WO1992012149A1

WO1992012149A1 - Azabicydic and azatricydic derivatives, process and intermediates for their preparation and pharmaceutical compositions containing them

Info

Publication number: WO1992012149A1
Application number: PCT/GB1992/000050
Authority: WO
Inventors: Francis David King
Original assignee: Smithkline Beecham Plc
Priority date: 1991-01-09
Filing date: 1992-01-09
Publication date: 1992-07-23
Also published as: AU1161292A; JPH06506443A; EP0566609A1

Abstract

Compounds of the formula (I): X-A-Z, and pharmaceutically acceptable salt thereof, wherein Z is of structure (a) or (b), 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; and R is hydrogen or methyl; having 5-HT3 receptor antagonist activity.

Description

AZABICYDIC AND AZATRICYDIC DERIVATIVES, PROCESS AND INTERMEDIATESFOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

This invention relates to novel compounds having useful pharmacological properties, to a process 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, PCT GB91/00636, PCT/GB91/02173 and PCT/GB91/02210 (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 (Duphar international Research B.V.), EP-A-307172 (Eli Lilly and Company), EP-A-323077, EP-A-306148, GB 2208385A and WO91/05783 (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

(Merrell Dow Pharmaceuticals Inc.), WO 90/06039, WO 91/16888 (Rorer International (Overseas), Inc.), EP-A-378111 (Zambon Group S.p.A.), EP-A-403882 (Fujisawa Pharmaceutical Co.

Ltd.), EP-A-419397 (A/S Ferrosan) and EP-A-458636 (Kyoma Hakko Kogyo Kabu Shiki Kaisha) 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.

A class of novel, structurally distinct compounds has now been discovered in which the saturated azabicyclic moiety is 8-azabicyclo [3.2.1] octan-6-yl or 6- azatricyclo [4.3.0^4,9]decan-8-yl. These compounds have 5-HT₃ receptor antagonist activity. Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:

X-A-Z (I) wherein Z is of structure (a) or (b) :

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; 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 alkylthic, 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 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). Z 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 heterocycle in structure (j) is joined to Z in a 'spiro' configuration.

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. In a particular aspect, the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof:

X₁-L-CO-Y-Z

(IA) 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), (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

C1-6 alky-L or R₈ and R₉ together are C_{2 -6}

polymethylene or C_{2 - 5} polymethylene interrupted by an -O- linkage; either R _{1 0} is hydrogen, C_{1 - 6} alkoxy, C_{3- 8} cycloalkyloxy or C3-8 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 R_{1 1} are joined to form -OCH (R₁₅R₁₆)-E- wherein E is

(CH₂)_n, (CH₂)_pO NR₁₇CO(CH₂)m wherein n is 1 or 2, p is 0 or 1 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} acylamino , 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 R₁ 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, R₁₁ and R₁₃ 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 (Eli Lilly and Company), EP-A-313393 (Yoshitomi Pharmaceutical Industries Limited), PCT/GB91/02173 and 02210 (Beecham Group p.I.c.).

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, C₁_₄ alkanoylamino such as formylamino, acetylamino, propionylamino, n- and

iso-butyrvlamino, 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-propoxy, 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.

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_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_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 also be realised that X-CO-Y- in compounds of formula (I) may adopt an α or β or configuration with respect to Z. The compounds of formula (I) are prepared by linking

together X and the azabicyclic side chain, usually by an ester or amide couplinσ when A is CO₂ or CONH, as described in the aforementioned patent publication references, in particular those in the name of Beecham Group p.I.e.

The azabicyclic side chain intermediates may be prepared from the corresponding ketones of formula (II) and (III):

according to the methods described in the aforementioned patent references i.e. by reduction to form the

corresponding alcohol, or by formation of the corresponding oxime followed by reduction, to form the corresponding amine.

The ketones of the formula (II) may be prepared according to the method described by G. H. Dewar, R.T. Parfitt, L. Sheh; Eur. J. Med. Chem., 1985, 20 , 228, and the ketone of formula (III) may be prepared according to the method described in the Description 2 hereinafter. 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, 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

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 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); the following Descriptions relate to the preparation of intermediates.

