W097/48683 (SmithKline Beecham), unpublished at the filing date of this application, discloses tetrahydroisoquinolinyl benzamides in which the benzamide moiety has a 2- alkoxy substituent, including the compounds: N-(7-iodo-2-methyl- 1,2,3,4- <BR> <BR> <BR> tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,2,3,4- <BR> <BR> <BR> <BR> <BR> tetiahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenaamide, N-(5iodo-1,23,4- tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4- tetrahydroisoquinolin-7-yl) -2-methoxy4-trifluoromethyldiazirinylbenzamide, N-(5-iodo- 1 ,2,3,4-tetrahydroisoquinolin-7-ylf 2-methoxy-5-trifluoromethyldiazirinyl- benzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5- trifluoromethyldiazirinyl-benzamide and N-(8-fluoro-2-methyl-1,2,3,4- tetrahydroisoquinolin-5-yl)4-t-butyl-2-methoxybenzamide.

It has now been surprisingly found that carboxamide compounds of formula (I) below possess anti-convulsant activity and are 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).

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

where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R1 is hydrogen, C1-6 alkyl (optionally substituted by hydroxy or C1.

4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO-, formyl, CF3CO- or C1-6alkylSO2-, R2 is hydrogen, hydroxy, or up to three substituents selected from halogen, N02, CN, N3, CF30-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1- 6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS-, C1-6alkylSO2, (C1- 4alkyl)2NSO2-, (C1-4alkyl)NHSO2-, (C1-4alkyl)2NCO-, (C1- 4alkyl)NHCO- or CONH2; or -NR3R4 where R3 is hydrogen or C1-4 alkyl, and R4 is hydrogen, C1-4alkyl, formyl, -CO2C1-4alkyl or -COC1-4alkyl; or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =0; and X is hydrogen, halogen, C1.6 alkoxy, C1.6 alkyl, amino or trifluoroacetylamino; but when X is hydrogen excluding compounds in which R2 is 2-alkoxy and when X is halogen excluding the compounds N-(7-iodo-2-methyl-1,2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4- tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazi rinylbenzamide, N-(5-iodo- 1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromet hyldiazirinylbenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-tr ifluoromethyldiazirinyl benzamide and N-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t -butyl-2- methoxybenzamide.

The compounds of this invention are typically, (tetrahydroisoquinolin-7-yl) carboxamides, especially (tetrahydroisoquinolin-7-yl)benzamides. When the substituent X is not

hydrogen it may be at the 5, 6, or 8 position of the tetrahydroisoquinoline moiety, especially position 5.

The ring system Q is typically optionally substituted phenyl or optionally substituted 2 <BR> <BR> heteroaryl, typically thiophenyl or 3-isoxazolyl. When two R groups form a carbocyclic ring, this is typically a 5-7 membered ring, and Q may be a naphthalene or an indane or indanone ring system or a bicyclic heteroaryl such as 5-dihydrobenzofuranyl.

In the formula (I), alkyl groups, including alkyl groups that are part of other moieties, such as alkoxy or acyl, may be straight chain or branched. Phenyl groups, including phenyl groups that are part of other moieties, in R2 may optionally be substituted with one or more independently selected from halogen or C16 alkyl, C16 alkoxy or C16 alkylcarbonyl.

Suitable C3.6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.

One suitable group of compounds of this invention are of formula (IA) and another suitable group are of formula (IB) A suitable group of compounds of formula (I) have R1 as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl,

R2 as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl, iso-butyl, t- butyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, , amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, peffluoroethyl, trifluoromethoxy, trifluoroacetyl, trifluoromethyldiazirinyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl; or two groups R2 form a benzene, cyclopentane or cyclopentanone ring; X as hydrogen, chloro, bromo, iodo, fluoro, amino, trifluoroacetylamino.

A preferred group of compounds of formula (I) have R1 as hydrogen, methyl, methoxyethyl, R2 as hydrogen or one or more of methyl, n-butyl, t-butyl, iso-propyl, phenyl, methoxy, ethoxy, iso-propoxy, phenoxy, acetyl, nitro, cyano, bromo, chloro, fluoro, iodo, pivaloyl, trifluoromethyl, azido, trifluoromethoxy.

X as hydrogen, iodo, chloro, bromo or trifluoroacetylamino.

Examples of compounds of formula (I) are:

N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-c arboxamide <BR> <BR> Ng2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamid e N-(2-methyl -1 .23,4-tetrahydroisoquinolin-7 -yl)benzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenz amide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-t-butylben zamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propox ybenzamide N-(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)4nitrobenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenz amide

N-(2-methyl- 1,273 ,4-tetrahydroisoquinolin-7-yl)-3 -methylbenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenz amide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenza mide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichloro benzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzam ide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenza mide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methylbenz amide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenza mide N-(2 -methyl- 1 ,273 ,4-tetrahydroisoquinolin-7-yl)tethoxcybenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylben zamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-acetoxyben zamide N- (2-methyl- 1 ,2,3,tetrahydroisoquinolin.7.yl)-3-trifluoromethAbenmmide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-difluoro benzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dimethox ybenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-t rifluoromethyl benzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-nitrobenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-di-trifl uoromethylbenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-dichloro -5-fluorobenzamide N-(2-methyl- 1,2,3,stetrahydroisoquinolin-7-ylp3-fluoro-5-trifluoromethyl benzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-me thoxybenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4,5-trimet hoxybenzamide N-(2-methyl- 1,2,3 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethoxybenzami de N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-pivaloylbe nzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-is o-propoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-acetoxyben zamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopenty loxybenzamide N- (2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-cyclopropylmethoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-me thoxybenzamide N-(2-Methyl- 1 72,3,4-tetrahydroisoquinolin-7-yl)-2-naphthamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-me thylbenzamide N- (2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene- 1-carboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-m ethoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butox ybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxyb enzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzotriazole -5-carboxamide N- (2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole-6-carboxamid e N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydrob enzofuran-5-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylbenzimidazole-5-c arboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i so-propoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-et hoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-e thoxybenzamide N-(2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethy l benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro -4-methoxybenzamide N-(2-Methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichlor o-4-ethoxybenzamide N-(2-Methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichlor o-4-iso-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzamide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-te rt-butylbenzamide

N- (2.Methyl. 1 ,2,3,4-tetrahydroisoquinolin-7 -yl)-2-bromo-5-methoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-m ethoxybenzamide, hydrochloride N- (2.Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)- 1 -methylpyrazole-4-carboxamide N-(2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)4trifluoromethylpyrazole-3 - carboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylthia zole-4-carboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-methylisox azole-3-carboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-tert-butyl isoxazole-3-carboxamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyiso xazole-5-carboxamide hydrochloride N-(2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide.

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4 -iso-propylbenzamide, hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-is o-propylbenzamide, hydrochloride N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoncybenza mide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n- propoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-et hoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n- propoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-et hylbenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-met hoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propox y-3-trifluoromethyl benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-m ethoxybenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxy- 3-trifluoromethyl benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-t ert-butylbenzamide, hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxyben zamide hydrochloride.

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro- 3-methylbenzamide, hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i so-propylbenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-et hylbenzamide hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propyl -3-trifluoromethyl- benzamide hydrochloride

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-tr ifluoromethylbenzamide hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-is o-propoxybenzamide hydrochloride N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoro methylbenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-m ethylsulfonyl-benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-me thylsulfonylbenzamide N- (2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4 Lso- propylbenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulf onyl-4-methoxybenzamide N-(2-Methyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- pentafluoroethyl- benzamide hydrochloride N-(2-n-Propyl- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-3 -bromo-4-ethoxybenzamide N-(2-n-Propyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3- trifluoromethylbenzamide N-(2-n-Propyl- 1,2,3 ,2,3,4tetrahydroisquinolin-7-yl)-3-chloro-4-iso-propoxybenza mide N-(2-Methyl- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-$iso-butylbenzam ide hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)4iso-butyl-3-trifluorometh yl- benzamide hydrochloride N- (2 -Ethyl- 1,2,3 ,4tetrahydroisoquinolin-7-yl)-3-bromo-4ethoxybenzamide N-(2-Ethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-methoxy-3- trifluoromethyl benzamide N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo- 4-ethoxybenzamide N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methox y-3-trifluoromethyl benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-m ethylsulfonyl-benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman -6-carboxamide hydrochloride N- (2-Formyl-- 1,2,3,4tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide N- (2-Hydroxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7 -yl)-3-bromo-4-ethoxybenzamide N-(2-Hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-brom o-4-ethylbenzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylmeth oxy-3-trifluoromethyl benzamide N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3- trifluoromethyl benzamide

N-(2-Methoxyethyl- 1,2,3 ,tetrahydroisoquinolin-7-yl)-3-bromoiso- propoxybenzamide N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlo ro-4-iso- propoxybenzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7 -yl)-4-methoxy-3- trifluoromethylbenzamide N-(5-Iodo-1,2,3,4tetrahydroisoquinolin-7-yl)4azidobenzamide, trifluoroacetate N-(2-Methyl-5-trifluoroacetylamino- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromoX methoxybenzamide N-(2-Methyl-5-chloro- 1 ,2,3,4tetrahydroisoquinolin-7-yl)-3-bromo-4ethoxybenzamide N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-b romo-4-ethylbenzamide When synthesised, these compounds are 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 mglkglday, more usually 0.1 to 6 mgtkg'day, for example 1 to 6 mg'kgIday.

It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, 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 formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides a method of 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), temporomandibularjoint dysfunction and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect the invention provides the use of a compound of formula (t), 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), temporomandibularjoint dysfunction and amyotrophic lateral sclerosis (ALS).

In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular 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).

Another aspect of the invention is a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (II) where R1A is R1 as defined for formula (I) or a group convertible to R1 and X is as defined in claim 1 with a compound of formula (111) where Q is as defined in formula (I), Y is C1 or OH, and R2A groups are independently R2 as defined for formula (I) or groups convertible to R2, and where required converting an R1A or R2A group to a R1 or R2 group, converting one R1 or R2 group to another R1 or R2 group, converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt Reaction of a compound of formula (m) which is an acid chloride (Y=CI) 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 (Ill) 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)ethyl- carbodiimide!hydroxybenzotriazole in a suitable solvent such as dimethyl formamide.

Conversions of an R1A or R2A group to a R1 or R2 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 R1 or R2 group to another typically arises when one compound of formula W 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.

Compounds of formula (II) in which X is hydrogen may be prepared from a nitro- tetrahydroisoquinoline of formula (IV). by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (V) which can be reduced, for example using either tin (II) chloride and HCL or hydrogen and a palladiumlactivated carbon catalyst, to obtain an amino-tetrahydroisoquinoline of formula (II).

When the intended RIA group is methyl, the compound of formula ('V) may also be reacted with formic acid and formaldehyde to introduce the N-methyl group.

The nitro-tetrahydroisoquinoline of formula (IV) may be prepared by hydrolysis of 2- trifluoroacetyl-nitro-tetrahydroisoquinoline obtained by reaction of an 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 (11) may also be prepared from the corresponding amino- isoquinoline (or its nitro-analogue)of formula (VI) where RN is NH2 or NO2 by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (VII) which can be reduced, for example using sodium borohydride, or hydrogenated, for example using hydrogen and a palladiumlactivated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II). When the compound of formula (VII) is replaced by a nitro-isoquinoline, the nitro group is converted to an amino group in the hydrogenation step.

When the intended R1 is hydrogen, the N of the tetrahydroisoquinoline or isoquinoline is preferably protected conventionally, prior to the coupling step that forms the carboxamide of formula (I), for example by tert.-butoxycarbonyl or trifluoroacetyl. The compound can be deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.

Aminolnitro-isoquinolines of formulae (VI) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature.

When the substituent X is other than hydrogen it may be introduced during any of the procedures above, for example by conventional substitution of the aromatic ring of compounds of formula (it), (V) or (VII) or may be present on commercially available starting materials usable in the above described procedures. Most suitably the substituent X is introduced to a compound of formula (II) in which X is hydrogen. For example X as halogen may be incorporated via an amino group using Sandmeyer chemistry 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 correpondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid.

Where the above described intermediates are novel compounds, they also form part of this invention, The preparation of compounds of this invention is further illustrated by the following Descriptions and Examples. The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples.

Description 1 N-2-(4Nitrophenyl)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 OOC. The mixture was stirred at 25"C overnight under argon and then washed with dilute citric acid (x2), brine and dried over Na2S04. The material in the organic phase gave the title compound as a pale yellow solid (19.04g).

Description 2 7-Nitro- 1,2,3,4-tetrahydro-trifluoroacetyIisoquinollne The nitro compound D1 (2.26g; 9.15 mmol) and paraformaldehyde (0.45g; 14.4 mmol) in acetic acid (lOml) and conc. H2S04 (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 as a white solid (2.17g).

1H NMR (CDC13) o: 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-1,2,3,4tetrahydroisoquinoline The trifluoroacetamide D2 (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 (1 lug).

Description 4 2-Methyl4-nltro- 1 ,2,3,4-tetrahydroisoquinoline The amine D3 (2.08g; 11.7 mmol) was treated with 88% formic acid (3.45ml) and 37% aqueous formaldehyde (5.88ml) at 80"C for 2h according to the procedure of G.M.

Carrera and D.S. Garvey, J. Het. Chem., 1992, 29, 847. Basification with 10% sodium hydroxide followed by work-up with ethyl acetate afforded an orange gum(2.3g).

Chromatography on Kiesegel 60 in 0-3% methanol - ethyl acetate gave the title compound as an orange solid (1.7g). m/z (CI): 193 (MH+).

