IE911399A1 - Novel compounds - Google Patents

Abstract

Isoquinoline derivatives (I) having 5-HT3 receptor antagonist activity, a process for their preparation and their use as pharmaceuticals. In formula (I) E is NH or O, R1 is hydrogen, halogen, alkyl, alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c) wherein; p is 1 or 2; q is 1 to 3; r is 1 to 3; R3 or R4 is hydrogen or alkyl, and Y is a group -CH2-X-CH2- wherein X is -CH2-, oxygen, sulphur or X is a bond; and (I) when the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, alkyl, or alkoxy, or R2 is in the 4-position and is hydrogen CF3, alkyl, acyl, acylamino (substituted) phenyl or (substituted) amino, (substituted) aminocarbonyl or (substituted) aminosulphonyl; (II) the group CO-E-Z- is in the 3-position and either R2 is in the 1-position and is hydrogen, alkyl or alkoxy or R2 is in the 4-position and is hydrogen or alkoxy.

Description

This invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions containing them, to a process and intermediates for their preparation, and to their use as pharmaceuticals.

GB 2145416A (Sandoz Ltd) describes a group of naphthylene, chromene and quinoline derivatives with saturated azabicyclic side chains, and having 5-ΗΤβ receptor antagonist activity.

A class of structurally distinct compounds having an isoquinoline moiety, has now been discovered. These compounds have 5-ΗΤβ receptor antagonist activity.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein E is NH or 0, R4 is hydrogen, halogen, Cx_4 alkyl, C1-4 alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain, such as a group of formula (a) , (b) or (c) : -2,E 911399 B2968 (Ο wherein p is 1 or 2; q is 1 to 3; r is 1 to 3; R3 or R4 is hydrogen or alkyl, and Y is a group -CH2_X-CH2- wherein X is oxygen, sulphur or X is a bond; and B2968 -3i) the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, C^_g alkyl or alkoxy, or R2 is in the 4-position and is hydrogen, halogen, CF3, Cj_g alkyl, acyl, C|_7 acylamino, phenyl optionally substituted by one or two C-^_g alkyl, C^_g alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C^_g alkyl or C2_g cycloalkyl groups or by C^_g polymethylene or by phenyl, Cj_g alkylsulphonyl, Cg_g alkylsulphinyl, C-^.g alkoxy, C^_g alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R2 is in the 1-position and is hydrogen, C^-g alkyl or C-|_g alkoxy, or R2 is in the 4-position and is hydrogen or C^_g alkoxy; having 5-HT3 receptor antagonist activity.

Suitable examples of the group Rj include hydrogen, bromo, chloro, methyl, ethyl, n- and iso-propyl, η-, iso-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, and η-, iso-, sec- and tert-butoxy.

Suitable examples of Z are described in the art relating to -HT3 receptor antagonists, ie. as follows: i) ii) iii) iv) v) vi) 35 GB 2125398A (Sandoz Limited) GB 2152049A (Sandoz Limited) EP-A-215545 (Beecham Group p.l.c.) EP-A-214772 (Beecham Group p.l.c.) EP-A-377967 (Beecham Group p.l.c.) EP-A-358903 (Dianippon Pharmaceutical Co. Ltd.) Particular side chains of interest are depicted thus: -4Tropane Granatane Oxa/thia~g^anatane Quinuclidine Isoguinuclidine B2968 Isoqranatane Oxa/thia-isoqranatane Isotropane wherein R is hydrogen or methyl; and X is oxygen or sulphur.

Side chains Z oxagranatane, of particular interest include tropane and where R is methyl.

E is preferably NH.

When the group CO-E-Z is in the 1-position suitable examples of the group R2 when in the 4-position, include the following groups; hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, alkanoylamino such as formylamino, acetylamino, propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or B2968 -6two methyl, ethyl, n- or iso-propyl, η-, sec-, iso- or tert-butyl or phenyl groups; nitro, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R2 is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.

When the group CO-E-Z is in the 3-position, suitable io examples of the group R2 when in the 1-position, include the groups hydrogen, methyl, ethyl, n- or iso- propyl, methoxy and ethoxy, or when R2 is in the 4-position, suitable examples include the following groups; hydrogen, methoxy and ethoxy .

