EP0607233A1 - 3,9-diazabicyclo(3.3.1)nonane derivatives with 5-ht3 receptor antagonist activity - Google Patents

Abstract

The invention relates to compounds of formula (I), and to pharmaceutically acceptable salts thereof. In said formula, X represents a phenyl group or a pentagonal or hexagonal monocyclic heteroaryl group, one or the other group of which is optionally welded to a saturated or unsaturated, carbocyclic or heterocyclic pentagonal or heptagonal ring; A represents a linking moiety; Z represents a carbocyclic acyl group; and R represents hydrogen or methyl. These compounds exhibit antagonistic activity of the 5-HT3 receptor.

Description

3,9-diazabicyclo(3.3.1)nonane derivatives with 5-HT3 receptor antagonist activity

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

EP-A- 158265, EP-A-200444, EP-A-247266, EP-A-235878, EP-A-254584, EP-A-255297, EP-A-289170, EP-A-315390, WO 91/17161, WO 92/10494 (Beecham Group p.l.c), EP-A- 158532 (A.H. Robins Company, Inc.), EP-A-67770 (Merrell Toraude et Compagnie), GB 2125398A and GB

2145416A (Sandoz Limited), EP-A-322016 and EP-A-436245 (Duphar international Research B.V.), EP-A-307172 (EU Lilly and Company), EP-A-323077, EP-A-306148, GB 2208385A and WO91/05738 (John Wyeth and Brother Limited), EP-A-234872 (Adria Laboratories Inc.),

EP-A-294292 (Adir et Compagnie), EP-A-339950 (Rorer International (overseas), Inc.), EP-A-309423 (Instituto de Angeli S.p-A.), EP-A-313393 and EP-A-407137 (Yoshitomi Pharmaceutical industries Limited),

EP-A-328200 and EP-A-337547 (Merck Sharp and Dohme Limited), EP-A-329932 (MerreU Dow Pharmaceuticals Inc.), WO 90/06039 and WO 91/04738 (Rorer International (Overseas), Inc.), EP-A-378111 (Zambon Group S.p.A.), EP-A-430190 (Syntex (U.S.A.) Inc.) and USA Patents 4920219 and 4920227 (Rorer Pharmaceutical Corp.) disclose classes of compounds which have a saturated azabicyclic moiety, such as tropanyl, granatyl or quinuclidinyl, and are 5-HT3 receptor antagonists.

WO 92/05174 (Beecham Group p.l.c) and EP-A-469449 Nisshin Flour Milling Co., Ltd) describe 5-HT3 receptor antagonists where the saturated azabicyclic moiety is endo-3,9-diazabicyclo[3.3.1]nonan-7-yl.

A class of novel compounds has now been discovered in which the

saturated azabicyclic moiety is endo-3,9-diazabicyclo[3.3.1]nonan-7-yl substituted by an acyl group. These compounds have 5-HT3 receptor antagonist activity.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

X is a phenyl group or a monocydic 5 or 6 membered heteroaryl group, either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;

A is a linking moiety;

Z is a carboxylic acyl group; and

R is hydrogen or methyl;

having 5-HT3 receptor antagonist activity.

X may be unsubstituted or substituted, usually by one or more

substituents selected from halogen, C_1-6 alkoxy, C_1-6 alkylthio, C_1-6 alkyl, hydroxy, amino, C_1-6 alkylamino, C_1-7 alkanoylamino, or two substituents on X (when fused), may be linked to form a saturated or unsaturated optionally substituted carbocyclic ring. Heteroatoms for heteroaryl and heterocyclic groups within X are selected from oxygen, nitrogen and sulphur.

Halo includes bromo, chloro and fluoro. X may be joined to A by an aromatic carbon atom, or (when X is fused), by a carbocyclic ring carbon atom, or by a heterocyclic ring carbon or nitrogen atom. When X is fused, and A is attached at an aromatic carbon atom, it is preferably attached at the aromatic carbon adjacent a 'fused' carbon atom, which is attached to the heteroatom of a heterocyclic ring in formula (I). The azagranatane side chain may be attached to A in a 'spiro' configuration.

X may also be further joined to A as defined in formula (IA) hereinafter, when Y-R₁₀ is N-B=N.

