2 receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al, Br. J. Pharmacol. 113 : 379- 384, 1994). [ 3 H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139- 148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [ 3 H]-emopamil binding site is localised to the endoplasmic reticulum. Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ 3 H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMD A receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. Summary of the Invention In one aspect the present invention comprises a class of compounds that show selective action at the [ H]-emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors, and which exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil. Accordingly, the present invention provides compounds of formula (I): (i) wherein: R 1 and R 2 are independently selected from hydrogen, optionally substituted Cι-6alkyl, optionally substituted C -6 alkenyl, optionally substituted C 3 .6alkynyl wherein said optional substituents are chosen from one or more groups selected from halo, nitro, hydroxy, Cj. 6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι -6 alkylamino, N,N-(Cι.6alkyl)2amino, Cι. alkoxycarbonyl, N-Cj. 6 alkylcarbamoyl or N,N-(Cι-6alkyl) 2 carbamoyl, or R or R 2 is a group of the formula: B-(CH 2 )- (IA) wherein B is aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C 3- ι 2 cycloalkyl or C 3 -ι 2 cycloalkyl fused to a benzene ring; q is 0, 1, 2, 3, 4, 5 or 6; and wherein said aryl, heteroaryl or heterocycle may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C 2-6 alkenyl, C2-6 lkynyl, 6 alkanoyl, Ci-ealkanoyloxy, N-(Cι- 6 alkyl)amino, N,N-(Cι^alkyl) 2 amino, Ci-βalkanoylamino, N- (Cι.6alkyl)carbamoyl, N,N-(Cι- 6 alkyl) 2 carbamoyl, Cι -6 alkylS(O) a wherein a is 0, 1 or 2, Ci- 6 alkoxycarbonyl, -V-(Ci -6 alkyl)sulphamoyl, N,N-(Cι.6alkyl) 2 sulphamoyl and phenylCι -6 alkyl; and a heterocycle or a heteroaryl ring containing an -NH- group may be optionally substituted on this nitrogen with Ci-ealkyl, C 2-6 alkenyl, C -6alkynyl, Cι -6 alkanoyl, Ci-βalkylsulphonyl or phenylCj-βalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι -6 alkyl, C 2-6 alkenyl, C . 6 alkynyl, Cι -6 alkoxy, Cι -6 alkanoyl, N- (Cι-6alkyl)amino, d-βalkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι. 6alkyl) 2 carbamoyl, C 1- 6alkylS(O) a wherein a is 0, 1 or 2, d-βalkoxycarbonyl, N-(Cι. 6 alkyl)sulphamoyl, N,N-(Cι. 6 alkyl) 2 sulphamoyl or phenylCι. 6 alkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with Cι -6 alkyl, C^alkenyl, C 2-6 alkynyl, Cι. 6 alkanoyl, Cι -6 alkylsulphonyl; R 3 is halo, hydroxy, cyano, nitro or C 2-6 alkenyl; R 4 is d-βalkyl; X is -CH 2 -, -O- or -S-; r is 0, 1, 2, 3 or 4, wherein the values of R 3 may be the same or different; and s is 0, 1, 2 or 3 wherein the values of R 4 may be the same or different; or a pharmaceutically-acceptable salt or an in v/ ' vo-hydrolysable ester, amide or carbamate thereof. In another aspect, the invention comprises a method for using compounds of Formula (I) for the treatment of neurological disorders such as stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and ALDS-related dementia In a further aspect, the invention comprises methods for making compounds of formula (I)- In yet another aspect, the invention comprises pharmaceutical compositions comprising compounds of formula (I) together excipients, diluents or stabilisers, as further disclosed herein. Detailed description of the Invention In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. A similar convention applies to "alkenyl", "alkynyl" and other radicals, for example "phenylCι- 6 alkyl" includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. The term "halo" refers to fluoro, chloro, bromo and iodo. The term aryl refers to an unsaturated carbon ring. Preferably aryl is phenyl, naphthyl or biphenyl. More preferably aryl is phenyl. The term "heteroaryl" or "heteroaryl ring" refers to, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of such heteroaryls include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyi, isoxazolyl, pyridyl, pyridyl- -oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl. The term "heterocyclyl" or "heterocyclic ring" refers to, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Examples of such heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. In the present invention, examples of Ci-βalkyl include methyl, ethyl, isopropyl and t- butyl; include benzyl, phenyl ethyl and phenylpropyl; examples of Ci-βalkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t- butoxycarbonyl; examples include methoxy, ethoxy and propoxy; examples of Cι. 6 alkanoylamino include formamido, acetamido and propionylamino; examples of Cι-6alkylS(O) a where a is 0, 1 or 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of Ci-βalkylsulphonyl include mesyl and ethylsulphonyl; examples of Cj-βalkanoyl include propionyl and acetyl; examples of Ci-βalkanoyloxy include propionyloxy and acetyloxy; examples of N-Cι -6 alkylamino include N-methylamino and N-ethylamino; examples ofN,N-(Cι -6 alkyl) 2 amino include N,N-dimethylamino, N,N-diethylamino and N-ethyl- N-methylamino; examples of C3_ι 2 cycloalkyl include cyclopropyl and cyclohexyl; examples of C 3 -ι 2 cycloalkyl fused to a benzene ring are 1,2,3,4-tetrahydronaphthyl and 2,3- dihydroindenyl; examples of C 3 -6alkenyl include allyl and 1-propenyl; examples of C 2- 6alkenyl include vinyl, allyl and 1-propenyl; examples of C 3- 6alkynyl include 1-propynyl and 2-propynyl; examples of C 2-6 alkynyl include ethynyl, 1-propynyl and 2-propynyl; examples of haloCι -6 alkyl include 2-chloroethyl, trifluoromethyl and 2-bromopropyl; examples ofN-(C 1-6 alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples ofN,N-(Cι. 6 alkyl) 2 sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N- ethylsulphamoyl; examples ofN-(C 1-6 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl, and examples of N,N-(Ci. 6 alkyl) 2 carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl. Preferably R 1 and R 2 are independently selected from hydrogen and optionally substituted C^aH yl or R 1 or R 2 is a group of the formula (IA) as defined hereinabove wherein B is aryl and q is 1 ; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring. More preferably R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-salkyl and benzyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring. Particularly R 1 and R 2 are independently selected from hydrogen, methyl, n-propyl, ISO- propyl, iso-amyl and benzyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form pipeπdine ring Preferably r is 0 Preferably s is 0 In one aspect of the invention preferably X is CH 2 In another aspect of the invention preferably X is S In a further aspect of the invention preferably X is O Therefore in a preferred aspect of the invention there is provided a compound of formula (I) wherein R 1 and R 2 are independently selected from hydrogen and optionally substituted Cj. 6 alkyl or R 1 or R 2 is a group of the formula (IA) as defined hereinabove wherein B is aryl and q or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, r is O, s is 0, and X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof In a more preferred aspect of the invention there is provided a compound of formula (I) wherein R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-salkyl and benzyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, r is O, s is 0, and X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof In a particular aspect of the invention there is provided a compound of formula (I) wherein R and R 2 are independently selected from hydrogen, methyl, n-propyl, iso-propyl, ISO- amyl and benzyl, or R and R 2 together with the nitrogen atom to which they are attached form pipeπdine ring, r is O, s is 0, and X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof Preferred compounds of the invention are those of Examples A preferred aspect of the invention relates to any one of the Examples Preferred aspects of the invention relate to a compound of formula (I) as hereinbefore defined or a pharmaceutically-acceptable salt thereof Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloπde, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpipeπdine, N-ethylpipeπdine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions A preferred pharmaceutically- acceptable salt is a sodium salt The compounds of formula (I) possess a chiral centre at the 1-position of the 1,2,3,4- tetrahydronaphthalene ring and the 4-positιon of the chroman and thiochroman ring Certain compounds of formula (I) may also have other chiral centres, for example certain of the values of R , R , R , R and certain of the optional substituents may possess chiral centres It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I) that inhibit the [ 3 H]-emopamιl binding site The invention further relates to all tautomeric forms of the compounds of formula (I). It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms It is to be understood that the invention encompasses all such solvated and unsolvated forms In v/vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound Such esters, amides and carbamates can be identified by administering, for example intravenously to a test ammal, the compound under test and subsequently examining the test animal's body fluids Suitable in v/vo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl An in v/vo-hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol Suitable pharmaceutically-acceptable esters for carboxy include Ci-βalkoxymethyi esters for example methoxymethyl, Ci 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phtha dyl esters, C 3 8 cycloalkoxy-carbonyloxyCι 6 lkyl esters for example 1 - cyclohexylcarbonyloxyethyl, l,3-dιoxolen-2-onylmethyl esters for example 5-methyl-l,3- dιoxolen-2-onylmethyl, and Cι -6 alkoxycarbonyloxyethyl esters for example 1 - methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention An /// v/vo-hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy A selection of in v/vo-hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylamιnoethyl)-A - alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof which process (wherein R 1 , R 2 , R 3 , R 4 , X, r and s are, unless otherwise specified, as defined in formula (I)) comprises of a) reacting a compound of formula (II) (II) wherein L is a leaving group; with a compound of formula (III): (III) wherein R 3 and R b are R 1 and R 2 , except hydrogen or R a and R b are an amino protecting groups; b) reacting a compound of formula (IV): (IV) wherein L is a leaving group; with a compound of formula (V): R V H Rb (V) wherein R a and R b are as hereinbefore defined; c) for compounds of formula (I) wherein R 1 and R 2 are not both hydrogen; reacting a compound of formula (VI): (VI) with a compound of formula (VII): R d -L (VII) wherein L is a leaving group and i) R c is R 1 except hydrogen or R c is an amino protecting group and R α is R except hydrogen; or ii) R c is R 2 except hydrogen or R c is an amino protecting group and R d is R except hydrogen; d) reacting a compound of formula (VIII): (VIII) with a compound of formula (III); e) reacting a compound of formula (IX): (IX) with a compound of formula (V); f) for compounds of formula (I) wherein one of R and R is optionally substituted Cι -6 alkyl or a group of formula (IA) as defined above and the other is not hydrogen wherein q>0; reacting a compound of formula (VI) with a compound of formula (X): (X) wherein: i) R c is R except hydrogen and R e is optionally substituted Cι -5 alkyl or a group of formula (IA) as defined above wherein q is 0-5; or ii) R c is R 2 except hydrogen and R e is optionally substituted Cι -5 alkyl or a group of formula (IA) as defined above wherein q is 0-5; or g) for compounds of formula (I) wherein one of R 1 and R is optionally substituted Cι. 6 alkyl or a group of formula (IA) as defined above wherein q>0; by reducing a compound of formula (XI): (XI) wherein: i) R >f i :s„ τ R> l and R ε is optionally substituted d. 5 alkyl or a group of formula (I A) as defined above wherein q is 0-5; or ii) R f is R 2 and R 8 is optionally substituted Cι. 5 alkyl or a group of formula (IA) as defined above wherein q is 0-5; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; or in) forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate L is a leaving group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group