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

EP-A-200444 (Beecham Group p.I.e.) describes a group of aryl amides and esters having an azabicyclic side chain and possessing 5-HT3 receptor antagonist activity. The compound of Example 6, which is now known by its generic name, granisetron, is being developed in the clinic as an antiemetic drug.

A compound which is not specifically disclosed in EP-A-200444 has now been discovered, this compound having 5-HT3 receptor antagonist activity.

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

(I)

The compound of formula (I) is preferably in pharmaceutically acceptable form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding

normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. A pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%. One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.

The pharmaceutically acceptable salts of the compound 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, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

The pharmaceutically acceptable salts of the compound of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.

Preferably the acid addition salt is the hydrochloride salt.

Pharmaceutically acceptable salts also include those formed with bases, such as alkali metal salts such as sodium or potassium, formed with the appropriate hydroxide.

Examples of pharmaceutically acceptable salts also include quaternary derivatives of the compound of

formula (I) such as the compounds quaternised by compounds R _a -Twherein R _a is Cι_ ₆ alkyl, phenyl-Cι_g alkyl or Cζ-~j cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R _a 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 of compound of formula (I) also include internal salts such as pharmaceutically acceptable N-oxides.

The compound of the formula (I) and its 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.

The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (II):

with a compound of formula (III)

(HI)

wherein Q is a leaving group and X is hydroxy or protected hydroxy; and thereafter optionally forming a pharmaceutically acceptable salt thereof.

Examples of leaving groups Q, displaceable by a nucleophile, include halogen such as chloro and bromo; ^c _l -4 alkoxy, such as CH3O and C2H5O-; PhO-; activated hydrocarbyloxy, such as Cl-Cf-O- or CI3CO-; succinimidyloxy; and imidazolyl. Preferably Q is halogen, most preferably chloro.

If a group Q is a halide or imidazolyl, 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 may be 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. Preferably, no acid acceptor is used, as it is not necessary. Temperatures of 0-100°C, in particular 10-80°C are suitable.

If a group Q is Cι_4 alkoxy, phenoxy, activated hydrocarbyloxy or succinimidyloxy then the reaction is preferably carried out in an inert solvent, such as toluene or dimethylformamide. In this instance, it is preferred that the group Q is CI3CO- or succinimidyloxy and that the reaction is carried out in toluene at reflux temperature.

X is preferably protected hydroxy, wherein the protecting group is preferably benzyl, which is removed conventionally by hydrogen, using a suitable catalyst, such as palladium on carbon.

The intermediates of the formula (II) are novel and form an aspect of the invention. They may be prepared from 7-bromo-7-methoxy-lH-indazole according to the method described in the Example hereinafter, or an obvious equivalent thereto.

The intermediate of the formula (III) is known and is prepared as described in GB 2125398A (Sandoz Limited).

The compound of formula (I) is preferably isolated in substantially pure form.

Pharmaceutically acceptable salts of the compound 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

emesis, migraine, cluster headaches, trigeminal neuralgia and visceral pain. Compounds which are 5-HT ₃ antagonists are also of potential use in the treatment of CNS disorders such as anxiety and psychosis; drug withdrawal syndrome; cardiac arrhythmia, obesity and gastrointestinal diseases, such as irritable bowel syndrome.

Antiemetic activity includes, in particular, that of preventing nausea and vomiting induced by cytotoxic agents used in cancer chemotherapy. Examples of cytotoxic agents include cisplatin, doxorubicin and cyclophosphamide.

Antiemetic activity also includes that of preventing radiation induced nausea and vomiting and motion sickness.

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 enteral 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 migraine, cluster headache, trigeminal neuralgia, visceral pain, emesis and/or anxiety in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders herein¬ before described depends on the relative efficacies of the compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal. However, a unit dose for a 70kg adult will normally contain 0.0005 to lOOmg for example 0.001 to 50mg, 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 10 ^~7 to 5mg/kg/day, more usually 10 ^~5 to 3mg/kg/day.