Description 5 7-Amino-2-methyl- 1,2,3,4tetrahydroisoquinoline The 7-nitro compound D4 (0.25g; 1.3 mmol) in methanol (40ml) was hydrogenated over 10% palladium on carbon (100mg) at atmospheric pressure overnight. The catalyst was removed by filtration through a pad of Kieselguhr and evaporation in vacuo gave the title compound as a white solid (213mg). m/z (CI): 163 (MH+) Description 6 7-Amino-2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin e The title compound was prepared from the compound of Description D3 using di t-butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25°C followed by catalytic hydrogenation according to the procedure described for D5.

Description 7 N-(2-t-Butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-7-yl) -5-chlorothiophene-2- carboxamide 5-Chlorothiophene-2-carboxylic acid (214mg; 1. 3mmol), ethyldimethylaminopropyl carbodiimide (250mg; 1.3mmol) and 1-hydroxybenzotriazole (176mg; 1.3 mmol) in dry DMF (25ml) was stirred at room temperature for 30 min. A solution of the N-boc amine D6 (300mg; 1.21mmol) in dichloromethane (Sml) was added and the mixture kept at room temperature overnight. Work-up gave a pink gum which was chromatographed on Kieselgel 60 in 30% ethyl acetate-hexane. Combination of appropriate fractions gave the title compound as an off white solid (0.5g).

1H NMR (400MHz, CDC13) 3:1.51 (9H, s), 2.82 (2H, t), 3.65 (2H, t), 4.56 (2H, s), 6.95 and 7.37 (2H, ABq), 7.12 (1H, d), 7.28 (1H, s), 7.46 (1H, br).

Description 8 7-Nitro-2-n-propyl-1,2,3,4-tetrahydroisoquinoline Nitro compound D3 (1.55g, 8.7mmol) and propionaldehyde (2.52g, 43.5mmol) in 1,2- dichloroethane (50ml) were treated with sodium triacetoxyborohydride (0.28g, 13.1 mmol) and glacial acetic acid (0.6ml, 9.0mmol). The mixture was stirred at 250C over the weekend and then diluted with dichloromethane (50ml). The mixture was washed with saturated NaHC03, dried (Na2S04) and evaporated in vacuo. Chromatography on Kieselgel 60 in ethyl acetate gave the title compound.

Description 9 7-Amino-2-n -propyl- 1,2,3,4-tetrahydroisoquinollne The nitro compound D8 (0.73g, 3.32mmol) in ethanol (100ml) was heated to 50°C and treated with a solution of tin (u) chloride (2.52g, 13.27mmol) in conc. HCl (10ml) and stirring continued for 3h. The mixture was basified with 40% NaOH and the product extracted into dichloromethane. Work-up and chromatography on Kieselgel 60 in 10% methanol:dichloromethane gave the title compound as a viscous yellow oil (0.26g; 41%). m/z (API+): 191 (MH+; 80%).

Description 10 7.Amino-2-iso-propyl-1,2,3,4tetrahydroisoquinoline The title compound was prepared from D3 and acetone in 10% overall yield using a method similar to that described in Descriptions 8 and 9.

Description 11 7-Amino-2ethyl-1,2,3,4-tetrahydroisoquinoline The title compound was prepared in 14% overall yield from D3 and acetaldehyde using a method similar to that described in Descriptions 5 and 8.

Description 12 2-Formyl4-nitro- 1,2,3,4-tetrahy(1roisoquinoline A mixture of acetic anhydride (1.4ml) and formic acid (0.7ml) was stirred at 500C for 15 min. After cooling to 0°C, a solution of D3 (1.78g) and 4-dimethylaminopyridine (O.lg) in dichloromethane (30ml) was added and stirring continued at 25"C for 2h. The reaction mixture was washed with aq. potassium carbonate, water, brine and dried (MgSO4). Evaporation in. vacuo gave the title compound (2.4g).

1H NMR (250 MHz, CDC13) 6: 3.0 (2H, m), 3.72(t) and 3.88 (t) (together 2H), 4.68 (t) and 4.80 (t) (together 2H), 7.28-7.40 (1H, m), 8.04 (2H, m), 8.22 (s) and 8.30 (s) (together 1H), m/z (API+): 207 (MH+; 80%).

Description 13 7-Amlno-2-formyl- 1 ,2,3,4-tetrahydroisoquinoline The compound D12 (2.3g) was dissolved in ethanol (50ml) and shaken at room temperature and SOpsi with hydrogen in the presence of 5% Pd/C catalyst (0.8g).

Filtration and evaporation then provided the title compound as a white solid (1.6g).

1H NMR (250 MHz, d6-DMSO) 6: 2.55(t) and 2.59(t) (together 2H), 3.56 (2H, t), 3.39 (s) and 3.41(s) (together 2H), 6.35-6.45 (2H, m), 6.79 (1H, d), 8.15 (s) and 8.18 (s) (together 1H), m/z(API+): 177 (MH+).

Description 14 2-(2-tert-Butyldimethylsilyloxyethyl)-7-nitro-1,2,3,4-tetrah ydrodisoquinoline 7-Nitro-tetrahydroisoquinoline (5.0g; 28.0mmol) was dissolved in DMF (lSOml). This solution was treated with (2-bromoethoxy)-tert-butyl-dimethylsilane (12.0ml; 56.0mmol), and stirred at 80°C overnight. The mixture was cooled to room temperature and the solvent removed in vacuo. Purification by column chromatography through SiO2, eluting with 50% diethyl ether/petroleum ether gave the title compound (4.2g, 44%).

1H NMR (250 MHz; CDCl3) o: 0.00 (6H, s), 0.83 (911, s), 2.66 (2H, t, J = 6 Hz), 2.79 (211, t, 1=6 Hz), 2.90 (2H, t, J = 6 Hz), 3.71 (2H, s), 3.77 (211, t, 1=6 Hz), 7.16 (1H, d, 1=9 Hz), 7.82 (1H, d, 1=2 Hz), 7.89 (1H, dd, J =9,2 Hz).

Description 15 7-Amino-2-(2-tert-butyldimethysilyloxyethyl)-1,2,3,4-tetrahy droisoquinoline 2-(2-tert-Butyldimethylsilyloxyethyl) compound D14 (2.88g; 8.57mmol) and 10% PdlC (O.Sg, 60% paste in water) in methanol (100ml) was hydrogenated in a manner similar to that of Description 5 to give the title compound (2.62g).

1H NMR (250 MHz, CDCl3) o: 0.00 (6H, s), 0.83 (9H, s), 2.61(211, t, J = 6 Hz), 2.71 (4H, s, overlapping signals), 3.55 (2H, s), 3.77 (2H, t, J = 6 Hz), 6.27 (1H, d, J = 2 Hz), 6.43 (1H, d, J = 8 Hz), 6.80 (1H, d, J = 8 Hz).

Description 16 2-(2-tert-Butyldimethylsilyloxyethyl)-1,2,3,4-tetrahydro-iso quinolin-7-yl)-3-bromo- 4-ethoxybenzamide Triethylamine (0.112ml; 0.81mmol) and 3-bromo-4-ethoxybenzoyl chloride (193mg; 0.73mmol) were dissolved in dichloromethane (100ml) with stirring. To this mixture was added the compound of D15 (204mg; 0.67mmol). The mixture was stirred overnight. and then evaporated in vacuo. The resultant residue was purified by chromatography on silica with 10% methanol:dichloromethane to give the title compound (123mg; 35%).

1H NMR (250 MHz; CDCl3) 6: 0.0 (611, s), 0.82 (9H, s), 1.42 (3H, t, J = 7 Hz), 2.80 (2H, t, J = 5 Hz), 2.91 (2H, t, J = 5 Hz), 2.95 (2H, t, J = 4Hz), 3.81 (2H, s), 3.87 (2H, t, J = 6 Hz), 4.08 (2H, q, J = 7 Hz), 6.84 (1H, d, J = 9 Hz), 7.00 (1H, d, J = 8 Hz), 7.29 (2H, d, I = 8 Hz), 7.33 (1H, s), 7.77 (1H, dd, I = 9, 2 Hz), 8.00 (IH, d, I = 2 Hz).

Description 17 7-Amino-2-(2omethoxyethyl)- 1,2,3,4-tetrahydroisoquinoline 1H NMR (250 MHz; CDCl3) o: 2.74 (6H, m), 3.38 (3H, s,), 3.60 (411, m), 3.20 - 3.70 (2H, br), 6.37 (1H, s). 6.50 (1H, dd, J = 8,2 Hz), 6.88 (1H, d, J = 8 Hz).

Description 18 5-Iodo-7-nitro- 1,2,3,4tetrahydroisoquinoline The nitro compound of Description 3 (750mg; 3.9mmol) and N-iodosuccinimide (1.13g) in triflic acid (5ml) was stirred at 250C overnight. The mixture was poured cautiously into saturated NaHCO3 and then extracted into ether (2x). The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporation in vacuo gave a residue. Chromatography on Kieselgel 60 in 2% methanol - dichloromethane gave the title compound (650mg).

Description 19 7-Amino-5-iodo-1,<,3,4-tetrahydroisoquinoline A solution of the nitro compound D18 (650mg, 2.14mmol) in ethanol (20ml) at 50°C was treated with a solution of tin (11) chloride (1.42g) inc. 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 20 7-Amino-5-iodo-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroiso quinoline The iodoamine D19 (580mg, 2.12mmol) in DMF (30ml) was treated with DMAP (20mg) and di-tert-butyl-dicarbonate (466mg, 2.13mmol) and the solution was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo.

Chromatography on Kieselgel 60 (2% methanol - dichloromethane) gave the title compound (745mg; 94%).

Description 21 5,7-Dinitro-1,2,3,4tetrahydroisoqliinoline 5-Nitro-1,2,3,4-tetrahydroisoquinoline (l.Og, 5.6mmol) in conc. sulfuric acid (3ml) was treated with conc. nitric acid (1 ml) and the mixture stirred at room temperature for lh.

The mixture was cooled, basified with 40% aqueous NaOH and work-up with dichloromethane gave the title compound (1.14g).

Description 22 5,7-Dinitro-2-methyl-1,2,3,4-tetrahydroisoquinoline The amine D21 (1.8g) in formic acid (5ml) and paraformaldehyde (7ml) were reacted in a similar manner to that of Description 2 to give the title compound (1.74g, 91%).

1H NMR (CDC13)8: 2.51 (3H, s), 2.75 (2H, t), 3.27 (2H, t), 3.75(2H, s), 8.16 (1H, d, J = 2Hz), 8.66 (1H, d, J= 2Hz); m/z (CI): 238.1(MH+; 100%).

Description 23 5-Amino-7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline The dinitro compound D22 (1.7g) was reduced with tin(lI)chloride (5.42g) in a manner similar to that of Description 19 to give the title compound (0.6g).

Description 24 S-Trinuoroacetylamino-7-nitro-2-methyl-1,2,3,4tetrahydroisoq uinoline The amine D23 (0.5g) in dichloromethane (10ml) and triethylamine (1.5eq) was treated with trifluoroacetic anhydride (l.leq) and the mixture stirred at 250C for 3h. Work-up with dichloromethane followed by chromatography on Kieselgel 60 in 3%- methanol:dichloromethane gave the title compound (0.7g, 96%). m/z (CI): 304 (MH+; 80%).

Description 25 7-Amino-5-trifluoroacetylamino-2-methyl-1,2,3,4-tetrahydrois oquinoline The nitro compound D24 (0.7g, 2.28mmol) in ethanol (20ml) was hydrogenated over 10% Pd/C (70mg). The catalyst was removed by filtration through Celite and evaporation in vacuo gave the title compound as a pale solid (0.6g, 93%).

Description 26 S-Chloro-7-nitro-2-methyl-1,2,3,4tetrahydroisoquinoline The 5-amino compound D23 (1.6g, 7.7mmol) in 5MHCl (25ml) at 0°C was treated with a solution of sodium nitrite (0.55g, 8.0mmol) in water (3ml) over 5min. The cold solution was then added gradually to a solution of copper(l)chloride (1.0g, lOmmol) in 5MHCl (25ml). The mixture was stirred at 25°C for 30min and then basified with 40% NaOH. Work-up with dichloromethane (300ml) followed by flash chromatography on Kieselgel 60 (5% methanol:dichloromethane) gave the title compound (l.lg, 62%) as a yellow solid.

1H NMR (CDC13)8: 2.32 (3H, s), 2.61 (2H, t), 2.79 (2H, t), 3.57(2H, s), 7.96 (1H, d, J = 2Hz), 8.08 (1H, d, J = 2Hz).

Description 27 7-Amino-s-chloro-2-methyl- 1,2,3,4tetrahydroisoquinoline The nitro D26 (0.80g, 3.5mmol) in ethanol (70ml) and conc. HC1 (7ml) was heated to 50°C and tin(II)chloride (2.66g, 14mmol) was added. The mixture was heated for 15min and allowed to cool; work-up similar to that described in Description 19 gave the title compound as a yellow oil (0.48g).

1H NMR (CDCl3)#: 2.42 (3H, s), 2.64 (2H, m), 2.77 (2H, m), 3.45(2H, d), 6.27 (1H, d, J = 2Hz), 6.59 (1H, d, J = 2Hz).

Preparation 1 3-Bromobenzyl TBMS ether To a solution of 3-bromobenzyl alcohol (5.00g, 0.027mole) in dichloromethane (30ml) and Et3N (4.2ml, 0.03 mole) was added a 1M solution tert-butyldimethylsilyl chloride in dichloromethane (28.0ml) dropwise. The mixture was allowed to stir at room temperature overnight, then water (30ml) was added. The organic layer was washed with brine, dried (Na2S04) and evaporated to give a red oil which was purified by flash chromatography on silica gel using 20% ether in hexane to give a colourless oil (8.0g).

