MXPA99008627A - Anti-convulsant isoquinolyl-benzamide derivatives - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, where R1 is hydrogen, C1-6alkyl (optionally substitutedby hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO-, formyl, CF3CO- or C1-6alkylSO2-;R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C¿1 -6?alkyl, 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-, 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 -NR5R6 where R5 is hydrogen or C1-4alkyl, and R6 is hydrogen, C1-4alkyl, formyl, -CO2C1-4alkyl or -COC1-4alkyl;or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or=O;and the two R3 groups and the two R4 groups are each independently hydrogen or C1-6alkyl or the two R3 groups and/or the two R4 groups together form a C3-6spiroalkyl group provided that at least one R3 and R4 group is not hydrogen, are useful in the treatment and prophylaxis of epilepsy and other disorders.

Description

ANTI-CONVULSIVE DERIVATIVES OF 1SOQUINOLYLBENZAMIDE DESCRIPTIVE MEMORY This invention relates to novel compounds, methods for preparing them, and their use as therapeutic agents. US-A-4022900 (Marion) describes benzamido-tetrahydroisoquinolines having hypertensive and vasodilating properties. WO97 / 48683 (Smith line Beecham), not published at the date of publication of this application, discloses that the following benzamide compounds of formula (A) possess anti-convulsive activity and are therefore believed to be useful for the treatment and / or prevention of anxiety, mania, and related depression disorders.

(TO) Where n and p are independently integers from 1 to 4 and (n + p) is from 2 to 5; R1 is C? -6O- alkyl; R is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, CF3, CF3O-, CF3S-, CF3CO-, C6-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4alkyl, C6-6CO- alkyl, C3-6CO- cycloalkyl, C3-6 cycloalkyl-C1-4CO- alkyl, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl, C-? 6S-, C-? - 6SO2- alkyl, (C? -4 alkyl) 2NSO2- or (C ^ NHSOa alkyl- R3 is hydrogen, halogen, NO2, CN, N3, trifluoromethyldiazirinyl, C? , C S- alkyl, C alquilo-r alquilo alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl- C 1-4 alkyl-, C al-6 alkenyl, C?-6 alkynyl, CF 3 CO-, alkyl of d-βCO-, cycloalkyl of C3-6CO, cycloalkyl C3-6-alkyl of C1-4CO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl, or -NR5R6 wherein R5 is hydrogen or C 1-4 alkyl, and R 6 is hydrogen, C 1-4 alkyl, -CHO, -CO 2 C 1-4 alkyl or -CO C 1-4 alkyl-, R 4 is hydrogen, C 1-6 alkyl, C alkenyl ? -6, or alkynyl d e C1-6 It has now been found that the carboxamide compounds of the following formula (I) possess anti-convulsive activity and therefore are believed to be useful in the treatment and / or prevention of anxiety, mania, depression, disorders of panic and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, the effects associated with abstinence from substances of excessive use 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 ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, disorders of sleep (including cardiac rhythm repetition disorders, insomnia & narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, pain from cancer, inappropriate neuronal activity resulting in neurodysesthesia in such diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). Likewise, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof: (Wherein R1 is hydrogen, C1-6 alkyl (optionally substituted by hydroxy or C1-4 alkoxy), C1-6 alkenyl, C1-6 alkynyl, Ci-βCO- alkyl, formyl, CF3CO- or C1-6SO2- alkyl, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C-? 6 alkyl, C? -6 alkenyl, C? -6 alkynyl, d-6 perfluoroalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C? -6O- alkyl, C-rsCO- alkyl, C3- cycloalkyl 6O-, C3-6 cycloalkyl CO-, C3-6 cycloalkyl- C1-4O- alkyl-, C3-6 cycloalkyl- C1-4CO- alkyl-, phenyl-, phenoxy-, benzyloxy-, benzoyl-, phenyl-C1-alkyl- -4, C-rßS- alkyl, d-6SO2- alkyl, (C? -4) 2 NSO2- alkyl, (d-4 alkyl) NHSO2-, (d-4 alkyl) 2NCO-, ( alkyl of d-4) NHCO- or CONH2; or -NR5R6 wherein R5 is hydrogen or C1-4 alkyl, and R6 is hydrogen, d-4 alkyl, formyl, -CO2 C1-4 alkyl or -CO alkyl of d-4; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and the two R3 groups and the two R4 groups are each independently hydrogen or C1-6 alkyl or two R3 groups and / or the two R4 groups together form a spiroalkyl group of C3-6 with the proviso that at least one group R3 and R4 is not hydrogen. The compounds of this invention are typically isoquinolinylcarboxamides, especially (tetrahydroisquinolin-7-yl) carboxamides. The carboxamide portion can be a benzamide. When two R2 groups form a carbocyclic ring, it is usually a 5-7 membered ring, and the carboxamide portion can be a naphthalenecarboxamide or an indanecarboxamide or indanonecarboxamide. In formula (I), alkyl groups, including alkyl groups that are part of other portions, such as alkoxy or acyl, can be straight or branched chain. Phenyl groups, including phenyl groups which are part of other portions, in R 2 may be optionally substituted with one or more independently selected halogen or C 1-6 alkyl, d-6 alkoxy or d-6 alkylcarbonyl. Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halogen substituents include fluorine, chlorine, iodine and bromine. It should be noted that the compounds of the present invention possess chiral centers and therefore can exist in different enantiomeric forms, the present invention encompassing each enantiomeric form and mixtures thereof including diastereoisomers and racemates. A suitable group of compounds of this invention is that of the formula (IA) (IA) wherein R 1 is hydrogen, d-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), d-β alkenyl, d-6 alkynyl, formyl, d-6CO alkyl, d-6SO 2 alkyl, or CF3CO-; R22 is alkyl of d-βO-, cycloalkyl of C3-6O- or cycloalkyl of C3-6- alkyl of C1-4O-; R23 is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, perfluoroalkyl of d-6) CF3O-, CF3S-, CF CO-, C6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4 alkyl , alkyl of d-βO-, alkyl of C?-6CO-, cycloalkyl of C3-6CO-, cycloalkyl of C3-6- alkyl of C1-4CO-, phenyl, phenoxy, benzyloxy, bezoyl, phenyl-alkyl of C- 1-4, d-ßS- alkyl, d-6SO2- alkyl, (C? -4 alkyl) 2NSO2, (d-4 alkyl) NHSO2, (d-4 alkyl) 2NCO-, d-4) NHCO- or CONH2; R24 is hydrogen, halogen, NO2, CN, N3, trifluoromethyldiazirinyl, CI-TO- alkyl, d-6S- alkyl, d-6 alkyl, C3-6 cycloalkyl, C3-6-cycloalkyl- d- alkyl 4, C- [alpha] 6 alkenyl, C1-6 alkynyl, CF3CO-, d-6CO- alkyl, C3-6CO- cycloalkyl, C3-6 cycloalkyl- C1-4CO- alkyl, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C 1-4 alkyl; or -NR 5 R 6 wherein R 5 is hydrogen, or C 1-4 alkyl, and R 6 is hydrogen, C 1-4 alkyl, formyl, -CO 2 C 1-4 alkyl or -CO C 1-4 alkyl; or R23 and R24 together form a carbocyclic ring that is unsaturated or saturated and unsubstituted or substituted by carbonyl or hydroxyl; R4 is C6 -6 alkyl. Another suitable group is that of the formula (IB) (IB) wherein R1 is hydrogen, d6 alkyl (optionally substituted by hydroxy or C1-4 alkoxy), C6-6 alkenyl, d-6 alkynyl) C1-6CO- alkyl, formyl, CF3CO or alkyl of d-6SO2-, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C6-6alkenyl, C1-6 alkynyl, C1-6 perfluoroalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, C1-6O- alkyl, d-? CO- alkyl, C3-6 cycloalkyl -, C3-6CO- cycloalkyl, C3-6cycloalkyl- C1-4O- alkyl-, C3-6cycloalkyl- C1-4CO- alkyl-, phenyl-, phenoxy-, benzyloxy-, benzoyl-, phenyl- C- 1 alkyl -4, d-βS alkyl-, d-6S02- alkyl, (d-4 alkyl) 2NS02-, (d-4 alkyl) NHS02-, (C 4 alkyl) 2NCO-, (C-alkyl) 4) NHCO- or CONH2; or -NR5R6 wherein R5 is hydrogen or C1-4alkyl, and R6 is hydrogen, C1-4alkyl, formyl, CO2 alkyl of d-4 or -CO alkyl d-4; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and each R3 is alkyl of Another suitable group is that of the formula (IC) (IC) wherein R 1 is hydrogen d-β alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), β-alkenyl, d-6CO- alkyl, formyl, CF 3 CO- or C?-6SO 2 alkyl- R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, d6 alkyl, C6-6 alkenyl, C1-6 alkynyl, perfluoroalkyl C? -6 > C3-6 cycloalkyl, C3-6 cycloalkyl-C4 alkyl, d-6O- alkyl, CI-TCO- alkyl, C3-6O- cycloalkyl, C3-6CO- cycloalkyl, C3-6 cycloalkyl -alkyl C1-4O-, C3-6 cycloalkyl- d-4CO- alkyl, phenyl, phenoxy, benzyloxy, benzoyl, phenylC1-4alkyl, d-6S- alkyl, d-6SO2- alkyl, of d-4) 2NSO2-, (C4 alkyl) NHSO2-, (d-4 alkyl) 2NCO-, (alkyl of C? -4) NHCO- or CONH2; or -NR5R6 wherein R5 is hydrogen or C1-C4 alkyl, and R6 is hydrogen, C1-4 alkyl, formyl, -CO2 C1-4 alkyl or -CO C1-4 alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and each R 4 is d-β alkyl. A suitable group of compounds of formulas (I), (IB) and (IC) has R 1 as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, formyl, acetyl, thifluoroacetyl or methanesulfonyl., R 2 as hydrogen or one or more of methyl, ethyl, n-butyl, / 'so-propyl, 1-butyl, phenyl, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, n-butoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, / so-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulphamoyl, R3 one or both are methyl, R4 one or both are methyl. In the compounds of formula (IA) the groups R1 and R4 are suitably selected from the above list, and R22, R23 and R24 are selected as appropriate values from the above listing for R2. A preferred group of compounds of formula (I) has R1 as hydrogen, methyl, ethyl, R2 as hydrogen one or more of methyl, ethyl, / -propyl, f-butyl, methoxy, ethoxy, / -propoxy, bromine, chlorine, cyano, trifluoromethyl, R3 one or both are methyl, R4 one or both are methyl. Examples of compounds of the formula (I) are: (+) N- (1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxy-benzamide (+) N- (1, 2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-bromo-2,4-dimethoxy-benzamide (+) N- (1, 2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxy-benzamide (+) N- (1, 2-d-methyl-1, 2, 3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4- / so-propoxy-2-methoxybenzamide (+) N- (1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline-5-) il) -4-fe / f-butyl-2-methoxybenzamide (+) N- (1,2-d-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-trifluoromethyl-2-methoxy - 4-methyI-benzamide N- (2,4,4-trimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide N- (2,4,4-trimethyl-4H-isoquinoline-7) -yl) -3-cyano-4- / so-propylbenzamide N- (2,4,4-trimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide N- (2, 4, 4- trimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide N- (2, 4, 4-trimethyl-4H-isoquinolin-7-yl) -3-chloro-4- / so-propoxybenzamide ( +) N- ( 1,2-dimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide (+) N- (1, 2-dimethyl-4H-isoquinolin-7-yl) -3-bromo- 4-ethoxybenzamide N- (1,1,1-dimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide When synthesized, these compounds are frequently found in salt form, such as the hydrochloride or tifluoroacetate, and said salts also form part of this invention. Said salts can be used to prepare pharmaceutically acceptable salts. The compounds and their salts can be obtained as solvates, such as hydrates, and these also form part of the invention.