No adverse toxicological effects are indicated at any of 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 migraine, cluster headache, trigeminal neuralgia, visceral pain, emesis and/or anxiety.

The following Example illustrates the preparation of the compound of formula (I).

Example

a) 3-Bromo-7-methoxy-lH-indazole

10% aqueous sodium hydroxide (700ml) was added to 7-methoxy-lH-indazole( ¹ ) (30g) dissolved in ethanol (185ml) and a solution of bromine (14.8ml) in 10% aqueous sodium hydroxide (290ml) was added slowly. Stirring was continued for 1.75 hours at room temperature. Solid sodium metabisulphate was added and the mixture acidified with 50% aqueous hydrochloric acid prior to extraction with diethyl ether. The combined organic extracts were washed with aqueous sodium metabisulphate and, saturated brine, dried (MgSθ ), treated with activated charcoal and filtered through a bed of kieselgel 60. Evaporation gave a gum which was chromatographed on kieselgel 60 eluted with 50% diethyl ether/60-80 petrol to give the product as a solid.

yield 28.8 g (62%) mp 107 - 108°C

6(CDC1 ₃ ); 3.95 (s, 3H) ; 6.75 (d, J=7Hz, 1H) ; 7.11 (t, J=7Hz, 1H); 7.19 (d, J=7Hz, 1H) ; 11.0 (b, 1H)

(1) E.G. Kovach and D.E. Barnes JACS 7_6, 1176 (1954)

b) 3-Cyano-7-methoxy-lH-indazole

Copper (I) cyanide (3.45g), sodium iodide (10mg), 3-bromo-7-methoxy-lH-indazole (8.8g) and N-methyl-pyrrolidone (70ml) were mixed and heated at reflux under a dry nitrogen atmosphere for 3 hours. The mixture was cooled to 70°C and treated with ferric chloride solution (130ml), prepared from ferric chloride (8g) water (120ml) and hydrochloric acid (SG 1.18, 20ml). After stirring for lh the aqueous mixture was extracted with diethyl ether and the combined organic layers washed with water followed by saturated brine. The resulting orange solution was filtered through kieselgel 60 and evaporated to the porduct as a brown solid.

yield 5.5g (82%) .p. 112 - 124°C

δ(CDCl ₃ ): 3.95 (s, 3H) ; 6.75 (d, J=8Hz, 1H) ; 7.16 (t, J=8Hz, 1H); 7.39 (d, J=8Hz, 1H, 11.97 (b, 1H)

c) 7-Methoxy-lH-indazole-3-carboxylic acid

3-Cyano-7-methoxy-lH-indazole (15.5g) was treated with hydrochloric acid (SG 1.18, 375ml) at reflux for 2 hours. The mixture cooled and poured into ice/water (1.5L). The aqueous layer was extracted with ethyl acetate and the combined organic layers extraced with 5% sodium hydroxide. The combined basic extracts were acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSθ4), treated with activated charcoal and evaporated to dryness. The resulting solid was treated with toluene and evaporated to give the product as an off-white solid.

- 12 -

yield 17.3g (quantitative) m.p. 207 - 212°C

δ(CD ₃ OD): 4.01 (S, 3H) ; 6.87 (d, J=8Hz, 1H) ; 7.20 (t, J=8Hz), 1H); 7.68 (d, J=8Hz, 1H)

d) Methyl 7-methoxy-lH-indazole-3-carboxylate

7-Methoxy-lH-indazole-3 carboxylic acid (4.4g) was dissolved in dimethylformamide (90ml). Anhydrous potassium carbonate (8.8g) was added followed by methyl iodide (4.4ml) . The resulting suspension was stirred at room temperature under a dry nitrogen atmosphere for 3 hours. The dimethylformamide was removed by evaporation under reduced pressure. The residue was partitioned between water/diethyl ether and treated with 5N hydrochloric acid to decompose the excess potassium carbonate. The aqueous layer was extracted with diethyl ether and the combined organic layers washed with water followed by saturated brine and dried (MgSθ4). Evaporation and subsequent recrystallisation from industrial methylated spirits afforded the product as an off-white solid.