Preparation 2 3-Pivaloylbenzyialcohol TBDMS Ether n-Butyllithium (2.80ml, 7.00mmol, 2.5M in hexane) was slowly added to a solution of Preparation 1 TBDMS ether (1.80g, 6.0mmol) in dry THF (10ml) over 5 min at -78°C.

The reaction mixture was maintained under argon at -78°C for lh. and N,O-dimethyl- hydroxy pivaloyl amide (0.86g, 6.60mmol) in THF (2ml) was added dropwise with stining at -78°C. The resulting mixture was allowed to stir at-78°C for 2.5h, quenched with NH4Cl solution and allowed to warm to room temperature. The mixture was extracted with ether (2x50ml), the combined organics were dried (Na2S04) and concentrated in vacuo to give the title compound as a colourless oil (1.75g m/z (API+): 307 (MH+; 8%).

Preparation 3 3-Pivaloylbenzylalcohol The ether of Preparation 2 (1.47g, 4.80mmol) was dissolved in methanol (25ml); conc.

HC1 (20 drops) was added and the whole allowed to stir at room temperature for 4h.

Saturated NaHC03 solution was added and the mixture extracted with ether (2x50ml).

The organic layer was dried over sodium sulfate and evaporation in vacuo gave title compound as a colourless oil (0.80g). m1z (API+): 193 (MH+; 17%).

Preparation 4 3-Pivaloylbenzoic acid 3-Pivaloylbenzyl alcohol (0.80g, 4.16mmol) was dissolved in dioxane (20ml). A solution of KOH (0.35g, 6.30mmol) in water (5ml) was added followed by KMnO4 (1.45g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with diL HC1 and extracted with ether (3x50ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80g).

1H NMR (250MHz, CDCl3)#: 1.38 (9H, s), 7.55 (1H, t), 7.92 (1H, d, J = 6.5Hz), 8.20 (1H, d, I = 6.5Hz), 8.44 (1H, s).

Preparation 5 3-Trifluoroacetylbenzoic add The title compound was prepared from diethyl trifluoroacetamide and 3-bromobenzyl TBDMS ether using a method similar to that described in Preparations 1,2,3 and 4. m1z (API-): 217 (M-H+; 20%).

Preparation 6 Methyl 3-Chloro-4-iso-propoxybenzoate Methyl 3-chloro-4-hydroxybenzoate (5g, 26.8mmol) in DMF (45ml) was treated with potassium carbonate (7.41g, 53.6mmol), 2-iodopropane (3.85ml, 40.2mmol) and then stirred at 250C for 18h. Work-up with ethyl acetate gave the title compound (6.1g).

Preparation 7 3-Chloro-4-iso-propoxybenzoic acid Methyl 3chloro4-Fo-propoxybenzoate (5.5g, 24. lmmol) was hydrolysed using 1M NaOH (36ml) in methanol (80ml). Extraction and work-up with ethyl acetate gave the title compound (4.3g).

'H NMR (DMSOD6) b: 1.33 (6H, d), 4.79 (1H, m), 7.24 (1H, d), 7.87 (2H, m).

Preparation 8 3-Bromo-4ethoxybenzoic acid The title compound was prepared from 4ethoxybenzoic acid in a manner similar to that of Procedure 1.

'H NMR (DMSO-D6) 5:1.45 (3H, t, J = 7 Hz), 4.26 (2H, q, J = 7 Hz), 7.26 (1H, d, J = 9 Hz), 7.98 (1H, dd, J = 2,9 Hz), 8.12 (1H d, J = 2 Hz) Preparation 9 3-Bromo-4-ethylbenzoic acid The title compound was prepared from 4-ethylbenzoic acid.

'H NMR (DMSO-D6) 6: 1.20 (3H, t, J = 7 Hz), 2.78 (2H, q, J = 7Hz), 7.50 (1H, d, J = 8 Hz), 7.90 (1H, dd, I = 2, 8 Hz), 8.07 (1H, d, I = 8 Hz Preparation 10 3-Cyano-4-iso-propylbenzoic acid The title compound was prepared from 4-iso-propylbenzoic acid similar to that described in Procedure 5.

'H NMR (DMSO-D6) 8: 1.07 (6H, d, J = 7 Hz), 3.13 (1H,m, overlapped), 7.48 (1H, d, J = 7 Hz), 7.96 (lH, dd, I = 2, 8 Hz)), 8.00 (1H, d, I = 2 Hz).

Preparation 11 4-Methoxy-3-trifluoromethylbenzoic acid The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similat to that of Procedures 3 and 4.

'H NMR (DMSO-D6) 6: 3.78 (3H, s), 7.18 (1H, d, J = 9 Hz), 7.90 (1H, d, J = 2 Hz), 8.00 (1H, dd, J = 2, 9 Hz), 12.70 - 13.10 (1H, br,exchangeable) Preparation 12 4-Methoxy-3-trifluoromethylbenzoyl chloride The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.

Preparation 13 Methyl 3-Bromo-4-iso-propoxybenzoate Methyl 3-bromo-4-hydroxybenzoate (2.5g, 10.8mmol) in DMF (35ml) was treated with potassium carbonate (3.0g, 21.6mmol), 2-iodopropane (2.76, 21.6mmol) and then stirred at 250C for 48h. Work-up with ethyl acetate gave the title compound (3.0g). lH NMR (250MHz, CDCl3) #: 1-41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H, m), 6.90 (1H, d, J = 8 Hz), 7.93 (1H, dd, J = 8,2 Hz), 8.22 (1H, d, J = 2 Hz) Preparation 14 Methyl 3-Cyano-4-iso-propoxybenzoate Methyl 3-bromoXiso-propoxybenzoate (2.0g, 7.3mmol) and copper(I)cyanide in N- methyl pyrrolidone (50ml) were heated under vigorous reflux for 4h. Work-up with ethyl acetate gave the title compound (1.0g).

H NMR (250MHz, CDCl3) b: 1-56 (6H, d, 5=7 Hz), 4.05 (3H, s), 4.88 (1H, m), 7.13 (1H, d, J = 8 Hz), 8.31 (1H, dd, J = 8,2 Hz), 8.38 (1H, d, J = 2 Hz) Preparation 15 Methyl 3,5 Dichloro-4-ethoxybenzoate The title compound was prepared in 69% yield from methyl 3,5-dichloroX hydroxybenzoic acid and iodoethane in a manner similar to that of Preparation 6. lH NMR (250MHz, CDCl3) b: 1-47 (3H, t, 1=7 Hz), 3.91 (3H, s), 4.16 (2H, q, J = 7 Hz), 7.96 (2H, s).

Preparation 16 3-Methanesulfonyl-4iso-propylbenzoic acid 3-chlorosulfonyl-4-iso-propylbenzoic acid (2.62g, 10mmol) [made from 4-iso-propyl benzoic acid in a manner similar to that described in Procedures 7 and 8] was added slowly to a slurry of NaHCO3 (2.52g, 30mmol) and Na2S03 (1.26g lOmmol) in water (9ml) at 75°C. The mixture was stirred for 1h and then treated with bromoacetic acid (2.08g, 15mmol) and NaOH (0.60g, l5mmol). The temperature was raised to 105°C and the mixture heated at reflux for 24h. The mixture was cooled, acidified to pH 1 and the resultant precipitate collected, washed and dried to give the title compound (1.43g, 59%).

'H NMR (250MHz, acetone-D6) #: 1.24 (6H, d, J=7 Hz), 3.13 (3H, s), 3.88 (1H, m), 7.72 (1H, d, I = 7 Hz), 8.15 (1H, dd, I = 7 Hz), 8.52 (1H, d, 1=2 Hz).

Preparation 17 4-Methyl-3-methanesulfonylbenzoic acid Prepared in 30% overall yield in a manner similar to that of Preparation 16.

'H NMR (250MHz, acetone-D6) â: 2.57 (3H, s), 2.99 (3H, s), 7.39 (1H, d, J = 7 Hz), 7.97 (1H, dd, J = 7, 2 Hz), 8.39 (lH, d, J = 2 Hz).

Preparation 18 4-Ethyl-3-methanesulfonylbenzoic acid Prepared in 44% overall yield in a manner similar to that of Preparation 16.

H NMR (250MHz, acetone-D6) 6: 1.22 (3H, t, J = 7 Hz), (3H, s), 3.05 (2H, q, J = 7 Hz), 3.12 (3H, s), 7.57 (1H, d, J = 7 Hz), 8.13 (1H, dd, J = 7, 2 Hz), 8.51 (1H, d, J = 2 Hz).

Preparation 19 3-Methanesulfonyl-4-methoxybenzoic acid Prepared in 20% overall yield in a manner similar to that of Preparation 16.

'H NMR (250MHz, acetone-D6) â: 3.00 (3H, s), 3.89 (3H, s), 7.17 (1H, d, J = 7 Hz), 8.06 (1H, dd, J = 7, 2 Hz), 8.31 (1H, d, J = 2 Hz).

Preparation 20 4-Ethoxy-3-methanesulfonylbenzoic acid Prepared in 20% overall yield in a manner similar to that of Preparation 16.

H NMR (250MHz, acetone-D6) a: 1.44 (3H, t, J = 7 Hz), (3H, s), 3.30 (3H, s), 4.35 <BR> <BR> (2H, q, I = 7 Hz), 7.40 (1H, d, I = 7 Hz), 8.20 (1H, dd, I = 7, 2 Hz), 8.37 (1H, d, I = 2 Hz).

Preparation 21 3-Chloro4-ethoxybenzoic acid 'H NMR (DMSO-D6) a: 1.39 (3H, t, J = 7 Hz), 4.20 (2H, q, J = 7 Hz), 7.22 (1H, d, J = 7 Hz), 7.87 (2H, m).

Preparation 22 4-iso-Propyloxy-3-trifluoromethylbenzoic acid Methyl 3-bromo-4-iso-propyloxybenzoate (828mg; 3.03 mmol) in DMF (25ml) was treated with potassium trifluoroacetate (922mg; 6.06 mmol), copper (I) iodide (l.lSg; 6.06 mmol) and toluene (50ml). The resulting mixture was heated at reflux for 1.5h (Dean and Stark with removal of ca 50ml of distillate) followed by reflux for 18h then cooled. The mixture was poured into Et20 (100ml) and H,O (100ml). The two-phase mixture was stirred at room temperature for 0.5h then filtered through Celite. The two phases were separated, the aq. phase further extracted with Et2O (50ml) and the organic extracts combined, washed with saturated, aq. Na2S2O3, H,O, saturated brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was dissolved in MeOH (ca 20ml) and treated with 2M NaOH (2ml; 4 mmol) and the resulting solution heated at reflux for 3h. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The phases were separated, the aq. phase acidified to pH1 with 2M HCl in the presence of EtOAc and the phases separated. The aq. phase was further extracted with EtOAc, the extracts combined, washed with H20, saturated brine, dried (MgSO4) and evaporated to dryness in vacuo to give the title compound as a white solid (671mg; 89%).

'H NMR (250MHz; (CD3)2CO) 6: 1.02 (6H, d, J = 6 Hz), 4.53 - 4.63 (1H, m), 7.01 (1H, d, J = 9 Hz), 7.85 - 7.88 (2H, m); m/z (API): 205.0 [M-P?].

Preparation 23 4-Ethyl-3-trifluoromethylbenzoic acid Prepared as described in Preparation 22 from methyl 4-ethyl-3-bromobenzoate (l.lOg; 4.52 mmol) and isolated as a white solid (923mg; 93%).

'H NMR (250MHz; (CD3)2CO) o: 0.98 (3H, t, 1=7 Hz), 2.60 (2H, q, J = 7 Hz), 7.36 (1H, d, J = 8 Hz), 7.89 and 7.93 (1H, m), 7.96 (1H, br s); mI (API): 217.1 [M-H].

Preparation 24 4-n-Propyloxy-3-trifluoromethylbenzoic acid Prepared as described in Preparation 22 from methyl 3-bromo-4-n-propyloxybenzoate (1.43g; 5.23 mmol) and isolated as a white solid (1.18g; 91%).

'H NMR (250MHz; (CD3)2SO) #: 1.09 (3H, t, 1=7 Hz), 1.79 - 1.93 (2H, m), 4.26 (2H, t, J = 6 Hz), 7.45 (1H, d, J = 9 Hz), 8.19 (1H, d, J = 2 Hz), 8.25 and 8.28 (1H, dd, J = 9, 2 Hz); m/z (API): 203.1 [M-CO2H].

Preparation 25 4-t-Butyl-3-trifluoromethylbenzoic acid Prepared as described in Preparation 22 from methyl 3-bromo-4-t-butylbenzoate (2.46g; 9.1 mmol) and isolated as a white solid (1.55g; 69%).

'H NMR (250MHz; (CD3)2SO) 6: 1.42 (9H, s), 7.86 - 7.90 (1H, m), 8.09 - 8.13 (1H, m), 8.23 (1H, d, J = 2 Hz); mi2 (API): 245.1 [M-H].

Preparation 26 4-Oxochroman-6-carboxyiic add 3-(4-Carboxyphenoxy)propionic acid (2.5g) [prepared according to the procedure of J.

Lichtenberger and R. Geyer. Bull. Soc. Chim. Fr., 1963 275] in conc. sulfuric acid (20ml) was heated to 1000C for 4h and then poured onto crushed ice. The resultant precipitate was filtered and dried in vacuo to give the title compound (1.6g).

'H NMR (DMS-D6) #: 2.99 (2H, t, J = 7 Hz), 4.77 (2H, t, J = 7 Hz), 7.28 (1H, d, J = 8 Hz), 8.21 (1H,dd, J = 8, 2 Hz), 8.46 (1H, d, J = 2 Hz).

