MXPA00012322A - Tetrahydronaphthyridinyl-carboxamides having anti-convulsant activity - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts and solvates:where R1 is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), phenyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl;R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3SO2-, CF3CO-, 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-, 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, optionally interrupted by O or NH;R3 groups and R4 groups are each independently hydrogen or C1-6alkyl and/or the two R3 groups and/or the two R4 groups together form a C3-6spiroalkyl group, provided that at least one R3 or R4 group is not hydrogen;and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy, are useful in the treatment and prophylaxis of epilepsy, migraine, and other disorders.

Description

TETRAHIDRONAFTIRIDINIL-CARBOXAMIDAS THAT HAVE ANTICONVULSIVE ACTIVITY FIELD OF THE INVENTION The invention relates to novel compounds, to processes for preparing them and to their use as therapeutic agents.

BACKGROUND OF THE INVENTION WO 97/48683 (SmithKine Beecham) discloses that benzamide compounds of the formula (A) below possess anticonvulsant activity, and therefore are believed to be useful in the treatment and / or prevention of anxiety, mania and related depressive disorders. .

(A) where n and p are independently integers from 1 to 4 and (n + p) is from 2 to 5; R1 is (C1-6) alkyl-O-; R2 is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, CF3, CF3O-, CF3S-, CF3CO-, d-β alkyl, C3-6 cycloalkyl, (C3-6) cycloalkyl- alkyl (C? -4) -, alkyl (C? -6) -0-, alkyl (C? -6) -CO-, cycloalkyl (C3-6) -CO-, cycloalkyl Cs-eJ-alkyl C- jO -, phenyl, phenoxy, benzyloxy, benzoyl, phenyl (C 1-4 alkyl) -, (C 1-6 alkyl) -S-, (C 1-6 alkyl) -S02-, (C 1-4 alkyl) 2-NSO 2- , or alqui ^ d. 4) NHS02-; R3 is hydrogen, halogen, NO2, CN, N3, thifluoromethyldiazirinyl, alkyl (C? -6) -0-, alkyl (C? 6) -S-, C? -6 alkyl, C3-6 cycloalkyl, (C3.6) cycloalkyl- (C2-) alkyl-, C-? 6 alkenyl, C? -6 alkynyl, CF3CO-, (C? -6) alkyl- CO-, (C3-6) cycloalkyl -CO-, cycloalkyl (C3-6) -alkyl (C? -4) -CO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl (C-? 4 alkyl) -, or -NR5R6, wherein R5 is hydrogen or C1-4alkyl, and R6 is hydrogen, C4-4alkyl, -CHO, -C??-C1-4alkyl, or -CO-C1-4alkyl; R 4 is hydrogen, C 1-6 alkyl, C-? 6 alkenyl, or C 1-6 alkynyl. Now, it has surprisingly been found that tetrahydronaphyridinyl carboxamide compounds of the formula (I) below possess anticonvulsant activity, and therefore are believed to be useful in the treatment and / or prevention of anxiety, mania, depression, panic disorders and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, effects associated with abstinence from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant agents, such as epilepsy , including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, ischemia brain, Alzheimer's disease, and other degenerative disorders such as Huntington's chorea, schizophrenia, obsessive-compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including heart rhythm disorders, insomnia and / or narcolepsy), tics ( for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) ) and motor neuron disease, ataxia, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). Accordingly, the present invention provides a compound of formula (I): (I) wherein R1 is hydrogen, C1-6alkyl (optionally substituted with hydroxy or C1- alkoxy), phenyl (C1- alkyl) -, C1-6 alkenyl or Ci-β alkynyl; R2 is hydrogen or up to three substituents selected from halogen, NO2) CN, N3, CF3O-, CF3S-, CF3SO2-, CF3CO-, C6-6 alkyl, C? -6 alkenyl, C? -6 alkynyl, C? -6 perfluoroalkyl, C3-6 cycloalkyl, cycloalkyl Cs-eJ-alkylCi ^) -, alkyl (C? -6) -0-, alkyl ( C? -6) -CO-, (C3-6) cycloalkyl-O-, (C3.6) cycloalkyl-CO-, cycloalkyl (C3-6) -alkyl (C? -4) -0-, c Cloalkyl (C3-6) - phenyl, phenoxy, benzyloxy, benzoyl, phenyl (C 1-4 alkyl) -, alkyl (C? 6) -S-, alkyl (C? -6) -S02-, (C 1 -C-NSO alkyl, alkyl) (C1-4) NHS02-, (C1-4 alkyl) 2-NCO-, (C1-4) alkyl -NHCO- or CONH2; or -NR5R6, wherein R5 is hydrogen or C? -4 alkyl, and R6 is hydrogen, C? -4 alkyl, formyl, -CO2-C? -4 alkyl, or -CO-alkyl or two R2 groups together form a carbocyclic ring that is saturated or unsaturated, optionally interrupted by O or NH; the groups R3 and R4 are each independently hydrogen or C? -6 alkyl, and / or the two groups R3 and / or the two groups R4, together form a spiroalkyl ring of C3-6; with the proviso that at least one group R3 or R4 is not hydrogen; and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy. The compounds of this invention are tetrahydronaphyridinyl carboxamides, especially (tetrahydronaphthyridin-3-yl) carboxamides. The carboxamide moiety is typically a benzamide, but when two R 2 groups form a carbocyclic ring, it is typically a 5-7 membered ring, and the carboxamide moiety can be a naphthalenecarboxamide or an indanecarboxamide, or when interrupted by O or NH, it can be a benzofuranocarboxamide or an indolecarboxamide.

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. The phenyl groups in R2, including the phenyl groups which are part of other portions, may be optionally substituted with one or more independently selected halogens, or C1-6 alkyl, C1-6 alkoxy, or C6-6 alkylcarbonyl. Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Suitable substituents of halogen include fluorine, chlorine, bromine and iodine. It should be appreciated that the compounds of the present invention possess chiral centers and as such, may exist in different enantiomeric forms; the present invention extends to each enantiomeric form and mixtures thereof, including diastereoisomers and racemates. Preferably, the two R3 groups are the same, and the two R4 groups are the same; typically, the two R3 groups are gem-dialkyl or spiralalkyl, preferably gem-dialkyl, and the two R4 groups are hydrogen, or vice versa. Therefore, an appropriate group of compounds is of formula (IA) An additional suitable group is of formula (IB) (IB) wherein R1, R2, R3, R4, and X are as defined above. A suitable group of compounds of formula (I) have: R 1 as hydrogen, methyl, ethyl, propyl, benzyl, hydroxyethyl, methoxyethyl, R 2 as hydrogen, or one or more of methyl, ethyl, n-butyl, / so-propyl, I-butyl, phenyl, methoxy, ethoxy, / so-propoxy, cyclopropylmethoxy, n-butoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, propionyl, n-butyroyl , / so-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulphamoyl, one or both R3, as hydrogen or methyl, one or both R4, as hydrogen or methyl. A preferred group of compounds of formula (I) have: R1 as hydrogen, methyl, R2 as hydrogen, or one or more of methyl, ethyl, / -propyl, t-butyl, methoxy, ethoxy, / -propoxy, bromine, chlorine , cyano, trifluoromethyl, the two R3 as methyl, the two R4 as hydrogen.

