Isoquinolinyl carboxamides and their use as anticonvulsants

Abstract: Compounds of formula (I): wherein Q is a monocyclic or bicyclic aryl or heteroaryl ring; R 1 is hydrogen; R 2 is hydrogen or up to three substituents selected from halogen, NO 2 , CN, N 3 , CF 3 O-, CF 3 S-, CF 3 SO 2 -, CF 3 CO-, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 perfluoroalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl-, C 1-6 alkylO-, C 1-6 alkylCO-, C 3-6 cycloalkylO-, C 3-6 cycloalkylCO-,C 3-6 cycloalkyl-C 1-4 alkylO-, C 3-6 cycloalkyl-C 1-4 alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl-, C 1-6 alkylS-, C 1-6 alkylSO 2 -, (C 1-4 alkyl) 2 NSO 2 -, (C 1-4 alkyl)NHSO 2 -, (C 1-4 alkyl) 2 NCO-, (C 1-4 alkyl)NHCO-, or CONH 2 , or -NR 3 R 4 where R 3 is hydrogen or C 1-4 alkyl, and R 4 is hydrogen, C 1-4 alkyl, formyl, -CO 2 C 1-4 alkyl, or -COC 1-4 alkyl, or two R 2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; X is halogen, C 1-6 alkoxy, C 1-6 alkyl, or C 1-6 perfluoroalkyl, and; Y is hydrogen, halogen, C 1-6 alkoxy, C 1-6 alkyl, or C 1-6 perfluoroalkyl; but excluding the compounds N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide and N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide; and pharmaceutically acceptable salts or solvates thereof possess anticonvulsant activity and are useful in the treatment of a variety of disorders.

Description: This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents. Prior art document United States patent 4,022,900 (Marion Laboratories Inc.) discloses benzamido-1,2,3,4-tetrahydroisoquinolines having anti-hypertensive properties. Prior art documents International Application Publication Numbers WO 97/48683, WO98/41507, WO 98/41508, WO 97/48683, WO 99/21836 and WO 99/31068 (SmithKline Beecham) disclose isoquinolinyl benzamide derivatives and their use as anticonvulsants. It has now been surprisingly found that carboxamide compound N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide possesses anticonvulsant activity and is therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). In a first aspect the present invention provides the compound N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4- iso -propoxybenzamide. When synthesised this compound is often in salt form such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates such as hydrates, and these also form part of this invention. The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention. The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration. An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day. It is greatly preferred that a compound of the invention is administered in the form of a unit dose composition, such as an oral unit dose including sub-lingual, rectal, topical or parenteral (especially intravenous) composition. 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, in particular shaped oral compositions, 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, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. 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. 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, carboxymethyl cellulose, 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 formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating. For parenteral administration, fluid unit dose forms are prepared containing the compound 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 to 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. As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned. Accordingly, the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) which comprises a compound of N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-iso-propoxybenzamide or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. In a further aspect the invention provides the use of N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4- iso -propoxybenzamideor a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). The present invention provides a process for the preparation of the compound of the invention as hereinbefore defined which process comprises reacting a compound of formula (II); wherein R 1A is hydrogen or preferably a group convertible to hydrogen, and X and Y are both chloro, with a compound of formula (III) wherein Q is phenyl; Y is a leaving group such as Cl or OH, and; R 2A represents 3-acetyl and 4-isopropoxy or groups convertible to 3-acetyl and 4-isopropoxy; and where required converting an R 1A or R 2A group to a hydrogen or 3-acetyl and 4-isopropoxy group respectively; converting a salt product to the free base or a pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt. Reaction of a compound of formula (III) which is an acid chloride (Y=Cl) will lead directly to the hydrochloride salt. Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the compound of formula (III) is an aromatic acid (Y=OH), conventional conditions for condensation of such acids with amines may be used, for example reacting the components in a mixture of (dimethylaminopropyl)-ethylcarbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formamide. Conversions of an R 1A or R 2A group to a hydrogen or 3-acetyl and 4-isopropoxy group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence. The compound of formula (II), wherein R 1A is hydrogen or trifluoroacetyl and X and Y are both chloro may be prepared from the compound of formula (II) wherein R 1A is hydrogen or trifluoroacetyl, X is chloro, and Y is hydrogen by reaction with N-chloromorpholine in glacial acetic acid. The compound of formula (II) wherein R 1A is hydrogen or trifluoroacetyl, X is chloro, and Y is hydrogen may be prepared from the compound of formula (IV) wherein R 1A is hydrogen or trifluoroacetyl, X is chloro and Y is hydrogen by reduction with tin (II) chloride in concentrated hydrochloric acid. The compound of formula (IV) wherein R 1A is hydrogen or trifluoroacetyl, X is chloro and Y is hydrogen may be prepared from the compound of formula (IV) wherein X is iodo and Y is hydrogen by heating in the presence of copper (I) chloride in an inert atmosphere. The compound of formula (IV) wherein R 1A is hydrogen or trifluoroacetyl, X is iodo and Y is hydrogen may be prepared from the compound of formula (V) wherein R 1A is hydrogen or trifluoroacetyl and Y is hydrogen by reaction with N-iodosuccinimide in triflic acid according to the procedure of G.A.Olah et al ., J.Org.Chem., 1993, 58, 3194. The compound of formula (V) wherein R 1A is hydrogen and Y is hydrogen may be prepared from the compound of formula (VI) wherein Y is hydrogen by hydrolysis with potassium carbonate in methanol. The compound of formula (VI) wherein Y is hydrogen may be prepared by reaction of N-(nitrophenyl)ethyl trifluoroacetamide and paraformaldehyde in acidic conditions using the procedure of Stokker, Tet.Lett.,1996, 37, 5453. N-(nitrophenyl)ethyl trifluoroacetamides can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below. Compounds of formula (II) may also be prepared from the corresponding aminoisoquinoline (or its nitro-analogue) of formula (VII) where R N is NH 2 or NO 2 and X and Y are as hereinbefore defined by reaction with a compound R 1A Z where Z is a leaving group such as halogen, especially iodo, or tosylate and R 1A is benzyl or 4-methoxybenzyl to obtain an intermediate of formula (VIII). which can be reduced, for example using sodium borohydride, or hydrogenated, for example using hydrogen and a palladium/activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II). When the compound of formula (VIII) is replaced by a nitroisoquinoline, the nitro group is converted to an amino group in the hydrogenation step. When the intended R 1 is hydrogen, the nitrogen atom of the tetrahydroisoquinoline or isoquinoline molecule is preferably protected conventionally, prior to the coupling step that forms the carboxamide of formula (I), for example by tert .-butoxycarbonyl, trifluoroacetyl or benzyl. The compound can be deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride or potassium carbonate in aqueous methanol, catalytic hydrogenolysis. Amino/nitro-isoquinolines of formula (VIII) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature. The substituents X and Y may be introduced during any of the procedures above, for example by conventional substitution of the aromatic ring of compounds of formula (IV), (V) or (VIII) or may be present on commercially available starting materials usable in the above described procedures. Most suitably the substituents X and Y are introduced to a compound of formula (IX) where R N and R 1A are as hereinbefore defined. For example X as halogen may be incorporated by reaction with a halosuccinimide, or X = CF 3 may be introduced by displacement of iodo with copper(I)trifluoroacetate as illustrated in the descriptions below. Compounds of formula (III) may be prepared by further substitution of commercially available benzoic acid or thiophene carboxylic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correspondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid. Examples of these procedures are documented in WO 98/41507 and WO98/41508. The preparation of compounds of this invention is illustrated by the following Descriptions and Examples.: Description 1 N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide A solution of trifluoroacetic anhydride (10.6ml) in dichloromethane (100ml) was added dropwise to a stirred solution of 2,6- lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2g; 75 mmol) at 0°C. The mixture was stirred at 25°C overnight under argon and then washed with dilute citric acid (x2), brine and dried over Na 2 SO 4 . The material in the organic phase gave the title compound D1 as a pale yellow solid (19.04g). Description 2 7-Nitro-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline The product from Description 1 (2.26g; 9.15 mmol) and paraformaldehyde (0.45g; 14.4 mmol) in acetic acid (10ml) and conc. H 2 SO 4 (15ml) were stirred at 25°C for 20h according to the procedure of G.E. Stokker., Tet. Lett., 1996, 37, 5453. Work up afforded the title compound D2 as a white solid (2.17g). 