This invention relates to novel, compounds having pharmacological activity, to a process for their preparation and their use as pharmaceuticals.

EP-A-220011 (Beecham Group p.I.e.) describes the use of a benzamide derivative, as a 5-HT receptor antagonist.

A group of novel compounds has 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 or C-*__g al oxy; R2 is halo; R3 is halo; 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-^ include methyl, ethyl, n- and iso-propyl, n.-, iso-, sec- and tert-butyl.

Suitable examples of halo moieties include fluoro, chloro and bromo.

In particular, R-^ is hydrogen, R2 is chloro and R3 is chloro; or R~_ is methoxy, R ₂ is fluoro or chloro and R3 is chloro.

Suitable examples of Z are described in the art relating to 5-H 3 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-qranatane

Quinuclidine

Isoguinuclidine

Isoqranatane

Oxa/thia-isoqranatane

Isotropane

wherein

R is hydrogen or methyl; and X is oxygen, sulphur or nitrogen optionally substituted by C-^.g alkyl, C ₃ _ ₈ cycloalkyl, C3_g cycloalkyl C _1-4 alkyl, phenyl, naphthyl, phenyl C* _j __ ₄ alkyl or naphthyl ~χ- alkyl wherein a phenyl c: naphthyl moiety is optionally substituted by one or more of halo, C"L_g alkoxy or ~__- _Q 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 NK.

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 p.I.e.).

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.

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*_g alkyl, phenyl-C-^.g alkyl or C^_ 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 cf 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 cf 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) :

NHR' ₄

with a compound of formula (III) :

HLZ' (III)

5 or a reactive derivative thereof, when L is 0;

wherein R _] , R ^R 3' ^an oYor Z' are R-^, R ₂ , R3 and/or Z respectively or groups or atoms, convertible thereto; R ₄ is hydrogen or an N-protecting group; Q*^ is a leaving group; 10 and the remaining variables are as hereinbefore defined; and thereafter optionally converting R^', R ₂ ' , R3' and/or Z' to another group or atom R- _j _, R ₂ , R3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I) .

Examples of R ₄ , when other than hydrogen, include ~-, -I _Q acyl such as alkanoyl, wherein the alkyl may be as listed for R-_ , preferably acetyl. R_. is usually hydrogen. 0

Examples of leaving groups Q-^, displaceable by a nucleophile, include halogen such as chloro and bromo, hydroxy, -__^ alkoxy, such as CH3O and C ₂ Hc;0-, PhO-, activated hydrocarbyloxy, such as Cl^CgO- or C1 C0-; or 5 COQ-j , forms a mixed anhydride, so that Q*^ is carboxylic acyloxy; or a nitrogen-linked heterocycle, such as imidazole.

If a group Q*^ is a halide, or C0Q*-_, forms a mixed anhydride, 0 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 5 acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or

picoline, some of which can also 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 _1-4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group Q**_ is CI3CO- and that the reaction is carried out in toluene at reflux temperature.

If a group Q* _j _ is hydroxy, then the reaction is generally carried out in an inert non-hydroxylic solvent, such as dichloromethane, THF or D F optionally in the presence of a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide. The reaction may be carried out at any non-extreme temperature, such as -10 to 100°C, for example, 0 to 80°C. Generally, higher reaction temperatures are employed with less active compounds whereas lower temperatures are employed with the more active compounds.

If a group Q**_ is carboxylic acyloxy, then the reaction is preferably carried in substantially the same manner as the reaction when (_}•_ is halide. Suitable examples of acyloxy leaving groups include C _1-4 alkanoyloxy and C1- alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C* _] __4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the corresponding compound wherein Q**_ is hydroxy with a C _1-4 alkyl chloroformate.

If a group Q*^ is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It ^' is also.preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.

When Y is 0 the compound of formula (III) may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.

An R ₂ ' or R ' group which is convertible R ₂ or R include a hydrogen substituent which 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 benzyl optionally substituted by one or two groups selected from halo, C _1-4 alkoxy and C-__^ alkyl. Such benzyl groups may, for example, be removed, when R ₁ /R 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, which comprises N-methylating a compound of formula (I) wherein R is hyirogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I) . In this further process of the invention

'N-methylation' may be achieved by reaction with a compound CH Q ₂ wherein Q ₂ is a leaving group.

Suitable values for Q ₂ include groups displaced by nucleophils such as Cl, Br, I, OS0 ₂ CH ₃ or OSO^ H^pCϊ^,

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 cr 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 to protect any amine function with a group readily removable by acidolysis such as a C ₂ _ ₇ alkanoyl group, before R/Z interconversion.

It is often convenient in the preparation of such a compound cf 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 benzoic acid derivative intermediates of formula (II) are known or are preparable analogously to, or routinely from, known compounds. When R ₂ is fluoro, the intermediate may be prepared by fluorination of the corresponding R is hydrogen compound, using a suitable fluorinating catalyst, such as trifluoromethyl hypofluorite, as described in Description 1 hereinafter.