Suitable examples of X are as described in the aforementioned patent publications relating to 5-HT₃ receptor antagonists, the subject matter of which is incorporated herein by reference.

Suitable examples of A include CONH (amide), COO (ester), NHCONH (ureide), CONHCONH (extended ureide), or a group of structure (j):

wherein the dotted circle represents two double bonds in any position in the 5 membered ring; two of G, H and I are selected from oxygen, sulphur, nitrogen and carbon and the other is oxygen, sulphur or nitrogen; and E is a bond or C_1-5 alkylene optionally substituted by phenyl or hydroxy; or E is absent and the heterocycle in structure (j) is joined to the azagranatane, in a 'spiro' configuration, when G is nitrogen, H is methylene and I is oxygen or sulphur.

For the avoidance of doubt, the suitable X values in formula (I) which are described in the referenced patent publications, are that part of the structure remaining when the saturated azabicyclic moiety and A (where A is one of the suitable examples listed above), are disregarded.

Z is often C_1-7 alkanoyl or benzyl optionally substituted in the phenyl ring by one or more of halo, C_1-6 alkoxy or C_1-6 alkyl. Z is often acetyl.

R is preferably methyl.

There is a group of compounds within formula (I) wherein Z is C_1-6 alkyl, phenyl or phenyl C_1-4 alkyl optionally substituted as defined in formula (I). In a particular aspect, the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof: wherein

Y is NH or O (or is joined to R₁₀ as defined below);

X₁ is a group of formula (a), (b), (c), (d), (e), (f), or (g) or (h):

wherein

R_a to R_e and R_g to R_h are selected from hydrogen, halogen or hydroxy; R₁ is hydrogen and R₂ is hydrogen or C_1-4 alkyl; or

R₁ and R₂ together are a bond;

R₃ to R₇ are independently hydrogen or C_1-6 alkyl; and

R₄ together with R₂ may be C_{2- 7} polymethylene or C_2-6 polymethylene interrupted by an -O- linkage when R₁ is hydrogen;

R₈ and R₉ are independently selected from hydrogen or

C_1-6 alkyl or R₈ and R₉ together are C_2-6 polymethylene or C_2-5 polymethylene interrupted by an -O- linkage;

either R₁₀ is hydrogen, C_1-6 alkoxy, C_3-8 cycloalkyloxy or C_3-8 cycloalkyl C_1-4 alkyloxy; or R₁₀ is joined to Y so that Y-R₁₀ is N-B=N where B is N or CH; and

R₁₁ is hydrogen, halo, C_1-6 alkoxy or C_1-6 alkyl; or

R₁₀ and R₁₁ are joined to form -OCH(R₁₅R₁₆)-E- wherein E is (CH₂)_n or NR₁₇CO(CH₂)m wherein n is 1 or 2 and m is 0 or 1 and R₁₅, R₁₆ and R₁₇ are independently selected from hydrogen or C_1-6 alkyl; R₁₂ is hydrogen, C_1-6 alkoxy or; amino optionally substituted by a C_1-6 alkyl group, or R₁₂ is alkanoylamino; and

R₁₃ is halo, C_1-6 alkyl, C_1-6 alkoxy or C_1-6 alkylthio;

R₁₄ is hydrogen or C_1-6 alkyl;

in formula (h):

CO-Y- is in the 1-position and either R₁₅ is in the 3-position and is

hydrogen, C_1-6 alkyl or C_1-6 alkoxy, or R₁₅ is in the 4-position and is hydrogen, halogen, CF₃, C_1-6 alkyl, C_1-7 acyl, C_1-7 ac-ylamino, phenyl optionally substituted by one or two C_1-6 alkyl, C_1-6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C_1-6 alkyl or C_3-8 cycloalkyl groups or by C_4-5 polymethylene or by phenyl, C_1-6 alkylsulphonyl, C_1-6 alkylsulphinyl, C_1-6 alkoxy, C_1-6 alkylthio, hydroxy or nitro; or CO-Y- is in the 3-position and either R₁₅ is in the 1-position and is hydrogen, C_1-6 alkyl or C_1-6 alkoxy, or R₁₅ is in the 4-position and is hydrogen or C_1-6 alkoxy;

L is CH or N; and

Z and R are as defined in formula (I).