1 H NMR (CDCl 3 ) δ: 3.10 (2H, m), 3.92 (2H, m), 4.85 + 4.92 (2H, 2xs), 7.38 (1H, t), 8.10 (2H, m); m / z (EI): 274 (M + ) Description 3 7-Nitro-1,2,3,4-tetrahydroisoquinoline The product from Description 2 (17.22g; 63 mmol) was hydrolysed at room temperature using a solution of potassium carbonate (46.6g) in 10% aqueous methanol (660ml). Work-up with dichloromethane gave the title compound (11g). Description 4 5-Iodo-7-nitro-1,2,3,4-tetrahydroisoquinoline The product from Description 3 (750mg; 3.9mmol) and N-iodosuccinimide (1.13g) in triflic acid (5ml) was stirred at 25°C overnight according to the procedure of G.A.Olah et al ., J.Org.Chem., 1993, 58, 3194. The mixture was poured cautiously into saturated NaHCO 3 and then extracted into ether (2x). The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO 4 ) and evaporation in vacuo gave a residue. Chromatography on Kieselgel 60 in 2% methanol - dichloromethane gave the title compound (650mg). Description 5 7-Amino-5-iodo-1,2,3,4-tetrahydroisoquinoline A solution of the product from Description 4 (650mg, 2.14mmol) in ethanol (20ml) at 50°C was treated with a solution of tin (II) chloride (1.42g) in c. HCl (3ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 (5% methanol - dichloromethane) gave the title compound (428mg; 73%). Description 6 5-Iodo-7-nitro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline The title compound was prepared from the product from Description 2 using a procedure similar to that of Description 4. m/z (API + ): 401 (MH + ; 45%). Description 7 5-Chloro-7-nitro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline The product from Description 6 (810mg) in dry DMF (15ml) was treated with copper (I) chloride (605mg) and heated at 125°C under argon for 18h. After cooling, the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was then washed with water (x 3), aqueous sodium thiosulfate, brine and dried (MgSO 4 ). Evaporation in vacuo gave the title compound as a red gum (519mg). 1 H NMR (CDCl 3 ) δ: 3.09 (2H, m), 3.96 (2H, m), 4.85, 4.92 (2H, 2s, rotamers), 7.99 (1H, m), 8.20 (1H, m). Description 8 7-Amino-5-chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline A solution of the product from Description 7 (2.14mmol) in ethanol (20ml) at 50°C was treated with a solution of tin (II) chloride (1.42g) in c. HCl (3ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 (5% methanol - dichloromethane) gave the title compound. 1 H NMR (CDCl 3 ) δ: 2.84 (2H, m), 3.67 (2H, brs), 3.83 (2H, m), 4.61, 4.67 (2H, 2s, rotamers), 6.33 (1H, m), 6.65 (1H, m). Description 9 7-Amino-5,8-dichloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline Chlorination of the product from Description 8 (150mg; 0.54 mmol) with N-chloromorpholine (100mg; 0.89 mmol) in glacial acetic acid (6ml) for 30 min at 25°C followed by basic work-up similar to that of Description 8 gave the title compound (70mg). m/z (API + ): 315, 313 (MH + ; 50% expected isotope pattern) Preparation 16 iso -Propyl 3-acetyl-4- iso -propoxybenzoate The bromo ester (2.5g, 8.3mmol) in dry dioxan (30ml) was treated with (1-ethoxyvinyl)-tributyl tin (3.58g, 9.9mmol) followed by tetrakis triphenylphosphine palladium(o) (0.48g, 0.4mmol) and heated at 100° for 18h. After cooling, the mixture was acidified and aqueous work-up and extraction into ethyl acetate gave a coloured oil (5.6g). Flash chromatography on Kieselgel 60 [hexane to 20% EtAc/hexane gave the title compound as a yellow oil (2.3g). m/z (API + ): 265.2 (MH + , 90%). Preparation 17 3-Acetyl-4- iso -propoxybenzoic acid Saponification of the ester P16 (2.3g) gave the title compound as a white solid (1.3g). 1 H NMR (250MHz, CDCl 3 ) δ: 1·48 (6H, d, J=7 Hz), 2.63 (3H, s), 4.80 (1H, m), 7.00 (1H, d, J = 8 Hz), 8.17 (1H, dd, J = 8, 2 Hz), 8·46 (1H, d, J = 2 Hz) Procedure 1a Methyl 2-methoxy-5-cyano-4- iso -propylbenzoate Copper (I) cyanide (550mg, 6mmol) was added to a solution of methyl 2-methoxy-5-bromo-4- iso -propylbenzoate (861 mg) in N-methyl-2-pyrrolidinone (30ml). The mixture was stirred under argon and boiled under reflux for 4h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO 4 ). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/n-hexane (1:4). The product was obtained as a white solid (523 mg). 