Preferred R2 groups, in any of the positions specified above, include hydrogen, methyl and methoxy. R2 is preferably in the 1-position.

For the avoidance of doubt, all alkyl and alkyl containing moieties are straight chained or branched.

Examples of R3/R4 when alkyl are methyl, ethyl, n- and iso-propyl, η-, iso-, sec- and tert-butyl, preferably . methyl.

Preferably p, q and r are 1 or 2.

The pharmaceutically acceptable salts of the compounds of 30 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, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose-l-phosphoric acids.

B2968 -7The 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.

Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds Ra~T wherein Ra is ^1-6 alkyl, phenyl-C4_g alkyl or C^_7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Ra include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl, preferably methyl. Suitable examples of T include halide such as chloride, bromide and iodide .

Examples of pharmaceutically acceptable salts of compounds of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.

The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.

It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods.

' BZytio -8It will also be realised that the isoquinoline nucleus in compounds of formula (I) may adopt an endo or exo configuration with respect to Z. The endo configuration is preferred.

A group of compounds within formula (I) is of formula (II): wherein the variables are as defined in formula (I).

Examples of the variables and preferred variables are as so described for corresponding variables in relation to formula (I) .

A further group of formula (III) : compounds within formula (I) is of wherein 35 defined ql is 1 or 2 and the remaining variables are as in formulae (I) and (II).

B2968 -9Examples of the variables and preferred variables are as so described for the corresponding variables in formula (I).

There is a further group of compounds within formula (I) of 5 formula (IV): wherein defined in formulae (I) and (II) . as Examples of the variables and preferred variables are so described as the corresponding variables in formula (I).

The invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (V): with a compound of formula A2-Z' wherein Z' is Z as defined in formula (I) wherein Rg and R4 are replaced by R^' and •Ε 911399 -10R4', Aj and A2 are moieties which react together to form an amide or ester linkage and R^' and R^' are R^ and R^ respectively, as defined in formula (I) or a hydrogenolysable protecting group; and thereafter as desired 5 or necessary, converting R3', or R^' when other than or R4 respectively, to R^ and R^ respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

Suitable values of A^ and A2 are, for example, as described in the aforementioned patent publications. For example, may be an actived carbonyl function such as an acid chloride or N-hydroxysuccinmide ester and A2 may be an amino group, when E in formula (I) is NH.

Intermediates of the formula (V) are generally known or are prepared by analogous methods to those used for structurally related known compounds.

Intermediates of formula A2~Z' may be prepared from the corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine, as described in the aforementioned patent references.

In a particular aspect, the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (VI): COQ R.

(VI) B2968 -11with a compound of formula HJ-Z', or when J is oxygen, an active derivative thereof, wherein J is oxygen or NH, Q is a leaving group; R3' and R^' respectively is R3 and R4 respectively, as defined, or a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R3' or R^', when other than R3 or R4, to R3, or R4 respectively, and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).

Examples of leaving groups Q, displaceable by a nucleophile, include halogen such as chloro and bromo, alkoxy, such as CH^O and C2H5O-, PhO-, or activated hydrocarbyloxy, such as Cl^CgO- or COQ forms a mixed anhydride, so that Q is carboxylic acyloxy.

If a group Q is a halide or COQ forms a mixed anhydride, 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 Q is C-j__4 alkoxy, phenoxy or activated hydrocarbyloxy, or activated ester, such as Nhydroxysuccinimide, then the reaction is preferably carried out in an inert polar solvent, such as toluene or dimethylformamide. It is also preferred that the group Q is CI3CO- and that the reaction is carried out in toluene at -12reflux temperature.

If a group Q is hydroxy, then the reaction is generally 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, optionally in the presence of Nhydroxysuccinimide. The reaction may be carried out at any non-extreme temperature, such as -10 to 100°C, for example, io 0 to 80°C. Generally, higher reaction temperatures are employed with less active compounds whereas lower temperatures are employed with the more active compounds.

