NZ241019A

NZ241019A - Azabicyclic-substituted benzoic acid or benzamide derivatives and pharmaceutical compositions

Info

Publication number: NZ241019A
Application number: NZ24101991A
Authority: NZ
Inventors: Francis David King
Original assignee: Beecham Group Plc
Priority date: 1990-12-19
Filing date: 1991-12-17
Publication date: 1994-07-26
Also published as: PT99831A; GB9027487D0; WO1992011259A1; ZA919884B; KR930703308A; MX9102630A; CA2098729A1; AU9053391A; JPH06503332A; TW226020B; IE914395A1; EP0563087A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £41 019 4 10 19 Fricniy DalcJ-:): .. /.*?. !%■; complete Cpsci;'!~i.'::cn r.'.cd: S.I'J C'fss: cgip^.l /?„V; .<?*/. .(M'ojJ Qrra^.siot,'... c?.7£<e??/oy/a . CoVfl&al?#,-.. /fc^/frepv W, *« ?£.??§;. Subpublication Date: ..JJJ k P.O. Journal, Mo: .. ^3«2r. .• '• /v • '■ y~$ "i 3 i; * ^ W i f «j' a a 'y *W*^ NEW ZEALAND PATENTS ACT, 1953 No.: ! f^) 2 p<- r^|M'r ChFvce_ COMPLETE SPECIFICATION ( lv-t- - \ Date: r 1 : DEC i°2' 1 PHARMACEUTICALS p" we:EiyEC_ We, BEECHAM GROUP p.l.c., British Company of Four New Horizons Court, Harlequin Avenue, Brentford, Middlesex TW8 9EP, England, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) B3118 -ia- PHARMACEUTICALS This invention relates to novel compounds having pharmacological activity, to a process for their preparation 5 and their use as pharmaceuticals. EP-A-220011 (Beecham Group p.l.c.) describes the use of a benzamide derivative, as a 5-HT3 receptor antagonist. 10 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: 15 20 (I) wherein R-^ is hydrogen or C^_g alkoxy; 25 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. 30 Suitable examples of alkyl moieties in R^ include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. B3118 -2- Suitable examples of halo moieties include fluoro, chloro and bromo. 5 In particular, R-^ is hydrogen, R2 is chloro and R3 is chloro; or R-^ is methoxy, R2 is fluoro or chloro and R3 is Suitable examples of Z are described in the art relating to 10 5-HT3 receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited) ii) GB 2152049A (Sandoz Limited) iii) EP-A-215545 (Beecham Group p.l.c.) 15 iv) EP-A-214772 (Beecham Group p.l.c.) v) EP-A-377 967 (Beecham Group p.l.c.) vi) PCT/GB91/01629 (Beecham Group p.l.c.) vii) EP-A-358903 (Dianippon) 20 Particular side chains of interest are depicted thus: chloro. Tropane 25 Granatane 30 35 / X' Quinuclidine 10 15 Isoquinuclidine 20 Isogranatane 25 Oxa/thia-isoqranatane 30 *2 7 APR j994 B3118 4 1 1 -4- Isotropane 5 or wherein R is hydrogen or methyl; and X is oxygen, sulphur or 10 nitrogen optionally substituted by C^_g alkyl, C3--8 cycloalkyl, C3_g cycloalkyl alkyl, phenyl, naphthyl, phenyl C1-4 alkyl or naphthyl alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C-^_g alkoxy or C^_g alkyl. 15 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. 20 L is preferably NH. Alternatively, COL in formula (I) may be replaced by a bioisostere therefor, for example, 1,2,4-oxadiazole and the 25 other groups of structure h) described in EP-A-377 967 (Beecham Group p.l.c.). The pharmaceutical^ acceptable salts of the compounds of the formula (I) include acid addition salts with 30 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, a-keto glutaric, a-glycerophosphoric, and glucose-l-phosphoric 35 acids. L -5- Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds Rx-T wherein Rx is C-L_g alkyl, phenyl-C1_g alkyl or C^_7 cycloalkyl, and T is a 5 radical corresponding to an anion of an acid. Suitable examples of R__ include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide. 10 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 15 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. 20 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 25 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 30 a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II): 35 NHR« B3118 -6- with a compound of formula (III) : HLZ' (III) 5 or a reactive derivative thereof, when L is 0; wherein R-^' , R2' , R3' and/or Z' are R-^, R2f R3 and/or Z respectively or groups or atoms convertible thereto; R4 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-j// R2', R3' and/_or Z' to another group or atom R-^, R2, R3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I). 15 Examples of R4, when other than hydrogen, include acyl such as C1_7 alkanoyl, wherein the alkyl may be as listed for R^, preferably acetyl. R4 is usually hydrogen. 20 Examples of leaving groups Q-^, displaceable by a nucleophile, include halogen such as chloro and bromo, hydroxy, C^_4 alkoxy, such as CH3O and C2H5O-, PhO-, activated hydrocarbyloxy, such as Cl^CgO- or CI3CO-; or 25 COQ^, forms a mixed anhydride, so that Q-^ is carboxylic acyloxy; or a nitrogen-linked heterocycle, such as imidazole. If a group is a halide, or COQ-^/ forms a mixed anhydride, 30 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 35 acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or B3118 -7- 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 5 suitable. If a group Q-^ is alkoxy, phenoxy or activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as toluene or 10 dimethylformamide. It is also preferred that the group is CI3CO- and that the reaction is carried out in toluene at reflux temperature. If a group is hydroxy, then the reaction is generally 15 carried out in an inert non-hydroxylic solvent, such as dichloromethane, THF or DMF 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 20 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 25 preferably carried in substantially the same manner as the reaction when Q-^ is halide. Suitable examples of acyloxy leaving groups include C-^_^ alkanoyloxy and alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at 30 a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C-l.4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the corresponding compound wherein Q-^ is hydroxy with a alkyl chloroformate. 35 B3118 4 10 1 -8- If a group 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 5 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. 10 An R2' or R3' group which is convertible R2 or R3 include a hydrogen substituent which is convertible to a halogen substituent by halogenation using conventional halogenating agents. 