Specific reaction conditions for the reactions a), b) and c), above, are as follows Amines and compounds with suitable leaving groups are reacted together under standard alkylation conditions For example in the presence of a base, such as an inorganic base for example sodium carbonate or sodium hydroxide or an organic base such as Hunig's base or excess amine, in the presence of an inert solvent for example tetrahydrofuran, dimethyl acetamide or toluene and at a temperature in the range of 50-120 °C, preferably at or near reflux Compounds of formula (IV) may be prepared according to the following scheme (IVb) Examples of suitable functional group interconversion are for example conversion to L = chloro by reaction of (IVb) with thionyl chloride, or conversion to L = -O-Tosyl by reaction of (IVb) with tosyl chloride Compounds of formula (VI) may be prepared according to the following scheme R Pg l) Reductive animation N (VIE) »- u) Deprotection + (VI) H (π) l) Alkylation (Via) u) Deprotection wherein Pg is an amino protecting group, suitable values are discussed hereinbelow Compounds of formula (II), (III), (IVa), (V), (Via) and (VII) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art Specific reaction conditions for the reactions d), e) and f), above, are as follows: Ketones or aldehydes may be reacted with amines under standard reductive amination conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature. Compounds of formula (IX) may be prepared according to the following scheme: Compounds of formula (VIII), (IXa), (IXb) and (X) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Specific reaction conditions for the reactions g), above, are as follows: Compounds of formula (XI) are reduced under standard reduction conditions for reducing an amide to an amine. For example, in the presence of a reducing agent such as borane, sodium borohydride or lithium aluminium hydride, in an inert solvent such as toluene or tetrahydrofiiran, and at a temperature in the range of 50-120 °C, preferably at or near reflux. Compounds of formula (XI) may be prepared according to the following scheme: It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoro acetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. In order to use a compound of the formula (I) or a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The pharmaceutical compositions of compounds of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions A preferred route of administration is intravenously in sterile lsotonic solution In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0 05 to 75 mg/kg body weight (and preferably of 0 1 to 30 mg/kg body weight) is received This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy A further feature of the present invention is a compound of formula (I) and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament Conveniently this is a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament to inhibit the [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being. According to a further feature of the invention there is provided a method of inhibiting of the [ 3 H]-emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore. The following Biological Test Methods, Data and Examples serve to illustrate the present invention. Biological Test Methods H-Emopamil binding to guinea pig liver membranes The method of (-)-Η-emopamil binding was a modification of Zech, C , Staudinger R., Muhlbacher, J. and Glossmann, H Novel sites for phenylalkylamines characterisation of a sodium-sensitive drug receptor with (-)- 3 H-emopamil. Eur. J. Pharm 208: 1 19-130, 1991. The reaction mixture contained. Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulphonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4°C Radioligand: 0 96 nM (-)- 3 H-emopamil (Amersham) Guinea pig liver membranes: 40mg/mL original wet weight. Compounds: 1-300 nM. Total volume: 500 μl. This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 ml of wash buffer containing 10 mM Tris-HCl, 10 mM MgCl 2 , 0.2% BSA, pH 7 4 at 25 °C. Specific binding was defined with 10 μM emopamil. In general compounds with an ICso below 300nM in this test were of interest. Guinea-pig liver membrane preparation: Male guinea pigs were sacrificed by CO 2 asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4°C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4°C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4°C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4°C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 ml were stored at -70°C. H-D-888 binding to rat brain cortical membranes The method of 3 H-D-888 binding was a modification of Reynolds, I.J., Snowman, A.M. and Synder, S.H. (-)-[ H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986. The assay tubes contained the following: assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 radioligand: lηM 3 H-D888 (Amersham) rat cortical membranes: 6 mg/ml original wet weight compounds: 0.3-100 μM Total volume: 1000 μl This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 ml of wash buffer containing 20 mM Hepes, 20 mM MgCl 2 , pH 7.4. Specific binding was measured with 10 μM methoxyverapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the Η-D888 binding site would show a lack of selectivity. Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice. The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/ ml. Gerbil Global Model of Cerebral Ischaemia Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ± 2 °C, and is on an automatic 12 hour light cycle. The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 ml/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia. When they have regained the righting reflex and are beginning to walk around, they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery. Twenty-four hours post ischaemia gerbils are tested for spontaneous locomotor activity, using a Photobeam Activity System from San Diego Instruments. They are individually placed in Plexiglas chambers measuring 27.5 cm x 27.5 cm x 15 cm deep. The chambers are surrounded by photocells, and every time a beam is broken one count is recorded. Each gerbil is tested for two hours, and cumulative counts are recorded at 30, 60, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour. For the next two days no specific testing is performed, but the gerbils are observed two to three times per day for any unusual behaviours or obvious neurological symptoms (i.e. ataxia, convulsions, stereotypic behaviour). Four days post ischaemia the gerbils are sacrificed by decapitation and their brains removed and preserved in 10% buffered formalin. Brains were removed, fixed and stained with hematoxylin and eosin. Under a light microscope, hippocampal fields were observed and graded for damage to the CA1 subfield: 0 to 4 scale, with 0 representing no damage and 4 representing extensive damage. Transient focal ischaemia in rats The method was as described by Lin, T-N., He, Y.Y., Wu, G., Khan, M. And Hsu, C.Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24: 1 17-121, 1993, which model is considered to be relevant to the clinical situation. Male Long-Evans rats 250-350 g were used. Surgery leading to focal ischaemia was conducted under anaesthesia with 100 mg/kg ketamine and 5 mg/kg i.m. xylazine. Rectal temperature was monitored and maintained at 37.0 + 0.5 °C. The right middle cerebral artery (MCA) was exposed using microsurgical techniques. The MCA trunk was ligated immediately above the rhinal fissure with 10-0 suture. Complete interruption of blood flow was confirmed under an operating microscope. Both common carotid arteries were then occluded using nontraumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries. Twenty-four hours post occlusion, rats were killed under ketamine anaesthesia by intracardiac perfusion with 200 ml of 0.9% NaCl. The brain was removed and processed with 2% triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours. Data The following results were obtained in the H-Emopamil binding to guinea pig liver membranes test. Examples The invention is now illustrated but not limited by the following Examples in which unless otherwise stated :- (i) concentrations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere otherwise stated; (iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the formula I were generally confirmed by NMR and mass spectral techniques - proton magnetic resonance spectra were determined in DMSO- δ 6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, dt, double of triplets, m, multiplet; bm, broad multiplet; only major diagnostic peaks are indicated and unless otherwise stated l NMR is quoted; (vi) TLC's were monitored on silica gel plates: Silica Gel GHLF (Analtech), 250 microns, plates (2.5 x 10 cm). The detection methods used were UV light, iodine, and chloroplatinate. (vii) Kugelrohr distillation was using apparatus supplied by Aldrich Chemical Co; it is bulb- to-bulb short path distillation; the air bath temperature at which the material distills is denoted as the boiling point; (viii) intermediates were not generally fully characterized and purity was in general assessed mass spectral (MS) or NMR analysis; (ix) Solvents were dried over magnesium sulphate unless otherwise stated; and (x) the following abbreviations (also used hereinabove) may be used :- DMSO is dimethylsulphoxide; CDC1 3 is deuterated chloroform; THF is tetrahydrofiiran; DCM is dichloromethane; MeOH is methanol; TLC is thin layer chromatography; EA is Elemental Analysis; and DMAC is dimethyl acetamide. Example 1 4-Piperidino-N-( 1 ,2.3 ,4-tetrahydro- 1 -naphthalenvDpiperidine A flask under a nitrogen atmosphere was charged with 4-piperidinopiperidine (4.25 g; 24 mmol) and DMAC (20 ml). Potassium iodide (300 mg) was added followed by the addition of a solution of 1 -chloro- 1, 2,3, 4-tetrahydronaphthalene (Method G) (2.0 g, 12 mmol) in DMAC (6 ml). This solution was then heated in an oil bath at 60 °C for 20 hours. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried. Filtration and evaporation of solvent gave a yellow liquid (3.6 g) which solidified on standing. This was purified by Kugelrohr distillation to give the title compound as a viscous yellow oil (2.4 g), bp (air bath temperature) 160 °C at 100 mtorr. TLC (CH 2 Cl 2 :CH 3 OH: ΝH 4 OH, 89: 10: 1) R f 0.60; EA Calcd for C 20 H 3 oN 2 : C, 80.48; H, 10.13; N, 9.39; found: C, 80.45; H, 9.96; N, 9.06. Example 2 4-(N-Benzyl-N-methvπamino-l-(1.2.3.4-tetrahydro-l-naphthalenyl)piperidine A flask under nitrogen atmosphere was charged sequentially with N-( 1,2,3,4- tetrahydro-l-naphthalenyl)-4-piperidone (Method A) (0.39 g; 1.7 mmol) in MeOH (10 ml) and N-methylbenzylamine (0.31 ml, 2.4 mmol). The solution was treated with ethanolic hydrochloric acid (4.5M, 0.53 ml). To this stirred solution, sodium cyanoborohydride (0.17 g, 2.7 mmol) was added as a solid and the solution was stirred for 22 hours. The content of the flask was then concentrated. The residue was treated with aqueous potassium carbonate and extracted several times with ethyl acetate which was then dried. Filtration and removal of solvent gave a yellow oil (0.61 g) which was Kugelrohr distilled to yield the title compound (0.40 g), bp (air bath temperature) 175-182 °C at 100 mtorr. TLC R f 0.25 (1 :2 ether : hexane); ΝMR (CDC1 3 ) 2.22 (s, 3H), 3.65 (s, 2H), 3.82-3.85 (m, 1H), 7.03-7.44 (m, 8H), 7.70-7.72 (d, 1H); m/z 335 (M+H) + ; EA Calcd for C 23 H 30 N 2 : C, 82.58; H, 9.04; N, 8.37; Found: C, 81.76; H, 9.01; N, 8.42. Examples 3-10 Following the procedure of Example 2 and the appropriate starting materials the following compounds were prepared. All Kugelrohr boiling points for distillations are quoted at air bath temperature. Example 11 (S)-4-N-Isoamylamino-l-ri.2.3.4-tetrahvdro-l-naphthalenyl)piperidine A dry flask under nitrogen was charged with (S)-l-(l,2,3,4-tetrahydro-l-naphthalenyl)- 4-piperidone (Method D) (1 0 g, 4 36 mmol), isoamylamine (5 0 ml, 43 2 mmol), THF (20 ml) and MeOH (10 ml). Sodium cyanoborohydride (0 41 g, 6 58 mmol) was added followed by acetic acid (0 3 ml) and the solution was stirred overnight at ambient temperature After concentration, the residue was treated with sodium carbonate solution and extracted three times with ethyl acetate The combined organic extract was washed with brine and dried After filtration and removal of solvent the residue (1 