Examples of compounds of formula (I) are: N-id.dj.d-tetrahydro-e.d.d-trimethylthyl .ejnaphyridin-S-i benzamide; N- (5,6) 7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthridin-3-yl) -3-cyano-4- / so-propylbenzamide; N-id. J.d-tetrahydro-β.d.d-trimethylthyl. Jnaphyridin-S-ylH-methoxy-S-trifluoromethylbenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-bromo-4-ethylbenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1, 6] naphthyridin-3-yl) -3-bromo-4-ethoxybenzamide; N- (5,6,7,3-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-chloro-4- / so-propyloxybenzamide; N- (5,6,7, d-tetrahydro-6, d, 8-trimethyl [1,6] naphthyridin-3-yl) -3-bromo-4- / so-propyloxybenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-acetyl-4- / so-propyloxybenzamide; N- (5,6,7, d-tThrehydro-6, d, d-trimethyl [1,6] naphthyridi-3-yl) -4-ethoxy-3-trifluoromethylbenzamide; N- (d, d-dimethyl-5,6,7, d-tetrahydro [1, 6] naphthyridin-3-yl) -4-methoxy-3-trifluoromethylbenzamide; N- (5,6,7, d-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-bromo-4-methoxybenzamide; N- (5,6,7,3-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-chloro-4-methoxybenzamide; N-5,6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] naphthridin-3-yl) -3-cyano-4-methoxybenzamide; N-id., And.d-tetrahydro-β-d.-trimethylCl.? Jnaphyridin-S-i -S-cyano ^ -ethylbenzamide; N-S.e.d-tetrahydro-β-d.d-trimethylthyl .ejnaphyridin-S-i -S-bromo ^ -methylbenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthridin-3-yl) -3-pivaloylbenzamide; N- (5,6,7, d-tetrahydro-6, d, d-thmethyl [1,6] naphthridin-3-yl) -5-chloro-2-methoxy-4- / so-propyloxybenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1, 6] naphthyridin-3-yl) -3-cyano-4-ethoxybenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1, 6] naphthyridin-3-yl) -4-methoxy-3-trifluoroacetylbenzamide; N-id.e.d-tetrahydro-e.d.d-trimethylthyl .ejnaphyridin-S-naphthalene -carboxamide; N- (5,6,7, d-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-cyano-4- / so-propyloxybenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-acetyl-4-ethylbenzamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthridin-3-yl) -2,3-dihydrobenzofuran-5-carboxamide; N- (5,6,7, d-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -3-n-butyroyl-4-methoxybenzamide; N- (5,6,7,3-tetrahydro-6, d, d-trimethyl [1,6] naphthyridin-3-yl) -4-methoxy-3-n-propionylbenzamide; N- (5,6 (7, d-tetrahydro-6, d, d -trimethyl [1, 6] naphthyridin-3-yl- / so-butyroyl-4-methoxybenzamide; N- (8,8 -dimethyl-5,6I7I8-tetrahydro [1, 6] naphthyridin-3-yl) -4-ethoxy-3-trifluoromethylbenzamide; N- (8, d-dimethyl-5,6,7, d-tetrahydro [1, 6] naphthyridin-3-yl) -3-acetyl-4 - / 'so-propyloxybenzamide; N- (8,8-dimethyl-5,6,7, d-tetrahydro [1,6] naphthyridine -3-yl) -3-bromo-4-methoxybenzamide; N-id.d-dimethyl-S.TJ.d-tetrahydrotl .ejnaphthyridin-Si-chloro-4-methoxybenzamide; N- (d, d-dimethyl) L-5,6,7, d-tetrahydro [1,6] naphthridin-3-yl) -4-methoxy-3-pentafluoroethylbenzamide; N- (8) 8-dimethyl-5,6,7, d-tetrahydro [1, 6] naphthyridin-3-yl) -4- / so-propoxy-3-trifluoromethylbenzamide; N- (8,8-dimethyl-5,6,7, d-tetrahydro [1,6] naphthyridin-3-yl) -4-ethyl-3-trifluoromethylbenzamide; N- (d, d-dimethyl-5,6,7, d-tetrahydro [1, 6] naphthyridin-3-yl) -3-bromo-4- / so-propylbenzamide; N-id., And D-tetrahydro-β-d.d-trimethylthyl .ejnaphyridin-S-i -S-chloro-xethoxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] nañyridin-3-yl) -3-fluoro-4-methoxybenzamide; N- (d, 6,7,8-tetrahydro-6, d, d-trimetyl [1,6] naphthyridin-3-yl) -4-methoxy-3-pentafluoroethylbenzamide; N- (d, d-dimethyl-d, 6,7,8-tetrahydro [1, 6] naphthyridin-3-yl) -3-fluoro-4-methoxybenzamide; N- (8, dd-methyl-d, 6) 7, d-tetrahydro [1, 6] naphthyridin-3-yl) -4-methoxy-3-propionylbenzamide, and N- (d, 6,7,3- tetrahydro-6, d, d-trimethyl [1, 6] naphthyridin-3-yl) -indol-2-carboxamide.

When these compounds are synthesized, they are generally in salt form, such as hydrochloride or trifluoroacetate, and said salts also form part of this invention. Said salts can be used in the preparation of pharmaceutically acceptable salts. The compounds and their salts can be obtained as solvates, such as hydrates, and these also form part of this invention.

The above-mentioned compounds, their pharmaceutically acceptable salts, especially the hydrochlorides, and the pharmaceutically acceptable solvates thereof, especially the hydrates, constitute a preferred aspect of the present invention. The administration of said compounds to a mammal can be via the oral, parenteral, sublingual, nasal, rectal, topical or transdermal. An amount effective to treat the above-mentioned disorders 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 usually contain from 1 to 1000 mg, conveniently from 1 to dOO mg; for example in an amount on the scale of 2 to 400 mg, such as 2, d, 10, 20, 30, 40, dO, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once a day or more, for example, 1, 2, 3, 4, 6 times a day, usually 1 to 4 times a day, so that the total daily dose is normally found on the scale, for a 70 kg adult, from 1 to 1000 mg; for example 1 to dOO mg, which is on the scale of about 0.01 to 1d mg / kg / day, usually 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 a sublingual, rectal, topical or parenteral (especially intravenous) composition.