The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, constitute a preferred aspect of the present invention. The administration of said compounds to a mammal can be by oral, parenteral, sublingual, nasal, rectal, topical or transdermal administration. An amount effective to treat the disorders described above depends on normal factors such as the nature and severity of the disorders treated and the weight of the mammal. However, a unit dose will usually contain from 1 to 1000 mg, preferably from 1 to 500 mg, for example an amount on the scale 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 times a day, for example 1, 2, 3, 4, 5 or 6 times a day, very frequently 1 to 4 times a day, so that the total daily dose is normally in the scale, for an adult of 70 kg from 1 to 1000 mg, for example 1 to 500 mg, ie on the scale of approximately 0.01 to 15 mg / kg / day, normally 0.1 to 6 mg / kg / day, for example 1 to 6 mg / kg / day. It is highly preferred that the compound of formula (I) be administered in the form of a unit dose composition, such as an oral unit dose, including sublingual, rectal, topical or parenteral (especially intravenous) composition.

Said compositions are prepared by mixing and 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 infusible solutions or suspensions or suppositories. . Orally administered compositions, in particular orally configured compositions, are preferred as 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, tablet-forming agents, lubricants, disintegrants, colorants, flavors, and wetting agents. The tablets can be coated according to methods well known 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 glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate. These oral solid compositions can be prepared by conventional methods of mixing, filling, tableting or the like. The repeated mixing operations can be used to distribute the active agent in those compositions using large amounts of fillers. Said 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. Said liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum 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, fatty esters such as glycerin esters, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if so desired conventional flavoring or coloring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating. For parenteral administration, unit dose forms of fluids are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and concentration, can be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle and sterilizing with a filter before filling in a suitable vial or vial and sealing. Advantageously, auxiliaries such as a local anesthetic, preservatives and pH regulating agents also dissolve in the vehicle. To increase the stability, the composition can be frozen after filling it in the way and the water removed in vacuum. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in a vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending them 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 in practice, the compositions will normally be accompanied by written or printed instructions for use in the medical treatment in question. Also, the present invention provides a pharmaceutical composition for use in the treatment and / or prophylaxis of anxiety, mania, depression, panic disorders and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, the effects associated with abstinence. of substances of excessive use 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 ischemia, Alzheimer's and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythm repetition disorders, insomnia &; narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, pain from cancer, inappropriate neuronal activity resulting in neurodysesthesia in such diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS), which comprises a compound of formula (I), or a salt pharmaceutically acceptable 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 subarachnoid hemorrhage or neural shock, the effects associated with abstinence from substances of excessive use such as 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 ischemia, Alzheimer's disease and other degenerative diseases such as such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythm repetition disorders, insomnia &narcolepsy), tics (eg, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, Tooth pain, pain from cancer, inappropriate neuronal activity resulting in neurodysesthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and sclerosis Amyotrophic lateral (ALS), which comprises administering to the patient a prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In another aspect the invention provides the use of a compound of formula (I), 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 subarachnoid hemorrhage or neural shock, effects associated with abstinence from overuse substances such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and / or preventable with anti-seizure agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythm repetition disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, cancer pain, inappropriate neuronal activity resulting in neurodysesthesia in diseases such as diabetes, multiple sclerosis (MS) and diseases of motor neurons, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). In another 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, disorders of panic and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, effects associated with abstinence from overuse substances such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and / or preventable with anti-seizure agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as chorea of Huntington, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythm repetition disorders, insomnia &; narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, pain from cancer, inappropriate neuronal activity resulting in neurodysesthesia in such diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle stiffness (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) as described above which consists in reacting a compound of formula (II) Where R1A, R3A, R4A, are R1, R3, R4 as defined for formula (I) or a group or groups convertible to R1, R3, R4. With a compound of formula (III) (III) wherein Y is Cl or OH, and groups R, 2A are independently R as defined for formula (I) or a group or groups convertible to R2, and when it is required to convert a group R1A, R2A, R3A, R4A to a group R1, R2, R3, R4, converting one group R1, R2, R3, R to another group R1, R2, R3, R4, or converting a salt product to the free base or another pharmaceutically acceptable salt, or separating any enantiomer , or converting a free base product to a pharmaceutically acceptable salt. The reaction of a compound of formula (III) which is a benzoyl chloride derivative (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 the formula (III) is a benzoic acid derivative (Y = OH), conventional conditions for the condensation of aromatic acids with amines can be used, for example by reacting the components in a mixture of ethyl- (dimethylaminopropyl) -carbodiimide / hydroxybenzotriazole in a suitable inert solvent such as dimethylformamide. Conversions of a group R1A R2A, R3A, R4A to a group R1, R2, R3, R4 normally arise when a protecting group is needed during the above coupling reaction or during the preparation of the reagents by the methods described above. The interconversion of one group R1, R2, R3, R4 to another normally arises when a compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence. Compounds of formula (II) when R4 = H or alkyl can be prepared from isoquinoline corresponding to formula (IV) (iv) by reaction with a compound R1AZ wherein Z is a residual group such as a halogen especially iodo, or tosylate to obtain a formula intermediate (V) (V) which is reacted with an R4A containing a Grignard reagent under conventional conditions to obtain a dihydroisoquinoline of formula (VI) which can be hydrogenated, for example using hydrogen and a palladium / activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II) which is a precursor for the compounds of formula (IA).