Preparation 27 3-Bromo-4-iso-propoxybenzoic acid The title compound was prepared using a method similar to that of Preparation 7.

'H NMR (DMSO-D6) 6: 1.29 (6H, d, J = 7 Hz), 4.77 (1H, sep, J = 7 Hz), 7.20 (1H, d, J = 8 Hz), 7.87 (1H, dd, I = 8, 2 Hz), 8.02 (lH, d, I = 2 Hz), 12.92 (1H, brs).

Preparation 28 4-Azidobenzoic acid To a solution of 4-aminobenzoic acid (2.00g, 14.00mmol) in trifluoroacetic acid (loll) at 50C, was added sodium nitrite (3.50g) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (3.79g,) was then added portionwise and the mixture stirred for a further 30 min at OOC. The mixture was diluted with water, and a white solid precipitated.

The solid was filtered, washed with cold water and dried, to afford the title compound (1.66g, 73%).

Procedure 5-Bromo-2,4-dimethoxybenzoic acid To a solution of 2,4-dimethoxybenzoic acid (4.0g, 0.022mol) in chloroform (60ml) was added bromine (1. l3ml, 0.022mol) in chloroform (20ml) dropwise. After stirring overnight

at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87g).

Procedure 2 5-Bromo-4iso-propyl-2-methoxybenzoic acid To a solution of 2-methoxy4tso-propyl benzoic acid (7.0g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight. Evaporation in vacuo afforded an oil (9.27g). m/z (CI): 275, 273 (MH+; 70%).

Procedure 3 Methyl 5-bromo-4iso-propyl-2-methoxy benzoate 5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268g 34.0 mmol) was dissolved in methanol (250 ml) and conc. H2S04 (2 ml) added. The mixture was refluxed for 5h and concentrated in vacuo. Residual material was taken up into ethyl acetate and water, and the organic layer, dried (MgS04). Concentration in vacuo afforded an oil, which was purified by Biotage Column Chromatography on silica gel using 10% ether in hexane to give an oil (5.5g).

Procedure 4 2,4-Dimethoxy-5-trifluoromethylbenzoic acid 2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5g; 5.4 mmol) in DMF (25ml) and toluene (8ml) under argon was treated with potassium trifluoroacetate (1.53g; 10.1 mmol) and copper (I) iodide (2.lug, 10.9 mmol). The mixture was heated to 1700C with removal of water (Dean/Stark), and then at 155"C overnight. The mixture was allowed to cool, poured into ether and water and filtered through Kieselguhr. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave a solid (1.03g) which was hydrolysed in 1:1 methanolic: aqueous NaOH (50ml) at 50"C. Work-up gave the title compound as a white solid (lug).

Procedure Sa Methyl 2-methoxy-5-cyano-4iso-propylbenzoate Copper (I) cyanide (550mg, 6mmol) was added to a solution of methyl 2-methoxy-5- bromo-4iso-propylbenzoate (861mg) 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(MgSO4). 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). lH NMR (250MHz, CDCl3) 8: 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 Sb 2-Methoxy-5-cyano-4-iso-propylbenzoic acid 2N NaOH (1.25ml) was added to a solution of the methyl ester PSa (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 (MgS04) and evaporated to dryness giving the product as a white solid (418mg).

H NMR (250MHz, CDCl3)#: 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 6a Ethyl 2-ethoxy-4-iso-propyl-5-cyanobenzoate Ethyl 2-ethoxy-4-iso-propyl-5-bromobenzoate (1.2g, 3.8mmol) was treated with copper (I) cyanide (682mg, 7.6 m.mol) in N-methyl-2-pyrrolidinone (40ml) as described in Procedure 5 to give the title compound as an oil (400mg). lH NMR (250MHz, CDCl3) 8:1.12 (6H, d, J=7Hz), 1.30 (3H, t, J=7Hz), 1.84 (3H, t, J=7Hz), 3.17 (1H, sep, J=7Hz), 3.99 (2H, q, J=9Hz), 4.16 (2H, q, J=7Hz), 6.69 (1H, s), 7.86 (1H, s); m/z (API+): 262 (MH+, 100%).

Procedure 6b 2-Ethoxy-4-iso-propyl-5-cyanobenzoic acid The ester P6a (370mg, l.4lmmol) was dissolved in methanol (Sml) and over a 24 h period 1N NaOH (2.lml, 2.1mmol) was added. The solution was concentrated under vacuum, diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (Mg SO4) and evaporated to give the title acid (306 mg). lH NMR (250MHz CDCl3) #: 1.39 (3H, d, J=7Hz), 1.66 (3H, t, J=7Hz), 3.47 (1H, sep, J=7Hz), 4.46 (2H, q, J=7Hz), 7.03 (1H, s), 8.47 (1H, s); m/z (API+): 234 (MH+, 100%).

Procedure 7 4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic acid 4-Ethoxy-2-methoxy-5-chlorosulfonyl benzoic acid was prepared in 49% yield using the procedure of M.W. Harrold et al., J. Med. Chem., 1989, 32 874. This was used according to the method of R.W. Brown, J. Org. Chem., 1991,56,4974, to the title compound in 19% yield.

'H NMR (DMSO-D6) 8:1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24 (2H, q), 6.73 (1H, s), 8.07 (1H, s).

Procedure 8 iso-Propyl-2-methoxy-S-methylsulfonylbenzwc add This was prepared in a similar manner to the procedure of C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall .1. Org. Chem., 1956, 21, 265 to afford the intermediate 5- chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid which was converted into the title compound using the method of Procedure 7.

'H NMR (DMSO-D6) 8:1.30 (6H, d), 3.21 (3H, s), 3.80 (1H, m), 3.94 (3H, s), 7.26 (1H, s), 8.19 (1H, s).

Example 1 N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-c arboxamide, monotrifluoroacetate The N-boc amine D7 (0.48g; 1.22 mmol) in dichloromethane (25ml) containing trifluoroacetic acid (2ml) was kept at 25°C for 18h. Evaporation in vacuo followed by crystallisation of the residue from ethyl acetate - ether gave the title compound as off- white crystals (0.46g; 92%), m.p. 153-5°C.

1H NMR (400MHz, DMSO-d6)8: 2.96 (2H, t), 3.38 (2H, t), 4.29 (2H, s), 7.23 (1H, d), 7.28 (1H, d, ABq), 7.51 (1H, dd), 7.63 (1H, d), 7.90 (1H, d, ABq), 9.01 (2H, br, s), 10.33 (1H, s); m/z (CI): 293 (MH+; 100%).

Example 2 N-(2-Methyl-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2- carboxamide The compound of Example 1 (200mg; 0.5 mmol), 98% formic acid (0.4ml) and aqueous formaldehyde (0.6ml) were treated according to the procedure of Description 4.

Chromatography on Kieselgel 60 in methanol - ethyl acetate followed by crystallisation from ethyl acetate - ether gave the title compound as an off-white powder, m.p. 138- 40°C.

1H NMR (250MHz, CDCl3)#: 2.46 (3H, s), 2.69 (2H, t), 2.89 (2H, t), 3.54 (2H, s), 6.93 and 7.37 (2H, ABq), 7.07 (1H, d), 7.25 (1H, dd), 7.34 (1H, d), 7.63 (1H, br, s); m/z (CI): 307 (MH+; 100%).

Example 3 N-(2-Methyl-1,2,3,4tetrahydroisoquinolin-7-yl)benzamide The N-methyl amine D5 in dichloromethane (25m1) containing triethylamine (0.5ml) was treated with benzoyl chloride and the mixture kept at 25°C for 18h. Normal work-up gave the product which was chromatographed on Kieselgel 60 by gradient elution in ethyl acetate:hexane. Combination of appropriate fractions gave the title compound.

1H NMR (250MHz, CDC13)o: 2.46 (3H, s), 2.69 (2H, t), 2.91 (2H, t), 3.58 (2H, s), 7.10 (1H, d), 7.30 (1H, dd), 7.40 - 7.60 (4H, overlapping m), 7.75 (1H, br s), 7.87 (2H, m).

The following Examples were made using procedures similar to the methods described earlier.

Example 4 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenz amide 1H NMR (250MHz, CDC13)6: 2.46 (3H, s), 2.68 (2H, t), 2.90 (2H, t), 3.57 (2H, s), 7.10 (1H, d), 7.29 (1H, dd, overlapping with CHC13), 7.39 (1H, s), 7.42 (1H, d), 7.52 (1H, m), 7.73 (1H, m), 7.83 (2H, m).

Example 5 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-t-butylben zamide 1H NMR (250MHz, CDCl3)5: 1.34 (9H, s), 2.44 (3H, s), 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7.07 (1H, d), 7.29 (1H, dd overlapping with CHCl3 signal), 7.38 - 7.53 (3H, m, overlapping signals), 7.75 - 7.90 (3H, m, overlapping signals).

Example 6 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propox ybenzamide 1H NMR (250MHz, CDCl3)#: 1.38 (6H, d), 2.46 (3H, s), 2.69 (2H, t), 2.90 (2H, t), 3.58 (2H, s), 4.64 (1H, septet), 6.94 (2H, m), 7.09 (1H, d), 7.23-7.34 (1H, m, overlapping CHC13), 7.42 (1H, s), 7.70 (1H, br s), 7.81 (2H, m); m/z (CI): 325 (MH+, 100%).

Example 7 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenoxyben zamide 1H NMR (250MHz, CDCl3)#: 2.46 (3H, s), 2.69 (2H, t), 2.91 (2H, t), 3.59 (2H, s), 7.00 - 7.50 (10H, overlapping m), 7.72 (1H, br s), 7.83 (2H, m).

Example 8 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-nitrobenza mide 1H NMR CDCl3)#: 2.45 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.60 (2H, s), 7.10 (2H, dd), 7.25 (1H, dd), 7.40 (1H, d), 8.00 (2H, dd), 8.35 (2H, dd), 7.80 (1H, s). m/z (CI): 312 (MH+, 70%).

Example 9 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenz amide 1H NMR CDCl3)#: 2.45 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.60 (2H, s), 6.30 (1H, d), 6.50 (1H, dd), 6.90 (1H, dd), 7.10 (1H, d), 7.40 (2H, m), 7.60 (1H, dd), 7.70 (1H, dd), 7.80 (1H, s), 7.90 (1H, d), 8.05 (1H, s); m/z (CI): 343 (MH+; 90%).

Example 10 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenz amide 1H NMR (CDCl3)#: 2.43 (3H, s), 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.60 (2H, s), 7.05 (1H, dd), 7.30 (1H, m), 7.35 (2H, m), 7.45 (1H, s), 7.65 (3H, m). m/z (CI): 281 (MH+; 90%).

Example 11 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenz amide 1H NMR (CDCl3)#: 2.50 (3H, s), 2.75 (2H, t), 2.90 (2H, t), 3.65 (2H, s), 7.10 (1H, dd), 7.28 (2H, m), 7.40 (2H, m), 7.60 (2H, m), 7.75 (1H, s); m/z (CI): 285 (MH+; 100%).

Example 12 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenza mide 1H NMR (CDC13)o: 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.60 (2H, s), 7.12 (1H, dd), 7.30 (1H, m), 7.40 (1H, s), 7.65 (1H, dt), 7.80 (2H, m), 8.10 (1H, d), 8.15 (1H, s). m/z (CI): 292 (MH+).

Example 13 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichloro benzamide 1H NMR (CDC13)o: 2.50 (3H, s), 2.80 (2H, t), 2.90 (2H, t), 3.70 (2H, s), 7.10 (1H, d), 7.30 (1H, dd), 7.40 (1H, s), 7.55 (1H, d), 7.70 (1H, dd), 8.00 (2H, m). m/z (CI): 335 (MH+).

Example 14 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzam ide 1H NMR (CDC13)6: 2.47 (3H, s), 2.71 (2H, t), 2.89 (2H, t), 3.58 (2H, s), 7.10 (1H, d), 7.30 (1H, m), 7.43 (1H, s), 7.60 and 7.85 (4H, ABq), 7.82 (1H, s). m/z (CI): 393 (MH+; 100%).

Example 15 N-(2-Methyl-1,2,3,4tetrahydroisoquinolin-7-yl)-4bromobenzami de 1H NMR (CDCl3)#: 2.47 (3H, s), 2.71 (2H, t), 2.89 (2H, t), 3.60 (2H, s), 7.10 (1H, d), 7.30 (1H, m), 7.43 (1H, s), 7.64 and 7.74 (4H, ABq), 7.70 (1H, s). m/z (CI): 347, 345 (MH+; 100%).

Example 16 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methylbenz amide 1H NMR (CDC13)o: 2.44 (3H, s), 2.48 (3H, s), 2.75 (2H, t), 2.90 (2H, t), 3.63 (2H, s), 7.10 (1H, d), 7.28 and 7.78 (4H, ABq), 7.30 (1H, m), 7.44 (1H, s), 7.74 (1H, m). m/z (CI): 281.2 (MH+; 100%).

Example 17 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenza mide 1H NMR (CDC13)s: 2.48 (3H, s), 2.71 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 7.13 (1H, d), 7.34 (1H, dd), 7.42 (1H, s), 7.71 (1H, t), 8.00 (1H, d), 8.26 (1H, d), 8.40 (1H, d), 8.70 (1H, t); m/z (CI): 312.1 (MH+; 100%).

Example 18 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxybenz amide 1H NMR (CDC13)8: 1.46 (3H, m), 2.47 (3H, s), 2.71 (2H, t), 2.90 (2H, t), 3.61 (2H, s), <BR> <BR> <BR> 4.11 (2H, m), 7.14 (1H, d), 7.30 (1H, m), 7.49 (1H, s), 7.68 (1H, s), 7.82 (2H, d), 8.10 (3H, m); m/z (CI): 311.2 (MH+; 100%).