Examples of moieties in alkyl or alkyl containing groups in Z or in Ri to R₁₅ include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert -butyl, preferably methyl. Cycloalkyl moieties include C₃, C₄, C₅, C₆, C₇ and C₈ cycloalkyl. Halo moieties include fluoro, chloro, bromo and iodo.

Suitable examples of R₂ and R₄ or R₈ and R₉ when joined include C₂, C₃, C₄, C₅ or C₆ polymethylene, preferably C₂, C₃, C₄ or C₅ polymethylene. R_a to R_e and R_g to R_h are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen. R_b may be 5-, 6- or

7-chloro or fluoro.

When X is of sub-formula (a), one of R₁ and R₃ is preferably hydrogen and one or both of R₂ and R₄ (most preferably both) are alkyl groups, such as methyl, or are joined to form C_2-7 polymethylene; or when one of R₂ and R₄ is hydrogen, the other is preferably ethyl or n- or iso- propyl.

When X is of sub-formula (b), R₅ is preferably hydrogen or a methyl or ethyl group.

When X is of sub-formula (c), one of CO-Y and R₆ is attached at the

1-position and the other is attached at the 3-position as depicted in sub-formula (c), and R₆ is preferably methyl or ethyl.

When X is of sub-formula (d), R₇ is preferably methyl.

When X is of sub-formula (e), R₈ and R₉ are preferably both methyl groups.

When X is of sub-formula (f), and R₁₀ is C_1-6 alkoxy or is joined to Y, R₁₂ is preferably amino and R₁₃ is preferably chloro or bromo, most preferably chloro. R₁₀ is preferably methoxy when C_1-6 alkoxy. When X is of sub-formula (f), and R₁₀ is hydrogen, R₉ and R₁₁ are preferably chloro or methyl and R₁₀ is preferably hydrogen. Other values of X within sub-formula (f) of interest are those described in EP-A-307172 (Eh Lilly and Company) and EP-A-313393 (Yoshitomi Pharmaceutical Industries limited).

When X is of sub-formula (g), R₁₄ is preferably hydrogen or methyl.

When X is of sub-formula (h), and CO-Y- is in the 1-position suitable examples of R₁₅ when in the 4-position, include the following: hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C_1-4 alkanoylamino such as formylamino, acetylamino, propionylamino, n- and wo-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl or phenyl groups; nitro, n- and iso-propory, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R₁₅ is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.

When X is at sub-formula (h), and the CO-Y- is in the 3-position, suitable examples of R₁₅ when in the 1-position, include hydrogen, methyl, ethyl, n- or iso- propyl, or when R₁₅ is in the 4-position, suitable examples include the following: hydrogen, methoxy and ethoxy.

Preferred R₁₅ groups, in any of the positions specified above, include hydrogen, methyl and methoxy. CO-Y- is preferably in the 1-position.

Y is preferably NH.

In an alternative aspect, the carbonyl group in CO-Y may be replaced by a carbonyl bioisostere, when Y is NH, as described in WO 92/14733

(Beecham Group p.l.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 quatemised by compounds R_x-T wherein R_x is C_1-6 alkyl, phenyl-C_1-6 alkyl or C_5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R_x 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.

It will be appreciated that mono- or di- salts may be formed owing to the presence of two salifiable nitrogens in the azagranatane side chain.

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) which process comprises reacting a compound X'-A₁ with a compound of formula (II):

wherein A₁ and A₂ are moieties which react together, usually by an amide or ester coupling, or by condensation to form a heterocycle (j) as

hereinbefore defined, to form A as defined; X is X or a group convertible thereto and R' and Z' are R and Z as defined or a hydrogenolysable protecting group; and thereafter as desired or necessary, converting X' to X, converting R'/Z', when other than R/Z, to R/Z, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

Suitable values of A₁ and A₂ are as described in the aforementioned patent publications. Intermediates of the formula X'-A₁ are generally known from the

aforementioned patent publications/references, or are prepared by analogous methods to those used for structurally related known

compounds. Intermediates of the formula (II) are generally prepared from the

compound of formula (III):

which is prepared by the condensation/cyclisation of as appropriate

2,6-disubstituted piperazine derivative, as described in the descriptions hereinafter. In a particular aspect, the invention also provides a process for the preparation of a compound of formula (IA), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (IV):