Description 1 a) 8-Methyl-8-azabicyclo[3.2.1]octan-6-one oxime

hydrochloride

To a stirred solution of the ketone (G.H. Dewar, R.T.

Parfitt , L . Sheh; Eur . J . Med . Chem . , 1985, 20 , 228 ) (5 . 3g) in EtOH (100ml) was added hydroxylamine hydrochloride (4.0g) and the reaction was then heated on a steam bath for 1½h.

The reaction mixture was allowed to cool to room

temperature, concentrated to half volume, and further cooled to -10°C. The crystals of the title compound were

collected, washed with Et₂O and dried under vacuum (5.8g, 80%). b) 6-Amino-8-methyl-8-azabicvclo[3.2.1]octane

Following the procedure outlined in Description 2f), the oxime (2.5g) was reduced with sodium in amyl alcohol to give the title compound (1.0g, 53%) isolated as the free base as a mixture of isomers.

¹H NMR (CDCl₃) 270MHz: 3.71, 3.30 (m, 1H), 3.17, 3.02 (m, 1H), 2.79, 2.70 (m, 1H), 2.47, 2.24 (s, 3H), 1.95-0.90 (m, 10H).

Description 2 a) 3-Benzyl-3-azabicyclo[3,2,1]octan-8-one Cyclopentanone (126, 1.5mol) and 40% aqueous formaldehyde (340mol) were heated under reflux in glacial acetic acid (2800ml) with benzylamine hydrochloride (216g, 1.5mol) for four hours. The reaction mixture was allowed to cool to room temperature and 12N HCl (120ml) was added. The

solution was concentrated on a rotary evaporator and water (400ml) added. The aqueous was washed with ethyl acetate (2 × 500ml), saturated with potassium carbonate and the product extracted into pentane (3 × 800ml) and dried (K₂CO₃). This solution was filtered through a bed of silica gel (500g) eluting with pentane/Et₂O 70:30. Distillation gave the title compound (20g, 6%) Bp 128-32°, 0.3mmHg.

¹H NMR 60MHz (CDCI₃) δ: 7.30 (s, 5H), 3.60 (s, 2H), 3.0-2.80 (m, 2H), 2.70-2.40 (m, 2H), 2.30-1.80 (m, 6H). b) 3-Benzyl-8-cyano-3-azabicyclo[3.2.1]octane

The ketone (19.9g, 0.093mol) and Tosmic (23.4g, 0.12 mol) were dissolved in a mixture of dry DME (140ml) and t-butanol (70ml). The stirred solution was cooled to 0°C and

potassium-t-butoxide (22g, 0.19mol) added portionwise. The reaction was stirred for a further two hours and poured into pentane (1000ml). The mixture was filtered through

Kieselguhr and evaporated to dryness. The residue was purified by flash column chromatography through tlc silica eluting with petrol/ CH₂Cl₂ 75:25, to give the title

compound (11. Og, 53%). c) Ethyl-3-benzyl-3-azabicyclo[3.2.1]octane-8-carboxylate

A solution of the nitrile (11g, 0.058mole) in ethanol (80ml) and C. H₂S0₄ (20ml) was heated under reflux for 20h. The mixture was poured onto ice water (400ml) and 40% NaOH solution (60ml) added. The product was extracted into ether and the ethereal extracts washed with saturated brine, dried over Na₂SO₄ and evaporated to dryness. The residue was distilled to give the title compound (10.3g, 78%) Bpt

144-8°, 0.5mmHg.

1H NMR, 60MHz (CDCI₃) δ: 7.20 (s, 5H), 4.30-3.80 (m, 2H), 3.40 (s, 2H), 2.70-1.60 (m, 11H), 1.20 (m, 3H). d) Ethyl-3-carbethoxymethyl-3-azabicyclo[3.2.1]octane-8-carboxylate The N-benzyl ester (10.0g, 0.037mol) was hydrogenated at atmosphere pressure in ethanol (200ml) and glacial acetic acid (25ml) over 10% Pd/C catalyst for one hour. Filtration through Kieselguhr and evaporation of the filtrate to dryness gave the NH product. A solution of the NH product, and ethyl bromoacetate (4.2ml, 0.037mol) in acetone (250ml) was stirred and heated under reflux with K₂CO₃ (16g, 0.11mol) for 16h. The reaction was cooled, filtered and evaporated to dryness. Distillation of the residue gave the title compound (6.1g, 62%) Bpt 126-8°, 0.5mmHH. e) 6-Azatricyclo [4, 3, 1, 0^4.9] decan-8-one oxime