Example 19 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-butylben zamide 1H NMR (CDCl3)#: 0.93 (3H, t), 1.25 - 1.48 (2H, m), 1.52 - 1.70 (2H, m), 2.51 (3H, s), 2.66 (2H, m), 2.80 (2H, t), 2.95 (2H, t), 3.69 (2H, s), 7.12 (1H, d), 7.20 (1H, d), 7.29 (2H, d), 7.32 (1H, m), 7.47 (1H, s), 7.78 (2H, d), 7.93 (1H, d); m/z (CI): 323.2 (MH+; 100%).

Example 20 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-acetoxyben zamide 1H NMR (CDCl3)#: 2.33 (3H, s), 2.48 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.61 (2H, s), <BR> <BR> <BR> 7.10 (1H, d), 7.16 (1H, d), 7.23 (1H, m), 7.32 - 7.45 (2H, m), 7.52 (1H, t), 7.83 (1H, d), 7.94 (1H, s); m/z (CI): 325.2 (MH+; 100%).

Example 21 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluorom ethylbenzamide 1H NMR (CDCl3)8: 2.48 (3H, s), 2.73 (2H, t), 2.92 (2H, t), 3.62 (2H, s), 7.11(1H, d), 7.32 (1H, d), 7.42 (1H, s), 7.63 (1H, t), 7.75 - 7.91 (2H, m), 8.07 (1H, t), 8.12 (1H, s). m/z (CI): 335.1 (MH+; 100%) Example 22 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-difluoro benzamide 1H NMR (CDC13)o: 2.47 (3H, s), 2.71 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 6.95 (1H, m), 7.00 - 7.18 (2H, m), 7.32 (1H, dd), 7.44 (1H, s), 8.14 - 8.36 (2H, m). m/z (CI): 303.1 (MH+; 100%).

Example 23 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dimethox ybenzamide m/z (CI): 327.2 (MH+; 100%).

Example 24 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-t rifluoromethyl benzamide 1H NMR (CDCl3)#: 2.47 (3H, s), 2.70 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 7.11 (1H, d), 7.35 (1H, dd), 7.45 (2H, s), 7.50 (1H, s), 7.59 (1H, d), 8.20 - 8.40 (2H, br m). m/z (CI): 353.1 (MH+; 100%).

Example 25 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-n itrobenzamide 1H NMR (CDC13)s: 2.48 (3H, s), 2.72 (2H, t), 2.94 (2H, t), 3.60 (2H, s), 7.10 (1H, d), 7.32 (1H, d), 7.38 (1H, s), 7.67 (1H, d), 7.95 - 8.13 (2H, br m), 8.38 (1H, d). m/z (CI): 348 (MH+; 33%), 346.1 (MH+; 100%).

Example 26 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-di-trifl uoromethylbenzamide 1H NMR (CDC13)s: 2.52 (3H, s), 2.78 (2H, t), 2.94 (2H, t), 3.66 (2H, s), 7.14 (1H, d), 7.36 (1H, d), 7.42 (1H, s), 7.94 (1H, m), 8.04 (1H, s), 8.32 (2H, s). m/z (CI): 403.1 (MH+; 100%).

Example 27 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-dichloro -5-fluorobenzamide 1H NMR (CDCl3)#: 2.47 (3H, s), 2.70 (2H, t), 2.91 (2H, t), 3.60 (2H, s), 7.11 (1H, d), 7.25 (1H, d), 7.38 (1H, s), 7.52 (1H, dd), 7.62 (1H, dd), 7.90 (1H, brs). m/z (CI): 353.0 (MH+; 100%).

Example 28 N- (2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)-3-fluoro-5-trifluoromeffi yl benzamide 1H NMR (CDCl3)#: 2.49 (3H, s), 2.73 (2H, t), 2.91 (2H, t), 3.62 (2H, s), 7.13 (1H, d), 7.32 (1H, dd), 7.40 (1H, s), 7.50 (1H, d), 7.80 (1H, m), 7.90 (1H, s), 8.02 (1H, s). m/z (CI): 353.1 (MH+; 100%).

Example 29 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-me thoxybenzamide 1H NMR (CDC13)6: 2.47 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.60 (2H, s), 3.97 (3H, s), 6.96 (1H, d), 7.10 (1H, d), 7.29 (1H, m), 7.40 (1H, s), 7.67 (1H, s), 7.84 (1H, dd), 8.02 (1H, s), 8.05 (1H, d); m/z (CI): 377, 375 (MH+; 30%).

Example 30 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,4,5-trimet hoxybenzamide 1H NMR (CDCl3)5: 2.42 (3H, s), 2.66 (2H, t), 2.88 (2H, t), 3.55 (2H, s), 3.83 (3H, s), 3.86 (6H, s), 7.00 (1H, s), 7.05 (1H, d), 7.19 (1H, s), 7.26 (1H, d), 7.34 (1H, s), 7.68 (1H, s), 7.94 (1H, s); m4 (CI): 357.2 (MH+; 100%).

Example 31 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluorom ethoxybenzamide 1H NMR (CDCl3)#: 2.47 (3H, s), 2.70 (2H, t), 2.91 (2H, t), 3.60 (2H,s), 7.10 (1H, d), 7.25 (1H, m), 7.32 (2H, d), 7.40 (1H, s), 7.74 (1H, s), 7.90 (2H, d); m/z (CI): 351.1 (MH+; 100%).

Example 32 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-pivaloylbe nzamide, hydrochloride The acid of Preparation 5 (200mg, 1.0mmol) and oxalyl chloride (140mg, 1. lmmol) in dichloromethane (10ml) containing DMF (5 drops) was stirred at 250C for lh and then evaporated to dryness in vacuo. The residue in dichloromethane was treated with the amine D5 (162mg, 1.0mmol) and kept at 250C overnight. Work-up similar to that of Example 2 gave the title compound (1 lOmg), m.p. 197 - 201°C (from methanol:ether).

1H NMR (free base; 250 MHz; CDC13)5: 1.38 (9H, s), 2.45 (3H, s), 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7.08 (lH, d), 7.30 (1H, d), 7.40 (1H, s), 7.49 (1H, t), 7.83 (1H, d), 7.95 (1H, d), 8.08 (1H, s), 8.14 (1H, s); m/z (CI): 351.2 (MH+; 100%).

Example 33 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-is o-propoxybenzamide 1H NMR (CDCl3) 3:1.42 (6H, d, J = 6 Hz), 2.47 (3H, s), 2.71 (2H, t, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.60 (2H, s), 4.67 (1H, dt, J = 6 Hz), 6.96 (1H, d, J = 9 Hz), 7.10 (1H, <BR> <BR> <BR> d, I = 8 Hz), 7.30 (1H, m), 7.40 (1H, d, 1=2 Hz), 7.71 (1H, s), 7.80 (1H, dd, I = 2 and 9 Hz), 8.05 (1H, d, J = 2 Hz).

Example 34 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-acetoxyben zamide 1H NMR (CDCl3) 6: 2.34 (3H, s), 2.48 (3H, s), 2.73 (2H, t, 1=6 Hz), 2.92 (2H, t, J = 6 HZ), 3.62 (2H, s), 7.11 (1H, d, J = 8 Hz), 7.21 (2H, m), 7.31 (1H, m), 7.43 (1H, s), 7.75 (1H, s), 7.88 (2H, m); m/z (CI: 325 (MH+; 100%)

Example 35 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopenty loxybenzamide 1H NMR (CDCl3) #: 1.56 - 1.68 (2H, bm), 1.74 - 1.97 (6H, bm), 2.61 (3H, s), 2.95 (4H, m), 3.79 (2H, s), 4.81 (1H, m), 6.38 (1H, s), 6.54 (1H, dd, J = 2 and 8 Hz), 6.85 (2H, m), 6.93 (2H, d, J = 8 Hz), 7.95 (2H, d, J = 8 Hz); m/z (CI): 349 (MH+; 20%) Example 36 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopropy lmethoxybenzamide 1H NMR (CDCl3) 6: 0.36 (2H, m), 0.66 (2H, m), 1.28 (1H, m), 2.44 (3H, s), 2.81 (2H, t, J = 6 Hz), 2.89 (2H, t, J = 6 Hz), 3.51 (2H, s), 3.86 (2H, m), 6.34 (1H, d, J = 2 Hz), 6.50 (1H, dd, J = 2 and 8 Hz), 6.92 (2H, m), 7.06 (1H, d, J = 8 Hz), 7.31 (1H, dd, J = 2 and 8 Hz), 7.82 (1H, m), 8.00 (1H, m); m/z (CI): 337 (MH+; 100%).

Example 37 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-me thoxybenzamide 1H NMR (CDCl3) b: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.59 (2H, s), 4.02 (3H, s), 7.09 (2H, t, J = 8 Hz), 7.29 (1H, dd, J = 2 and 8 Hz), 7.39 (1H, d, J = 2 Hz), 7.80 (1H, s), 8.10 (2H, m); m/z (CI): 322 (MH+; 100%) Example 38 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-naphthamid e 1H NMR (CDCl3) 6: 2.50 (3H, s), 2.75 (2H, t, 1=6 Hz), 2.94 (2H, t, 1=6 Hz), 3.65 (2H, s), 7.13 (1H, d, J = 8 Hz), 7.38 (1H, dd, J = 2 and 8 Hz), 7.50 (1H, d, J = 2 Hz), 7.56 - 7.22 (3H, bm), 7.88 - 8.07 (4H, bm), 8.38 (1H, s); m/z (CI): 317 (MH+; 100%) Example 39 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-me thylbenzamide 1H NMR (CDCl3) b: 2.47 (6H, bs), 2.71 (2H, t, 1=6 Hz), 2.91 (2H, t, J = 6 Hz), 3.60 (2H, s), 7.10 (1H, d, 1=8 Hz), 7.23-7.39 (2H, bm), 7.42 (1H, s), 7.70 (2H, dd, 1=2 and 8 Hz), 8.02 (1H, d, J = 2 Hz); m/z (CI): 359, 361 (MH+; 100%)

Example 40 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene- 1-carboxamide 1H NMR (CDCl3) a: 2.50 (3H, s), 2.75 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.66 <BR> <BR> <BR> (2H, 5), 7.12 (lH, d, I = 8 Hz), 7.35 (1H, d, I = 8 Hz), 7.45 - 7.70 (5H, m), 7.75 (1H, d, I = 8 Hz), 7.90 (1H, m), 7.96 (1H, d, J = 7 Hz), 8.36 (1H, d, J = 8 Hz). m/z (API+): 317.2 (MH+; 100%).

Example 41 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-m ethoxybenzamide 1H NMR (CDCl3) a: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.59 (2H, s), 3.97 (3H, s), 6.99 (1H, d, J = 9 Hz), 7.09 (1H, d, J = 8 Hz), 7.32 (1H, dd, J = 2 and 8 Hz), 7.40 (1H, s), 7.79 (2H, m), 7.90 (1H, d, J = 2 Hz).

Example 42 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butox ybenzamide 1H NMR (CDCl3) a: 1.41 (9H, s), 2.47 (3H, s), 2.71 (2H, t, 1=6 Hz), 2.91 (2H, t, 1=6 Hz), 3.61 (2H, s), 7.03-7.12 (3H, b m), 7.30 (1H, dd, J = 2 and 8 Hz), 7.43 (1H, d, J = 2 Hz), 7.68 (1H, s), 7.79 (2H, d, J = 9 Hz); m/z (CI): 339 (MH+; 100%).

Example 43 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxyb enzamide 1H NMR (CDCl3) a: 1.01 (3H, t, J = 7 Hz), 1.83 (2H, m), 2.87 (3H, s), 3.19 (2H, m), 3.44 (2H, t, J = 7 Hz), 3.61 (2H, s), 3.87 (2H, m), 4.40 (2H, s), 6.93 (2H, d), 7.09 (1H, d), 7.51 (1H, dd, J = 8, 2 Hz), 7.61 (1H, d,), 7.92 (2H, d), 8.39 (1H, s).

Example 44 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide m/z (CI): 308 (MH+; 65%)

Example 45 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole -6-carboxamide 1H NMR (CDCl3) #: 2.48 (3H, s), 2.72 (2H, t, J = 6 Hz), 2.93 (2H, t, 1=6 Hz), 3.62 (2H, s), 7.13 (1H, d, J = 8 Hz), 7.34 (1H, dd, J = 2 and 8 Hz), 7.45 (1H, d, J = 2 Hz), 7.88 (1H, s), 7.97 (1H, dd, J = 2 and 8 Hz), 8.22 (1H, d, J = 8 Hz), 8.56 (1H, d, J = 2 Hz), 9.15 (1H, s); m/z (CI): 322 (MH-: 100%) Example 46 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydrob enzofuran-5- carboxamide 1H NMr (CDCl3) a: 2.48 (3H, s), 2.73 (2H, t, 1=6 Hz), 2.91 (2H, t, J = 6 Hz), 3.27 (2H, t, J = 9 Hz), 3.62 (2H, s), 4.66 (2H, t, J = 9 Hz), 6.83 (1H, d, J = 8 Hz), 7.08 (1H, d, J = 8 Hz), 7.28 (1H, dd, 1=2 and 8 Hz), 7A2 (1H, s), 7.64 (1H, d, I = 8 Hz), 7.76 (2H, m). m/z (CI): 309 (MH+; 100%).