X₁'-COQ₁

(IV) with a compound of formula (V):

or a reactive derivative thereof, when Y is O; wherein X₁' is X₁ or a group convertible thereto; Q₁ is a leaving group; R' is R as defined, or a hydrogenolysable protecting group; and the

remaining variables are as hereinbefore defined; and thereafter optionally converting X₁' to X₁, including any R_a, R_b, R_c, R_d, R_e, R_g, R_h or R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ group to another such group, converting R'/Z', when other than R/Z, to R/Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (IA). Examples of leaving groups Q₁, displaceable by a nucleophile, include halogen such as chloro and bromo, C_1-4 alkoxy, such as CH₃O and

C₂H₅O-, PhO-, or activated hydrocarbyloxy, such as Cl₅C₆O- or CI₃CO-

If a group Q₁ 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 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 Q₁ is C_1-4 alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene ordimetiiylformamide. It is also preferred that the group Q₁ is CI₃CO- and that the reaction is carried out in toluene at reflux

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

Usually, X₁' will be X₁, but when R₁₀ is joined to Y, in formula (IA), Xi' is of sub-formula (f) wherein R₁₀ is nitro or amino, which may be

subsequently be linked to Y as described in EP-A-315390.

It will be apparent that compounds of the formula (IA) containing an R_a to R_e, R_g, R_h or R₁₀ to R₁₅ group which is convertible to another such group are useful novel intermediates. i.e. a hydrogen substituent is convertible to a halogen substituent by halogenation using conventional halogenating agents; or a C_1-7 alkanoylamino substituent is convertible to amino by conventional hydrolysis. R'/Z' when other than R/Z may be a hydrogenolysable protecting group which is benzyl 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 R_a to R_e, R_g, R_h, R₁₁ to R₁₅ is not halogen, by conventional transition metal catalysed hydrogenolysis to give the corresponding compound wherein R'/Z' is hydrogen.

A further process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, therefore comprises N-acylating a compound of formula (I), wherein Z is hydrogen and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). In this further process of the invention 'N-acylation' comprises the substitution of the azabicyclic N-atoms by a group Z as hereinbefore defined. This maybe achieved by reaction with a compound ZQ₃ wherein Z is as hereinbefore defined and Q₃ is a leaving group. Suitable values for

Q₃ include groups displaced by nucleophiles such as halo or ZQ₃ may be an acid anhydride, e.g. acetic anhydride. The reaction may be carried out under conventional acylation conditions for example in an inert solvent such as dichloromethane in the presence of an acid acceptor such as triethylamine. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.

Interconverting R or Z in the compotmd of the formula (V) before coupling with the compound of the formula (IV) is also possible. Such

interconversions are effected conveniently under conventional conditions, using appropriate protection of amine function(s).

The compounds of formula (IV) are known or are preparable analogously to, or routinely from, known compounds.

Compounds of the formula (I) may also be prepared by the processes analogous to those described in the aforementioned European Patent Publications.

It will be realised that in the compound of the formula (I) the -A- 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). 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 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 and/or arrhythmia. Some of the compounds of the invention may also have gastric prokinetic activity, useful in the treatment of gastrointestinal disorders, for example when R₁₄ is C_1-6 alkyl.

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 monooleate, 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 hereinbefore 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 1000mg 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 at any of the aforementioned dosage ranges.

The invention also provides a pharmaceutical composition for use in the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders which composition comprises an effect non-toxic amount of a compound of formula (D or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier. 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); the following descriptions illustrate the preparation of intermediates.