15 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, alkoxy and C^_4 alkyl. Such benzyl groups may, 20 for example, be removed, when R^/R2 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 25 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 hydrogen, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula 30 (I). In this further process of the invention 'N-methylation' may be achieved by reaction with a compound CH3Q2 wherein Q2 is a leaving group. Suitable values for Q2 include groups displaced by 35 nucleophils such as CI, Br, I, OSO2CH3 or OSC^CgH^pCf^, B3118 4 1 -9- preferably CI, Br or I. The reaction may be carried out under conventional alkylation conditions for example in an inert solvent such 5 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 or slightly above. io 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 15 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£_7 alkanoyl group, before R/Z interconversion. 20 It is often convenient in the preparation of such a compound 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 25 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 30 from, known compounds. When R£ is fluoro, the intermediate may be prepared by fluorination of the corresponding R2 is hydrogen compound, using a suitable fluorinating catalyst, such as trifluoromethyl hypofluorite, as described in Description 1 hereinafter. 35 Compounds of the formula (III) are generally prepared from the corresponding exocyclic keto derivative of the B3118 k 1 1 -10- 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. 5 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 10 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 15 of the compound of the formula (II). Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains. 20 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 25 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 30 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 35 such cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also B3118 1 0 1 -11- 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 5 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 10 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 15 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 20 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. 25 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 30 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 35 include starch, polyvinylpolypyrrolidone and starch B3118 -12- derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include 5 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 10 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 15 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, 20 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 25 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. 30 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 35 quantities of fillers. Such operations are, of course, B3118 9 -13- conventional in the art. For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and 5 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. 10 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. 15 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 20 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 25 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. 30 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. 35 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 -14- 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. 5 No adverse toxicological effects are indicated within the aforementioned dosage ranges. The invention also provides a compound of formula (I) or a 10 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. 15 The following Examples illustrate the preparation of compounds of formula (I). Examples Ex. No. R1 r2 on (4 L Z 1 H CI CI NH NmT 2 H CI CI NH Q 3 och3 CI CI NH NmT 4 och3 CI CI NH NmO 5 och3 F CI NH NmT 30 NmT = N-methyltropane Q = Quinuclidin-3-yl NmO = N-methyloxagranatane -15- Description a) Methyl-4-acetamido-5-chloro-3-fluoro-2-methoxvbenzoate 5 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 10 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 15 with increasing amounts of methanol as eluant. The product was isolated as an off white solid. 1H NMR (CDCI3) 250MHz 208: 7.64 (d, 1H), 7.37 (bs, 1H), 3.98 (bs, 3H), 3.9 (s, 3H) , 2.2 (s, 3H) b) 4-Amino-5-chloro-3-fluoro-2-methoxybenzoic acid 25 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 30 precipitated solid was collected by filtration to give 1.48g product. 1H NMR (DMSO) 250MHz 358: 7.49 (d, 1H), 6.19 (bs, 1H), 3.80 (s, 3H) B3118 24 1 0 1 9 -16- Example 1 endo-N-(8-Methyl-8-azabicyclof3.2.11octan-3-vl)-4-amino-3,5-dichlorobenzamide (El) 5 15 To a stirred solution of 4-amino-3,5-dichlorobenzoic acid (l.lg) in CH2C12 (50 ml) and EtgN (0.8 ml) at 0°C was added Et02CCl (0.48 ml). After stirring to room temperature for lh, a solution of the endo-8-methyl-8- azabicyclo[3.2.1]octan-3-amine (0.7 g) in CH2CI2 (10 ml) was 20 added and the whole stirred overnight. The reaction mixture was washed with sat. NaHCO^ solution, dried and evaporated. Recrystallisation of the residue (EtoAc/petrol) gave the title compound (0.35 g) mp 192-193°C. 25 1H NMR (CDCI3) 6 7.55 (s, 2H) 10 2 30 6.25 (brd 1H) 4.76 (brs, 2H) 4.22 (q, 1H) 3.21 (brs, 2H) 2.33 (s, 3H) 2.35-2.10 (m, 4H) 1.88-1.68 (m, 4H) B3118 Prepared similarly was: Example 2 5 N-(1-Azabicvclo f 2.2.21octan-3-yl)-4-amino-3,5~ dichlorobenzamide (E2) mp 233-235°C. 10 Example 3 endo-N-(8-Methyl-8-azabicyclo f3.2.11octan-3-yl)-4-amino-3,5-dichloro-2-methoxybenzamide (E3) 15 A solution of endo-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-amino-5-chloro-2-methoxybenzamide (0.8g) in CH^COOH (25 mL) was treated with a solution of Cl2 (0.18 g) in CH^COOH (5 mL). After standing at room temperature 20 overnight, the solvent was removed by rotary evaporation and the residue partitioned between EtOAc and aqueous NaHCC^ solution. The organic extract was separated, dried (K2CO3) evaporated and the residue purified by flash chromatography (SiC>2, 5-10% MeOH/CHCl-j) to give the title compound 25 (0.065 g) mp 148-151°C. Prepared similarly was: Example 4 30 endo-N-(9-Methyl-9-aza-3-azabicvclo T3.3.11nonan-7-yl)-4-amino-3,5-dichloro-2-methoxybenzamide (E4) mp 170-172°C. 35 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> B3118 -18- Example 5 endo-4-Amino-5-chloro-3-fluoro-2-methoxy-N-(8-methyl-8-azablcvclo T3.2.11octan-3-yl)benzamide (E5) 5 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. 10 The product was isolated as the hydrochloride salt, mp 202-203°C. 1H NMR (free base), (CDCI3), 250 MHz 15 5: 8.61 (bd, 1H), 7.81 (d, 1H), 4.34 (bs, 2H), 4.20 (dd, 1H), 3.98 (d, 3H), 3.10 (b, 2H), 1.53-2.21 (m, 11H inc.s, 2.21, 3H). 20 5-HT 3 Receptor Antagonist Activity Compounds are evaluated for antagonism of the von Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised 25 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. 30 Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (usually 6}ig/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 35 control response (ED^q) is then determined. B3118 claim -19- 1 1 Claims,