Example 47 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylbenz imidazole-5- carboxamide 1H NMR (d4MeOH) a: 2.51 (3H, s), 2.61 (3H, s), 2.92 (2H, t, J = 6 Hz), 2.96 (2H, t, J = 6 Hz), 3.69 (2H, s), 7.14 (1H, d, I = 9Hz), 7.47 (3H, m), 7.56 (lH, d, I = 8 Hz), 7.80 (1H, dd, J = 2 and 8 Hz), 8.10 (1H, s); m/z (CI): 321 (MH+; 100%).

Example 48 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i so-propoxybenzamide 1H NMR (CDCl3) &: 1.42 (6H, d, J = 6 Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6 Hz), 2.92 <BR> <BR> <BR> (2H, t, 1=6 Hz), 3.63 (2H, s), 4.67 (1H, quintet, 1=6 Hz), 6.98 (1H, d, 1=9 Hz), 7.09 (1H, d, I = 8 Hz), 7.28 (1H, dd, I = 2 and 8 Hz), 7.40 (1H, d, I = 2 Hz), 7.67 - 7.81 (2H, bm), 7.88 (1H, d, J = 2 Hz); m/z (CI): 359 (MH+; 100%).

Example 49 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-et hoxybenzamide 1H NMR (CDCl3) a: 1.51 (3H, t, 1=7 Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.62 (2H, s), 4.17 (2H, q, J = 7 Hz), 6.93 (1H, d, J = 9 Hz), 7.09 (1H, d,

J = 8 Hz), 7.28 (1H, dd, J = 2 and 8 Hz), 7.39 (1H, d, J = 2 Hz), 7.71 (1H, s), 7.80 (1H, dd, J = 2 and 9 Hz), 8.05 (1H, d, J = 2 Hz); m/z(CI): 389,391 (MH+; 100%) Example 50 N-(2-Methyl 1 ,2,3,4tetrahydroisoquinolin-7-yl)-3-chloro-4ethoxybenzamide 1H NMR (CDCl3) #: 1.51 (3H, t, 1=7 Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6 Hz), 2.92 (2H, t, 1=6 Hz), 3.62 (2H, s), 4.18 (2H, q, J = 7 Hz), 6.96 (1H, d, J = 9 Hz), 7.09 (1H, d, J = 8 Hz), 7.31 (1H, dd, J = 2 and 8 Hz), 7.39 (1H, d, J = 2 Hz), 7.76 (2H, m), 7.89 (1H, d, J = 2 Hz); m/z (CI): 345 (MH+; 100%).

Example 51 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethyl benzamide 1H NMR (CDCl3) â: 2.48 (3H, s), 2.72 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.60 (2H, s), 3.98 (3H, s), 7.09 (2H, m), 7.32 (1H, dd, J = 2 and 8 Hz), 7.41 (1H, d, J = 2 Hz), 7.83 (1H, s), 8.07 (2H, m); m/z (CI): 365 (MH+; 100%) Example 52 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro -4-methoxybenzamide 1H NMR (CDCl3) â: 2.46 (3H, s), 2.69 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.57 (2H, s), 3.96 (3H, s), 7.09 (1H, d, J = 8 Hz), 7.30 (1H, dd, J = 2 and 8 Hz), 7.34 (1H, d, J = 2 Hz), 7.81 (2H, s), 7.89 (1H, s); m/z (CI): 365 (MH+; 100%) Example 53 N-(2-Methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichlor o-4-ethoxybenzamide 1H NMR (CDCl3) a: 1.49 (3H, t, 1=7 Hz), 2.46 (3H, s), 2.69 (2H, t, J = 7 Hz), 2.90 (2H, t, J = 6 Hz), 3.56 (2H, s), 4.17 (2H, q, J = 7 Hz), 7.09 (1H, d, J = 8 Hz), 7.29 (1H, dd, J = 2 and 8 Hz), 7.32 (1H, s), 7.80 (2H, s), 7.86 (1H, s); m/z (CI): 379 (MH+; 100%) Example 54 N-(2-Methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichlor o-4-iso- propoxybenzamide

1H NMR (CDCl3) â: 1.39 (6H, d, J = 6 Hz), 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 <BR> <BR> <BR> (2H, t, 1=6 Hz), 3.59 (2H, s), 4.72 (1H, quintet, 1=6 Hz), 7.10 (lH, d, I = 8 Hz), 7.30 <BR> <BR> <BR> <BR> (1H, dd, I = 2 and 8 Hz), 7.36 (lH, s), 7.76 (d, I = 2 Hz), 7.80 (2H, s). miz (Cl): 393 (MH+, 100%) Example 55 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulf onylbenzamide 1H NMR (CDCl3) 6: 2.48 (3H, s), 2.71 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.12 (3H, s), 3.60 (2H, s), 7.12 (1H, d, J = 8 Hz), 7.35 (1H, dd, J = 2 and 8 Hz), 7.42 (1H, s), <BR> <BR> <BR> 7.73 (1H, t, I = 8 Hz), 8.05 (1H, s), 8.11 (1H, d, I = 8 Hz), 8.22 (1H, d, I = 8 Hz), 8.40 (1H, s); m/z (CI): 345 (MH+; 100%) Example 56 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-te rt-butylbenzamide A solution of the amine D5 (162mg; 1.0 mmol) and 3-bromo-4-tert-butylbenzoic acid (257mg; 1.0 mmol) in anhydrous N,N-dimethylformamide (7ml), was treated with 1- hydroxybenzotriazole (135mg; 1.0 mmol) and 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide (192mg; 1.0 mmol) at 25°C. The mixture was shaken for 48h before extracting the product into dichloromethane and washing with 10% aqueous NaHCO3, water and finally brine. The organic layer was dried over MgSO4 and evaporated in vacuo to afford 373mg of the title compound in 93% yield.

1H NMR (CDCl3) 6: 1.54 (9H, s), 2.47 (3H, s), 2.71 (2H, t, 1=6 Hz), 2.91 (2H, t, J = 6 Hz), 3.60 (2H, s), 7.10 (1H, d, J = 8 Hz), 7.31 (1H, dd, J = 2 and 8 Hz), 7.41 (1H, d, J = 2 Hz), 7.54 (1H, d, I = 8 Hz), 7.72 (2H, m), 8.06 (1H, d, I = 2 Hz).

Example 57 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-bromo-5-me thoxybenzamide H NMR (CDCl3) #: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.61 (2H, s), 3.83 (3H, s), 6.88 (1H, dd), 7.11 (1H, d, J = 8 Hz), 7.21 (1H, d), 7.31 (1H, dd, J = 8, 2 Hz), 7.44 (1H, d,), 7.50 (1H, d), 7.71 (1H, s); m/z (API+): 375.0 (MH+; 100%)

Example 58 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-m ethoxybenzamide, hydrochloride 1H NMR (free base CDCl3) 6: 2.53 (3H, s), 2.76 (2H, t, J = 6 Hz), 2.97 (2H, t, 1=6 Hz), 3.63 (2H, s), 4.01 (3H, s), 7.16 (1H, dd, J = 6, 2Hz), 7.21 (1H, d), 7.32 - 7.50 (3H, m), 7.64 (1H, dd, J = 6, 2Hz), 8.00 (1H, brs); m/z (API+): 315.1 (MH+; 100%) Example 59 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-methylpyra zole-4-carboxamide 1H NMR (250 MHz, CDCl3) 6: 2.30 (3H, s), 2.53 (2H, m), 3.40 (2H, s), 3.78 (3H, s), 6.91 (1H, d, J = 8 Hz), 7.11 (1H, m), 7.21 (1H, d), 7.20 (1H, brs), 7.46 (1H, br), 7.68 (1H, s), 7.76 (1H, s); m/z (API+): 271 (MH+; 100%) Example 60 N-(2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)-4trifluoromethylpyrazole- 3- carboxamide 1H NMR (250 MHz, D6 DMSO) b: 2.41 (3H, s), 2.81 - 2.85 (4H, m), 7.13 (1H, d, J = 8 Hz), 7.46 (2H, m), 8.64 (1H, s); m/z (API+): 325 (MH+; 100%) Example 61 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylthia zole-4-carboxamide 1H NMR (250 MHz, CDCl3) 6: 2.47 (3H, s), 2.67 - 2.76 (5H, m), 2.89 (2H, m), 3.60 <BR> <BR> <BR> (2H, s), 7.10 (1H, d, I = 8 Hz), 7.40 (1H, dd, I = 8, 2 Hz), 7.49 (1H, brs), 8.02 (1H, br), 9.12 (1H, br); m/z (API+): 288 (MH+; 100%) Example 62 <BR> <BR> <BR> N-(2-Metbyl-i,2,3,4-tetrahydroisoquinolin-7-yl)-S-methylisox azole-3-carboxamlde 1H NMR (250 MHz, CDCl3) 6: 2.46 (3H, s), 2.51 (3H, s), 2.68 (2H, m), 2.90 (2H, m), 3.58 (2H, s), 6.51 (1H, s), 7.10 (1H, d, J = 8 Hz), 7.33 (1H, dd, J = 8, 2 Hz), 7.41 (1H, brs), 8.47 (1H, brs); m/z (API+): 272 (MH+; 100%)

Example 63 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-tert-butyl isoxazole-3- carboxamide 1H NMR (250 MHz, CDCl3) 6: 1.38 (9H, s), 2.46 (3H, s), 2.66 - 2.71 (2H, m), 2.89 (2H, m), 3.59 (2H, s), 6.48 (1H, s), 7.10 (1H, d, J = 8 Hz), 7.30 (2H, brd, J = 8 Hz), 7.41 (1H, brs), 8.43 (1H, brs); m/z (API+): 314 (MH+; 100%) Example 64 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyiso xazole-5-carboxamide hydrochloride 1H NMR (250 MHz, DMSO-d6) 6: interalia 2.81 (3H, brs), 3.88 (3H, s), 7.00 (1H, s), 7.16 (2H, d, J = 8 Hz), 7.52 (2H, m); m/z (API+): 288 (MH+; 100%) Example 65 N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carb oxamide.

D5 was converted into the title compound by reaction with indole-2-carboxylic acid, in a similar manner to the procedure of Description 7.

1H NMR (D6 DMSO) 6: 2.84 (3H, s), 3.07 (2H, t, J = 6 Hz), 3.29 (2H,t, J = 6 Hz), 3.97 (2H, s), 5.01 (1H, m), 7.53 (2H, m), 7.70 (2H, m), 8.08 (4H, m), 9.90 ( 1H, brs). m/z (API+): 306 (MH+; 100%) Example 66 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-is o-propylbenzamide, hydrochloride 1H NMR (free base, CDCl3) 6: 1.26 (6H, d, J = 7 Hz), 2.48 (3H, s), 2.75 (2H, m), 2.90 (2H, m), 3.41 (1H, sep, J = 7 Hz), 3.62 (2H, s), 7.09 (1H, d, J = 8 Hz), 7.31 (2H, dd, J = <BR> <BR> <BR> 8, 2 Hz), 7.37 (2H, m), 7.76 (lH, dd, I = 8, 2 Hz), 7.90 (1H, brs), 8.02 (1H, d, I = 2 Hz); m/z (API+): 387, 389 (MH+; 100%)

Example 67 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-is o-propylbenzamide, hydrochloride 1H NMR (free base, CDCl3) 6: 1.25 (6H, d, J = 7 Hz), 2.37 (3H, s), 2.60 (2H, m), 2.80 (2H, m), 3.45 (1H, sep, J =7 Hz), 3.62 (2H, s), 7.00 (1H, d, J = 8 Hz), 7.25 (2H, m), 7.41 (1H, d), 7.97 (1H, dd, J = 8, 2 Hz), 8.03 (1H, d, J = 2 Hz), 8.10 (1H, brs); m/z (API+): 334 (MH+; 100%) Example 68 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-m ethoxybenzamide H NMR (250 MHz CDCl3) #: 2.48 (3H, s), 2.73 (2H, t, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.61 (2H, s), 3.96 (3H, s), 7.05 (2H, m), 7.30 (1H, dd, J = 6, 2Hz), 7.40 (1H, s), 7.63 (2H, d), 7.80 (1H, d); m/z (API+): 315.2 (MH+; 100%) Example 69 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n- propoxybenzamide 1H NMR (250 MHz CDCl3) #: 1.10 (3H, t, J = 8 Hz), 1.92 (2H, m), 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.58 (2H, s), 4.10 (2H,, J = 8 Hz), 7.02 (1H, d,), 7.09 (1H, d), 7.33 (1H, dd, I = 6, 2Hz), 7.38 (lH, s), 8.02 (1H, s), 8.08 (2H, m); m/z (API+): 350.2 (MH+; 100%) Example 70 N-(2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)-3-cyano-4ethoxybenzamide 1H NMR (250 MHz CDCl3) b: 1.53 (3H, t, 1=8 Hz), 2.49 (3H, s), 2.74 (2H, t, 1=6 <BR> <BR> <BR> Hz), 2.92 (2H, t, I = 6Hz), 3.62 (2H, s), 4.23 (2H, q, 1=8 Hz), 7.04 (lH, d), 7.10 (lH, d), 7.32 (1H, dd, J = 6, 2Hz), 7.40 (1H, d), 7.92 (1H, s), 8.09 (2H, m); m/z (API+): 336.2 (MH+; 100%) Example 71 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n- propoxybenzamide 1H NMR (250 MHz CDCl3) #: 1.10 (3H, t, J = 8 Hz), 1.90 (2H, m), 2.46 (3H, s), 2.69 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.58 (2H, s), 4.05 (2H, t, J = 8 Hz), 6.93 (1H, d),