Such compositions are prepared by mixing and are suitably adapted for oral or parenteral administration, and as such, may be in the form of tablets, capsules, liquid oral preparations, powders, granules, lozenges, reconstitutable powders, injectable solutions or suspensions or instillables, or suppositories. Orally administered compositions, in particular shaped oral 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, compression 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 d starch, polyvinyl pyrrolidone 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 solid oral compositions can be prepared by conventional methods of mixing, filling, compression or the like. Repeated mixing operations can be used to distribute the active agent uniformly in all those compositions that use large amounts of filler. Of course, said operations are conventional in the art. Oral liquid preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, d 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, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats or oils, 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 glycerin esters, propylene glycol, or ethyl alcohol; preservatives such as, for example, methyl or d-propyl p-hydroxybenzoate or sorbic acid; and if desired, conventional flavoring or coloring agents. Oral formulations also include sustained release formulations, such as tablets or granules that have an enteric coating. For parenteral administration, fluid unit dose 0 forms containing the compound and a sterile vehicle are prepared. The compound can be suspended or dissolved, depending on the vehicle and the concentration. Parenteral solutions are usually prepared by dissolving the compound in a vehicle and filter sterilizing before empty in an appropriate vial or ampoule, and seal them. Conveniently, adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the vehicle. To improve the stability, the composition can be frozen after emptying it in the flask, and then removing the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, but the compound is suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. Conveniently, 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 instructions for use in the medical treatment in question. d Therefore, the present invention also 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, effects associated with substance withdrawal of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 disease, schizophrenia, obsessive-compulsive disorder (OCD), neurological deficits associated with AIDS, sleep disorders (including heart rhythm disorders, insomnia and / or narcolepsy), tics (eg, Giles de la Tourette syndrome), damage traumatic brain, tinnitus, neuralgia, especially neuralgia. Trigeminal pain, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and lateral or amyotrophic sclerosis (ALS); comprising 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 subarachnoid hemorrhage or neural shock, effects associated with abstinence from substances of abuse such as cocaine. , nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 deficits associated with AIDS, sleep disorders (including heart rhythm disorders, insomnia and / or narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) dy motor neuron disease, ataxia, muscle rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS); which comprises administering to the patient 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 (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, d effects associated with abstinence from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 deficits associated with AIDS, sleep disorders (including heart rhythm disorders, insomnia and / or narcolepsy), tics (for example, Giles syndrome of the Tourette), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease, ataxia, muscle rigidity (spasticity), dysfunction of the temporomandibular joint, and amyotrophic lateral sclerosis (ALS). In yet 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 , panic disorders and / or aggression, disorders associated with subarachnoid hemorrhage or neural shock, effects associated with abstinence from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 deficits associated with AIDS, sleep disorders (including disorders of heart rhythm, insomnia and / or narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, neuronal activity inappropriate that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease, ataxia, 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 the formula (I) described above, which comprises reacting a compound of formula (II), (II) wherein R1A, R3A and R4A are R1, R3 and R4 as defined for formula (I), or a group or groups convertible into R1, R3 and R4, and X is as defined for formula (I ), with a compound of formula (III) (III) where Y is a leaving group such as Cl or OH, and groups R2A are independently R2 as defined for formula (I), or a group or groups convertible to R2, and wherein it is required to convert a group R1A, R2A, R3A, R4A, into a group R1, R2, R3, R4, convert a group R1, R2, R3, R4, X, into another group R1, R2, R3, R4, X, or to separate any enantiomer, or to convert a salt product into the free base or another pharmaceutically acceptable salt, or to convert a free base product into a pharmaceutically acceptable salt. Conventional conditions can be used for condensation of amines with carboxylic acids or active derivatives thereof, such as acid chlorides. For example, the amides and acids may be reacted in the presence of a mixture of ethyl (dimethylaminopropyl) -0 carbodiimide / hydroxybenzotriazole, in a suitable solvent such as dimethylformamide; and the amines and acid chlorides can be reacted in a suitable solvent such as ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. The conversions of a group R1A, R2A, R3A, R4A, in a group R1, R2, R3, R4, generally take place when a protecting group is required during the coupling reaction mentioned above, or during the preparation of reagents by means of of the procedures described below. The interconversion from one group to another R1, R2, R3, R4, X, usually takes place 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.

The reaction of a compound of formula (III) which is an acid chloride (Y = Cl), typically results in the formation of the hydrochloride salt of the compound of formula (I). The hydrochloride salts can also be obtained by passing HCl gas into a solution of the free base product, or by adding a solution of HCl in ether. The compounds of formula (II) can be prepared from a compound of formula (IV), by reaction with a dinitro-1-methylpyrid-2-one compound of formula (V), in a solution of ammonia, in a suitable solvent such as methanol, to obtain a compound of formula (VI) using a procedure similar to that of S. Takada et al., J. Med. Chem. 1996, 39, 2844.

The compounds of formula (VI) can be converted to the compounds of formula (II) by hydrogenation or reduction of the nitro group. For example, a compound of formula (VI) can be hydrogenated by treatment with hydrogen in a suitable solvent such as methanol, in the presence of a palladium / carbon catalyst. Alternatively, a compound of formula (VI) can be hydrogenated with stannous chloride in concentrated hydrochloric acid, in a suitable solvent such as ethanol. The compounds of formula (IV) can be prepared using the methods of Katvalyan et al., Bull. Acad. Sci., USSR (Engl) 1968, 2436. Compounds of formula (V) can be prepared using the procedure of E. Matsumara, M. Ariga and Y. Tohda, Bull. Chem. Soc., Japan, 52 (8), 2413-2419 (1979). The compounds of formula (III) can be prepared by further substitution of commercially available benzoic acid derivatives, using conventional procedures, or by oxidation of the corresponding substituted benzylic alcohols. Alternatively, the benzoic acids can be prepared from the corresponding substituted phenols, for example, by forming the acetate, converting it into an acetophenone, and then into the desired acid.

When the intermediates described above are novel compounds, they are also part of the present invention. The preparation of the compounds of formula (II) is illustrated in the following section of Descriptions; the preparation of the compounds of formula (III) is illustrated in the following sections of Preparations and Methods; the preparation of the compounds of this invention is illustrated in the following section of Examples. The utility of the compounds of this invention is shown in the Pharmacological Data section after the Examples.

DESCRIPTION 1, 3,3-Trimethylpiperidin-4-one The title compound was prepared according to the procedure of Katvalayan et al., Bull. Acad. Sci. USSR (Engl) 1968, 2436. p. eb 70 ° C to 16 mm Hg; m / z (API +): 142.1 (MH +).