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

5

10

R

NH2

(I)

wherein is hydrogen or C^_g alkoxy;

15 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.

20

2. A compound according to claim 1 wherein R-^ is hydrogen, R2 is chloro and R3 is chloro.

3. A compound according to claim 1 wherein R-^ is methoxy, 25 R2 is fluoro or chloro and R3 is chloro.

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,

30 isogranatane, oxa/thia-isogranatane or isotropane.

5. A compound according to claim 4 wherein Z is tropane, oxagranatane or azagranatane.

9 A 1 fl 1

-20-

6. A compound according to any one of claims 1 to 5 wherein L is NH.

7. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-5 amino-3,5-dichlorobenzamide.

8. N-(1-Azabicyclo[2.2.2]octan-3-yl)-4-amino-3,5-dichlorobenzamide.

10 9. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-amino-3,5-dichloro-2-methoxybenzamide.

10. endo-N-(9-Methyl-9-aza-3-azabicyclo[3.3.1]nonan-7-yl) 4-amino-3,5-dichloro-2-methoxybenzamide.

15

11. endo-4-Amino-5-chloro-3-fluoro-2-methoxy-N-(8-methyl-azabicyclo[3.2.1]octan-3-yl)benzamide.

12. A pharmaceutically acceptable salt of a compound 20 according to any one of claims 7 to 11.

13. A compound according to claim 1 substantially as defined herein with reference to any one of the Examples.

25

14. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (II):

with a compound of formula

(III) :

-21-

or a reactive derivative thereof, when L is 0;

wherein R-j/, R2'' R3' anc*/or Z' are R^, R2, R3 and/or Z respectively or groups or atoms convertible thereto; R^ is hydrogen or an N-protecting group; Q-^ is a leaving group; and the remaining variables are as defined in claim 1; and thereafter optionally converting R]/, ^2'' R3' anc*/or Z' to another group or atom R-^, R2, R3 or Z; and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 13 for use as an active therapeutic substance.

17. A compound according to any one of claims 1 to 13 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.

18. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.

19. A process for the preparation of a compound according to claim 1, substantially as described herein with reference to any one of the Examples.

Reference has been directed, in pursuance of section_^A_pf the

Patents Act 19 53, to sf)fe.ifjLcation x O''-

No. 239915.

Assistant Co f'^atbit

A ) it s6n

OATED THIS DAY .0

A. J. /f)A

PER

AGEKI'T^^Mapplicants

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