Alternatively the compound of formula (IV) can be a nitro-isoquinoline, and the nitrogen group is converted to an amino group in the hydrogenation step. When said R1 is hydrogen, the N of the isoquinoline is preferably protected in a conventional manner, for example by making R1Abenzyl, or 4-methoxybenzyl during the introduction of the R4 group through the Grignard reagent. Again preferably the protection is provided before the formation of the benzamide, for example by fe / t-butoxycarbonyl and the deprotection under standard conditions, for example using trifluoroacetic acid / methylene chloride. Amino / nitro-isoquinolines of formula (IV) and the reagents used are commercially available, or they can be prepared from commercially available materials using conventional procedures described in the literature (eg, IW Matheson et al., J. Med. Chem. 1973 , 16, 332). The compounds of formula (II) which are precursors for compounds of formula (IB) can be prepared from the corresponding nitro-isoquinolinodione of formula (VII) with di-R3 substitution, converting the nitrogen group to amino by catalytic hydrogenation and subsequently removing the Dione groups by reduction with diborane. Nitro-dione can be obtained by treatment of an isoquinolinodione di-R3 [prepared using the procedure of H. Takechi et al., Synthesis. 1992,778] with fuming nitric acid. The R1A groups can be introduced as described above.

(VII) The compounds of formula (11) which are precursors for compounds of formula (IC) can be prepared from the corresponding nitro-3,4-dihydroisoquinoline by reduction with tin (II) chloride to the amino compound followed by quatemization with a R1A-X halide and subsequent treatment with a Grignard R4 reagent. The compounds of formula (II) wherein both R 4 are alkyl can be prepared from corresponding 1-alkyl-3,4-dihydroisoquinoline by nitration [using the procedures by R.D. Larsen et al., J.Org. Chem., 1991 56 6034 and A.P. Venkov and S.S.Abeghe, Syn. Commun., 1996 26 127] followed by quatemization and treatment with a Grignard R4 reagent as described above. The compounds of formula (III) can be prepared by further substitution of commercially available benzoic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzylic alcohols. Alternatively, benzoic acids can be prepared from correspondingly substituted phenols, for example by forming the acetate, converting to an acetophenone and then to the desired acid. Wherein the intermediates described above are novel compounds, and also form part of this invention. The preparation of compounds of this invention is further shown by the following preparations, descriptions and examples. The utility of the compounds of this invention is shown in the pharmacological data that follow from the examples.

DESCRIPTION 1 (+) 5-Amino-2-benzyl-1-methyl-1,2-dihydroisoquinoline To the solution of 5-aminoisoquinoline (15 g, 104 mmol) in acetone (400 ml) was added benzyl bromide (18.6 ml, 156 mmol). The mixture was stirred at room temperature for 2 hours before the precipitate was filtered giving an orange solid (8.64 g). A second precipitate (4.02 g) was filtered after another 2 hours. To a solution of this 5-amino-2-benzyl-isoquinolinium bromide (8.46 g, 26.8 mmol) in THF (75 mL) at 0 ° C under argon was added methylmagnesium chloride (17.89 mL, 56.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 2 hours. The mixture was then poured into ammonium chloride solution and extracted with ether. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as a light brown solid (5.0 g).

DESCRIPTION 2 (±) 5-Amino-1-methi 1-1, 2,3,4-tetrahydroisoquinoline -Amino-2-benzyl-1-methyl-1,2-dihydroisoquinoline (4.5 g, 17.9 mmol) was dissolved in ethanol (250 mL); 10% Palladium catalyst on activated carbon (1 g) was added and the mixture was hydrogenated at atmospheric pressure for 24 hours. The catalyst was then removed by filtration through Kieselguhr and the solvent was removed in vacuo to form a brown solid. This residue was then subjected to column chromatography eluting with 5 to 10% methanol-dichloromethane. The remaining fractions were combined and concentrated in vacuo to give a brown solid (1.26 g).

DESCRIPTION 3 (+) 5-Amino-2- (butoxycarbonyl) -1-methyl-1, 2,3,4-tetrahydroisoquinoline -amino-1-methyl-1, 2,3,4-tetrahydroisoquinoline (0.39 g, 2. 4 mmole) in 1,4-dioxane (25 ml) and sodium hydroxide solution (3M, 0.8 ml) and cooled in an ice bath. Di-f-butyldicarbonate (0.53 g, 2.4 mmol) was added and the mixture was stirred at room temperature for 2 hours.

Then the mixture was poured into water and extracted with ether. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a white solid (0.251 g).

DESCRIPTION 4 (±) 5-Amino-1,2-dihydro-1,2-dimethyl isoquinoline -aminoisoquinoline (25 g, 173 mmol) was dissolved in acetone (500 ml) and methyl iodide (25 ml, 410 mmol) was added. After stirring at room temperature for 1 hour the orange precipitate was filtered, washed with acetone and dried under vacuum, giving an orange solid (40.3 g). A second precipitate was filtered after 2 hours to give an orange solid (0.84 g). To a solution of this 5-amino-2-methylisoquinolinium iodide (21.013 g, 73.19 mmol) in THF (150 mL) at 0 ° C under argon was added methylmagnesium chloride (36.6 mL, 109.8 mmol) by dropwise. The mixture was allowed to stir at room temperature for 2 hours before being poured into the ammonium chloride and extracted with ether. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a dark brown oil (8.52 g).

DESCRIPTION 5 (±) 5-Amino-1,2-dimethyl-1, 2,3,4-tetrahydroisoquinoline To an ice-cooled solution of 5-amino-1,2-dihydro-1,2-dimethylisoquinoline (4 g, 23.2 mmol) in methanol (80 ml) was added sodium borohydride by portions (3.51 g, 92.8 mmol). The mixture was stirred at room temperature overnight before concentration in vacuo; the residue was separated between water and dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a light brown oil (4.023 g).