The di-ester (6.1g, 0.023mol) in dry toluene (100ml) was added to a suspension of potassium-t-butoxide (6.4g,

0.057mol) in dry toluene (500ml) heated under reflux under N₂. The mixture was heated under reflux for a further three hours and allowed to cool. Dilute HCl (150ml) was added with vigorous stirring, the aqueous layer was separated and heated under reflux for 72 hours. The resulting solution was concentrated to a small volume and saturated with potassium carbonate. The product was extracted into ether (2 × 300ml) dried over Na₂SO₄ and evaporated to dryness to give the ketone (2.14g, 62%) which was then converted to the oxime derivative (1.97g, 84%) with hydroxylamine

hydrochloride. f) 8-Amino-6-azatricyclo[4 , 3 , 1 , 0⁴ , ⁹] decane

The oxime (1.97g, 0.012mol) was dissolved in amyl alcohol (80ml) and heated to reflux under N₂. Sodium metal (6.5g, 0.28mol) was added portionwise over a 20 minute period and heating was continued for a further 1.5h. The solution was allowed to cool slightly and water (20ml) was added

carefully. The aqueous layer was separated and the organic layer extracted with dilute HCl (3 × 25ml). The extract was evaporated to dryness to give the title compound (3.5g, 100%).

Example 1

(±) 4-Acetamido-5-chloro-2-methoxy-N-(8-methyl-8-azabicvclo[3.2.1]octan-6-yl)benzamide (E1)

4-Acetamido-5-chloro-2-methoxybenzoic acid (1.70g) was dissolved in thionyl chloride (8ml) and stirred at room temperature for 30 min. Petrol (15ml) was added and the precipitated acid chloride, filtered off and washed with petrol.

To a stirred solution of the acid chloride in CH₂Cl₂ (30ml) cooled to 0°C were added dropwise the amine (D8) (1.0g) and Et₃N (1.0ml). The reaction mixture was allowed to warm to room temperature and stirred overnight.

The mixture was washed with saturated aqueous NaHCO₃, dried (Na₂S0₄) filtered and concentrated under reduced pressure. The residue was chromatographed on alumina using CH₂Cl₂ to 1:1 CH₂Cl₂:CHCl₃ as eluant, followed by recrystallisation from EtOAc/petrol to yield the title compound (1.2g, 45%).

¹H NMR (CDCI₃) 270MHz δ: 8.30 (s, 1H), 8.20 (s, 1H), 8.09 (d, 1H), 7.80 (s, 1H), 4.90 (m, 1H), 3.97 (s, 3H), 3.32 (m, 1H), 3.09 (s, 1H), 2.53 (s, 3H), 2.27 (s, 3H), 2.00-1.15 (m, 8H).

Example 2 (±) 4-Amino-5-chloro-2-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]octan-6-yl)benzamide hydrochloride (E2)

To a stirred solution of the amide (E2) (1.2g) in EtOH

(20ml) was added NaOH (aq) (10%) (3.2ml) and the reaction heated to reflux overnight. The reaction was allowed to cool and evaporated under reduced pressure. The residue was taken up in H₂O and the product extracted into CH₂Cl₂. The organic layer was dried (Na₂SO₄), filtered and evaporated under reduced pressure.

The residual oil was taken up in a small volume of EtOH and ethanolic HCl added. Ether was added and the precipitate filtered off, washed with Et₂O and dried under reduced pressure to yield the title compound (E2) (0.6g, 53%). m.p. 238-240°.