7.09 (1H, d), 7.30 (1H, dd, J = 6, 2Hz), 7.39 (1H, d), 7.72 (1H, s), 7.80 (1H, dd, J = 6, 2Hz), 8.05 (1H, d); m/z (API+): 403.1 (MH+; 90%) Example 72 N- (2-Methyl- 1,2,3,4tetrahydroisoquinolin-7"yl)-3-bromo-4ethylbenzamide 1H NMR (250 MHz CDCl3) 6: 1.26 (3H, t, J = 8 Hz), 2.46 (3H, s), 2.69 (2H, t, J = 6 Hz), 2.82 (2H, q, J = 8 Hz), 2.90 (2H, t, J = 6.Hz), 3.59 (2H, s), 7.10 (1H, d), 7.28 (1H, dd, J = 6, 2 Hz), 7.34 (1H, d), 7.41 (1H, d), 7.74 (2H, dd), 8.03 (lH,s); m/z (API+): 373.1 (MH+; 100%) Example 73 N-(2-Methyl- 1,2,3,4tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide 1H NMR (250 MHz CDCl3) 6: 2.50 (3H, s), 2.79 (2H, t, J = 6 Hz), 2.93 (2H, t, J = 6 Hz), 3.64 (2H, s), 3.94 (3H, s), 6.85 (1H, d), 7.21 (1H, d), 7.08 (1H, d), 7.34 (1H, dd, J = 6, 2Hz), 7.38 (1H, d), 7.89 (1H, dd), 8.12 (1H, s), 8.29 (1H, d); m/z (API+): 423.0 (MH+; 100%) Example 74 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propox y-3-trifluoromethyl benzamide 1H NMR (250 MHz CDCl3) 6: 1.39 (6H, d, J = 8 Hz), 2.48 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.87 (2H, t, J = 6 Hz), 3.54 (2H, s), 4.72 (1H, m), 7.06 (2H, t), 7.30 (1H, dd,J = 6, 2Hz), 7.37 (1H, s), 8.03 (3H, m); m/z (API+): 393.2 (MH+; 100%) Example 75 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-m ethoxybenzamide 1H NMR (250 MHz CDCl3) b: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.88 (2H, t, J = 6 Hz), 3.59 (2H, s), 3.98 (3H, s), 7.11 (1H, d), 7.21 (1H, d), 7.30 (2H, m), 7.40 (1H, d), 7.45 (1H, d), 7.75 (1H, s); m/z (API+): 331.1 (MH+; 100%)

Example 76 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxy- 3-trifluoromethyl benzamide 1H NMR (250 MHz CDC13) b: 1.08 (3H, t, J = 8 Hz), 1.86 (2H, m), 2.46 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.58 (2H, s), 4.08 (2H, t, J = 8 Hz), 7.07 (2H, m), 7.29 (1H, dd, J = 6, 2Hz), 7.41 (1H, d), 7.97 (1H, s), 8.03 (1H, d), 8.07 (1H, s); m/z (API+): 393.2 (MH+; 100%) Example 77 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-t ert-butylbenzamide, hydrochloride 1H NMR (250 MHz, DMSO-d6) 6: inter alia 1.68 (9H, s), 7.36 (1H, d, J = 8 Hz), 7.77 (3H, m), 8.00 (1H, dd, J = 8, 2 Hz), 8.11 (1H, d, J = 2 Hz); m1z (API+): 357 (MH+; 100%) Example 78 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxyben zamide hydrochloride.

D5 was converted into the title compound in 95% yield by reaction with 4 methoxybenzoyl chloride in a manner similar to that described in Example 3.

1H NMR (D2O) b: 3.13 (3H, s), 3.25 (2H, brs), 3.68 (2H, brs), 3.96 (3H, s), 4.48 (2H, brs), 7.15 (2H, d, J = 9 Hz), 7.35-7.50 (3H, m), 7.90 (2H, d, J = 9 Hz).

Example 79 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-m ethylbenzamide, hydrochloride 1H NMR (free base CDCl3) 6: 2.34 (3H, s), 2.46 (3H, s) 2.69 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.58 (2H, s), 7.08 (2H, m), 7.30 (1H, dd), 7.40 (1H, d, ), 7.60 - 7.80 (2H, m), 7.74 (1H, s); m/z (API+): 299.2 (MH+; 100%)

Example 80 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i so-propylbenzamide 1H NMR (free base 250 MHz CDCl3) b: 1.40 (6H, d, J = 7 Hz), 2.59 (3H, s), 2.82 (2H, m), 3.03 (2H, m), 3.58 (1H, sep, J = 7 Hz), 3.71 (2H, s), 7.23 (1H, d, J = 8 Hz), 7.42 (1H, dd, J = 8, 2 Hz), 7.33 (2H, m), 7.82 (2H, m), 7.96 (1H, d, J = 2 Hz); m/z (API+): 343, 345 (MH+; 100, 50%) Example 81 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-et hylbenzamide hydrochloride 1H NMR (free base 250 MHz, CDCl3) 6: 1.31 (3H, t, J = 8 Hz), 2.43 (3H, s), 2.66 (2H, m), 2.90 (4H, m), 3.55 (2H, s), 7.09 (1H, d, J = 8 Hz), 7.28 (2H, dd, J = 8, 2 Hz), 7.36 <BR> <BR> <BR> (lH, brs), 7.44 (1H, d, I = 8 Hz), 7.86 (1H, brs), 8.00 (IH, dd, I = 8, 2 Hz), 8.09 (lH, d, J = 2 Hz); m/z (API+): 320 (MH+; 100%) Example 82 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-propyl -3-trifluoromethyl- benzamide hydrochloride 1H NMR (free base 250 MHz, CDCl3) 6: inter alia 1.38 (6H, d, J = 6 Hz), 2.32 (3H, s), 2.57 (2H, m), 2.76 (2H, m), 3.25 (1H, m), 3.45 (2H, s), 6.95 (1H, d, J = 8 Hz), 7.16 (1H, brd, J = 8 Hz), 7.26 (1H, brs), 7.43 (1H, d, J = 8 Hz), 7.72 (1H, brs), 7.84 (1H, d, J = 8 Hz), 7.93 (1H, brs); m/z (API+): 377 (MH+; 100%) Example 83 <BR> <BR> <BR> N-(2-Methyl-1,2,3,4tetrahydroisoquinolin-7-yl)-4ethyl-3- <BR> <BR> <BR> <BR> trifluoromethylbenzamide hydrochloride 1H NMR (free base 250 MHz, CDCl3) 6: inter alia 1.25 (3H, t, J = 8 Hz), 2.46 (3H, s), 2.68 (2H, m), 2.90 (2H, m), 3.38 (2H, brs), 7.10 (lH, d, I = 8 Hz), 7.30 (1H, dd, I = 8, 2 <BR> <BR> <BR> Hz), 7.47 (1H, d, J = 8 Hz), 7.40 (1H, brs), 7.78 (1H, brs), 7.97 (1H, dd), 8.08 (1H, brs); m/z (API-): 361 (MH-; 100%)

Example 84 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-is o-propoxybenzamide hydrochloride 1H NMR (250 MHz CDCl3) 6: 1.45 (6H, d, J = 8 Hz), 2.47 (3H, s), 2.70 (2H, t, J = 6 <BR> <BR> <BR> <BR> Hz), 2.91 (2H, t, J = 6 Hz), 3.59 (2H, s), 4.75 (1H, m), 7.04 (1H, d), 7.10 (1H, d), 7.29 (1H, dd, J = 6, 2Hz), 7.37 (1H, d), 7.71 (1H, s), 8.05 (2H, m); m1z (API+): 350.2 (MH+; 100%) Example 85 N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoro methylbenzamide 1H NMR (250 MHz CDCl3) b: 2.65 (2H, t, J = 6 Hz), 3.00 (2H, t, J = 6 Hz), 3.85 (3H, s), 3.89 (2H, s), 6.95 (2H, d), 7.17 (1H, dd, J= 6, 2Hz), 7.25 (1H, s), 7.57 (1H, s), 7.93 (2H, m); m1z (API+): 351.1 (MH+; 100%) Example 86 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-m ethylsulfonyl benzamide 1H NMR (CDCl3) #: 2.48 (3H, s), 2.71 (2H, t, J = 7 Hz), 2.80 (3H, s), 2.92 (2H, t, J = 7 Hz), 3.15 (3H, s), 3.61 (2H, s), 7.13 (2H, d), 7.35 (1H, dd), 7.43 (1H, s), 7.52 (1H, d), 7.93 (1H, s), 8.14 (1H, dd), 8.45 (1H, d); m/z (API+): 359.2 (MH+; 100%) Example 87 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-me thylsulfonylbenzamide 1H NMR (CDCl3) 6: 1.49 (3H, t, J = 8 Hz), 2.59 (3H, s), 2.81 (2H, t, J = 7 Hz), 3.03 (2H, t, J = 7 Hz), 3.27 (5H, m), 3.71 (2H, s), 7.23 (2H, d), 7.46 (1H, dd), 7.54 (1H, d), 7.69 (1H, d), 8.04 (1H, s), 8.29 (1H, dd), 8.55 (1H, d); m/z (API+): 373.2 (MH+; 100%) Example 88 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulf onyl-4-iso- propylbenzamide 1H NMR (CDCl3) 5:1.27 (6H, d, J = 8 Hz), 2.37 (3H, s), 2.60 (2H, t, J = 7 Hz), 2.81 (2H, t, J =7 Hz), 3.06 (3H, s), 3.46 (2H, s), 3.85 (1H, m), 7.00 (2H, d), 7.26 (1H, dd), 7.31 (1H, d), 7.57 (1H, d), 8.10 (1H, dd), 8.21 (1H, s), 8.37 (1H, d);

m/z (API+): 387.2 (MH+; 100%) Example 89 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulf onyl-4- methoxybenzamide 1H NMR (CDCl3) b: 2.31 (3H, s), 2.54 (2H, t, J = 7 Hz), 2.75 (2H, t, J = 7 Hz), 3.09 (3H, s), 3.42 (2H, s), 3.87 (3H, s), 6.95 (2H, m), 7.12 (1H, s), 7.21 (1H, d), 8.08 (2H, m), 8.23 (1H, d); m/z (API+): 375.2 (MH+; 75%) Example 90 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoroa cetylbenzamide, hydrochloride 1H NMR (free base CDCl3) o: 2.47 (3H, s), 2.46 (3H, s) 2.77 (2H, t, J = 6 Hz), 2.94 (2H, <BR> <BR> t,I=6Hz), 3.63(2H,s),7.13 (lH, d,I=6Hz),7.45 (1H,d,I=6Hz),7.54(lH,t,I=6 Hz), 7.81 (1H, d, J = 6 Hz), 7.97 (1H, d, J = 6 Hz); 8.20 (1H, s); m/z (API+): 363.2 (MH+; 60%) Example 91 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- pentafluoroethyl- benzamide hydrochloride 1H NMR (free base 250 MHz, CDCl3) 6: 2.46 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.59 (2H, s), 3.94 (3H, s), 7.10 (2H, m), 7.30 (1H, dd, J = 8, 2 Hz), 7.39 (1H, brs), 7.73 (1H, brs), 8.01 (1H, d, J = 2 Hz), 8.06 (1H, dd, J = 9, 2 Hz); m/z (API+): 415 (MH+; 1004) Example 92 N-(2-n-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethoxybenzamide 1H NMR (CDCl3) b: 0.95 (3H, t, J = 7 Hz), 1.51 (3H, t, J = 7 Hz), 1.62 (2H, m), 2.47 (2H, t, J = 8 Hz), 2.72 (2H, t, 1=6 Hz), 2.88 (2H, t, J = 6 Hz), 3.61 (2H, s), 4.17 (2H, q, J = 7 Hz), 6.92 (1H, d, J = 9 Hz), 7.07 (1H, d, J = 8 Hz), 7.26 (1H, dd, J = 8, 2 Hz), 7.39 (1H, d, J = 2 Hz), 7.72 (1H, brs), 7.79 (1H, dd, J = 9, 2 Hz), 8.04 (1H, d, J = 2 Hz). m/z (API+): 417, 419 (MH+; 95%)

Example 93 N-(2-n-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy- 3- trifluoromethylbenzamide 1H NMR (CDCl3) 6: 0.96 (3H, t, J = 7 Hz), 1.61 (2H, m), 2.47 (2H, t, J = 8 Hz), 2.73 (2H, t, J = 6 Hz), 2.88 (2H, t, J = 6 Hz), 3.62 (2H, s), 3.98 (3H, s), 7.08 (2H, m), 7.30 (1H, m), 7.41 (1H, d, J = 2 Hz), 7.76 (1H, brs), 8.05 (2H, m); m/z (API+): 393 (MH+; 100%) Example 94 N-(2-n-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4 -iso-propoxybenzamide 1H NMR (CDCl3) 6: 0.95 (3H, t, J = 7 Hz), 1.42 (6H, d, J = 6 Hz), 1.62 (2H, m), 2.48 (2H, t, J = 8 Hz), 2.73 (2H, t, J = 6 Hz), 2.88 (2H, t, J = 6 Hz), 3.63 (2H, s), 4.66 (1H, <BR> <BR> <BR> sept, J = 6 Hz), 6.98 (1H, d, J = 9 Hz), 7.08 (1H, d, J = 8 Hz), 7.26 (lH, m), 7.41 (lH, d, <BR> <BR> <BR> <BR> <BR> <BR> J = 2 Hz), 7.65 (1H, brs), 7.73 (1H, dd, J = 9, 2 Hz), 7.87 (1H, d, J = 2 Hz). m/z (API+): 387 (MH+; 90%) Example 95 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-is o-butylbenzamide hydrochloride 1H NMR (250 MHz, DMSO-d6) b: inter alia 0.95 (6H, d, J = 7 Hz), 1.99 (1H, sep, J = 7 Hz), 2.77 (2H, brs), 7.26 (1H, d, J = 8 Hz), 7.65 (3H, m), 8.21 (1H, dd, J = 8, 2 Hz), 8.41 (1H, d, J = 8 Hz); m/z (API+): 348 (MH+; 100%) Example 96 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-iso-butyl- 3-trifluoromethyl- benzamide hydrochloride 1H NMR (250 MHz, DMSO-d6) 6: inter alia 1.01 (6H, d, J = 6.5 Hz), 2.09 (1H, sep, J = 6.5 Hz), 7.35 (1H, d, J = 8 Hz), 7.75 (3H, m), 8.32 (1H, d, J = 8 Hz); m/z (API+): 391 (MH+; 100%)