DESCRIPTION 6 7-nitro-2,4,4-trimethyl-4 H -soquinolin-1,3-dione 2,4,4-Trimethyl-4H-1,3-isoquinoline-1,3-dione (5 g, 24.6 mmol) [prepared according to H. Takechi et al., Synthesis. 1992, 778] in concentrated sulfuric acid (50 ml) at 0 ° C. Fuming nitric acid (2.5 ml) was added by dripping for 5 minutes and the reaction was heated to 25 ° C. After mixing for 30 minutes at 25 ° C the reaction mixture was poured into ice water (100 ml) and the organics were extracted into dichloromethane (3x50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (5.31 g, 86%). 1 H NMR (250 MHz, CDCl 3) d: 1.70 (6 H, s), 3.42 (3 H, s), 7.69 (1 H, d, J = 9 Hz), 8.46 (1 H, dd, J = 9.2 Hz ), 9.07 (1 H, d, J = 2 Hz); ml_ (API +): 249 (M + H) + DESCRIPTION 7 7-Amino-2,4,4-trimethyl-4H-isoquinoline-1,3-dione 7-Nitro-2,4,4-trimethyl-4H-isoquinolino-1,3-dione (45 g, 20 mmol) was dissolved in a mixture of methanol (500 ml) / dichloromethane (100 ml) and treated with 10 ml of methanol. % Pd / C (0.5 g). The reaction mixture was hydrogenated for 2 hours before removal of the palladium catalyst by filtration through celite. The filtrate was evaporated to dryness in vacuo to give the title compound (4.4 g, quant). 1 H NMR (250 MHz, CDCl 3) d: 1.58 (6 H, s), 3.36 (3 H, s), 3.83 (2 H, brs), 6.95 (1 H, dd, J = 6.3 Hz), 7.24 (1 H, d, J = 6 Hz), 7.48 (1 H, d, J = 3 Hz); m / Z (API +): 219 (M + H) + DESCRIPTION 8 7-Amino-2,4,4-trimetyl-4H-isoquinoline hydrochloride 7-Amino-2,4,4-trimethyl-4H-isoquinoline-1,3-dione (4 g, 18.3 mmol) was dissolved in tetrahydrofuran (400 mL) and heated to reflux (-61 ° C). Boron-tetrahydrofuran complex (88 ml, 1M solution in THF) was added by dripping into the mixture and heating continued for another 3 hours. The cooled reaction (0 ° C) was treated with methanol (400 ml) by dropping to destroy residual borane, followed by evaporation in vacuo. The resulting residue was heated to reflux in 3N HCl (400 ml) for 30 minutes. The mixture was cooled to 0 ° C and treated with NaOH pellets until basic (pH 9). The free amine was extracted into dichloromethane (4x100 ml) before drying over magnesium sulfate and evaporating in vacuo. The resulting light brown oil was dissolved in dichloromethane (50 ml) and treated with hydrogen chloride (1M solution in ether) until acidified (pH 2). The solvent was removed in vacuo followed by trituration with ether yielding the title compound as an off-white powder (3.3 g, 79%). 1 H NMR (250 MHz free base, CDCl 3) d: 1.25 (6 H, s), 2.37 (2 H, s), 2.39 (3 H, s), 3.43 (2 H, s), 3.51 (2 H, brs ), 6.32 (1 H, d, J = 2 Hz), 6.54 (1 H, dd, J = 8.2 Hz), 7.09 (1 H, d, J = 8 Hz); ml_ (API +): 191 (M + H) + DESCRIPTION 9 7-Amino-3,4-dihydroisoquinoline 7-Nitro-3,4-dihydroisoquinoline (0.60 g, 3.4 mmol) [prepared according to the procedure of A. P. Venkov et al., Syn. Commun., 1996 26 127] was dissolved in ethanol (100 ml) and heated to 60 ° C. This hot solution was treated with a tin (II) chloride solution dihydrate (3.08 g, 13. 7 mmol) in concentrated HCl (10 ml). The resulting mixture was heated at 60 ° C for 1 hour. After cooling, the reaction mixture was poured into water (100 ml) and basified (pH 9) with KOH pellets, releasing an oily residue. This residue was extracted into dichloromethane and dried over magnesium sulfate. Purification by chromatography through silica gel, eluting with (0.5% concentrated ammonia: 4.5% methanol: 95% dichloromethane) afforded the title compound as a dark yellow oil (0.44 g, 88%). 1 H NMR (250 MHz, CDCl 3) d: 2.63 (2 H, t, J = 7 Hz), 3.67 (2 H, brs), 3.73 (2 H, dt, J = 7.2 Hz), 6.62 (1 H, d , J = 2 Hz), 6.70 (1 H, dd, J = 8.2 Hz), 6.95 (1 H, d, J = 8 Hz), 8.24 (1 H, s); ml_ (API): 147 (M + H) +, 148 (M + 2H) 2+ DESCRIPTION 10 7-Amino-2-methyl-3,4-dihydroxyquinolinium iodide 7-Amino-3,4-dihydroisoquinoline (0.40g, 2.74 mmoles) in acetone (125 ml) was treated with iodomethane (0.50 ml, 8.03 mmol) and allowed to stir at room temperature for 18 hours. The resulting yellow precipitate was pooled by filtration and dried under vacuum at room temperature (0.73 g, 92%). m / z (API) = 161 (M) + DESCRIPTION 11 (±) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline Iodide of (±) 7-Amino-2-methyl-dichloroisoquinolinium (0.50 g, 1.7 mmol) in anhydrous tetrahydrofuran (50 ml) was suspended and cooled to -78 ° C. The cooled solution was treated with methylmagnesium chloride (2.14 ml of a 3M solution in THF, 6.96 mmol), added as an individual portion. The reaction was allowed to reach room temperature for 18 hours before being poured into water (50 ml). The organic solvent was removed in vacuo and the organic product was extracted into dichloromethane. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as a pale yellow oil (0.3 g, 98%). To facilitate the handling of the product, it became a monohydrochloride. 1 H NMR (250 MHz, CDCl 3) d: 1.37 (3 H, d, J = 7 Hz), 2.46 (3 H, s), 2.54-2.83 (3 H, m), 3.00 (1 H, m), 3.50 (3 H, m ), 6.45 (1 H, d, J = 2 Hz), 6.51 (1 H, dd, J = 8.2 Hz), 6.88 (1 H, d, J = 8 Hz); ml_ (API): 177 (M + H) + DESCRIPTION 12 (+) 1-Methyl-7-nitre-3,4-dihydroisoquinoline A solution of (±) 1-methyl-3,4-dihydroisoquinoline (2.57 g, 17.7 mmol) in concentrated sulfuric acid (10 mL) was added dropwise to a stirred mixture of potassium nitrate (1.93 g, 19.1 mmol) in concentrated sulfuric acid (10 ml) at -5 ° C. The mixture was allowed to reach room temperature for 2 hours and then heated at 60 ° C for 4 hours. The reaction mixture was poured into ice water (100 ml) and basified (pH 9) with KOH pellets. Extraction in dichloromethane (3 x 50 ml), drying over anhydrous sodium sulfate and evaporation in vacuo gave the crude product. Purification by chromatography through silica gel, eluting with (0.5% 0.88 NH 3: 4.5% CH 3 OH: 95% CH 2 Cl 2), gave the title compound as a dark brown oil (1.92 g, 57%). 1 H NMR (250MHz, CDCl 3) d: 2.48 (3H, s), 2.82 (2H, t, J = 8 Hz), 3.75 (2H, dt, J = 8.1 Hz), 7.38 (1 H, d, J = 8 Hz), 8.24 (1 H, dd, J = 8.2 Hz), 8.33 (1 H, d, J = 2 Hz); m / z (API): 191 (M + H) + DESCRIPTION 13 (+) 7-Amino-1-methyl-3,4-dihydroisoquinoline (±) 1-Methyl-7-nitro-3,4-dihydroisoquinoline (2.0 g, 10.5 mmol) was dissolved in ethanol (150 ml) and heated to 60 ° C, before treatment with a tin chloride solution ( II) Dihydrate (9.5 g, 42.1 mmol) in concentrated HCl (30 mL). The resulting mixture was heated at 60 ° C for 1 hour. After cooling, the reaction mixture was poured into water (200 ml) and basified (pH 9) with KOH pellets, releasing an oily residue. This residue was extracted into dichloromethane and dried over magnesium sulfate. Purification by chromatography through silica gel, eluting with (0.5% 0.88 NH 3: 4.5% CH 3 OH: 95% CH 2 Cl 2), afforded the title compound as a dark brown oil (0.93 g, 55%). 1 H NMR (250MHz, CDCl 3) d: 2.35 (3H, s), 2.59 (2H, t, J = 7 Hz), 3.62 (2H, t, J = 7 Hz), 3.60 (2H, brs), 6.71 (1 H, dd, J = 8.2 Hz), 6.83 (1 H, d, J = 2 Hz), 6.98 (1 H, d, J = 8 Hz).

DESCRIPTION 14 (+) 7-Amino-1,2-dimethyl-3,4-dihydroisoquinoline 8oodide (±) 7-Amino-1-methyl-3,4-dihydroisoquinoline (0.90 g, 5.6 mmol) in acetone (125 ml) and iodomethane (1.0 ml, 16 mmol) was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration and dried under vacuum at room temperature. The title compound was isolated as an orange powder (1.44 g, 85%). m / z (API): 175 (M) + DESCRIPTION 15 7-Amino-1, 1 -2-trimethyl-1, 2,3,4-tetrahydroisoquinoline 7-amino-1,2-dimethyl-3,4-dihydroisoquinolinio iodide (1.44 g) was suspended, 4.8 mmol) in THF (200 ml), cooled to -78 ° C and treated with methyl magnesium chloride (10 ml of a 3M solution in THF) added as an individual portion. The reaction was allowed to reach room temperature for 18 hours and poured into water (200 ml). The organic solvent was removed in vacuo and the resulting oily residue was extracted into dichloromethane (3x50 ml). Evaporation under vacuum and chromatography through silica gel eluting with (0.5% 0.88 NH 3: 4.5% CH 3 OH: 95% CH 2 Cl 2) afforded the title compound as a yellow oil (0.07 g, 8%). To facilitate the use the product became a monohydrochloride. 1 H NMR (250MHz, CDCl 3) d: 1.45 (6H, s), 2.48 (3H, s), 2.80 (2H, t, J = 6 Hz), 2.96 (2H, t, J = 6Hz), 6.51 (1H , dd, J = 8.2 Hz), 6.57 (1 H, d, J = 2 Hz), 6.86 (1 H, d, J = 8 Hz).

PREPARATION 1 Methyl 3-chloro-4- / so-propoxybenzoate Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) was treated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane (3.85 ml, 40.2 mmol) and then stirred at 25 ° C for 18 hours. Treatment with ethyl acetate gave the title compound (6.1 g).

PREPARATION 2 3-chloro-4- / so-propoxy benzoic acid Methyl 3-chloro-4- / so-propoxybenzoate (5.5 g, 24.1 mmol) was hydrolyzed using 1 M NaOH (36 mL) in methanol (80 mL). Extraction and treatment with ethyl acetate gave the title compound (4.3 g). 1 H-NMR (DMSO) d: 1.33 (6H, d), 4.79 (1 H, m), 7.24 (1 H, d), 7.87 (2H, m).

PREPARATION 3 3-Bromo-4-ethoxybenzoic acid The title compound was prepared with 4-ethylbenzoic acid in a manner similar to procedure 1. 1 H NMR (DMSO) d: 1.45 (3H, t, J = 7Hz), 4.26 (2H, q, J = 7 Hz), 7.26 ( 1 H, d, J = 9 Hz), 7.98 (1 H, dd, J = 2.9 Hz), 8.12 (1 H, d, J = 2 Hz) PREPARATION 4 3-Bromo-4-ethylbenzoic acid The title compound was prepared with 4-ethylbenzoic acid in a similar manner to procedure 1. 1 H NMR (DMSO) d: 1.20 (3H, t, J = 7 Hz), 2.78 (2H, q, J = 7Hz), 7.50 (1 H, d, J = 8 Hz), 7.90 (1 H, dd, J = 2.8 Hz), 8.07 (1 H, d, J = 8 Hz).