7 g) was heated in a Kugelrohr to 70 °C at 100 mtorr to remove volatiles This residue was Kugelrohr distilled to give a yellow oil (1 05 g), bp (air bath temperature) 155 °C at 70 mtorr [α] D 23 + 52° (c, 0 443 in MeOH), NMR (CDC1 3 ) 0 88-0 91 (d, 6H), 3 81-3 84 (m, IH), 7 01-7 16 (m, 3H), 7 69-7 71 (d, IH), EA Calcd for C 20 H 32 N 2 C, 79 94, H, 10 73, N, 9 33, Found C, 79 79, H, 10 64, N, 9 29 Example 12 4-N.N-Dimethylamino-l-(3,4-dihvdro-2-//-benzothiopyran-4-yl)pipendine A dry flask under nitrogen was charged with l-(3,4-dιhydro-2-H-benzothιopyran-4-yl)- 4-pιpeπdone (Method F) (0 6 g, 2 4 mmol), dimethylamine hydrochloπde (0 24 g, 2 94 mmol), and 20 ml MeOH Sodium cyanoborohydride, 0 23 g (3 6 mmol) was added and the solution was stirred overnight at ambient temperature This was partitioned between saturated sodium carbonate solution and ethyl acetate The aqueous portion was again extracted with ethyl acetate an the combined organic extract was washed with brine and dried After filtration and removal of solvent the residue (0 7 g) which was Kugelrohr distilled to give a yellow oil (0 53 g), bp (air bath temperature) 140-150 °C at 90 mtorr, ΝMR (CDC1 3 ) 2 28 (s, 6H), 3 62-3 66 (m, IH), 7 01-7 16 (m, 3H), 7 49-7 53 (d, IH) Example 13 4-N-/7-Propylamιno- 1 -(3.4-dιhvdro-2-H-benzothιopyran-4-yDpιpeπdιne A dry flask under nitrogen was charged with l-(3,4-dιhydro-2-H-benzothιopyran-4-yl)- 4-pιpeπdone (Method F) (0 75 g, 3 0 mmol), THE (16 ml) and MeOH (8 ml) Added sequentially was A?-propylamιne (2 6 ml, 31 6 mmol), sodium cyanoborohydπde (0 30 g, 4 8 mmol) and acetic acid (0 3 ml) and the solution was stirred overnight at ambient temperature The contents were concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate The organic extract was washed with brine and dried After filtration and removal of solvent gave 0 90 g which was Kugelrohr distilled to give a yellow oil (0 49 g), bp (air bath temperature) 150-160 °C at 100 mtorr, ΝMR (CDC1 3 ) 0 89- 0 94 (t, 3H), 3 63-3 66 (m, IH), 6 97-7 08 (m, 3H), 7 50-7 53 (d, IH) Example 14 4-N-Isoamylamιno- 1 -( ,4-dιhydro-2-H-benzothιopyran-4-yl)pιpeπdιne Following the procedure in Example 13, a dry flask under nitrogen was charged with 1- (3,4-dιhydro-2- J-benzothιopyran-4-yl)-4-pιpeπdone (Method F) (1 0 g, 4 O mmol), THF (20 ml) and MeOH ( 10 ml) Added sequentially was isoamylamine (4 7 ml, 40 5 mmol), sodium cyanoborohydride (0 40 g, 6 42 mmol) and acetic acid (0 5 ml) and the solution was stirred overnight at ambient temperature Following the prescribed workup there was obtained an oil (1 65 g) which was Kugelrohr distilled to give a yellow oil (0 92 g), bp (air bath temperature) 170-180 °C at 100 mtorr NMR (CDC1 3 ) 0 88-0 90 (d, 6H), 3 63-3 67 (m, IH), 6 96-7 12 (m, 3H), 7 50-7 53 (d, IH), EA Calcd for Cι 9 H 30 N 2 S C, 71 65, H, 9 49, N, 8 79, Found C, 71 09, H, 9 46, N, 8 87 Example 15 4-(N-Benzyl-N-methvπamιno-l-(1.2.3.4-tetrahvdro-l-naphthalenyl)pιpeπdιne bismaleate salt A portion of 4-(N-benzyl-N-methyl)amιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl) pipeπdme (0 30 g) in ethanol (5 ml) was treated with a saturated solution of maleic acid in ether (12 ml) followed by dilution with additional ether (5 ml) After 20 hours at ambient temperature, the resulting white solid was collected by filtration, washed with ether and dried in vacuo to give 0 42 g Mp 195 5-196 1 °C, EA Calcd for C 23 H 3 oΝ 2 0 2C H4O 4 C, 65 71, H, 6 76, N, 4 94, Found C, 65 31, H, 6 81, N, 4 96 Examples 16-27 Using the procedure of Example 15, salts of the Examples were prepared The following bismaleate salts are provided by way of illustration Example 28 (S -4-N,N-Dimethylamino-l-(3,4-dihydro-2-H-benzothiopyran-4-yl piperidine A dry flask under nitrogen was charged with (S)-(-)-l-(3,4-dihydro-2-H- benzothiopyran-4-yl)-4-piperidone (Method G) (1.05 g, 4.24 mmol), and 16 ml of THF and 9 ml of methanol. Dimethylamine, 2.55 ml (5.1 mmol) of a 2M solution in THF, was added followed by sodium cyanoborohydride (0.40 g, 6.4 mmol). Acetic acid, 0.34 ml (6.4 mmol) was added and the solution was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was partitioned between sodium bicarbonate solution and ethyl acetate. The aqueous portion was again extracted with ethyl acetate an the combined organic extract was washed with brine and dried. After filtration and removal of solvent the residue (1.08 g) was purified by column chromatography on silica gel, eluting with methanolxhlorform (1 : 10) to give 0.29 g of a yellow oil; TLC (silica gel, 1 : 10 CH 3 OH:CHCl 3 ) R f 0.21; m/z 277 (M + H) + ; [α] D 24 + 9.0° (c = 0.56, methanol). EA Calcd for Cι 6 H 24 Ν 2 S: C, 69.52; H, 8.74; Ν, 10.13; Found: C, 69.1 1; H, 8.79; Ν, 9.84. This base, 0.26 g, was dissolved in 1.7 ml of ethanol and treated with 20 ml of an ethereal solution saturated with maleic acid. The resulting solid was collected and dried to give 0.36 g, mp 194.5-195.1 °C. EA Calcd for Cι 6 H 24 Ν 2 S-2C 4 H4θ4: C, 56.68; H, 6.34; N, 5.51; Found: C, 56.46; H, 6.33; N, 5.42. Example 29 (Sy4-N-Isoamylamino-l-(3,4-dihvdro-2-H-benzopyran-4-vDpiperidine A dry flask under nitrogen was charged with (S)-(-)-l-(3,4-dihydro-2-H-benzopyran-4- yl)-4-piperidone (Method I) (1.06 g, 4.58 mmol), and 17 ml of THF and 8.5 ml of methanol. Isoamylamine (0.44 g, 5.0 mmol) was added followed by sodium cyanoborohydride (0.43 g, 6.9 mmol). Acetic acid, 0.34 ml (6.4 mmol) was added and the solution was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was partitioned between sodium bicarbonate solution and ethyl acetate. The aqueous portion was again extracted with ethyl acetate an the combined organic extract was washed with brine and dried. Removal of solvent gave a residue (1.52 g) which was purified by Kugelrohr distillation to give 0.90 g of a yellow oil, bp 151-157 °C (air bath temperature) at 100 mtorr, homogeneous by TLC (silica gel, ethyl acetate) R f 0.11 ; m/z 303 (M + H) + ; [α] D 24 + 29° (c = 0.48, methanol). EA Calcd for C 19 H 30 N 2 O: C, 75.45; H, 10.00; N, 9.26; Found: C, 74.87; H, 10.03; N, 9.31. This base, 0.83 g, was dissolved in 4 ml of ethanol and treated with 45 ml of an ethereal solution saturated with maleic acid. The resulting solid was collected and dried to give 1.20 g, mp 176.5-177.6 °C. EA Calcd for Cι 9 H3 0 N 2 O 1.7C 4 H 4 O 4 : C, 62.00; H, 7.42; N, 5.61 ; Found: C, 61.88; H, 7.55; N, 6.01. Preparation of Starting Materials The starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of the starting materials used in the above reactions. Method A l-π,2.3,4-Tetrahvdro-l-naphthalenyD-4-piperidone A dry flask under a nitrogen atmosphere was charged with oxalyl chloride (1.5 ml, 23. 