Description a) To methyl-4-bromocrotonate (50g) in diethyl ether (500ml) was added, dropwise benzylamine (22ml) in diethyl ether (20ml) at 0°C. The reaction mixture was stirred at room temperature for 72h. The precipitate was removed by filtration and the filtrate washed with water (75 ml). The organic phase was dried (MgSO₄), the solvent evaporated under reduced pressure and the residue purified using flash chromatography on silica eluting with light petrol and diethyl ether to afford dimethyl-4,4'-benzyliminodi-trans-2-butenoate (17.1g). b) To dimethyl-4,4'-benzyliminodi-trans-2-butenoate (17.1g) in methanol (250 ml) was added dropwise methylamine (7.5 ml, 33% w/w in IMS) at 0°C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue chromatographed on silica using light petrol and diethyl ether as the eluant to afford dimethyl-1-benzyl-4-methyl piperazinyl-3,5-diacetate as a mixture of cis and trans isomers (9.29g). c) To potassium tert-butoxide (9.67g) in toluene (350 ml) was added dimethyl-4-benzyl-1-methyl piperazinyl-2,6-diacetate (9.26g) in toluene (150 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to reflux for 3h. The reaction mixture was cooled and washed with 5N HCl (4×75ml). The combined aqueous extracts were heated to reflux for 13h. The reaction mixture was cooled, the solvent concentrated under reduced pressure and the residue saturated with solid potassium carbonate. The product was extracted into chloroform

(4×75ml), the organic phase dried (MgSO₄) and the solvent evaporated under reduced pressure. Flash chromatography on silica using chloroform with increasing volumes of ethanol (up to 10%) eluant gave 3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-one (1.8g). d) To a stirred solution of the above ketone (1.80g) in ethanol (50ml) was added hydroxylamine hydrochloride (0.54g). The reaction mixture was then heated to reflux for 2h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether to give 3-benzyl-9-methyl-3,9-diazabicydo[3.3.1]nonan- 7-one oxime hydrochloride (1.87g). e) To a stirred solution of alane [generated by the action of cone.

H₂SO₄ (0.93ml) on lithium aluminium hydride (0.88g) in dry THF (30ml)] was added 3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-one oxime [generated by the treatment of 3-benzyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-one oxime hydrochloride with potassium carbonate). The reaction mixture was then heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled and 40% aqueous NaOH solution (2ml) and water (1ml) were added dropwise.

Diethyl ether (5ml) was added and the mixture stirred for 1h. The resultant precipitate was removed by filtration through keiselguhr and the filtrate concentrated under reduced pressure to afford crude endo-3- benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-amine (0.90g).

Example 1 endo-N-3,3-Dimethylindolin-1-yl(3-acetyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (E1) a) A solution of 3,3-dimethylindoline (1.5g) and triethylamine (1.42ml) in CH₂CI₂ (15ml) was added dropwise to a cooled stirred solution of phosgene (9ml, 12.5% w/w in toluene) in CH₂CI₂ (15ml). The reaction mixture was stirred for 1h at 0°C and then poured into pentane (100ml), washed with 5N sulphuric acid (5ml) and brine (5ml). The organic phase was dried (MgSO₄) and the solvent evaporated under reduced pressure to give crude 1-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride (1.7g). b) To a stirred solution of 1-(2,3-dihydro-3,3-dimethyl)indolylcarbonyl chloride (771mg) in CH₂CI₂ (15ml) at ambient temperature was added endo-3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-amine (902mg) and triethylamine (512μl) in CH₂CI₂ (15ml). The reaction mixture was stirred at room temperature overnight. The resulting solution was washed with aqueous NaHCO₃ solution, dried (MgSO₄) and the solvent removed by rotary evaporation. Flash chromatography on silica using chloroform and ethanol as the eluant gave endo-N-3,3-dimethylindolin-1-yl(3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide

(360mg) mp 188-191°C.

¹H NMR (CDCl₃) 250MHz; δ: 1.29 (s, 6H), 1.48 (d, 2H), 2.40-2.57 (m, 5H), 2.62-2.78 (m, 4H), 2.83-2.90 (m, 2H), 3.53 (s, 2H), 3.70 (s, 2H), 4.39-4.42 (m, 1H), 6.90 (t, 1H), 7.05-7.46 (m, 8H), 7.81 (d, 1H), 8.78 (d, 1H). c) endo-N-3,3-Dimethylindolin-1-yl(3-benzyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide (E13) (350 mg) was

hydrogenated at atmospheric pressure in methanol (50ml) over 5% Pd/C catalyst for 4h. The catalyst was removed by filtration and the filtrate evaporated to give endo-N-3,3-dimethylindolin-1-yl-(9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide (149mg). mp 248-251°C

¹H NMR (CDCI₃) 250 MHz; δ: 1.35 (s, 6H), 1.68 (d, 2H), 2.50-2.67 (m, 3H), 2.75 (s, 3H), 2.99 (d, 2H), 3.17-3.26 (m, 2H), 3.58 (s, 2H), 3.61-3.71 (m, 2H), 4.37-4.49 (m, 1H), 6.89-6.97 (m, 1H), 7.06-7.20 (m, 2H), 7.88 (m, 1H).