PREPARATION 5 3-Cyano-4- / so-propylbenzoic acid The title compound was prepared with 4- / so-propylbenzoic acid in a manner similar to that described in procedures 1 and 5. 1 H-NMR (DMSO) d: 1.07 (6H, d, J = 7 Hz), 3.13 (1 H, m, overlapped), 7.48 (1 H, d, J = 7 Hz), 7.96 (1 H, dd, J = 2.8 Hz), 8.00 (1 H, d, J = 2 Hz).

PREPARATION 6 4-Methoxy-3-trifluoromethylbenzoic acid The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similar to that of procedures 3 and 4. 1 H-NMR (DMSO) d: 3.78 (3H, s), 7.18 (1H, d, J = 9 Hz), 7.90 (1 H, d, J = 2 Hz), 8.00 (1 H, dd, J = 2.9 Hz), 12.70-13.10 (1 H, br, interchangeable) PREPARATION 7 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 followed by evaporation in vacuo.

PROCEDURE 1 5-bromo-2,4-dimethoxybenzoic acid To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) in chloroform (60 ml) was added dropwise bromine (1.13 ml, 0.022 mol) in chloroform (20 ml). After stirring overnight at room temperature the precipitate was filtered and dried to give the title compound as a white solid (2.87 g).

PROCEDURE 2 5-Bromo-4- / so-propyl-2-methoxybenzoic acid To a solution of 2-methoxy-4- / so-propylbenzoic acid (7.0 g, 36. 0 mmol) in chloroform (100 ml) was added dropwise to bromine (1.86 ml) in chloroform (20 ml). The reaction was stirred at room temperature overnight. Evaporation under vacuum gave an oil (9.27 g).

% (Cl): 275, 273 (MH +, 70%).

PROCEDURE 3 Methyl-5-bromo-4- / so-propyl-2-methoxybenzoate -Bromo-4- / so-propyl-2-methoxybenzoic acid (9.268 g 34.0 mmoles) was dissolved in ethanol (250 ml) and concentrated H2S? 4 (2 ml) was added. The mixture was refluxed for 5 hours and concentrated in vacuo. The residual material was taken up in ethyl acetate and water, and the organic layer was dried (MgSO4). Concentration in vacuo gave an oil, which was purified by Biotage column chromatography on silica gel using 10% ether in hexane to give an oil (5.5 g).

PROCEDURE 4 2,4-Dimethoxy-5-trifluoromethylbenzoic acid Methyl ester of 2,4-dimethoxy-5-bromobenzoic acid (1.5 g, 5.4 mmol) in DMF (25 ml) and toluene (8 ml) under argon was treated with potassium trifluoroacetate (1.53 g, 10.1 mmol) and sodium iodide. copper (I) (2.1 g, 10.9 mmol). The mixture was heated to 170 ° C with water removal (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 (Na2SO) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with 1: 1 ether / petrol gave a white solid (1.03 g) which was hydrolyzed in 1: 1 methanolic NaOH: aqueous NaOH (50 ml) at 50 ° C. The treatment gave the title compound as a white solid (1 g).

PROCEDURE 5a methyl 2-methoxy-5-cyano-4- / so-propylbenzoate Copper cyanide (1) (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4- / so-propy-benzoate (861 mg) in N-methyl-2-pyrrolidinone (30 ml ). The mixture was stirred under argon and boiled under reflux for 4 hours. The mixture was cooled, poured into the excess ice / water and ethyl acetate and filtered. The organic phase was separated, washed with water and brine and dried (MgSO). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate / n-hexane (1: 4). The product was obtained as a white solid (523 mg). 1 H NMR (250 MHz, CDCl 3) d: 1.33 (6H, d, J = 7Hz), 3.38 (1 H, Sep, J = 7Hz), 3.89 (3H, s), 3.98 (3H, s), 6.91 (1 H, s), 8.08 (1 H, s); m / z (API +): 234 (MH +, 30%) PROCEDURE 5b 2-Methoxy-5-cyano-4- / so-propylbenzoic acid 2N NaOH (1.25 ml) was added to a solution of methyl ester P5a (490 mg) in methanol (10 ml). 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 acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to dry giving the product as a white solid (418 mg). 1 H NMR (250 MHz, CDCl 3) d: 1.35 (6H, d, J = 7Hz), 3.43 (1 H, sep, J = 7Hz), 7.00 (1 H, s), 8.41 (1 H, s); m / z (API +): 220 (MH +, 100%).

PROCEDURE 6a ethyl 2-ethoxy-4- / so-propyl-5-cyanobenzoate Ethyl 2-ethoxy-4- / so-propyl-5-bromobenzoate (1.2 g, 3.8 mmol) was treated with copper (I) cyanide (682 mg, 7.6 mmol) in N-methyl-2-pyrrolidinone (40 ml). ) as described in procedure 5 to give the title compound as an oil (400 mg). 1 H NMR (250 MHz, CDCl 3) d: 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- / so-propyl-5-cyanobenzoic acid The P6a ester (370 mg, 1.41 mmol) was dissolved in methanol (5 ml) and for a period of 24 hours 1 N NaOH (2.1 ml, 2.1 mmol) was added. The solution was concentrated in vacuo, 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 (MgSO), evaporated to give the title acid (306 mg). 1 H NMR (250 MHz, CDCl 3) d: 1.39 (3 H, d, J = 7 Hz), 1.66 (3 H, t, J = 7 Hz), 3.47 (1 H, Sep, J = 7 Hz), 4.46 (2 H, q, J = 7Hz), 7.03 (1 H, s), 8.47 (1 H, s); m / z (API +): 234 (MH +, 100%) PROCEDURE 7 4-Ethoxy-2-methoxy-5-methylsulfonylbenzoic acid 4-Ethoxy-2-methoxy-5-chlorosulfonylbenzoic acid was prepared in 49% yield using the method of M.W. Harrold et al., J.

Med. Chem., 1989, 32 874. This was used according to the method of R.W. Rown, J. Org. Chem., 1991, 56, 4974, to the title compound in a yield of 19%. 1 H NMR (DMSO) d: 1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24 (2H, q), 6.73 (1 H, s), 8.07 (1 H, s) PROCEDURE 8 4- / So-propyl-2-methoxy-5-methylsulfonylbenzoic acid This was prepared in a manner similar to the procedure of C. Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall. J. Org. Chem., 1956, 21, 265 to reach the intermediate 5-chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid which was converted to the title compound using the method of procedure 7. 1H-NMR (DMSO) d: 1.30 (6H, d), 3.21 (3H, s), 3.80 (1 H, M), 3.94 (3H, s), 7.26 (1 H, s), 8.19 (1 H, s) EXAMPLE 1 (a) (+) 2-f f-ButoxycarboniO-N-d -methyl-1,2,3,4-tetrahydroisoquinolin-5-iD-5-chloro-4-ethoxy-2-methoxybenzamide To a solution of 5-amino2- (t-butoxycarbonyl) -1-methyl-1, 2,3,4-tetrahydro-isoquinoline (0.251 g, 0.9 mmol) in dichloromethane (8 ml) and triethylamine (0.75 ml) was added 5-chloro-4-ethoxy-2-methoxybenzoyl chloride (0.262 g, 1.05 ml) and the mixture was stirred at room temperature overnight. After diluting with more dichloromethane, the mixture was washed with sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to give a beige solid. This was then recrystallized from ethyl acetate and gasoline to give a white solid (0.124 g). (b) Trifluoroacetate of (+) N-f 1 -methyl-1, 2,3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxybenzamide Trifluoroacetic acid (0.37 ml) was added dropwise to a solution of the above-protected boc compound (0.124 g, 0.47 mmol) in dichloromethane (5 ml) at 0 ° C. The solution was stirred at room temperature for 3 hours and the solvent was removed in vacuo to present a beige solid (0.192 g). 1H-NMR (DMSO-d6) d: 1.42 (3H, t, J = 6Hz), 1.60 (3H, d, J = 6Hz), 2.94 (2H, m), 3.48 (2H, m), 4.08 (3H, s) ), 4.28 (2H, m), 6.95 (1 H, s), 7.19 (1 H, d, J = 6Hz), 7.32 (1 H, t, J = 6Hz), 7.28 (1 H, d, J = 6Hz), 7.48 (1 H, s), 9.00 (1 H, m), 9.30 (1 H, m), 9.73 (1 H, s); m / z (Cl): 375 (MH +) EXAMPLE 2 (±) N-f1, 2-dimethyl-1, 2,3,4-tetrahydroisosquinolin-5-yl) -5-bromo-2,4-dimethoxy-benzamide hydrochloride The title compound was prepared in a similar manner to Example 1 from 5-amino-1,2-dimethyl-1, 2,3,4-tetrahydroxyquinoline and 2,4-dimethoxy-5-bromobenzoic acid. The crude product was recrystallized from methanol and ethyl acetate to give a white solid (101 mg). 1H-NMR (DMSO-d6) d: 1.62 (3H, m), 2.85 (3H, br.s), 3.00 (2H, m), 3.18 (2H, s), 4.02 (3H, s), 4.12 (3H, s), 4.63 (1 H, m), 6.93 (1 H, s), 7.15 (1 H, d, J = 6 Hz), 7.35 (1 H, t, J = 6 Hz), 7.88 (1 H, d, J = 6Hz), 8.09 (1 H, s), 9.75 (1 H, s), 10.91 (1 H, br.s); m / z (Cl): 419 (MH +).