If a group Q is carboxylic acyloxy, then the reaction is preferably carried in substantially the same manner as the reaction when is halide. Suitable examples of acyloxy leaving groups include C4_4 alkanoyloxy and C4_4 alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C4_4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the corresponding compound wherein Q is hydroxy with a C|_4 alkyl chloroformate.

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

When J is 0 the compound of formula HJ-Z', may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.

B2968 -13R3' and R^' when other than R3 and R^ respectively, may be 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, for example, be removed, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (VII) or (VIII) respectively: (VII) (VIII) wherein the variables are as hereinbefore defined.

This invention also provides a further process for the preparation of a compound of the formula (I) wherein Z is a) or c) or a pharmaceutically acceptable salt thereof, which comprises N-alkylating a compound of formula (VII) or (VIII) B2968 -14respectively, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I) · In this further process of the invention 'N-alkylation' comprises the substitution of the N-atom depicted in formula (VII) or (VIII) respectively, by a group R3 or R^ respectively as hereinbefore defined. This may be achieved by reaction with a compound R3Q3 or R4Q3 as necessary wherein R3 and R^ are as hereinbefore defined and Q3 is a leaving group.

Suitable values for Q3 include groups displaced by nucleophiles such as Cl, Br, I, OSO2CH3 or OSC^CgH^pCH^.

Favoured values for Q3 include Cl, Br and I.

The reaction may be carried out under conventional alkylation conditions, for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above.

Alternatively, 'N-alkylation' may be effected under conventional reductive alkylation conditions.

Interconverting R3 and R4 respectively in the compound of the formula (VII), or (VIII) respectively, before coupling with the compound of the formula (VI) is also possible.

Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C2_7 alkanoyl group, before R3 or R4 interconversions.

It is often convenient in the preparation of such a compound of formula (VII) or (VIII) to prepare the corresponding B2968 -15compound wherein the methylene group is replaced by -CO-, or for R3 or R^ is methyl, where the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (VII) or (VIII) respectively.

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

It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia-granatane side chain, the -COE- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding geometric isomeric pairs are possible for the isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.

Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition 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; B2968 -16emesis, includes in particular that of preventing vomiting and nausea associated with cancer therapy, and motion sickness. Examples of such cancer therapy include that using cytotoxic agents, such as cisplatin, doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis, senile dementia and drug dependence. Gastrointestinal disorders include irritable bowel syndrome and diarrohea. -ΗΤβ receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.

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 suitably 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 B2968 -17include 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 io 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 B2968 -18quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are 5 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.

Tin 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 tsz 5DO _19_ 0.05 to lOOOmg for example 0.1 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 (I) 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 invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis 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. ίΕ9ΐΐ3 Β2968 -20Description 1 4-Methyl-l-isoquinoline carboxaldehyde (DI) To a solution of 1,4-dimethyl isoquinoline (9.46g) (K.C.

Agrawal, P.D. Mooney and A. C. Sartorelli, J. Med. Chem., 1976, 19, 970) in 1,4-dioxane (250 ml) was added selenium dioxide (6.65g) and the mixture heated under reflux, under an atmosphere of nitrogen, for 4h. After allowing the reaction mixture to cool to room temperature, the precipitated selenium was removed by filtration and the filtrate concentrated to dryness. The residue was purified by flash chromatography on silica gel, using light petroleum ether (bp 60-80°C) and diethyl ether (up to 20% v/v) as eluent, to afford the aldehyde (DI) (3.78g) as a tan solid. Mp. 61-63°.

M.S. M+ 171 n.m.r. (CDCl^, 250 MHz) δ 2.74 (s, 3H) 7.71-7.87 (m, 2H) 8.05 (d, IH) 8.63 (s, IH) 9.38 (d, IH) 25 10.35 (s, IH) Description 2 4-Methyl-l-isoquinoline carboxylic acid (D2) To an aqueous solution of silver oxide (prepared by the addition of silver nitrate (5g) in water (10 ml) to a stirred solution of sodium hydroxide (2.40g) in water (10 ml)) was added, at 0°C, 4-methyl-l-isoquinoline B2968 -21carboxaldehyde (D.l) (2.50g), in portions. The reaction mixture was stirred at ambient temperatures overnight. The silver suspension was removed by filtration and washed with hot water (3x5 ml). The combined filtrate and washings were acidified with cone. HCl and extracted with chloroform (3x50 ml). The organic phase was dried (MgSO^) and concentrated in vacuo to afford the title compound (D2) (980 mg) as a beige solid mp. 155-57°.