1 H NMR (250MHz, CDCl 3 ) δ: 1·33 (6H, d, J=7Hz), 3·38 (1H, sep, J=7Hz), 3·89 (3H, s), 3·98 (3H, s), 6·91 (1H, s), 8·08 (1H, s); m / z (API + ): 234 (MH + , 30%). Procedure 1b 2-Methoxy-5-cyano-4- iso -propylbenzoic acid 2N NaOH (1·25ml) was added to a solution of the methyl ester P1a (490mg) in methanol (10ml). The solution was stirred overnight at room temperature. The solution was then diluted with water, concentrated in vacuo and washed with ethyl acetate. The aqueous phase was then acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO 4 ) and evaporated to dryness giving the product as a white solid (418mg). 1 H NMR (250MHz, CDCl 3 ) δ: 1·35 (6H, d, J=7Hz), 3·43 (1H, sep, J=7Hz), 4·14 (3H,s), 7·00 (1H, s), 8·41 (1H, s); m / z (API + ): 220 (MH + , 100%). Procedure 2 N-(5-Chloro-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide 5-Chloro-2-thenoic acid (90mg, 0.55mmol) and oxalyl chloride (0.05ml, 0.6mmol) in dichloromethane (2ml) was treated with 2 drops of DMF and stirred at at 25°C for 30min. Evaporation in vacuo gave a solid which was added to a solution of D8 (155mg, 0.55mmol) in dichloromethane (10ml) containing triethylamine (0.1ml). After 20h at room temperature, the mixture was diluted with ethyl acetate (100ml) and washed with 1N HCl (100ml), water (100ml), brine (50ml) and dried (MgSO 4 ). Evaporation in vacuo gave the title compound as a white solid (148mg). 1 H NMR (CDCl 3 ) δ: 2.96 (2H, m), 3.88 (2H, m), 4.73, 4.77 (2H, 2s, rotamers), 6.95 (1H, d, J = 5 Hz), 7.20 - 7.60 (3H, m), 7.70 (1H, br); m / z (API + ): 424.8, 422.9 (MH + ; 100%). Reference Example 1 N-(5-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide A suspension of the compound of Procedure 2 (148mg, 0.35mmol) and potassium carbonate (800mg, 5.8mmol) in 20% aqueous methanol (50ml) was stirred at 25°C for 18h. Work-up similar to Description 3 gave the title compound as a white solid (68mg). 1 H NMR (d 6 DMSO) δ: 2.57 (2H, t), 2.97 (2H, t), 3.81 (2H, s), 7.28 (1H, d, J = 5 Hz), 7.35 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 2 Hz), 7.89 (1H, d, J = 5 Hz), 10.31 (1H, s); m/z (API + ): 329.1, 327.1 (MH + ; 30%). The following Example was prepared using the methods previously described in the Descriptions, Preparations, Procedures, and Reference Example 1. Example 1 N-(5,8-Dichloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4- iso -propoxybenzamide 1 H NMR (CDCl 3 ) δ: 1.46 (6H, d, J = 6 Hz), 2.67 (3H, s), 2.75 (2H, t), 3.14 (2H, t), 4.03 (2H, s), 4.82 (1H, m), 7.09 (1H, d), 8.11 (1H, dd), 8.23 (!H, d), 8.40 (1H, s), 8.48 (1H, s); m/z (API + ): 421.0 (M + ; 100%) PHARMACOLOGICAL DATA 2. MEST Test The maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties 1 . In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold. Method for mouse model Mice (naive male, Charles River, U.K. CD-1 strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 300 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC 50 ) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948) 2 . Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3. In control animals the CC 50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested. Studies are carried out using a Hugo Sachs Electronik Constant Current Shock Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used. Results The compounds of this invention dosed at 10 mg/kg by the oral route as a suspension in methyl cellulose and tested one hour post dosing showed an increase in seizure threshold. References 1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2 , 145-181 2. Dixon, W.J. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43 , 109-126 3. Litchfield, J.T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther., 96 , 99-113 4. N.Upton, T.P.Blackburn, C.A.Campbell, D.Cooper, M.L.Evans, H.J.Herdon, P.D.King, A.M.Ray, T.O.Stean, W.N.Chan, J.M.Evans and M.Thompson. (1997). B. J. Pharmacol., 121, 1679-1686

Claims: N-(5,8-di-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-acetyl-4-isopropoxy benzamide or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression , panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS), which comprises a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Use of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression , panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS). A process for the preparation of a compound according to claim 1, which comprises reacting a compound of formula (II): wherein R 1A is hydrogen or a group convertible to hydrogen, X is hydrogen or chloro, with a compound of formula (III): wherein Q is phenyl; Y is a leaving group and; R 2A represents 3-acetyl and 4-isopropoxy or groups convertible to 3-acetyl and 4-isopropoxy; converting a salt product to the free base or a pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt. A process according to claim 4 wherein Y is Cl or OH.

Inventors: HARLING JOHN DAVID, THOMPSON MERVYN, HARLING, JOHN DAVID, THOMPSON, MERVYN, HARLING, John David, GlaxoSmithKline, THOMPSON, Mervyn, GlaxoSmithKline
Applicants: SMITHKLINE BEECHAM PLC
Application year: 2000
Main classification: C07D217
IPC codes: C07D217, A61P25, A61K31, C07D409