EXAMPLE 3 (+) N-f1,2-Dimethyl-1, 2,3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxybenzamide hydrochloride The title compound was prepared in a manner similar to Example 1 of 5-amino-1,2-dimethyl-1, 2,3,4-tetrahydroxyquinoline and 5-chloro-4-ethoxy-2-methoxybenzoic acid. The crude product was recrystallized from methanol and ethyl acetate to give a pale brown solid (319 mg). 1H-NMR (DMSO-d6) d: 1.42 (3H, t, J = 6Hz), 1.56 (1H, d, J = 6Hz), 1.70 (2H, d, J = 6Hz), 2.80 (2H, m), 3.03 (2H, m), 3.32-3.62 (3H, m) 4.09 (3Hz, s), 4.29 (2H, m), 4.65 (1 H, m), 6.96 (1 H, s), 7.12 (1 H, m), 7.35 (1 H, t, J = 6 Hz), 7.90 (2 H, m), 9.25 (1 H, m), 1 1.42 (1 H, br.s); m / z (Cl): 389 (MH +) The following examples were prepared using similar methods those described above.

EXAMPLE 4 (+) N- (1,2-dimethyl-1, 2,3,4-tretrahydroisolquinolyl-5-in-5-chloro-4- / so-propoxy-2-methoxybenzamide hydrochloride 1H-NMR (DMSO-d6) d: 1.32 (6H, d), 1.6 (3H, m), 2.66 (3H, m), 3. 02 (2H, m), 3.58 (2H, m), 4.04 (3H, s), 4.60 (1 H, m), 4.97 (1 H, m) 7.17- 7.90 (5H, m), 9.75 (1 H, m), 11.30 (1 H, br s); m / z (Cl): 403 (MH +).

EXAMPLE 5 (±) N- (1, 2-dimethyl-1, 2,3,4-tretrahydroisolquinolin-5-in-4-fert-butyl-2-methoxybenzamide hydrochloride 1H-NMR (DMSO-d6) d: 1.32 (9H, s), 1.61 (3H, m), 2.82 (3H, m), 3.07 (2H, m), 3.50 (2H, m), 4.05 (3H, s) , 4.64 (1 H, m), 7.12 (3 H, m) 7.34 (1 H, m), 7.88 (2 H, m), 9.85 (1 H, br s) 1 1.08 (1 H, br s); m / z (Cl): 367 (MH +).

EXAMPLE 6 (+) N- (1, 2-Dimethyl-1, 2,3,4-tretrahydroisolquinolin-5-yl) -5- trifluromethyl-2-methoxy-4-methylbenzamide hydrochloride 1H-NMR (DMSO-d6) d: 1.60 (4H, m), 2.80 (4H, m), 3.00 (2H, m), 3.50 (3H, m), 4.06 (3H, s), 4.55 (1H, m ), 7.20 (3H, m), 7.73 (1 H, m) 8.08 (1 H, m), 9.81 (1 H, m), 1 1.27 (1 H, m); m / z (Cl): 393 (MH +) EXAMPLE 7 N- (2-A4-Trimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide hydrochloride D8 amine hydrochloride (226 mg, 1.0 mmol) in dichloromethane (10 ml) was treated sequentially with 4-methoxy-3-trifluoromethylbenzoyl chloride (283 mg, 1.0 mmol) and triethylamine (0.4 ml, 2.9 mmol). The mixture was stirred at 25 ° C for 18 hours and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel eluting with dichloromethane: ammonia: methanol (0.5% Concentrated ammonia: 4.5% methanol: 95% dichloromethane). The title compound was obtained as an off-white foam (337 mg, 86%) which was converted to the hydrochloride. 1 H NMR (250 MHz, d 6 DMSO) d: 1.26 (3H, s), 1.37 (3H, s), 2.43 (5H, overlapping DMSO), 3.91 (3H, s), 4.30 (2H, m), 7.36 ( 1 H, d, J = 9 Hz), 7.42 (1 H, d, J = 9 Hz), 7.58 (2 H, m) 8.18 (1 H, s), 8.23 (1 H, d, J = 9 Hz), 9.80 (1 H, brs); ml_ (API +): 393 (M + H) + EXAMPLE 8 N- (2,4,4-Trimethyl-4H-isoquinolin-7-yl) -3-cyano-4- / so-propylbenzamide It was prepared in a similar manner to Example 7, using 3-cyano-4- / so-propylbenzoyl chloride, and was isolated giving a yield of 70%. 1 H NMR (250 MHz, CDCl 3) d: 1.31 (6H, s), 1.35 (6H, d, J = 7Hz), 2.40 (2H, s), 2.42 (3H, s), 3.44 (1H, m), 3.55 (2H, s), 7.37 (3H, s), 7.53 (1 H, d, J = 8 Hz), 7.67 (1 H, brs), 8.02 (1 H, d, J = 2Hz), 8.09 (1 H, d, J = 2 Hz); m / z (API +): 362 (M + H) + EXAMPLE 9 N- (2A4-trimethyl-4 H -soquinolin-7-iQ-3-bromo-4-ethylbenzamide It was prepared in a similar manner to Example 7, using 3-bromo-4-ethyl benzoyl chloride, and was isolated giving a yield of 89%. 1H NMR (250MHz, CDCI3) d: 1.26 (3H, t, J = 8Hz), 1.30 (6H, s), 2.39 (2H, s), 2.42 (3H, s), 2.82 (2H, q, J = 8Hz ), 3.54 (2H, s), 7.37 (3H, m), 7.51 (1 H, d, J = 2 Hz), 7.80 (1 H, brs), 8.03 (1 H, br s); ml_ (API +): 402, 404 (M + H) +.

EXAMPLE 10 N- (2A4-Tr'methyl-4H-isoquinolin-7-yl) -3-bromo-4-ethoxybenzamide The amine hydrochloride D8 (226 mg, 1.0 mmol) in dichloromethane (10 ml) was treated sequentially with 3-bromo-4-ethoxybenzoyl chloride, (270 mg, 1.0 mmol) and triethylamine (0.4 ml, 2.9 mmol). The mixture was stirred at 25 ° C for 18 hours and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel eluting with ammonia: methanol: dichloromethane (0.5% 0.88 ammonia: 4.5% methanol: 95% dichloromethane). The title of the compound was obtained as a whitish foam (291 mg, 70%). 1 H NMR [free base] (250 MHz, CDCl 3) d: 1.30 (6H, s), 1.51 (3H, t, J = 7 Hz), 2.39 (2H, s), 2.41 (3H, s), 3.53 (2H) , s), 4.17 (2H, q, J = 7Hz), 6.93 (1 H, d, J = 9Hz), 7.34 (3H, m), 7.65 (1 H, brs), 7.80 (1 H, dd, J = 9.2 Hz) 8.04 (1 H, d, J = 2 Hz); ml_ (API +): 418, 420 (M + H) + A portion of the title compound was converted to the hydrochloride salt. 1 H NMR (250 MHz, d 6 DMSO) d: 1.21 (3H, s), 1.28 (3H, t, J = 7 Hz), 1.34 (3H, s), 2.34-2.44 (2H, brs), 2.83 (3H, d , J = 4 Hz), 4.10 (2H, q, J = 7 Hz), 4.15-4.37 (2H, m), 7.13 (1 H, d, J = 9 Hz), 7.37 (1 H, d, J = 8 Hz), 7.52 (1 H, brs), 7.54 (1 H, d, J = 9 Hz), 7.89 (1 H, dd, J = 9.2 Hz), 8.12 (1 H, d, J = 2 Hz), 10.18 (1 H, s), 10.35 (1 H, brs).