M.S. MH+ 188 n.m.r. (CDCI3, 250 MHz) 2.75 (s, 3H) 7.79-7.92 (m, 2H) 8.07 (d, IH) 8.43 (s, IH) 9.67 (d, IH) 10.58 (bs, IE Example 1 endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)isoguinolin1-carboxamide (El) -Me (El) ,E 911399 -22A solution of isoquinolin-l-carboxylic acid (2g), N-hydroxysuccinimide (1.5g) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.6g) was stirred in dry DMF (50ml) at room temperature for 4 hours.

The reaction mixture was cooled at 0°C, endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (2g) in CH2CI2 (30ml) was added and the mixture stirred at room temperature overnight. The solvent was removed and the residue dissolved in CH2CI2, washed with saturated aqueous NaHCO^ solution, dried and concentrated. The residue was recrystallised from Ethyl acetate and petrol (Bpt. range 60-80°C), to give the title compound (2.4g). m.p. 155-157°C.

Examples 2 to 6 The following compounds are prepared analogously to example 1 or as hereinbefore described.

Example Point of R21Z1 25 attachment of CO-NH-Zjl E2 1 H N-methyltropane 30 E3 3 H N-methyltropane E4 1 H quinuclidin-3-yl E5 1 4-CH3 N-methyltropane 35 E6 1 H N-methyloxagranatane B2yfc>b -23Example 2 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)isoguinolin1-carboxamide (E2) mp 87-88° 1H-NMR (CDCI3) δ 9.67 (d, IH) 10 8.75 (d, IH) 8.48 (d, IH) 7.9-7.6 (m, 4H) 4.42-4.28 (m, IH) 3.25 (brs, 2H) 15 2.42-1.70 (m, IIH including 2.

Example 3 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)20 isocfuinolin-3-carboxamide (E3) mp 133-136° 1H-NMR (CDC13) δ 9.19 8.85 8.60 8.10-7.95 7.80-7.65 4.36 3.25 2.44-1.95 (m, 1.85 (s, IH) (brd, IH) (s, IH) (m, 2H) (m, 2H) (dt, IH) (brs, 2H) 9H including 2.36,s, 3H) (brd, 2H) B2968 -24Example 4 N-(Quinuclidin-3-yl)isoquinolin-l-carboxamide(E4) mp 115-117° 1H-NMR (CDC13) δ 9.62 lh) 8.51-8.40 (m, 2h) 10 7.9-7.62 (m, 4h) 4.35-4.15 (m, lh) 3.58-3.41 (m, lh) 3.10-2.82 (m, 4h) 2.75 (dd, lh 15 2.41-1.5 (m, 5h) Example 5 endo-N- (9-Methyl-9-aza-3-oxabicyclo [3.3.1] nonan-7-yl) isoquinolin-l-carboxamide (E5) mp 148-150°1H-NMR (CDC13) 25 δ 10.03 (brd, IH) 9.42 (d, IH) 8.50 (d, IH) 7.9-7.62 (m, 4H) 4.88-4.72 (m, IH) 30 4.10 (d, 2H) 3.68 (d, 2H) 2.75 (brs, 2H) 2.67-2.50 (m, 5H including 2. 1.60 (d, 2H) B2968 -25Example 6 endo-N-(8-Methyl-8-azabicyclo(3.2.1]octan-3-yl)-4-methyl1-isoquinolin-l-carboxamide hydrochloride (E6) A solution of 4-methyl-l-isoquinoline carboxylic acid (500 mg) (D2) and N-hydroxy succinimide (368 mg) in dry DMF (15 ml) was stirred under an atmosphere of nitrogen at ambient temperatures for 30 min. l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (768 mg) was added in one portion and stirring continued for lh. The reaction mixture was cooled to 0°C and a solution of endo-8-methyl-8-azabicyclo[3.2.1]octan-3amine (374 mg) in DMF (5 ml) was added dropwise and stirring continued for 20h at ambient temperatures. The solvent was removed in vacuo and the residue partitioned between chloroform (50 ml) and 10% aq. NaOH (5 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, using chloroform and ethanol (up to 10% v/v) as the eluent to afford an oil. Treatment with ethanolic HCl gave the title compound (200 mg) as a pale yellow solid, m.p. 140-43°.

