PHARMACEUTICALS

Abstract: Compounds of formula (I) and pharmaceutically acceptable salts thereof wherein the variable groups are as defined in the specification.

Description: PHARMACEUTICALS This invention relates to novel compounds having pharmacological activity, to a process for their preparation and their use as pharmaceuticals. UK Patent No. 1571447 (Societe D'Etudes Scientifiques et Industrielles de L'Ile-de-France) describes a group of benzamide derivatives having dopamine antagonist activity. A group of novel compounds have now been discovered, which compounds are 5-HT3 receptor antagonists. Accordingly, the present invention provides a compound of formula (I) , or a pharmaceutically acceptable salt thereof: wherein R- | _ is hydrogen, halo, nitro, a ino, C^_g alkyl or C-^-g alkoxy; R2 is halo, C-^.g alkyl or -^_ alkoxy; A is (poly) ethylene of 1-3 carbon atoms, optionally substituted by one or two C^_g alkyl group(s); L is 0 or NH; and Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity. Suitable examples of alkyl moieties in R 1 and R 2 and A include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- an ter -butyl. Suitable examples of halo moieties include fluoro, chloro and bromo, preferably chloro or bro o. Often Ri is hydrogen and R 2 is chloro or bromo. A is preferably unsubstituted polymethylene of 1 or 2 carbo atoms (i.e. 0-A-O is methylenedioxy or ethylenedioxy) . Suitable examples of Z are described in the art relating to 5-H receptor antagonists, ie. as follows: i> GB 2125398A (Sandoz Limited) ii) GB 2152049A (Sandoz Limited) iii) EP-A-215545 (Beecham Group p.I.e.) iv) EP-A-214772 (Beecham Group p.I.e.) v) EP-A-377967 (Beecham Group p.I.e.) vi) PCT/GB91/01629 (Beecham Group p.I.e.) vii) EP-A-358903 (Dianippon) Particular side chains of interest are depicted thus: Tropane Granatane Oxa/thia/aza-qranatane Quinuclidine Isoquinuclidine Isogranatane Oxa/thia-isoqranatane Isotropane wherein R is hydrogen or methyl; and X is oxygen, sulphur or nitrogen optionally substituted by C-^. alkyl, C^- _ Q cycloalkyl, C3_g cycloalkyl C 1-4 alkyl, phenyl, naphthyl, phenyl C^_^ alkyl or naphthyl C^_ 4 alkyl wherein a phenyl o naphthyl moiety is optionally substituted by one or more of halo, C-L_ alkoxy or C- j __g alkyl. Side chains Z of particular interest include tropane, oxagranatane and azagranatane, where R is methyl. Suitable values for N-substituents when X is N are as described in PCT/GB91/01629, for example, iso-propyl or ethyl. L is preferably NH. Alternatively, COL in formula (I) may be replaced by a bioisostere therefor, for example, 1,2,4-oxadiazole and the other groups of structure h) described in EP-A-377967 (Beecham Group .1.c.) . The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids. The pharmaceutically acceptable salts of the compounds of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid. Preferably the acid addition salt is the hydrochloride salt. Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R χ -T wherein R χ is c l- β al^yi r phenyl-C j . alkyl or C 5 _ 7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R χ include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide. Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides. The compounds of the formula (I) , their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to. It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers) , and to mixtures thereof (including racemates) . The different stereoisomeric forms may be separated one from the other by the usual methods. The invention also provides a process for the preparation of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II) : with a compound of formula (III) : HLZ' (III) or a reactive derivative thereof, when L is 0; wherein R ] , R 2 ' and/or Z' are R-^, R and/or Z respectively or groups or atoms convertible thereto; Q^ is a leaving group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R^ f , R 2 ' and/or Z' to another group or atom R-^, R 2 , 3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I) . Examples of leaving groups Q^, displaceable by a nucleophile, include halogen such as chloro and bromo, C-^_q alkoxy, such as CH3O and C H^0-, PhO-, activated hydrocarbyloxy, such as Clc-CgO- or CI3CO-, or a nitrogen- linked heterocycle, such as imidazole. If a group Q-^ is a halide, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether, tetrahydrofuran (THF) or dimethylformamide (DMF) . It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine trimethylamine, pyridine or picoline, some of which can als function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C in particular 10-80°C are suitable. If a group Q-^ is C^_ 4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene ordimethylformamide. It is also preferred that the group Q is CI3CO- and that the reaction is carried out in toluene a reflux temperature. When is 0 the compound of formula (III) may be in the for of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt. It will be apparent that compounds of the formula (I) containing an R-^ or R group which is convertible to anothe such group are useful novel intermediates, i.e. a hydrogen substituent is convertible to a halogen substituent by halogenation using conventional halogenating agents. Z' when other than Z may be wherein R is replaced by R' which is a hydrogenolysable protecting group which is benzy optionally substituted by one or two groups selected from halo, C 1-4 alkoxy and C 1-4 alkyl. Such benzyl groups may, for example, be removed, when τ/ 2 is not halogen, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (I) wherein R is hydrogen. This invention also provides a further process for the preparation of a compound of the formula (I) wherein R is methyl or a pharmaceutically acceptable salt thereof, whi comprises N-methylating a compound of formula (I) wherein is hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula 5 (I) . In this further process of the invention 'N-methylation' may be achieved by reaction with a compoun CH3Q3 wherein Q 3 is a leaving group. Suitable values for Q3 include groups displaced by nucleophiles such as Cl, Br, I, OS0 2 CH 3 or OS0 2 CgH 4 pCH 3 , preferably Cl, Br or I. The reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient slightly above. Alternatively, 'N-methylation' may be effected under conventional reductive alkylation conditions. Interconverting R in the compound of the formula (III) before coupling with the compound of the formula (II) is also possible. Such interconversions are effected conveniently under the above conditions. It is desirable t protect any amine function with a group readily removable b acidolysis such as a C _ 7 alkanoyl group, before R/Z interconversion. It is often convenient in the preparation of such a compoun of formula (III) to prepare the corresponding compound wherein the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (II) . The compounds of formula (II) are known or are preparable analogously to, or routinely from, known compounds, such as described in UK 1571278. Compounds of the formula (III) are generally prepared from the corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine. They may be prepared by processes described in the aforementioned Patent Publications relating to values of the side chain Z. It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia/aza-granatane side chain, the -COL- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II) . Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains. Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid. The compounds of the present invention are 5-HT3 receptor antagonists and it is thus believed may generally be used i the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, 5 cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomitin and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine. Examples of such cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory impairment (AAMI) , and drug dependence. Gastrointestinal disorders include irritable bowel syndrome and diarrohea. 5-HT3 receptor antagonists may also be of potential use in the treatment of obesity, arrhythmia, and/or disorders associated with myocardial instability. The invention also provides a pharmaceutical composition comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Such compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use. Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan moπooleate, or acacia; non-aqueous vehicles (which may include edible oils) , for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such -12- as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) , preservatives, a flavouring or colouring agents. 5 The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art. For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention an a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolve Parenteral solutions are normally prepared by dissolving th compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in th vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention. The invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, whic comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptabl salt thereof. An amount effective to treat the disorders herein- before described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.05 to lOOOmg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day. No adverse toxicological effects are indicated within the aforementioned dosage ranges. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders. The following Examples illustrate the preparation of compounds of formula (I) . Example 1 endo-N- (9-Methyl-9-azabicvclo [3.3.1]nonan-3-yl) -7-chloro- 1 r4-benzodioxan-5-carboxamide (El) A solution of 7-chloro-l, 4-benzodioxan-5-carboxylic acid (UK patent 1,571,278, Societe D'Etudes Scientifiques et Industrielles de L'Ile-de-France) (0.25g) in S0C1 2 (5 L) was stirred at room temperature for 2h. The reaction mixture was evaporated to dryness and re-evaporated with xylene (2 x 20 mL) . The residue was dissolved in CH 2 C1 (20 mL) and treated with a solution of endo- -methy1-9- azabicyclo[3.3.1]nonan-3-amine (0.2g) in CH 2 C1 2 (10 mL) . After standing at room temperature overnight, the reaction mixture was washed with sat. NaHCθ3 (50 mL) , dried (K 2 Cθ3) and evaporated to dryness. The residue was purified by column chromatography ( I2O3, eluting with CH 2 C1 2 ) to give the title compound, converted to its HCl salt with ethanolic HCl, precipitation with Et 2 0. (0.31 g) . 1 H NMR (d β -DMSO)δ8.40, 8.20 (2-d, 1H) 7.10 (s, 2H) 4.65-4.15 (m, 5H including 4.30, brs, 4H) 3.65-3.45 (m, 2H) 2.81, 2.79 (2-s, 3H) 2.55-2.30 (m, 4H) 2.20-1.95 (m, 2H) 1.82-1.53 (m, 2H) 1.55-1.35 (m, 2H) -15- Prepared similarly was; Example 2 endo-N- (9-Methyl-9-azabicvclo [3.3.1]nonan-3-yl) -6-chloro- 1, 3-benzodioxole-4-carboxamide (E2) 1 H NMR (CDCl 3 )δ7.51 (d, 1H) 6.88 (d, 1H) 6.72 (brd, 1H) 6.13 (s, 2H) 4.58-4.38 (m, 1H) 3.09 (brd, 2H) 2.60-2.40 ( , 5H including 2.50 s, 3H) 1.98 (brd 3H) 1.59-1.42 (m, 1H) 1.31 (dt, 2H) 1.03 (brd, 2H) 5-HT3 Receptor Antagonist Activity Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method: Male rats 250-350g, are anaesthetised with urethane (1.25g/kg intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980) . A submaximal dos of 5-HT (usually 6μg/kg) is given repeatedly by the intravenous route and changes in heart rate quantified. Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED^ Q ) is then determined. The compounds of the Examples are both active at a dose of lOμg/kg i.v.

Claims: Claims 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R^ is hydrogen, halo, nitro, amino, C- j __ alkyl or C-^_g alkoxy; R 2 is halo, CL- - Q alkyl or C^_g alkoxy; A is (poly)methylene of 1-3 carbon atoms, optionally substituted by one or two C-^_ alkyl group(s); L is 0 or NH; and Z is a di-azacyclic or azabicyclic side chain; having 5-HT3 receptor antagonist activity. 2. A compound according to claim 1 wherein R-^ is hydrogen and R 2 is chloro or bromo. 3. A compound according to claim 1 or 2 wherein O-A-O is methylenedioxy or ethylenedioxy. 4. A compound according to any one of claims 1 to 3 wherein the side chain Z is tropane, granatane, oxa/thia/aza-granatane, quinuclidine, isoquinuclidine, isogranatane, oxa/thia-isogranatane or isotropane. -18- 5. A compound according to claim 4 wherein Z is tropane, oxagranatane or azagranatane. 6. A compound according to any one of claims 1 to 5 5 wherein L is NH. 7. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-7- chloro-l,4-benzodioxan-5-carboxamide. 108. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)-6- chloro-1,3-benzodioxole-4-carboxamide. 9. A pharmaceutically acceptable salt of a compound according to claim 7 or 8. 5 10. A compound according to claim 1 substantially as defined herein with reference to the Examples. 11. A process for the preparation of a comound according to 0 claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II) : with a compound of formula (III) : HLZ' (III) or a reactive derivative thereof, when L is 0; wherein R^', R 2 ' and/or Z' are R^, R 2 and/or Z respectivel or groups or atoms convertible thereto; Q-_ is a leaving 5 group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R^' , ^2' and/or Z' to another group or atom R-^, R , R or Z; and optionally forming a pharmaceutically acceptable salt of t resultant compound of formula (I) . 10 12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 1513. A method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound according to claim 1. 20 14. A compound according to any one of claims 1 to 11 for use as an active therapeutic substance. 15. A compound according to any one of claims 1 to 11 for use in the treatment of pain, emesis, CNS disorders and/or 25 gastrointestinal disorders. 16. The use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or 0 gastrointestinal disorders.

Inventors: KING FRANCIS DAVID, KING, FRANCIS, DAVID
Applicants: BEECHAM GROUP PLC, BEECHAM GROUP P.L.C.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P43, C07D451, C07D453, C07D471, C07D498, C07D513