EXAMPLE 11 N-f2,4,4-Trimethyl-4H-isoquinolin-7-yl) -3-chloro-4-fso-propoxybenzamide It was prepared in a manner similar to Example 7, using 3-chloro-4- / so-propoxybenzoyl chloride, and isolated to give an 84% yield. H-NMR (250 MHz, CDCl 3) d: 1.30 (6H, s), 1.42 (6H, d, J = 6 Hz), 2.39 (2H, s), 2.41 (3H, s), 3.53 (2H, s), 4.66 (1 H, septet, J = 6 Hz), 6.98 (1 H, d, J = 9 Hz), 7.35 (3 H, m), 7.68 (1 H, brs), 7.74 (1 H, dd, J = 9.2 Hz), 7.87 (1 H, d, J = 2 Hz). m / z (API +): 387.389 (M + H) + EXAMPLE 12 (±) N- (1, 2-Dimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide (+) 7-Amino-1,2-dimethyl-tetrahydroisoquinoline monohydrochloride (0.106g, 0.50 mmol) in dichloromethane (10 ml) was treated sequentially with 3-bromo-4-ethylbenzoyl chloride (0.124 g, 0.50 mmol) and triethylamine (0.3 ml, 2.2 mmol). The mixture was stirred at room temperature for 18 hours. Evaporation under vacuum gave an oily residue which was purified by chromatography through silica gel eluting with (0.5% concentrated ammonia: 4.5% methanol: 95% dichloromethane). The title compound was obtained as a whitish foam (0.149 g, 77%). 1 H NMR (250 MHz, CDCl 3) d: 1.23 (3H, t, J = 8 Hz), 1.36 (3H, d, J = 7 Hz), 2.46 (3H, s), 2.60 (1 H, m), 2.80 (4H, m), 3.54 (1 H, q, J = 7 Hz), 7.02 (1 H, d, J = 8 Hz), 7.25 (1 H, d, J = 8 Hz), 7.32 (1 H, dd, J = 8.2 Hz), 8.00 (1 H, d, J = 2 Hz), 8.17 (1 H, s); ml_ (API): 387.389 (M + H) + EXAMPLE 13 (±) N- (1, 2-Dimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethoxybenzamide Prepare as described in Example 12 using 3-bromo-4-ethoxybenzoyl chloride and isolate to give a 90% yield. 1 H NMR (250 MHz, CDCl 3) d: 1.36 (3 H, d, J = 7 Hz), 1.49 (3 H, t, J = 7 Hz), 2.46 (3 H, s), 2.64 (1 H, m), 2.80 (2H, m), 3.00 (1 H, m), 3.55 (1 H, q, J = 7 Hz), 4.13 (2H, q, J = 7 Hz), 6.85 (1 H, d, J = 9 Hz ), 7.02 (1 H, d, J = 8 Hz), 7.32 (1 H, d, J = 8.2 Hz), 7.45 (1 H, s), 7.77 (1 H, dd, J = 9.2 Hz), 8.06 (1 H, s), 8.08 (1 H, d, J = 2 Hz); m / z (API): 403,405 (M + H) + EXAMPLE 14 N- (1,1,2-Trimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide The title compound was prepared from monohydrochloride of 7-amino-1,2,3-trimethyl-tetrahydroquinoline (0.077 g, 0.3 mmol) and 3-trifluoromethyl-4-methoxybenzoyl chloride (0.083 g, 0.3 mmol) in a manner similar to that of Example 12 as a whitish foam (0.132 g, 99%). 1 H NMR (250 MHz, CDCl 3) d: 1.40 (6H, s), 2.44 (3H, s), 2.78-2.93 (4H, m), 3.95 (3H, s), 7.00 (1 H, s), 7.03 ( 1 H, s), 7.33 (1 H, dd, J = 8.2 Hz), 7.59 (1 H, d, J = 2 Hz), 8.03-8.10 (3H, m); ml_ (API): 393 (M + H) + PHARMACOLOGICAL DATA 1.- Binding test method WO 92/22293 (SmithKIine Beecham) describes compounds having an anti-convulsive activity, including, among others, the compound IaraA7S - (+) - 6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol (hereinafter 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 (SmithKine Beecham). The affinity of the test compounds with the novel receptor site is established as indicated below.

Method Complete rat forebrain tissue is obtained. First the tissue is homogenized in a pH regulator (usually 50 mM Tris / HCl, pH 7.4). The homogenized tissue is washed by centrifugation and resuspension in the same pH regulator, then stored at -70 ° C until used. To carry out the radioligand binding test, aliquots of the tissue prepared as defined above (usually at a concentration of 1-2 mg protein / ml) are mixed with aliquots of [3 H] -compound A dissolved in pH regulator . The final concentration of [3 H] -compound A in the mixture is usually 20 nM. The mixture is incubated at room temperature for 1 hour. The [3 H] -compound A is bound to the tissue and then separated from the [3 H] -compound A not bound by filtration through Whatman GF / B glass fiber filters. The filters are washed quickly with an ice-cooled regulator. The amount of radioactivity bound to the tissue trapped in the filters is measured by the addition of liquid scintillation mixture to the filters followed by counting in a liquid scintillation counter. In order to determine the amount of "specific" binding of [3 H] -compound A, parallel tests are performed as above, wherein [3 H] -compound A and the tissue are incubated together in the presence of unlabeled compound A ( usually 3 μM). The amount of binding of [3H] -compound A remaining in the presence of this unlabeled compound is defined as the "non-specific" binding. This quantity is subtracted from the total binding amount of [3 H] -com put A (ie, that which is present in the absence of unlabeled compound) to obtain the "specific" binding amount of the [3 H] -compound To the novel site. The affinity of the binding of the test compounds to the novel site can be estimated by co-incubating the [3H] -Compound A with tissue in the presence of a variety of concentrations of the compound to be tested. The decrease in the level of specific binding of [3H] -compound A as a result of competition increasing concentrations of the compound under test is plotted, and non-linear regression analysis of the resulting curve is used to provide an estimate of the affinity of the compound in terms of the value of pKi.

Results The compounds of this invention were active in this test. For example, the compounds of Examples 1 to 14 gave pKi values greater than 7. 2. - MEST test The access threshold test with maximum electric shock (MEST) in rodents is particularly sensitive to detect potential anti-seizure properties1. In this model, anti-convulsive agents raise the threshold to create electrically induced accesses while proconvulsants lower this access threshold.

Method for mouse model Mice (unaffected males, Charles River, RU strain CD-1, 25-30 g) are designated randomly in groups of 10-20 and dosed orally or intraperitoneally at a dose volume of 10 ml / kg with several doses of the compound (0.3-300 mg / kg) or vehicle. After 30 to 60 minutes of the dose the mice undergo a single electro-shock (0.1 seconds, 50 Hz, sinusoidal waveform) administered by corneal electrodes. The mean of the current and the standard error required to induce a tonic measurement in 50% (CC50) of the mice in a particular treatment group are determined by the "top down" method of Dixon and Mood (1948) 2. Statistical comparisons are made between the groups treated with vehicle and with drugs using the method of Litchfield and Wilcoxon (1949) 3. In control animals the CC50 is normally 14-18 mA. Therefore, the first animal in the control group is subjected to a current of 16 mA. If a tonic access does not occur, the current is increased for a subsequent mouse. If a tonic seizure does not occur, then the current decreases, and so on until all the animals in the group have been tested. Studies are conducted using a Hugo Sachs Electronik constant current shock generator with fully variable shock level control from 0 to 300 mA and 2 mA steps are normally used.

Results The compounds of this invention made at doses of 10 mg / kg by oral route as a suspension in methylcellulose and tested one hour after dosing showed an increase in the access threshold. In a dose of 10 mg / kg / p.o. in 2 h, the compounds of examples 4, 5 and 6 showed percentage increases of 47, 46 and 36% respectively.

Method for rat model The threshold for access with maximum electric shock (extension of tonic hind limbs) in male rats (Sprague Dawley, 80-150 g, 6 weeks of age) was determined by a Hugo Sachs Electronik stimulator that produced a constant current ( 0.3 seconds in duration, 1-300 mA in steps of 5-20 mA). The procedure is similar to that previously used for mice and the full details are presented in Upton and another 4. The percentage increase or decrease in CC50 is calculated for each group compared to the control. The drugs were suspended in 1% methylcellulose.

Results With a dose of 2 mg / kg p.o. in 2 h, the compounds of Examples 7 to 11 showed the increments shown in the table.