M.S. M+ 309 (Free base) 1H-NMR (d4-MeOH, 250 MHz) 33-2.52 (m, 5H) 59-2.65 (m, 2H) 84 (s, 3H) 92 (s, 3H) 02 (d, 1H) 89-4.06 (m, 2H) 40-4.53 (m, 1H) 10 (t, 1H) 30 (t, 1H) 44-8.60 (m, 3H) B2968 -265-HT-j 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 6gg/kg) is given repeatedly by the intravenous route and changes in heart rate quantified. Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED^q) is then determined.

Claims (9)

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: (I) wherein E is NH or 0, 15 is hydrogen, halogen, Cj_ 4 alkyl, C 2 _ 4 alkoxy, hydroxy or nitro; Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the 1-position and either R 2 is 20 in the 3-position and is hydrogen, C^_g alkyl or C 2 _g alkoxy, or R 2 is in the 4-position and is hydrogen, halogen, CF^, Cj_g alkyl, acyl, C 4 _ 7 acylamino, phenyl optionally substituted by one or two C 4 _g alkyl, C^_g alkoxy or halogen groups, or amino,. 25 aminocarbonyl or aminosulphonyl, optionally substituted by one or two C 4 _g alkyl or Cg_g cycloalkyl groups or by C 4 _g polymethylene or by phenyl, C 2 _g alkylsulphonyl, C 4 _g alkylsulphinyl, Cj_g alkoxy, Cj_g alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R 2 is in the 1-position and is hydrogen, C^_g alkyl or C-^g alkoxy, or R 2 is in the 4-position and is hydrogen or C 4 _g alkoxy; having 5-HTg receptor antagonist activity. ΙΕ 911399 Β2968 -282. Α compound according to claim 1 wherein E is NH.

2. 3. A compound according to claim 1 in the 1-position. or 2 wherein CO-E-Z is

3. 4. A compound according to wherein R^ is hydrogen. any one of claims 1 to 3

4. 5. A compound according to any one of claims 1 to 4 10 wherein Z is tropane, granatane, oxa/thia-granatane, quinuclidine, isoquinuclidine, isogranatane, oxa/thiaisogranatane or isotropane.

5. 6. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)iso15 quinolin-l-carboxamide.

6. 7. endo-N-(

7. 8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)isoquinolin-l-carboxamide. 20 8. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)isoquinolin-3-carboxamide.

8. 9. N-(Quinuclidin-3-yl) isoquinolin-l-carboxamide. 25 10. endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.l]nonan-7-yl)isoquinolin-l-carboxamide. 11. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4methyl-1-isoquinolin-l-carboxamide. 12. A pharmaceutically acceptable salt of a compound according to any one of claims 6 to 11. -2913. A compound according to claim 1 substantially as defined herein with reference to the Examples. 14. A process for the preparation of a compound according 5 to claim 1, which process comprises reacting a compound of formula (V): (V) 15 with a compound of formula A 2 ~Z' wherein Z' is Z as defined in claim 1 wherein R3 and R^ are replaced by R3' and R4' , Aand A 2 are moieties which react together to form an amide or ester linkage and R3' and R^' are R3 and R^ respectively, as defined in claim 1, or a hydrogenolysable protecting group; 20 and thereafter as desired or necessary, converting R3', or R4' when other than R3 or R^ respectively, to R3 and R^ respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I). 25 15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier . 16. A method of treatment or prophylaxis of pain, emesis, 30 CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound according to claim 1. -30- ’ B2968 17. A compound according to any one of claims 1 to 13 for use as an active therapeutic substance. 18. A compound according to any one of claims 1 to 13 for 5 use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders. 19. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment

9. 10 and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.