¹H-NMR (DMSO) 270MHz δ: 8.22 (d, 1H), 7.80 (s, 1H), 6.63 (s, 1H), 6.15 (s, 2H), 4.9, 4.49 (m, 1H), 3.96 (s, 3H), 3.47 (s, 3H), 2.45-1.40 (m, 10H). Example 3

N-(6-Azatricvclo[4,3,1,0^4,9]decan-8-yl)-1-methylindazole-3-carboxamide hydrochloride (E3) 1-Methylindazol-3-oyl chloride (0.86g, 0.0044mol) was dissolved in dry CH₂Cl₂ (50ml) and the amine dihydrochloride D6 (1.0g, 0.0044mol) added followed by triethylamine (2.0ml, 0.014mol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 5% NaHCO₃ solution and the organic layer separated and dried (Na₂S0₄). After evaporation, the residue was purified by

chromatography on silica (30g) eluting with CHCI₃ (0.4g, 26%). Mpt 280-2°. Treatment with ethanolic HCl afforded the title compound.

1H NMR, 270MHz (DMSO-d⁶) δ: 8.95 (d, 1H), 8.25 (d, 1H), 7.85 (d, 1H), 7.60-7.53 (m, 1H), 7.41-7.33 (m, 1H), 4.85-4.76 (m, 1H), 4.27 (s, 3H), 3.80-3.40 (m, 4H), 3.28-3.20 (m, 1H), 2.99-2.83 (m, 2H), 2.60-2.48 (m, 1H), 2.25-2.19 (m, 1H), 2.09-1.81 (m, 2H), 2.75-2.64 (m, 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 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

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

X-A-Z (I) wherein Z is of structure (a) or (b) :

wherein

X is a phenyl group or a monocyclic 5 or 6 membered

A is a linking moiety; and

R is hydrogen or methyl;

having 5-HT₃ receptor antagonist activity.

2. A compound according to claim 1 wherein A is CONH, COO, NHCONH, CONHCONH 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 ^C1-5 alkylene optionally substituted by phenyl or hydroxy.

3. A compound according to claim 1, of formula (IA), or a pharmaceutically acceptable salt thereof:

X₁-CO-Y-

(IA) 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), (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

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 R_a is in the 4-position and is hydrogen, halogen, CF₃' C_1-6 alkyl, C_{1 -7} acyl, C_1-7 acylamino, 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 claim 1.

4. A compound according to claim 3 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.

5. A compound according to claim 3 wherein X is of sub-formula (b), and R₅ is hydrogen or a methyl or ethyl group.

6. A compound according to claim 3 wherein X is of sub-formula (d) and R₇ is methyl.

7. A compound according to claim 3 wherein X is of sub-formula (f) wherein R₁₀ is methoxy, R₁₂ is amino and R₁₃ is chloro or bromo.

8. A compound according to claim 3 wherein X is of sub-formula (g) wherein R₁₄ is hydrogen or methyl.

9. (±) 4-Amino-5-chloro-2-methoxy-N-(8-methyl-8-aza-bicyclo[3.2.1]octan-6-yl) benzamide.

10. N- (6-Azatricyclo [4, 3, 1, 0^4,9]decan-8-yl)-1-methyl-indazole-3-carboxamide.

11. A pharmaceutically acceptable salt of a compound according to claim 9 or 10.

12. A compound according to claim 1, substantially as described herein with reference to any one of the Examples.

13. A process for the preparation of a compound according to claim 1 which process comprises linking together X and the azabicyclic side chain according to known methods.

14. 6-Amino-8-methyl-8-azabicyclo [3.2.1] octane.

15. 8-Amino-6-azatricyclo [4, 3, 1, 0 4, 9] decane.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and a

pharmaceutically acceptable carrier.

17. A pharmaceutical composition for use in the treatment of pain, emesis, CNS disorders or gastrointestinal disorders comprising an effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.

18. A compound according to any one of claims 1 to 12, for use as an active therapeutic substance.

19. A compound according to any one of claims 1 to 12, for use in the treatment of pain, emesis, CNS disorders or gastrointestinal disorders.

20. Use of a compound according to any one of claims 1 to 12, in the manufacture of a medicament for the treatment of pain, emesis, CNS disorders or gastrointestinal disorders.

21. A method of treatment of pain, emesis, CNS disorders or gastrointestinal disorders in mammals, which comprises the administration of an effective amount of a compound according to claim 1.