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 βxo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired iso er 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 in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine. Examples of such cancer therapy includ.e 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 excipiehts 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 onooleate, 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 as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) , preservatives, and flavouring or colouring agents.

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 and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the 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 the 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, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable 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 cf compounds of formula (I) .

NmT = N-methyltropane

Q = Quinuclidin-3-yl NmO = N-methyloxagranatane

Description

a) Methyl-4-acetamido-5-chloro-3-fluoro-2-methoxybenzoate

Methyl-4-acetamido-5-chloro-2-methoxy benzoate (10.9g) was dissolved in chloroform (40 ml), cooled to -10°C under • nitrogen. A three molar excess of trifluoromethyl hypofluorite was slowly bubbled through the stirred, cooled solution for 6 hours. A slow positive nitrogen stream was maintained throughout the reaction. After warming to room temperature and thoroughly purging with nitrogen, the chloroform was removed in vacuo.

The residue was chromatographed on silica using chloroform with increasing amounts of methanol as eluant. The product was isolated as an off white solid.

¹ H NMR (CDC1 ₃ ) 250MHz

δ: 7.64 (d, IH), 7.37 (bs, IH) , 3.98 (bs, 3H) , 3.9 (s, 3H) , 2.2 (s, 3H)

b) 4-Amino-5-chloro-3-fluoro-2-methoxybenzoic acid

Methyl-4-acetamido-5-chloro-3-fluoro-2-methoxybenzoate (1.89g) in 25 ml ethanol was treated with a solution of sodium hydroxide (1.15g) in 15 ml water. 'The mixture was heated under reflux for 16 hours then cooled. The solvent was removed in vacuo and the residue acidified. The precipitated solid was collected by filtration to give 1.48g product.

¹ H NMR (DMSO) 250MHz

δ: 7.49 (d, IH) , 6.19 (bs, IH) , 3.80 (s, 3H)

Example 1

endo-N-(8-Methyl-8-azabicvclor3.2.11octan-3-yl)-4-amino-3 , 5- dichlorobenzamide (El)

To a stirred solution of 4-amino-3,5-dichlorobenzoic acid (l.lg) in CH ₂ C1 ₂ (50 ml) and Et ₃ N (0.8 ml) at 0°C was added

Et0 CCl (0.48 ml). After stirring to room temperature for

Ih, a solution of the endo-8-methyl-8- azabicyclo[3.2.1]octan-3-amine (0.7 g) in CH ₂ C1 ₂ (10 ml) was added and the whole stirred overnight. The reaction mixture was washed with sat. NaHCθ3 solution, dried and evaporated.

Recrystallisation of the residue (EtoAc/petrol) gave the title compound (0.35 g) mp 192-193°C.

¹ H NMR (CDC1 ₃ ) δ 7.55 (S, 2H)

6.25 (brd IH) 4.76 (brs, 2H) 4.22 (q, IH) 3.21 (brs, 2H) 2.33 (s, 3H) 2.35-2.10 (m, 4H) 1.88-1.68 (m, 4H)

Prepared similarly was:

Example 2

N- (1-Azabievclo[2.2.21octan-3-yl)-4-amino-3,5- dichlorobenzamide (E2)

mp 233-235°C.

Example 3

endo-N-(8-Methyl-8-azabicvclor3.2.11octan-3-yl)-4-amino-3 .5- dichloro-2-methoxybenzamide (E3)

A solution of endo-N- (8-methyl-8-azabicyclo[3.2.1]octan-3- yl)-4-amino-5-chloro-2-methoxybenzamide (0.8g) in CH3COOH (25 mL) was treated with a solution of Cl ₂ (0.18 g) in CH3COQH (5 mL) . After standing at room temperature overnight, the solvent was removed by rotary evaporation and the residue partitioned between EtOAc and aqueous NaHC0 ₃ solution. The organic extract was separated, dried (K2CO ) evaporated and the residue purified by flash chromatography (Si0 ₂ , 5-10% MeOH/CHCl ₃ ) to give the title compound (0.065 g) mp 148-151°C.

Prepared similarly was:

Example 4

endo-N- (9-Methyl-9-aza-3-azabicvclof3.3.11nonan-7-yl)-4- amino-3,5-dichloro-2-methoxybenzamide (E4)

mp 170-172°C.

Example 5

endo-4-Amino-5-chloro-3-fluoro-2-methoxy-N-(8-methyl-8- azabicvcloT3.2.11octan-3-yl)benzamide (E5)

The title compound was prepared from 4-amino-5-chloro-3- fluoro-2-methoxybenzoic acid via an analagous procedure to that described for Example 1.

The product was isolated as the hydrochloride salt, mp 202- 203°C.

^: H NMR (free base)., (CDCI3), 250 MHz

δ: 8.61 (bd, IH) , 7.81 (d, IH) , 4.34 (bs, 2H) , 4.20 (dd, IH) , 3.98 (d, 3H), 3.10 (b, 2H) , 1.53-2.21 ( , 11H inc.s, 2.21, 3H) .

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 dose 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 (EDC ) is then determined.