DESCRIPTION 2 3-Nitro-5,6,7,8-tetrahydro-6,8,8-trimetiiri, 61-naphthyridine It was suspended in MeOH (dO ml), 3, d-dinitro-1-methylpyridin-2-one [prepared by the method of E. Matsumara, M. Ariga and Y. Tohda, Bull.

Chem. Soc, Japan, 1979, 52, 2413-2419] (2 g, 10 mmol), and treated with O.dd ammonia ac. (10 ml, 1d7 mmol). 1, 3,3-trimethylpiperidin-4-one (1.7 g, 12 mmol) was added and the mixture was heated at 70 ° C for d hours. The mixture was cooled to room temperature, then evaporated to dryness in vacuo. The residue was taken up in dichloromethane (2 × 60 ml) and the hot solution was decanted from the red gum. The extracts were combined, evaporated to dryness in vacuo, and the residue was purified by chromatography on Si02 with 60% ethyl acetate: petroleum at 60-80 ° C to give the title compound as a yellow oil, which solidified at rest (1.06 g, 48%). 1 H NMR (260 MHz, CDCl 3) d: 1.38 (6H, S), 2.47 (3H.S), 2.dd (2H.S), 3.64 (2H.S), 8.09 (1H, d, J = 3Hz ), 9.26 (1 H, d J = 3 Hz); m / z (API +): 222.1 (MH +).

DESCRIPTION 3 3-Amino-5,6,7,8-tetrahydro-6,8,8-tritytiri, 61-naphthyridine The product of description 2 (930 mg, 4.20 mmol), was dissolved in MeOH (30 ml), and the mixture was treated with 10% palladium on carbon (150 mg), then hydrogenated under normal temperature and pressure, until the incorporation of hydrogen ended. The catalyst was removed by filtration through Celite, and the filtrate and washings were combined and evaporated to dryness in vacuo. The residue was crushed under diethyl ether containing a little dichloromethane, and the title compound was collected by filtration, washed with diethyl ether and dried under vacuum (796 mg, 84%). 1 H NMR (260 MHz: CD 3 OD) dH: 1.73-1.99 (2H, M), 2.34-2.55 (5H, M) 2.63 (1 H, d, J = 17 Hz), 3.29 and 3.36 (1 H, dd, J = 17.5 Hz), 3.66 - 3.71 (1 H, m), 3.99 (1 H, d, J = 6 Hz), 6.95 (1 H, d, J = 3 Hz), 7.95 (1 H, d, J = 3 Hz); m / z (API +): 190.16 (MH +).

PREPARATION 1 TBMS ether 3-bromobenzyl To a solution of 3-bromobenzyl alcohol (5.00 g, 0.027 mol) in dichloromethane (30 ml), Et3N (4.2 ml, 0.03 mol), a 1 M solution of tert-butyldimethylsilyl chloride in dichloromethane (28.0) was added dropwise. ml). The mixture was allowed to stir at room temperature overnight and then water (30 ml) was added. The organic layer was washed with brine, dried (Na2SO4), and evaporated to give a red oil which was purified by flash chromatography on a silica gel using 20% ether in hexane, to give a colorless oil ( dO g).

PREPARATION 2 TBDMS ether 3-pivaloylbenzyl alcohol N-Butyllithium (2.d0 ml, 7.00 mmol, 2.5M in d-hexane) was slowly added to a solution of the TBDMS ether of preparation 1 (1.d0 g, 6.0 mmol) in dry THF (10 ml) for 5 hours. minutes at -78 ° C. The reaction mixture was kept under argon at -78 ° C for 1 hour, and N.O-dimethylhydroxypivaloylamide (0.d6 g, 6.60 mmol) in THF (2 ml) was added dropwise with stirring at -78 ° C. The resulting mixture was left stirring at -78 ° C for 2.5 hours, quenched with NH 4 Cl solution and allowed to warm to room temperature. The mixture was extracted with ether (2 x 50 ml), the combined organic extracts were dried (Na 2 SO 4); it was concentrated in vacuo to give the title compound as a colorless oil (1.75 g). m / z (API +) 307 (MH +, 6%). 5 PREPARATION 3 3-Pivaloylbenzyl alcohol The ether of preparation 2 (1.47 g, 4.80 mmol) was dissolved in 0 methanol (25 ml); HCl conc. (20 drops) and everything was left stirring at room temperature for 4 hours. Saturated NaHCO3 was added, and the mixture was extracted with ether (2 x 50 ml). The organic layer was dried over sulfate of sodium and evaporated in vacuo to give the title compound as a colorless oil (0.80 g). m / z (API +): 193 (MH +, 17%).

PREPARATION 4 3-Pivaloylbenzoic acid 3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was added, followed by KMnO4 (1.45 g, 9.17 mmol). The mixture was stirred at room temperature over a weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. And it was extracted with ether (3 x 50 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.80 g). 1 H NMR (250 MHz, CDCl 3) d: 1.38 (9 H, s), 7.55 (1 H, t), 7.92 (1 H, d, J = 6.5 Hz), d.20 (1 H, d, J = 6.5 Hz ), 8.44 (1 H, s).

PREPARATION 5 3-Trifluoroacetylbenzoic acid The title compound was prepared starting with diethyltrifluoroacetamide and TBDMS ether of 3-bromobenzyl, using a method similar to that described in preparations 1, 2, 3 and 4. m / z (API-): 217 (M-H +) : twenty%).

PREPARATION 6 3-Chloro-4-; methyl-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) and 2-iodopropane (3.85 ml, 40.2 mmol), and then stirred at 25 ° C for 18 hours. The title compound was produced by treatment with ethyl acetate (6-1 g).

PREPARATION 7 3-Chloro-4- / so-propoxybenzoic acid Methyl 3-chloro-4- / so-propoxybenzoate (5.6 g, 24.1 mmol) was hydrolyzed using 1 M NaOH (36 mL) in methanol (80 mL). By extraction and treatment with ethyl acetate, the title compound (4.3 g) was produced. 1 H NMR (DMSO-D 6) d: 1.33 (6H, d), 4.79 (1 H, m), 7.24 (1 H, d), 7.67 (2H, m).

PREPARATION 8 3-Bromo-4-ethoxybenzoic acid The title compound was prepared from 4-ethylbenzoic acid in a manner similar to that of procedure 1. 1 H NMR (DMSO-D6) d: 1.45 (3H, t, J = 7 Hz). 4.26 (2H, q, J = 7 Hz), 7.26 (1 H, d, J = 9 Hz). 7.93 (1 H, dd, J = 2.9 Hz), 8.12 (1 H, d, J = 2 Hz).