Example 97 N-(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-eth oxybenzamide H NMR (CDCl3) #: 1.20 (3H, t, J = 7 Hz), 1.51 (3H, t, J = 7 Hz), 2.61 (2H, q, J = 7 <BR> <BR> <BR> <BR> Hz), 2.76 (2H, m), 2.90 (2H, m), 3.64 (2H, s), 4.16 (2H, q, J = 7 Hz), 6.91 (1H, d, J = 9 <BR> <BR> <BR> <BR> <BR> Hz), 7.07 (1H, d, J = 8 Hz), 7.26 (1H, m), 7.40 (1H, d, J = 2 Hz), 7.79 (2H, m), 8.05 (1H, d, J = 2 Hz); m/z (API+): 403,405 (MH+; 65%) Example 98 N-(2-Ethyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-4-methoxy-3- trifluoromethyl benzamide 1H NMR (CDCl3) 6: 1.21 (3H, t, J = 7 Hz), 2.65 (2H, q, J = 7 Hz), 2.80 (2H, d, J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.67 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7.30 (1H, m), 7.41 (1H, d, J = 2 Hz), 7.89 (1H, brs), 8.06 (2H, m); m/z (API+): 379 (MH+; 100%) Example 99 N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo- 4-ethoxybenzamide 1H NMR (CDCl3) 6: 1.13 (6H, d, J = 7 Hz), 1.51 (3H, t, J = 7 Hz), 2.84 (5H, m), 3.71 <BR> <BR> <BR> <BR> (2H, s), 4.16 (2H, q, I = 7 Hz), 6.91 (1H, d, I = 9 Hz), 7.06 (1H, d, I = 8 Hz), 7.25 (1H, <BR> <BR> <BR> <BR> <BR> <BR> m), 7.42 (1H, d, I = 2 Hz), 7.78 (2H, m), 8.04 (1H, d, I = 2 Hz). m/z (API+): 419 (MH+; 90%) Example 100 N-(2-iso-Propyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methox y-3-trifluoromethyl benzamide 1H NMR (CDCl3) 6: 1.13 (6H, d, J = 7 Hz), 2.84 (5H, m), 3.72 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7.26 (1H, m), 7.43 (1H, d, J = 2 Hz), 7.83 (1H, brs), 8.04 (2H, m) m/z (API+): 393 (MH+; 100%)

Example 101 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-m ethylsulfonyl- benzamide 1H NMR (CDC13) 6: 1.52 (3H, t, J = 8 Hz), 2.46 (3H, s), 2.69 (2H, t, J = 7 Hz), 2.90 (2H, t, J =7 Hz), 3.26 (3H, s), 3.57 (2H, s), 4.27 (2H, q, J =7 Hz), 7.09 (2H, dd), 7.36 (1H, dd), 7.42 (1H, s), 7.83 (1H, brs), 8.12 (1H, s), 8.20 (1H, dd), 8.37 (1H, d); m1z (API+): 389.2 (MH+; 100%) Example 102 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman -6-carboxamide hydrochloride 1H NMR (D6 DMSO) 6: 2.63 (3H, narrow d), 3.02 (2H, t, J = 7Hz), 3.14 (2H, brm), 3.60 (2H, brm), 4.54 (2h, brs), 4.77 (2H, d, J = 7 Hz), 7.25 (1H, m), 7.31 (1H, d, J = 8 Hz), 7.44 (2H, d, I = 6 Hz), 8.20 (1H, dd, I = 8, 2 Hz), 8.59 (lH, d, I = 2 Hz), 10.31 (1H, s), 10.95 (1H, brs); m/z (API+): 337.4 (MH+; 100%) Example 103 N-(2-Formyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifliioromethylbenaamide 7-Amino-2-formyl-1,2,3,4-tetrahydroisoquinoline (0.176g) was converted into the title compound by reaction with 4-methoxy-3-trifluoromethylbenzoyl chloride, following the procedure of Example 3. The product was isolated as a white solid (0.035g).

1H NMR (d6-DMSO) 6: 2.80 (2H, m), 3.65 (2H, broad t), 4.00 (3H, s), 4.59 (2H, d), 7.17 (1H, d, J = 8 Hz), 7.45 (1H, d, J = 8 Hz), 7.60 (2H, m), 8.26 (3H, m), 10.30 (1H, s). m/z (API+): 379 (MH+).

Example 104 N-(2-Hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-brom o-4-ethoxybenzamide The compound D16 (1 lSmg; 0.22 mmol) was dissolved in THF with stirring and tetra- butylammonium fluoride (1 M in THF; 0.216 mmol) added. The reaction was stirred overnight and the mixture purified by column chromatography through SiO, eluting with 10% methanol:dichloromethane. Trituration with petroleum ether, gave the title compound (48mg; 49%).

1H NMR (250 MHz, CDCl3) 8:1.51 (3H, t, J = 7 Hz), 2.77 (2H, t, J = 5 Hz), 2.90 (4H, m, overlapping signal), 3.74 (4H, m, overlapping signal), 4.17 (2H, q, J = 7 Hz), 6.93 <BR> <BR> <BR> (lH, d, J = 10Hz), 7.10 (lH, d, J = 8 Hz), 7.36 (lH, dd, J = 8, 2Hz), 7.48 (lH, d, J = 2 Hz), 7.87 (1H, dd, J = 9, 2 Hz), 7.97 (1H, s), 8.08 (1H, d, J = 2 Hz) Example 105 N-(2-Hydroxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-brom o-4-ethylbenzamide The title compound was prepared in 40% overall yield from D15 in a manner similar to that of Descriptions 16 and Example 106.

1H NMR (250 MHz, CDCl3) 6: 2.77 (10H, m, overlapping signals), 3.68 (5H, m, overlapping signals), 7.08 (1H, d, J = 8 Hz), 7.30 (2H, m, overlapping signals), 7.48 (1H, d, J = 2 Hz), 7.75 (H, dd, J = 8, 2 Hz), 8.02 (1H, d, J = 2 Hz), 8.17 (1H, s).

Example 106 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylmeth oxy-3-trifluoromethyl benzamide 1H NMR (CDCl3) o: 2.50 (3H, s), 2.75 (2H, t, J = 6 Hz), 2.94 (2H, t, J = 6 Hz), 3.64 (2H, s), 7.10 (2H, d, J = 8 Hz), 7.30 - 7.60 (7H, m, overlapping), 7.70 (1H, brs), 8.04 (1H, dd, J = 8, 2 Hz), 8.10 (1H, d, J = 2 Hz); m'z (CI): 441.2 (MH+; 100%) Example 107 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3- trifluoromethyl benzamide m/z (CI): 351.1 (MH+; 100%) Example 108 N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-brom o-4-iso- propoxybenzamide 1H NMR (250 MHz, CDCl3) o: 1.41 (6H, d, J = 6 Hz), 2.75 (4H, t, overlapping, J = 6 Hz), 2.83 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t, overlapping, J = 6 Hz), 4.64

(1H,m), 6.91 (1H, d, J = 9 Hz), 7.01 (1H, d, J = 8 Hz), 7.20 (1H, dd, J = 8,2 Hz), 7.29 (1H, d, I = 2 Hz), 7.80 (1H, dd, I = 9, 2Hz), 8.07 (1H, d, I = 2 Hz), 8.10 (lH, s); m/z (API+): 447,449 (MH+, 90%) Example 109 N-(2-Methoxyethyl- 1,2,3,4tetrahydroisoquinolin-7yl)-3-chloro-4iso- propoxybenzamide 1H NMR (250 MHz, CDCl3) o: 1.41 (6H, d, J = 6 Hz), 2.75 (4H, t, overlapping, J = 6 Hz), 2.83 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t, overlapping, J = 5 Hz), 4.64 (1H, m), 6.94 (1H, d, J = 9 Hz), 7.01 (1H, d, J = 8 Hz), 7.20 (1H, d, J = 8 Hz), 7.30 (1H, s), 7.75 (1H, dd, J = 9, 2 Hz), 7.90 (1H, d, J = 2 Hz); m/z (API+): 403,405 (MH+) Example 110 N-(2-Methoxyethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-meth oxy-3- trinuoromethylbenzamide 1H NMR (250 MHz, CDCl3) b: 2.75 (4H, m), 2.85 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t, overlapping), 3.96 (3H, s), 7.04 (2H, m), 7.25 (1H, d, J = 10Hz), 7.35 (1H, s), 8.07 (3H, m); m/z (API+): 409 (MH+, 100%) Example 111 (a) N-(2-t-Butyloxycarbonyl-5-iodo-1,2,3,4-tetrahydroisoquinolin -7-yl)-4- azidobenzamide The title compound was prepared in 81% yield from the acid Preparation 28 and amine D6.

(b) N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-azidobenzami de, trifluoroacetate.

The title compound was prepared in 91% yield from using a method similar to that of Example 1. mlz (CI): 420 (MH+; 100%).

Example 112 N-(2-Methyl-5-trifluoroacetylamino-1,2,3,4-tetrahydroisoquin olin-7-yl)-3-bromo-4- methoxybenzamide The title compound (0.66g) was prepared from D25 (0.50g) and 3-bromo-4- methoxybenzoic acid (0.63g) using a procedure similar to that of Description 7. m/z (CI): 486, 488 (MH+; 90%).

Example 113 N-(2-Methyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-b romo-4- ethoxybenzamide m/z (CI): 425 (MH+; expected isotope pattern).

Example 114 <BR> <BR> <BR> N"(2-Methyl-5Xchloro- 1,2,3,4-tetrahydroisoquinolin-7-yl)-3bromo=4ethylbenzamide 1H NMR (CDC13)o: 1.25 (3H, t, J = 7Hz), 2.48 (3H, s), 2.70-3.00 (6H, m, overlapping signals), 3.59 (2H, s), 7.29 (1H, d, J = 2Hz), 7.33 (1H, d, J = 7Hz), 7.51 (1H, d, J = 2Hz), 7.71 (1H, dd, J = 7,2Hz), 7.83 (1H,brs), 8.01 (lH,dJ = 2Hz); m/z (CI): 409 (MH+; expected isotope pattern).

PHARMACOLOGICAL DATA 1. Binding Assay Method WO 92122293 (SmithKline Beecham) discloses compounds having antisonvulsant activity, including inter alia the compound trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol (hereinafter referred to as Compound A). It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (SmithKline Beecham).

The affinity of test compounds to the novel receptor site is assessed as follows.

Method Whole forebrain tissue is obtained from rats. The tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4). The homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.

To carry out the radioligand binding assay, aliquots of tissue prepared as above (usually at a concentration of 1-2mg protein/ml) are mixed with aliquots of [3Hl-Compound A dissolved in buffer. The final concentration of [3H]-Compound A in the mixture is usually 20nM. The mixture is incubated at room temperature for 1 hour. [3Hl-Compound A bound to the tissue is then separated from unbound [3H]-Compound A by filtration through Whatman GF/B glass fibre filters. The filters are then washed rapidly with ice-cold buffer. The amount of radioactivity bound to the tissue trapped on the filters is measured by addition of liquid scintillation cocktail to the filters followed by counting in a liquid scintillation counter.

In order to determine the amount of "specific" binding of [3H]-Compound A, parallel assays are carried out as above in which [3Hl-Compound A and tissue are incubated together in the presence of unlabelled Compound A (usually 3 pM). The amount of binding of [3H]<ompound A remaining in the presence of this unlabelled compound is defined as "non-specific" binding. This amount is subtracted from the total amount of [3H]-Compound A binding (i.e. that present in the absence of unlabelled compound) to obtain the amount of "specific" binding of [3H]-Compound A to the novel site.

The affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H]-Compound A and tissue in the presence of a range of concentrations of the compound to be tested. The decrease in the level of specific [3H]- Compound A binding as a result of competition by increasing concentrations of the compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.

Results Compounds of this invention were active in this test. For example, compounds of Examples 1, 4, 5, 6, 7, 10 and 13 gave pKi values greater than 7.

2. MEST Test The maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant propertiesl. 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 mlikg 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% (CC50) 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 CC50 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 Compounds of this invention dosed at 10 mglkg by the oral route as a suspension in methyl cellulose and tested one hour post dosing showed an increase in seizure threshold.

For example, the compounds of Examples 4, 5, 6 and 7 show increases of 24%, 36%, 90% and 23% respectively.

Method for rat model The threshold for maximal (tonic hindlimb extension) electroshock seizures in male rats (Sprague Dawley, 80 - 150g, 6 weeks old) was determined by a Hugo Sachs Electronik stimulator which delivered a constant current (0.3 sec duration; from 1-300mA in steps of 5-20mA). The procedure is similar to that outlined above for mouse and full details are as published by Upton et al,.4 The percentage increase or decrease in CC50 for each group compared to the control is calculated.

Drugs are suspended in 1% methyl cellulose.

Results At a dosage of 2 mg/kg p.o. at 2h, the compounds of Examples 48, 49, 51 and 67 show increases of 389%, 325%, 545% and 303% increases respectively.

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, kM.Ray, T.O.Stean, W.N.Chan, J.M.Evans and M.Thompson. (1997). B. J. Pharmacol., 121, 1679-1686