PICTURE References 1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181 2. Dixon, W.J. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43, 109-126 3. Litchfield, J.T. and Wilcoxon, F. (1949). J. Pharmacol. exp. Ther., 96, 99-113 4. N. Upton, T.P. Blackburn, C.A. Campbell, D. Cooper, M.L. Evans, H.J. Herdon, P.D. King, A.M. Ray, T.O. Stean, W.N. Chan, J.M. Evans and M. Thompson. (1997). B.J. Pharmacol., 121, 1679-1686.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) or pharmaceutically acceptable salt thereof: (I) wherein R 1 is hydrogen, d-β alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), alkenyl of d-6, alkynyl of C 1-6, alkyl of d-6CO-, formyl, CF 3 CO- or alkyl of d-6SO 2 -, R 2 is hydrogen or up to three substituents selected from halogen, NO 2, CN, N 3, CF 3 O-, CF 3 S-, CF 3 CO-, trifluoromethyldiazirinyl, C 1-6 alkyl, C 1-6 alkenyl, alkynyl C1-6, C1-6 perfluoroalkyl, C3-6 cycloalkyl. C3-6cycloalkyl-C1-4alkyl, d-ioO- alkyl, C6-6CO- alkyl, C3-TO- cycloalkyl, C3-6 cycloalkyl CO-, C3-6 cycloalkyl- C1-4O-, C3-6 cycloalkyl-C1-4CO- alkyl, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl, d-6S- alkyl, C6-6SO2- alkyl, ( C? -4) 2 NSO2- alkyl, (d-4 alkyl) NHSO2-, (d-4 alkyl) 2NCO-, (d-4 alkyl) NHCO- or CONH2; or -NR5R6 wherein R5 is hydrogen or C1-4 alkyl, and R6 is hydrogen, C1-4 alkyl, formyl, -CO2 C1-4 alkyl or -CO alkyl of d-; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and the two R3 groups and the two R4 groups are each independently hydrogen or C1-6 alkyl or two R3 groups and / or the two R4 groups together form a spiroalkyl group of C3-6 with the proviso that at least one group R3 and R4 is not hydrogen.

2. A compound of formula (IA) (IA) wherein R 1 is hydrogen, C 1-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C 1-6 alkenyl, C? -6 alkynyl, formyl, C 1-6 alkyl, d-6 SO 2 alkyl , or CF3CO-; R22 is alkyl of d-βO-, cycloalkyl of C3-6O- or cycloalkyl of C3-6- alkyl of C1-4O-; R23 is hydrogen, halogen, CN, N3) trifluoromethyldiazirinyl, perfluoroalkyl Cr6, CF3O-, CF3S-, CF3CO-, alkyl of d-6, cycloalkyl of C3-6, cycloalkyl of C3-6- C1-4 alkyl, alkyl of d-6O-, C1-6CO- alkyl, cycloalkyl of QrSCO-, cycloalkyl of C3-6- alkyl of C1-4CO-, phenyl, phenoxy, benzyloxy, bezoyl, phenyl-C1-4alkyl, alkyl of Cr6S -, C 6 S0 2 alkyl, (C 4 -4 alkyl) 2NS 0, (d 4 alkyl) NHSO 2, (d 4 alkyl) 2 NCO-, (C 1-4 alkyl) NHCO- or CONH 2; R24 is hydrogen, halogen, NO2, CN, N3, trifluoromethyldiazirinyl, Ci-βO- alkyl, d-βS- alkyl, C?-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1 alkyl -4, alkenyl of d-6, alkynyl of d-6, CF3CO-, alkyl of d-6CO-, cycloalkyl of C3-6CO-, cycloalkyl of C3-6-alkyl of C1-4CO-, phenyl, phenoxy, benzyloxy , benzoyl, phenyl-C 1-4 alkyl; or -NR 5 R 6 wherein R 5 is hydrogen, or C 1-4 alkyl, and R 6 is hydrogen, C 1-4 alkyl, formyl, -CO 2 C 1-4 alkyl or -CO C 1-4 alkyl; or R23 and R24 together form a carbocyclic ring that is unsaturated or saturated and unsubstituted or substituted by carbonyl or hydroxyl; R4 is d-β- 3 alkyl- A compound of formula (IB) (IB) wherein R 1 is hydrogen, d-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C 1-6 alkenyl, C 1-6 alkynyl, d-6CO- alkyl, formyl, CF 3 CO- or C? -6S? 2-, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF30-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, alkynyl C? -6, C1-6 perfluoroalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- d- alkyl, d-6O- alkyl, d-6CO- alkyl, C3-6O- cycloalkyl, cycloalkyl of C3-dCO-, C3-6cycloalkyl- C1-4O- alkyl-, C3-6cycloalkyl- C1-4CO- alkyl-, phenyl-, phenoxy-, benzyloxy-, benzoyl-, phenyl- C1-4alkyl-, alkyl- d-6S-, C1-6SO2- alkyl, (d-4 alkyl) 2NS? 2-, (d-4 alkyl) NHSO2-, (d- ^ NCO- alkyl, (C4 alkyl) NHCO - or CONH2; or -NR5R6 wherein R5 is hydrogen or C1-4 alkyl, and R6 is hydrogen, C1-4 alkyl, formyl, CO2 C1-4 alkyl or -CO C1-4 alkyl, or two R2 groups together they form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and each R3 is d6 alkyl. 4. A compound of formula (IC) (IC) wherein R 1 is hydrogen C 1-6 alkyl (optionally substituted by hydroxy or C 1-4 alkoxy), C-? 6 alkenyl, C 1-6 alkyl-, formyl, CF 3 CO- or C? -6S02-, R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, d6 alkyl, d-6 alkenyl, C1- alkynyl 6, C-6 perfluoroalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, d-60- alkyl, C1-6CO- alkyl, C3-6O- cycloalkyl, C3 cycloalkyl -6CO-, C3-6 cycloalkyl-C1-4Oalkyl-, C3-6cycloalkyl- C1-4CO- alkyl-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl- C1-4alkyl, C- alkyl? -6S-, alkyl of d-6SO2-, (alkyl of d-4) 2NS? 2-, (alkyl of d-4) NHSO2-, (alkyl of d-4) 2NCO-, (alkyl of d-4) NHCO- or CONH2; or -NR 5 R 6 wherein R 5 is hydrogen or d-d alkyl, and R 6 is hydrogen, C 1-4 alkyl, formyl, -CO 2 C 1-4 alkyl or -CO C 1-4 alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated and substituted or unsubstituted by -OH or = O; and each R 4 is C 1-6 alkyl. 5. A compound selected from the group consisting of: (+) N- (1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxy-benzamide (+) N- (1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-bromo-2,4-dimethoxy-benzamide (+) N- (1, 2-dimethyl- 1, 2, 3, 4-tetrahydroisoquinolin-5-yl) -5-chloro-4-ethoxy-2-methoxy-benzamide (+) N- (1, 2-dimethyl-1,2,3,4-tetrahydroisoquinoline) 5-yl) -5-chloro-4- / so-propoxy-2-methoxybenzamide (+) N- (1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-ferf- butyl-2-methoxybenzamide (+) N- (1,2-dimethyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-trifluoromethyl-2-methoxy-4-methyl-benzamide N- ( 2,4-Trimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide N- (2, 4, 4-trimethyl-4H-isoquinolin-7-yl) -3-cyano-4- / so-propylbenzamide N- (2,4,4-trimethyl-4H-isoquinolin-7-yl) - 3-bromo-4-ethylbenzamide N- (2,4,4-trimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide N- (2, 4, 4-trimethyl-4H- isoquinolin-7-yl) -3-chloro-4- / so-propoxybenzamide (±) N- (1, 2-dimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethylbenzamide (+) N- (1,2-dimethyl-4H-isoquinolin-7-yl) -3-bromo-4-ethoxybenzamide N- (1,1,1-dimethyl-4H-isoquinolin-7-yl) -4-methoxy-3-trifluoromethylbenzamide 6. 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 hemorrhage or neural shock, the effects associated with the withdrawal of substances of use excessive amounts 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, mig raña, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythm repetition disorders, insomnia & narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, cancer pain, inappropriate neuronal activity resulting in neurodysesthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxias, muscle stiffness (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising a compound according to any of the preceding claims and a pharmaceutically acceptable vehicle. 7. The use of a compound according to any of claims 1 to 5, for the preparation of a medicament for the treatment and / or prophylaxis of anxiety, mania, depression, panic disorders and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, effects associated with abstinence from overuse substances such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and / or preventable with anti-seizure agents, such as epilepsy including epilepsy post-traumatic, Parkinson's disease, psychosis, migraine, cerebral ischemia, Alzheimer's disease and other degenerative diseases such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficiencies associated with AIDS, sleep disorders (including cardiac rhythmic repetition, insomnia &; narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, tooth pain, pain from cancer, inappropriate neuronal activity resulting in neurodysesthesia in such diseases such as diabetes, multiple sclerosis (MS) and motor neuron diseases, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). 8. A process for the preparation of compounds according to any of claims 1 to 5, further characterized in that it comprises the reaction of a compound of formula (II) wherein R1A, R3A, R4A, are R1, R3, R4 as defined for formula (I) or a group or groups convertible to R1, R3, R4. With a compound of formula (III) (III) wherein Y is Cl or OH, and groups R2A are independently R2 as defined for formula (I) or a group or groups convertible to R2, and when it is required to convert a group R1A, R2A, R3A, R4A to a group R1 , R2, R3, R4, converting one group R1, R2, R3, R to another group R1, R2, R3, R4, or converting a salt product to the free base or another pharmaceutically acceptable salt, or separating any enantiomer, or converting a free base product to a pharmaceutically acceptable salt.