yield 1.89g (37%) m.p. 127 - 128°C

δ(CDCl ₃ ): 4.05 (s, 3H) , 4.12 (s, 3H) ; 6.82 (d, J=8Hz, 1H); 7.26 (t, J=8Hz, 1H); 7.84 (d, J=8Hz, 1H)

e) 7-Methoxy-l-methyl-lH-indazole-3-carboxylate

Methyl 7-methoxy-lH-indazole-3-carboxylate (7.6g) was dissolved in methanol (100ml), 10% aqueous sodium hydroxide (40ml) added and the resulting solution warmed until hydrolysis of the ester was complete. The

methanol was removed by evaporation and water was added to the aqueous residue. This solution was acidified with 5N hydrochloric acid to give a precipitate which was collected by filtration washed with water and dried under suction to give the product as a white solid.

yield 7.03g (98%) m.p. 217 - 219°C

δ(DMSO): 4.04 (s, 3H) ; 4.37 (s, 3H) ; 6.98 (d. J=8Hz, 1H); 7.26 (t, J=8Hz, 1H); 7.70 (d, J=8Hz, 1H) ; 13.05 (b, 1H)

f) 7-Hydroxy-l-methyl-lH-indazole-3-carboxylic acid

7-Methoxy-l-methyl-lH-indazole-3-carboxylic acid (7.0g) was treated with 47% hydriodic acid (400ml) for 2 hours at reflux under a nitrogen atmosphere. The resulting mixture was cooled, poured into water (800ml) and extracted with diethyl ether and dichloromethane. The combined organic extracts were washed with aqueous sodium metabisulphate solution and saturated brine then dried (MgSθ4). Evaporation followed by trituration of the resulting residue afforded the product as an off-white solid.

yield 5.5g (84%) m.p. 264 - 266°C

δ(DMSO): 4.42 (S, 3H) ; 6.84 (d, J=8Hz, 1H) ; 7.15 (t, J=8Hz, 1H); 7.58 (d, J=8Hz, 1H) 10.57 (b, 1H)

g) Benzyl 7-benzyloxy-l-methyl-lH-indazole-3- carboxylate

7-Hydroxy-l-methyl-lH-indazole-3-carboxylic acid was dissolved in dimethylformamide (7ml) and anhydrous

potassium carbonate (80mg) added followed by benzyl bromide (0.07ml). The resulting suspension was stirred at room temperature under a dry nitrogen atmosphere for 5.5 hours. The dimethylformamide was removed by evaporation under reduced pressure. The residue was partitioned between water/dichloromethane and treated with 5N hydrochloric acid to decompose the excess potassium carbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers washed with saturated brine and dried (NaSθ4). Evaporation afforded the product as a viscous oil which solidified on standing.

yield lOOmg (quantitative)

δ(CDCl ₃ ): 4.4 (s, 3H) ; 5.2(s, 2H) ; 5.5 (s, 2H) ; 6.82 (d, J=8Hz, 1H); 7.15 (t, J=8Hz, 1H) ; 7.4 (d, J=8Hz, 1H)

h) 7-Benzyloxy-l-methyl-lH-indazole-3-carboxylic acid

Benzyl 7-benzyloxy-l-methyl-lH-indazole-3-carboxylate (11.7g) was dissolved in ethanol (440ml). Water (35ml) and 10% aqueous sodium hydroxide (35ml) and the resulting solution warmed until hydrolysis of the ester was complete. The ethanol was removed by evaporation and the aqueous residue made basic by the addition of 10% aqueous sodium hydroxide (20ml). this was then extracted with diethyl ether and the aqueous layer acidified with 5N hydrochloric acid. The resulting suspension was extracted with dichloromethane, and the combined extracts washed with saturated brine and dried (MgS0 ₄ ). Evaporation afforded the product as a white solid.