PREPARATION 9 3-Bromo-4-ethylbenzoic acid The title compound was prepared from 4-ethylbenzoic acid in a manner similar to that of procedure 1. 1 H NMR (DMSO-D6) 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 10 3-Cyano-4- / so-propylbenzoic acid The title compound was prepared from 4- / so-propylbenzoic acid using a form similar to that described in procedures 1 and d. 1 H NMR (DMSO-D 6) d: 1.07 (6H, d, J = 7 Hz), 3.13 (1 H, m, overlapped), 7.43 (1 H, d, J = 7 Hz), 7.96 (1 H, dd , J = 2.8 Hz), 8.00 (1 H, d, J = 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 similar to that of procedures 3 and 4. 1 H NMR (DMSO-D6) d: 3.78 (3H, s), 7.18 (1 H, 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, exchangeable br).

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 vacuum evaporation.

PREPARATION 13 3-Bromo-4-iso-propoxybenzoate methyl Methyl 3-bromo-4-hydroxybenzoate (2.d g, 10.8 mmol) in DMF (3d mL) was treated with potassium carbonate (3.0 g, 21.6 mmol) and 2-iodopropane (2.76, 21.6 mmol); then it was stirred at 25 ° C for 48 hours. Treatment with ethyl acetate gave the title compound (3.0 g). 1 H NMR (260 MHz. CDCl 3) d: 1.41 (6 H, d, J = 7 Hz), 3.89 (3 H, s), 4.66 (1 H, m), 6.90 (1 H, d, J = 8 Hz) 7.93 (1 H, dd, J = 8.2 Hz), d.22 (1 H, d, J = 2 Hz).

PREPARATION 14 3-Cyano-4- / methyl-so-propoxybenzoate Heating, under vigorous reflux for 4 hours, methyl 3-bromo-4- / so-propoxybenzoate (2.0 g, 7.3 mmol) and copper cyanide (I) in N-methylpyrrolidone (60 ml) was heated. Treatment with ethyl acetate gave the title compound (1.0 g). 1 H NMR (260 MHz, CDCl 3) d: 1.56 (6H, d, J = 7 Hz), 4.05 (3H, s), 4.88 (1 H, m), 7.13 (1 H, d, J = 8 Hz), 8.31 (1 H, dd, J = 8.2 Hz), 8.33 (1 H, d, J = 2 Hz).

PREPARATION 15 methyl 3,5-Dichloro-4-ethoxybenzoate The title compound was prepared in a 69% yield from 3,5-dichloro-4-hydroxybenzoic acid methyl ester and iodoethane, similar to that of preparation 6. 1 H NMR (250 MHz, CDCl 3) d : 1.47 (3H, t, J = 7 Hz), 3.91 (3H, s), 4.16 (2H, q, J = 7 Hz), 7.96 (2H, s).

PREPARATION 16 3-methanesulfonyl-4- / so-propylbenzoic acid 3-Chlorosulfonyl-4- / so-propylbenzoic acid (2.62 g, 10 mmol) [preparation of 4- so-propyl benzoic acid in a manner similar to that described in procedures 7 and 8] was added slowly to a suspension NaHCO 3 (2.52 g, 30 mmol) and Na 2 SO 3 (1.26 g, 10 mmol) in water (9 ml) at 75 ° C. The mixture was stirred 1 hour and then treated with bromoacetic acid (2.0d g, 16 mmol) and NaOH (0.60 g, 15 mmol). The temperature was raised to 105 ° C and the mixture was heated to reflux for 24 hours. The mixture was cooled, acidified to pH 1, and the resulting precipitate was collected, washed and dried to give the title compound (1.43 g, 69%). 1 H NMR (260 MHz, acetone-D 6) d: 1.24 (6H, d, J = 7 Hz), 3.13 (3H, s), 3.3d (1 H, m), 7.72 (1 H, d, J = 7 Hz), 8.15 (1 H, dd, J = 7 Hz), 8.52 (1 H, d, J = 7 Hz).

PREPARATION 17 3-Chloro-4-ethoxybenzoic acid 1 H NMR (DMSO-D6) d: 1.39 (3H, t, J = 7 Hz), 4.20 (2H, q, J = 7 Hz), 7.22 (1 H, d, J = 7 Hz), 7.87 (2H, m).

PREPARATION 18 3-bromo-4- / so-propoxybenzoic acid The title compound was prepared using a method similar to that of preparation 7. 1 H NMR (DMSO-D6): 1.29 (6H, d, J = 7 Hz), 4.77 (1 H, sep, J = 7 Hz), 7.20 (1 H, d, J = 8 Hz), 7.87 (1 H, dd, J = 8.2 Hz), 8.02 (1 H, d, J = 2 Hz), 12.92 (1 H, brs).

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), bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) was added dropwise. After stirring overnight at room temperature, the precipitate was filtered off and dried to yield 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), bromine (1.86 mL) was added dropwise to chloroform (20 ml). The reaction was stirred at room temperature overnight. Evaporation under vacuum gave an oil (9.27 g). m / z (Cl): 275, 273 (MH +, 70%).

PROCEDURE 3 methyl 5-Bromo-4- / so-propyl-2-methoxybenzoate Ethanol (250 ml) was dissolved in 5-bromo-4- / so-propyl-2-methoxybenzoic acid (9.268 g, 34.0 mmol) and conc. H2SO4 was added. (2 ml). 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 (d.d g).

PROCEDURE 4 2,4-Dimethoxy-5-trifluoromethylbenzoic acid 2,4-Dimethoxy-d-bromobenzoic acid methyl ester (1.5 g, 5.4 mmol) in DMF (25 ml) and toluene under argon, with potassium trifluoroacetate (1.53 g, 10.1 mmol) and copper iodide (I) were treated. ) (2.1 g, 10.9 mmoles).

The mixture was heated to 170 ° C with water removal (Dean / Stark), and then at 155 ° C overnight. The mixture was allowed to cool, was emptied into ether and water, and it was filtered through Kieselguhr. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with ether / petroleum 1: 1 gave a solid (1.03 g) which was hydrolyzed in methanolic NaOH: aqueous 1: 1 (60 ml) at dO ° C. By treatment, the title compound was obtained as a white solid (1 g).