1 mmol) in DCM (15 ml) and was cooled to -76 °C. DMSO (3.0 ml, 42.2 mmol) in dichloromethane (15 ml) was added dropwise over 15 minutes. 4-Hydroxy-l-(l,2,3,4- tetrahydro-l-naphthalenyl)piperidine (Method B) (2.0 g, 8.6 mmol) in dichloromethane (20 ml) was added over 15 minutes. After 25 minutes triethylamine, (10.0 ml, 71.7 mmol), was added dropwise. The reaction was allowed to warm to ambient temperature and stirring continued overnight. The reaction was quenched with water (30 ml) and extracted twice with DCM which was then dried (MgSO 4 ). Filtration and removal of solvent gave a yellow oil (1.95 g). TLC: R f 0.70 (ethyl acetate); NMR (CDC1 3 ) 1.62-1.72 (m, 2H), 1.96-2.02 (m, 2H), 2.43-2.48 (m, 4H), 2.74-2.94 (m, 6H), 4.00-4.05 (m, IH), 7.03-7.32 (m, 3H), 7.77-7.85 (d, IH). Method B 4-Hydroxy- 1 -( 1.2, 3.4-tetrahvdro- 1 -naphthalenyPpiperidine Following the procedure of Example 1, 4-hydroxy piperidine (2.5 g, 12 mmol) and potassium iodide (0.25 g) in DMAC (10 ml) were reacted with l-chloro-1,2,3,4- tetrahydronaphthalene in DMAC (10 ml). The product, 2.7 g, was heated in a Kugelrohr at 90 °C at 150 mtorr to remove volatiles, leaving a residual beige solid (2.2g). Trituration of this material twice with ethyl acetate (2 x 5 ml), gave an off-white solid which was dried at 55 °C at 150 mtorr to give 1.38 g. Mp 109.5-1 10.5 °C; TLC R f 0.40 (ethyl acetate); NMR (CDC1 3 ): 3.65-3.69 (m, IH), 3.83-3.85 (m, IH); EA Calcd for C 15 H 2 ιNO: C, 77.88; H, 9.15; N, 6.05; Found: C, 77.58; H, 8.94; N, 5.99. Method C 1 -( 1.2.3 ,4-Tetrahydro- 1 -naphthalenyl)-4-piperidone A three-necked 250 ml flask equipped with a condenser, addition funnel and magnetic stirring bar was charged with l-amino-l,2,3,4-tetrahydronaphthalene (7.50 g, 50.7 mmol) potassium carbonate (0.5 g, 3.6 mmol) and ethanol (60 ml) and the content was brought to reflux. N-Methyl-N-ethyl-4-oxo-piperidinium iodide (Taschaen et al, J. Org. Chem. 1995, 60, 4324-4330.), (20.5 g, 76.2 mmol) in water (50 ml) was added dropwise over 45 minutes resulting in a reddish-brown coloration. After one hour, heating ceased and the reaction proceeded at ambient temperature overnight. After concentration, the residue was partitioned between water and ether which was dried. Removal of solvent afforded an oil (10.28 g). TLC: R f 0.58 (1 : 1 ethyl acetate exane); ΝMR (CDCK) 1.62-1.72 (m, 2H), 1.94-2.01 ( , 2H), 2.40- 2.51 (m, 4H), 2.74-2.93 (m, 6H), 4.00-4.04 (m, IH), 6.92-7.45 (m, 3H), 7.76-7.88 (d, IH). Method D (S)- 1 -( 1.2.3.4-Tetrahydro- 1 -naphthalenyl)-4-piperidone Using the procedure of Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.21 g, 30.5 mmol) was reacted with S(+)-l-amino-l,2,3,4-tetrahydronapthalene (3.0 g, 20.3 mmol), to give the title compound (4.60g). ΝMR (300 MHz) superimposable with that of Method C. Method E (R)- 1 -( 1.2.3.4-Tetrahvdro- 1 -naphthalenylV4-piperidone Using the procedure of Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.20 g, 30.48 mmol), was reacted with R(-)-l-amino-l,2,3,4-tetrahydronapthalene (2.9 g, 19.62 mmol) to give the title compound (4.49 g). TLC: R f 0.70 (ethyl acetate); ΝMR (CDC1 3 ) superimposable to that of Method C. Method F 1 -(3.4-dihydro-2-//-benzothiopyran-4-yl)-4-piperidone Using the procedure of Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.53 g, 31.7 mmol) was reacted with 4-amino-3,4-dihydro-2- -benzothiopyran (3.5 g, 21.2 mmol) to give the title compound (4.53 g). TLC, R f 0.78 (ethyl acetate); ΝMR (CDC1 3 ) 2.16-2.21 (m, 2H), 2.44-2.49 (m, 4H), 2.71-2.79 (m, 2H), 2.88-2.96 (m, 2H), 3.08-3.18 (m, 2H), 3.85-3.89 (m, IH), 6.97-7.12 (m, 3H), 7.58-7.62 (d, IH). Method G (S -l-(3,4-dihydro-2-H-benzothiopyran-4-yl)-4-piperidone Using the procedure of Method C, Λ^-ethyl-N-methyl-4-oxo-piperidinium iodide (11.9, 44 mmol) was reacted with S-(-)-4-amino-3,4-dihydro-2-H-benzothiopyran (4.87 g, 29.5 mmol) to give the title compound (6.76 g). NMR (300 MHz) is superimposable with that of the racemic material (Method F). Method H 1 -Chloro- 1.2,3, 4-tetrahydronaphthalene A flask under a nitrogen atmosphere was charged with 1,2,3,4-tetrahydro-l-naphthol (34.3 g; 0.23 mol) in dry diethyl ether (420 ml). Pyridine (4.7 ml) was added and the flask was cooled to 16 °C in a bath of water and ice. A solution of thionyl chloride (50.7 ml, 0.70 mol) in ether (140 ml) was then added dropwise in 25 minutes and stirring continued overnight while allowing the bath to warm to ambient temperature. The reaction mixture was then poured into cold brine (400 g ice and 800 ml brine) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2 x 150 ml) and the combined organic extract was dried with sodium sulphate. Filtration and removal of solvent in vacuo gave the title compound (36.9 g) as an oil. This material was used without further purification. Method I (S)-l-(3.4-dihvdro-2-H-benzopyran-4-yl)-4-piperidone Using the procedure of Method C, N-ethyl-N-methyl-4-oxo-piperidinium iodide (10.93 g, 40.6 mmol) was reacted with S-(-)-4-amino-3,4-dihydro-2-H-benzothiopyran (4.04 g, 27. 1 mmol) to give the title compound (6.40 g); TLC (silica gel, ether-hexane, 1 : 1) Rf 0.50; m/z 231 (M + H) + . Example 28 Following conventional procedures well known in the pharmaceutical art the following representative pharmaceutical dosage forms containing a compound of formula (I) can be prepared: (a) Tablet mg/tablet Compound of formula (I) 50.0 Mannitol, USP 223.75 Croscarmellose sodium 60 Maize starch 15.0 Hydroxypropylmethylcellulose (HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule mg/capsule Compound of formula (I) 10.0 Mannitol, USP 488.5 Croscarmellose sodium 15.0 Magnesium stearate 1.5 (c) Injection For intravenous administration, a compound of formula (I) is dissolved in an isotonic sterile solution (5 mg/ml).