M+ 329 d) To a solution of endo-N-3,3-dimethylindolin-1-yl(9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide (50mg) in CH₂CI₂ (6ml) was added triethylamine (23 μl) and acetic anhydride (16μl). The reaction mixture was stirred at ambient temperature for 2h. The solvent was evaporated under reduced pressure and the residue partitioned between water (5 ml) and chloroform (10ml). The organic phase was dried

(MgSO₄) and the solvent removed by rotary evaporation to yield crude title compound. This was subjected to flash chromatography on silica eluting with chloroform and ethanol. The resulting product was triturated with light petrol (bp 60-80°) to give the title compound (29mg). mp 165-168°

¹H NMR (CDCl₃) 250MHz; δ: 1.36 (s, 6H), 1.58-1.71 (m, 1H), 2.10 (s, 3H), 2.44-2.61 (m, 5H), 2.95-3.10 (m, 2H), 3.14-3.28 (m, 1H), 3.37-3.68 (m, 4H), 4.14-4.25 (m, 2H), 4.79-4.88 (m, 1H), 6.93 (t, 1H), 7.05-7.21 (m, 2H), 7.93 (d, 1H).

MH+ 371

Example 2 endo-N-3,3-Dimethylindolin-1-yl(3-benzoyl-9-methyl-3,9- diazabicyclo[3.3.1]nonan-7-yl)carboxamide (E2) FoHowing the procedure outlined in Example 1(d), reaction of endo-N-3,3- dimethylindolin-1-yl(9-methyl-3,9-diaza bicyclo[3.3.1]nonan-7-yl)carboxamide (40mg) with benzoyl chloride (15 μl) and triethylamine (18 μl) afforded the title compound (E2) (35mg). mp 182-185°

¹H NMR (CDCI₃) 250MHz; δ: 1.31 (s, 6H), 1.43-1.60 (m, 1H), 2.44-2.70 (m, 5H), 2.88-2.98 (m, 1H), 3.09-3.13 (m, 1H), 3.35-3.80 (m, 5H), 4.20-4.35 (m, 1H), 4.38-4.52 (m, 1H), 4.81-4.93 (m, 1H), 6.94 (t, 1H), 7.06 (d, 1H), 7.17 (t, 1H), 7.28-7.48 (m, 5H), 7.92 (d, 1H).

MH+ 433 5-HT₃ RECEPTOR ANTAGONIST ACITVITY

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 (ED₅₀) is then determined.

Claims

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

X is a phenyl group or a monocyclic 5 or 6 membered heteroaryl group, either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;

A is a linking moiety;

Z is a carboxylic acyl group; and

R is hydrogen or methyl;

having 5-HT₃ receptor antagonist activity.

2. A compound according to claim 1, of formula (IA), or a

pharmaceutically acceptable salt thereof:

wherein

Y is NH or O (or is joined to R₁₀ as defined below);

Xl is a group of formula (a), (b), (c), (d), (e), (f), or (g) or (h), as defined in the specification.

3. A compound according to claim 2 wherein X is of sub-formula (a), one of R₁ and R₃ is hydrogen and R₂ and R₄ are both C_1-6 alkyl groups or are joined to form C_2-7 polymethylene.

4. A compound according to claim 3 selected from: endo-N-3,3-dimethylindolin-1-yl(3-acetyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide and endo-N-3,3-dimethylindolin-1-yl(3-benzoyl-9-methyl-3,9-diazabicyclo[3.3.1]nonan-7-yl)carboxamide.

5. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

6. A compound according to any one of claims 1 to 4 for use as an active therapeutic substance.

7. A compound according to any one of claims 1 to 4 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

8. The use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.