PROCEDURE 5a methyl 2-methoxy-5-cyano-4-iso-propylbenzoate Copper (I) cyanide (550 mg, 6 mmol) was added to a solution of methyl 2-methoxy-5-bromo-4 - / "so-propylbenzoate (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, was poured into excess ice / water and ethyl acetate, and filtered.The organic phase was separated, washed with water brine and dried (MgSO4). A crude brown solid was obtained which was purified by chromatography on silica eluting with ethyl acetate / n-hexane (1: 4) .The product was obtained as a white solid. (623 mg). 1 H NMR (260 MHz, CDCl 3) d: 1.33 (6H, d, J = 7 Hz), 3.38 (1 H, sep, J = 7 Hz), 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 the 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. Then the aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO 4) and evaporated to dryness giving the product as a white solid (418 mg). 1 H NMR (250 MHz, CDCl 3) d: 1.35 (6H, d.J = 7 Hz), 3.43 (1 H, sep, J = 7 Hz), 4.14 (3H, s), 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 d, to give the title compound as an oil (400 mg). 1 H NMR (260 MHz. CDCl 3) d: 1.12 (6 H, d, J = 7 Hz), 1.30 (3 H, t J = 7 Hz), 1.84 (3 H, t, J = 7 Hz), 3.17 (1 H, Sep. J = 7 Hz), 3.99 (2H, q, J = 9 Hz), 4.16 (2H, q, J = 7 Hz), 6.69 (1 H, 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 (d ml) and 1 N NaOH (2.1 ml, 2.1 mmol) was added over a period of 24 hours. 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 (MgSO 4) and evaporated to give the title acid (306 mg). 1 H NMR (250 MHz CDCI 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 = 7 Hz), 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-Etbxy-2-methoxy-d-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.

Brown, J. Org. Chem., 1991, 56, 4974, to obtain the title compound in 19% yield. 1 H NMR (DMSO-D 6) d: 1.30 (3 H, t), 3.10 (3 H, s), 3.83 (3 H, s), 4.24 (2 H, q), 6.73 (1 H, s), 8.07 (1 H, s). d PROCEDURE 8 4- / So-propyl-2-methoxy-5-methylsulfonylbenzoic acid This was prepared in a manner similar to that of the procedure of C. 0 Hansch, B. Schmidhalter, F. Reiter, W. Saltonstall, J. Org. Chem. 1966, 21, 266, to produce the intermediate d-chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid, which was converted to the title compound using the procedure method 7. 1 H NMR (DMSO-De) d: 1.30 (6H, d) , 3.21 (3H, s), 3.80 (1 H, m), 5 3.94 (3H.s), 7.26 (1 H, s), 8.19 (1 H, s).

EXAMPLE 1 N- (5,6,7,8-tetrahydro-6,8,8-trimetimIM, 61-naphthyridin-3-Q-benzamide hydrochloride 0 3-amino-5,6,7,8-tetrahydrochloride was dissolved. dro-6,8,8-trimetyl [1,6] naphthyridine (96 mg, O.DO mmole) in dry THF (d ml), and the solution was treated with benzoyl chloride (70.3 mg, O.dO mmoles) The mixture was stirred at room temperature for 2 hours and then the precipitate was collected by filtration, washed with THF, diethyl ether, and dried under vacuum (132 mg, 80%). 1 H NMR (250 MHz; (CD 3) 2 SO) d: 1.42 and 1.64 (2x 3 H, s), 3.02 (3 H, brs), 3.6 d (2 H, brm), 4.40 - 4.70 (2 H, brm), 7.60 - 7.71 (3H, m), 8.00 - 8.10 (2H, m), 8.18 (1 H, brs), 8.91 (1 H, brs), 10.60 - 10.90 (2H, brm, exchangeable); m / z (API +): 296.1 (MH +).

EXAMPLE 2 N- (5,6,7,8-Tetrahydro-6,8,8-trimethopr. 61-naphthyridin-3-yl) -3-cyano-4- / so-propylbenzamide hydrochloride It was prepared in a manner similar to that of Example 1, starting with 3-cyano-4- / so-propylbenzoic acid, as a white powder (171 mg, 86%). 1 H NMR (250 MHz; (CD 3) 2 SO) d: 1.30 (6H, d, J = 7 Hz), 1.33 and 1.46 (2x 3H, s), 2.94 (3H, d, J = 4 Hz), 3.20 - 3.70 (3H, brm), 4.30 - 4.60 (2H, m), 7.73 (1 H, d, J = 8 Hz), 8.09 (1 H, d, J = 2 Hz), 8.24 (1 H, dd, J = 10.2 Hz), 8.40 (1 H, d, J = 2 Hz), 8.83 (1 H, d, J = 2 Hz); m / z (API +): 363.2 (MH +).

EXAMPLE 3 N- (5,6,7,8-Tetrahydro-6,8,8-trimethyl.1.61naphthyridin-3-yl) -4-methoxy-3-trifluoromethylbenzamide hydrochloride It was prepared in a manner similar to that of Example 1, starting with 4-methoxy-3-trifluoromethylbenzoic acid. The product was purified by chromatography on Si02, eluting with 0.88 aqueous ammonia / methanol / d, chloromethane (0.5: 4.5: 96), and converted to the hydrochloride salt by addition of 1 M hydrogen chloride in diethyl ether (1 equivalent) . The title compound was collected by filtration (98 mg, 46%). 1 H NMR (250 MHz: (CD 3) 2 SO) d: 1.36 and 1.48 (2x 3H, s), 2.96 (3H, d, J = 3 Hz), 3.40 and 3.70 (2x 1 H, brm), 3.99 (3H, s), 4.30 - 4.60 (2H, br), 7.46 (1 H, d, J = 9 Hz), 8.10 (1 H, d, J = 2 Hz), 8.28 (1 H, brs), 8.34 (1 H , br dd), 8.85 (1 H, d, J = 2 Hz), 10.60 - 10.80 (2 H, br, exchangeable): m / z (API +): 394.2 (MH +).

EXAMPLE 4 N- (5,6,7,8-Tetrahydro-6,8,8-trimethylH, β1-naphthyridin-3-yl) -3-bromo-4-ethylbenzamide hydrochloride It was prepared in a manner similar to that of Example 3, starting with 3-bromo-4-ethylbenzoic acid, and isolated as an off-white powder (104 mg, 46%). 1 H NMR (250 MHz; (CD 3) 2 SO) d: 1.25 (3H, t, J = 7 Hz), 1.40 and 1. 54 (2X 3H, s), 2.83 (2H, q, J = 7 Hz), 3.00 (3H, d, J = 4 Hz), 3.30 - 3.80 (2H, brm), 4.30 - 4.70 (2H, m), 7.59 (1 H, d, J = 8 Hz), 8.02 (1 H, d, J = 8 Hz), 8.16 (1 H, d, J = 2 Hz), 8.26 (1 H, d, J = 1 Hz), 8.90 (1 H, d, J = 2 Hz); m / z (API +): 402.1, 404.1 (MH +).