yield β.lg (91%) m.p. 189 - 191°C

δ(DMSO): 4.4 (s, 3H) ; 5.4 (s, 2H) ; 7.1 (d, J=8Hz, 1H) ; 7.28 (t,J=8Hz, 1H); 7.50 (m, 3H) ; 7.67 (m, 2H) 7.73(d, J=8Hz, 1H); 13.1 (b, 1H)

i) 7-Benzyloxy-l-methyl-N-(9-methyl-9-azabicyclo- T3.3.πnon-3-endo-lH-indazole-3-carboxamide

7-Benzyloxy-l-methyl-lH-indazole-3-carboxylic acid (900mg) was dissolved in dichloromethane (25ml). Dimethylformamide (3 drops) and thionyl chloride (0.233ml) were added and the resulting misture was stirred and heated under reflux for 2 hours under a dry nitrogen atmosphere before cooling to ambient tempreature. A solution of 3-endo-amino-9-methyl- 9-azabicyclo[3.3.1]nonane (2) (720mg) in dichloromethane (5ml) was added slowly keeping the reaction temperature below 20°C. The resulting suspension was stirred at ambient temperature for 18 hours before extraction with 5% aqueous sodium hydroxide solution. The combined aqueous extracts were extracted with dichloromethane and the combined organic layers washed with saturated brine and then dried (K2CO3). Evaporation afforded the product as a gum; Crystallisation from isopropanol resulted in white crystalline solid which was dried under suction and finally under vacuum.

yield 1.14g (85%) m.p. 134 - 136°C

δ(CDCl ₃ ): 1.05 (m, 2H) ; 1.35 (m, 2H) ; 1.51 (m, 1H) ;

1.96 ( , 3H); 2.53 (m, 5H); 3.08 ( , 2H) ; 4.30 (s, 3H) ; 4.55 ( , 1H); 5.2 (s, 2H); 6.75 (3, J=9Hz, 1H) ; 6.80 (d, J=8Hz, 1H); 7.12 (t, J=8Hz, 1H) ; 7.4 (m, 5H) ;

7.97 (d, J=8Hz, 1H)

(2) GB 2125398A (1983)

j ) 7-Hydroxy-l-methyl-N-(9-methyl-9-azabicyclo- f .3.1lnon-3-endo-yl-lH-indazole-3-carboxamide hydrochloride

7-Benzyloxy-l-methyl-N-(9-methyl-9-azabicyclo- [3.3.11non-3-endo-yl-lH-indazole-3-carboxamide (1.Og) was dissolved in ethanol (50ml). Hydrochloric acid (S.G. = 1.18, 0.35ml) and 10% palladium on carbon (O.lg) were added and the mixture hydrogenated at atmospheric pressure and ambient temperature for 2 days. The catalyst was removed by filtration and the filtrate evaporated to give a pink solid. This was redissolved in aqueous ethanol containing toluene. Evaporation afforded the product as a cream solid.

yield 890mg (quant.) m.p. 301 - 302°C

δ(CD ₃ OD/NaOD) : 1.05 (m, 2H); 1.45 (m, 3H) ; 2.00 (m, 3H); 2.45 (m, 5H) ; 3.05 (m, 2H); 4.45 (m, 4H); 6.45 (d, J=8Hz, IH); 6.90 (t, J=8Hz, IH; 7.18 (d, J=8Hz, IH)

Pharmacology

Antagonism of the von Bezold-Jarisch reflex

The compounds were 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, were anaesthetised with urethane (1.25g/kg intraperitoneally) and blood pressure and heart rate 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) was given repeatedly by the intravenous route and changes in heart rate quantified. Compounds were given intravenously and the concentration required to reduce the 5HT-evoked response to 50% of the control response (ED50) was then determined.

The compound of the Example gave an ED5 ₀ value of 0.52 ± 0.13 μg/kg (n-8) .