Claims: CLAIMS: A compound of formula (I): (i) wherein: R and R are independently selected from hydrogen, Cι -6 alkyl, C 3 . 6 alkenyl and C 3 . βalkynyl wherein said Ci-βalkyl, C3-6 lkenyl and C 3-6 alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, Cj- 6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Ci-βalkylamino, N,N- (Cι -6 alkyl)2amino, Cι -6 alkoxycarbonyl, N-Cι.6alkylcarbamoyl, N,N-(Cι. 6 alkyl) 2 carbamoyl, a group of the formula (IA): B-(CH 2 )— (IA) wherein B is aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3-i 2 cycloalkyl or C 3- ι 2 cycloalkyl fused to a benzene ring; q is 0, 1, 2, 3, 4, 5 or 6; and wherein said aryl, heteroaryl or heterocycle is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C !-fi alkyl, C 2-6 alkenyl, Ci-βalkanoyl, Ci-βalkanoyloxy, ^-(C^alky^amino, N,N-(Cι^alkyl) 2 amino, C 1-6 alkanoylamino, N-(Cι. 6alkyl)carbamoyl, A N-(Cι-6alkyl) 2 carbamoyl, Ci -6 alkylS(0) a wherein a is 0, 1 or 2, Ci. βalkoxycarbonyl, N,N-(Ci-6alkyl) 2 sulphamoyl and phenylCi-βalkyl; and a heterocycle or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with C 2-6 alkenyl, C 2- 6alkynyl, Cι -6 alkanoyl, Ci-βalkylsulphonyl or phenylCi-βalkyl and a group wherein R 1 and R 2 together with the nitrogen atom to which they are attached in combination form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C 2- 6alkenyl, C 2 .6alkynyl, Cι. 6 alkoxy, Cj. βalkanoyl, Cι. 6 alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl) 2 amino, Ci-βalkanoylamino, N- (Cι^alkyl)carbamoyl, N,N-(Ci-6alkyl) 2 carbamoyl, Cι-6alkylS(O) a wherein a is 0, 1 or 2, Cι_ 6 alkoxycarbonyl, N,N-(Cι- 6 alkyl) 2 Sulphamoyl or phenylCj-βalkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with Cj-ealkyl, C 2- 6alkenyl, C 2 _6alkynyl, Cι_ 6 alkanoyl, Cι. 6 alkylsulphonyl; R 3 is selected from halo, hydroxy, Cι. 6 alkyl, Cι. c alkoxy, haloCι -6 alkyl, cyano, nitro and C 2-6 alkenyl; R is Cι -6 alkyl; X is -CH 2 -, -O- or -S-; r is 0, 1 , 2, 3 or 4, wherein each R 3 moiety may be the same or different; and s is 0, 1 , 2 or 3 wherein each R 4 moiety may be the same or different; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate of any foregoing compound. 2. A compound according to Claim 1, wherein: R 1 and R 2 are independently selected from hydrogen and optionally substituted C t- 6 alkyl, or R 1 or R 2 is a group of the formula (IA) wherein B is aryl and q is 1 ; or R 1 and R 2 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; r is O; s is 0; and X is selected from CH 2 , S or O; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof. 3. A compound according to Claim 2, wherein: R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-salkyl and benzyl; or R 1 and R 2 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof. 4. A compound according to Claim 3, wherein: R 1 and R 2 are independently selected from hydrogen, methyl, n-propyl, iso-propyl, iso- amyl and benzyl; or R 1 and R 2 and the nitrogen atom to which they are attached in combination form a piperidine ring; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof. 5. A compound according to Claim 1, selected from: 4-Piperidino-N-( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine; 4-(N-Benzyl-N-methyl)amino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; 4-N,N-Dimethylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; (S)-4-N,N-Dimethylamino- 1 -( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine; 4-(N-Isopropyl-N-methyl) amino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; 4-N-»-Propylamino- 1 -( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine; (S)-4-N-«-Propylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; (R)-4-N-/?-Propylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; 4-N-Isoamylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)ρiperidine; (S)-4-N-Benzylamino- 1 -( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine; (S)-4-N-Isoamylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl)piperidine; 4-N,N-Dimethylamino-l-(3,4-dihydro-2-H-benzothiopyran-4-yl)piperidine; 4-N-«-Propylamino- 1 -(3 ,4-dihydro-2-H-benzothiopyran-4-yl)piperidine; 4-N-Isoamylamino- 1 -(3 ,4-dihydro-2-H-benzothiopyran-4-yl)piperidine; 4-(N-Benzyl-N-methyl)amino- 1 -( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine bismaleate salt; 4-N,N-Dimethylamino-l-(l,2,3,4-tetrahydro-l-naphthalenyl) piperidine bismaleate salt; (S)-4-N,N-dimethylamino- 1 -( 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)piperidine bismaleate salt; 4-(N-Isopropyl-N-methyl)amino- 1 -( 1 ,2,3 ,4-tetrahydro- 1 -naphthalenyl)piperidine bismaleate salt, 4-N-«-Propylamιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl) piperidine bismaleate salt, (S)-4-N-«-Propylamino- 1 -( 1 ,2,3,4-tetrahydro- 1 -naphthalenyl)pιpeπdιne bismaleate salt, (R)-4-N-«-Propylamιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl)pιpeπdιne bismaleate salt, 4-N-Isoamylamιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl) piperidine bismaleate salt, (S)-4-N-Benzylamιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl) piperidine bismaleate salt, (S)-4-N-Isoamylamιno-l-(l,2,3,4-tetrahydro-l-naphthalenyl) piperidine bismaleate salt, 4-N,N-Dιmethylamιno-l-(3,4-dιhydro-2-H-benzothιopyran-4-yl)pιpeπdιne bismaleate salt, 4-N-«-Propylamιno-l-(3,4-dιhydro-2-H-benzothιopyran-4-yl)pιpeπdιne bismaleate salt, 4-N-Isoamylamιno- 1 -(3 ,4-dιhydro-2-H-benzothιopyran-4-yl)pιpeπdιne bismaleate salt, (S)-4-N,N-Dιmethylamιno-l-(3,4-dιhydro-2-H-benzothιopyran-4-yl)pφeπdιne, and (S)-4-N-Isoamylamιno-l-(3,4-dιhydro-2-/ -benzopyran-4-yl)pιpeπdιne 6 A process for preparing a compound of formula (I) as defined in Claim 1, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or a carbamate thereof which process compnses a) reacting a compound of formula (II) (II) wherein L is a leaving group, with a compound of formula (III) (III) wherein R a and R b are R 1 and R 2 , except hydrogen or R a and R b are amino protecting groups, or b) reacting a compound of formula (IV) (IV) wherein L is a leaving group; with a compound of formula (V): N H (V) wherein R a and R are as hereinbefore defined; or c) for compounds of formula (I) wherein R 1 and R 2 are not both hydrogen; reacting a compound of formula (VI): (VI) with a compound of formula (VII): R d -L (VII) wherein L is a leaving group and i) R c is R 1 except hydrogen or R c is an amino protecting group and R , d α i •s R except hydrogen; or ii) R c is R except hydrogen or R c is an amino protecting group and R d is R 1 except hydrogen; or d) reacting a compound of formula (VIII): (VIII) with a compound of formula (III); or e) reacting a compound of formula (IX): (IX) with a compound of formula (V); or f) for compounds of formula (I) wherein one of R 1 and R 2 is optionally substituted Cι -6 alkyl or a group of formula (I A) as defined in Claim 1 wherein q is 1, 2, 3, 4, 5 or 6 and the other is not hydrogen; reacting a compound of formula (VI) (VI) with a compound of formula (X): (X) wherein: i) R c is R 1 except hydrogen and R e is optionally substituted Cι. 5 alkyl or a group of formula (IA) as defined above wherein q is 1, 2, 3, 4, 5 or 6; or ii) R c is R 2 except hydrogen and R e is optionally substituted Cj.salkyl or a group of formula (IA) as defined above wherein q is 1, 2, 3, 4, 5 or 6; or g) for compounds of formula (I) wherein one of R 1 and R 2 is optionally substituted or a group of formula (IA) as defined in Claim 1 wherein q is 1, 2, 3, 4, 5 or 6; by reducing a compound of formula (XI): (XI) wherein: i) R f is R 1 and R 8 is optionally substituted Ci-salkyl or a group of formula (IA) as defined above wherein q is 1, 2, 3, 4, 5 or 6; or ii) R f is R 2 and R g is optionally substituted C 1-5 alkyl or a group of formula (IA) as defined above wherein q is 1, 2, 3, 4, 5 or 6; and thereafter if necessary: converting a compound of the formula (I) into another compound of the formula (I); removing any protecting groups; or forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate. 7 A pharmaceutical composition compnsmg a compound of the formula (I) according to Claim 1, a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier 8 A compound of formula (I) according to Claim 1, a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament to inhibit the [ H]-emopamil binding site in a warm-blooded animal 9 The use of a compound of formula (I) according to Claim 1, or a pharmaceutically- acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [Η]-emopamil binding site in a warm-blooded animal 10 A method of treating neurological disorders comprising administering to a subject suffering therefrom a therapeutically-effective amount of a compound of the formula (I) according to Claim 1 , a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof 11 The method according to Claim 10, for treating stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and ATDS-related dementia 12. The method according to Claim 10, for treating neurological disorders treatable by inhibiting the [ 3 H] -emopamil binding site

Inventors: MCLAREN CHARLES DAVID, SIMON-BIERENBAUM RICHARD ELLIO, WARAWA EDWARD JOHN, MCLAREN, CHARLES, DAVID, SIMON-BIERENBAUM, RICHARD, ELLIOT, WARAWA, EDWARD, JOHN
Applicants: ASTRAZENECA UK LTD, MCLAREN CHARLES DAVID, SIMON BIERENBAUM RICHARD ELLIO, WARAWA EDWARD JOHN, ASTRAZENECA UK LIMITED, MCLAREN, CHARLES, DAVID, SIMON-BIERENBAUM, RICHARD, ELLIOT, WARAWA, EDWARD, JOHN
Application year: 2000
Main classification: C07D211
IPC codes: A61K31, A61P9, A61P25, A61P31, A61P43, C07D211, C07D405, C07D409