EXAMPLE 5 N- (5,6,7,8-Tetrahydro-6,8,8-trimetiip. 61-naphthyridin-3-in-3-bromo-4-ethoxybenzamide hydrochloride It was prepared in a manner similar to that of Example 3, starting with 3-bromo-4-ethoxybenzoic acid, and isolated as an off-white powder (100 mg, 44%). 1 H NMR (260 MHz: (CD 3) 2 SO) d: 1.42 and 1.66 (2x 3H, s), 1.46 (3H, t, J = 7 Hz), 3.01 (3H, brd), 3.30 - 3.80 (2H, m) , 4.29 (2H, q, J = 2 Hz), 4.30 -4.70 (2H, brm), 7.33 (1 H, d, J = 9Hz), 8.10 (1 H, dd, J = 9.2 Hz), 8.16 (1 H, d, J = 2 Hz), 8.33 (1 H, d, J = 2 Hz), 8.91 (1 H, d, J = 2 Hz), 10.64 (1 H, s, interchangeable), 10.86 (1 H , br, interchangeable), m / z (API +): 418.1, 420.1 (MH +).

EXAMPLE 6 N- (5,6,7,8-tetrahydro-6,8,8-trimethyl-1, 61-naphthyridin-3-yl) -3-chloro-4- / so-propyloxybenzamide hydrochloride It was prepared in a manner similar to that of Example 3, starting with 3-chloro-4- / so-propyloxybenzoic acid, and isolated as an off-white powder (67 mg, 32%). 1 H NMR (260 MHz; (CD 3) 2 SO) d: 1.17 (6H, d, J = 6 Hz), 1.22 and 1. 60 (2x 3H, s), 2.78 (3H, brs), 3.40 (2H, brs), 4.20 - 4.60 (2H, brm), 4.63 -4.73 (1 H, m), 7.18 (1 H, d, J = 9 Hz), 7.86 (1 H, dd, J = 9.2 Hz), 7.97 (1 H, d, J = 2 Hz), 8.04 (1 H, d, J = 2 Hz), 8.76 (1 H, d, J = 2 Hz), m / z (API +): 388.2, 390.2 (MH +).

EXAMPLE 7 N- (5,6 J, 8-tetrahydro-6,8,8-trimethylH, 6-naphthyridin-3-yl) -3-bromo-4- / so-propyloxybenzamide hydrochloride It was prepared in a manner similar to that of Example 3, starting with 3-bromo-4- / so-propyloxybenzoic acid, and isolated as an off-white powder (224 mg, 82%). 1 H NMR (260 MHz; (CD 3) 2 SO) d: 1.24 (6H, d, J = 6Hz), 1.26 and 1.35 (2x 3H, s), 2.89 (3H, brd), 3.30 (2H, brm), 4.20 - 4.50 (2H, brm), 4.74 (1 H, m), 7.20 (1 H, d, J = 9 Hz), 7.90 (1 H, dd, J = 9.2 Hz), 7.92 (1 H, d, J = 2 Hz), 8.15 (1 H, d, J = 2 Hz), 8.72 (1 H, d, J = 2 Hz); m / z (API +): 434, 432 (MH +, 80%).

EXAMPLE 8 N- (5,6,7,8-tetrahydro-6,8,8-trimethyl-M, 61-naphthyridin-3-yl) -3-acetyl-4 - / 'so-propyloxybenzamide hydrochloride It was prepared in a manner similar to that of Example 3, starting with 3-acetyl-4- / so-propyloxybenzoic acid (222 mg, 1.0 mmol), but the reaction was carried out in dichloromethane and in the presence of triethylamine (101 mg, 1.0 mmol , 0. 14 ml). The title compound was isolated as a white powder (247 mg, 57%). 1 H NMR [free base] (250 MHz: CD3OD) d: 1.22 (6H, s), 1.32 (6H, d, J = 6 Hz), 2.31 (3H, s), 2.44 (2H, s), 2.50 (3H , s), 3.45 (2H, s), 4.77 (1 H, m), 7.12 (1 H, d, J = 9 Hz), 7.79 (1 H, d, J = 2 Hz), 7.95 and 7.99 (1 H, dd, J = 9.2 Hz), 8.16 (1 H, d, J = 2 Hz), 8.56 (1 H, d, J = 2 Hz); m / z (API) +: 396.2 (MH +, 80%).

EXAMPLE 9 N- (5,6,7,8-Tetrahydro-6,8,8-tritymethyl, 6-naphthyridin-3-yl) -4-ethoxy-3-trifluoromethylbenzamide hydrochloride It was prepared as described in example 8, starting from acid 4-Ethoxy-3-trifluoromethylbenzoic acid (237 mg, 1.0 mmol), and was isolated as a white powder (416 mg, 87%). 1 H NMR [free base] (260 MHz; CD 3 OD) d: 1.23 (6H, s), 1.34 (3H, t, J = 7 Hz), 2.32 (3H, s), 2.46 (2H, s), 3.46 (2H , s), 4.13 (2H, q, J = 7 Hz), 7.16 (1 H, d, J = 9 Hz), 7.80 (1 H, d, J = 2 Hz), 8.09 (2H, m), 8.57 (1 H, d, J = 2 Hz), m / z (API) +: 408.2 (MH +, 80%).

EXAMPLE 10 N-, 8,8-dimethyl-5,6,7,8-tetrahydro, 1, 6-naphthyridin-3-yl) -4-methoxy-3-trifluoromethylbenzamide hydrochloride N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -4-methoxy-3-trifluoromethylbenzamide (172 mg, 0.44 mmol) was suspended in 1 ml. , 2-dichloromethane (30 ml), and the mixture was treated with 1-chloroethyl chloroformate (62.6 mg, 47 ml, 0.44 mmol). The mixture was heated to reflux and more chloroformate was added until little or none of the starting material remained. At this point, the volatiles were removed under reduced pressure and the residue was dissolved in methanol (30 ml); it was heated to reflux for 15 minutes.

The volatiles were removed under reduced pressure and the residue was treated with a mixture of 0.88 aqueous ammonia / methanol / d-chloromethane (0.6: 4.5: 96), and the resulting beige solid was collected by filtration. The free base (123 mg, 0.32 mmol) was dissolved in methanol (minimum volume) and treated with 1 M hydrogen chloride in diethyl ether (0.32 ml, 0.32 mmol); the mixture was diluted with diethyl ether until turbidity, and refrigerated. The title compound was obtained as a white powder (130 mg, 71%). 1 H NMR [free base] (250 MHz; CD 3 OD) d: 1.37 (6H, s), 3.35 (2H, s), 4.35 (2H, s), 7.25 (1 H, d, J = 9 Hz), 8.07 ( 1 H, d, J = 2 Hz), 8.15 - 8.18 (2H, m), 8.70 (1 H, d, J = 2 Hz): m / z (API) +: 378.1 (MH +, 100%).

The following examples were prepared using the methods described above: EXAMPLE 11 N- (5,6,7,8-Tetrahydro-6,8,8-trimethyl-l, 6-naphthyridin-3-yl) -3-bromo-4-methoxybenzamide hydrochloride 1 H NMR [free base] (250 MHz: CD3OD) d: 1.04 (6H, s), 2.13 (3H, s), 2.26 (2H, s), 3.27 (2H, s), 3.65 (3H, s), 6.84 (1 H, d, J = 9 Hz), 7.59 (1 H, d, J = 2 Hz), 7.66 (1 H, dd, J = 9.2 Hz), 7.88 (1 H, d, J = 2 Hz) , 8.37 (1 H, d, J = 2 Hz); m / z (API) +: 426.7, 428 (M + Na +).

EXAMPLE 12 N- (5,6,7,8-Tetrahydro-6,8,8-trimethyl-M-61-naphthyridin-3-yl) -3-chloro-4-methoxybenzamide hydrochloride 1 H NMR [free base] (250 MHz; CD3OD) d: 1.41 (6H, s), 2.50 (3H, s), 2.64 (2H, s), 3.56 (2H, s) 4.03 (3H, s), 7.26 ( 1 H, d, J = 9 Hz), 7.97 - 8.09 (3H, m), 8.73 (1 H, d, J = 2 Hz); m / z (API) +: 382.1, 384.2 (M + Na) +.

EXAMPLE 13 N- (5,6,7,8-tetrahydro-6,8,8-trimethyl-1, 61-naphthyridin-3-yl) -3-cyano-4-methoxybenzamide hydrochloride 1 H NMR [free base] (250 MHz: CD3OD) d: 1.33 (6H, s), 2.43 (3H, s), 2.56 (2H, s), 3.58 (2H, s), 4.03 (3H, s) 7.31 ( 1 H, d, J = 9 Hz), 7.90 (1 H, d, J = 2 Hz), 8.23 (2 H, m), 8.66 (1 H, d, J = 2 Hz); m / z (API) +: 351.1 (MH \ 80%), 373.2 (M + Na) +.

EXAMPLE 14 N- (5,6,7,8-Tetrahydro-6,8,8-trimethylH, 61naphthyridin-3-yl) -3-cyano-4-ethylbenzamide hydrochloride 1 H NMR [free base] (250 MHz; CD 3 OD) d: 1.10 (9H, m), 2.20 (3H, s), 2.34 (2H, s), 2.71 (2H, q, J = 8 Hz), 3.36 (2H , s), 7.37 (1 H, d, J = 8 Hz), 7.70 (1 H, d, J = 2 Hz), 7.93 (1 H, dd, J = 8, 2 Hz), 8.04 (1 H, d, J = 2 Hz), 8.45 (1 H, d , J = 2 Hz); m / z (API) +: 3.49 (MH +).

EXAMPLE 15 N- (5,6,7,8-tetrahydro-6,8,8-trimetiiri, 61naphyridin-3-yl) -3-bromo-4-methylbenzamide hydrochloride 1 H NMR [free base] (250 MHz; CD 3 OD) d: 1.23 (6H, s), 2.32, 2.33 (2x 3H, s), 2.45 (2H, s), 3.44 (2H, s), 7.30 (1 H, d, J = 8 Hz), 7.72 (1 H, dd, J = 8.2 Hz), 7.79 (1 H, d, J = 2 Hz), 8.02 (1 H, d, J = 2 Hz), 8.56 (1 H, d, J = 2 Hz); m / z (API "): 386.0, 387.9 (M-H) \ EXAMPLE 16 N- (5,6,7,8-Tetrahydro-6,8,8-trimethyl.1.61naphthyridin-3-yl) -3- pivaloylbenzamide hydrochloride 1 H NMR (260 MHz, CDCl 3) d: 1.36 (6H, s), 1.38 (9H, s), 2.45 (3H, s), 2.52 (2H, s), 3.59 (2H, s), 7.5d (1 H t J = 8 Hz), 7.88 (1 H, m), 7.97 (2 H, m), 8.17 (1 H, s), 8.44 (1 H, d, J = 2 Hz); m / z (API +): 380.4 (MH +: 30%).

EXAMPLE 17 N-.5,6,7,8-tetrahydro-6,8,8-trimetiip, 61-naphthyridin-3-yl) -5-chloro-2-methoxy-4-iso-propyloxybenzamide hydrochloride 1 H NMR [free base] (250 MHz; CDCl 3) d: 1.35 (6H, s), 1.44 (6H, d, J = 6 Hz), 2.44 (3H, s), 2.51 (2H, s), 3.57 (2H , s), 4.05 (3H, s), 4.66 (1 H, m), 6.57 (1 H, s), 8.06 (1 H, d, J = 2 Hz), 8.26 (1 H, s), 8.34 ( 1 H, d, J = 2 Hz); m / z (API +): 416.1, 418.2 (M + H]) +.

EXAMPLE 18 N-.5,6,7,8-Tetrahydro-6,8,8-trimethopr, 61-naphthyridin-3-yl) -3-cyano-4-ethoxybenzamide hydrochloride 1 H NMR [free base] (250 MHz; CD 3 OD) d: 1.27 (6H, s), 1.42 (3H, t, J = 7 Hz), 2.37 (3H, s), 2.50 (2H, s), 3.52 (2H , s), 4.22 (2H, q, J = 7 Hz), 7.22 (1 H, d, J = 9 Hz), 7.84 (1 H, d, J = 2 Hz), 8.16 (2H, m), 8.60 (1 H, d, J = 2 Hz); m / z (API +): 365.1 (M + H) +.

EXAMPLE 19 N- (5,6,7,8-Tetrahydro-6,8,8-trimetiip, 61naphyridin-3-yn-4-methoxy-3-trifluoroacetylbenzamide 1 H NMR (250 MHz: CDCl 3) d: 1.34 (6 H, s), 2.44 (3 H, s), 2.51 (2 H, s), 3.55 (2 H, s) 3.99 (3 H, s), 7.10 (1 H, d , J = 8 Hz), 7.93 (1 H, d, J = 8 Hz), 8.23 (2 H, brm), 8.44 (1 H, brs), 8.51 (1 H, d, J = 2 Hz); m / z (API +): 422.1 (MH +: 100%).

EXAMPLE 20 N-5,6,7,8-Tetrahydro-6,8,8-trimetiiri.61naphthyridin-3-yl) naphthalene-2-carboxamide 1 H NMR (250 MHz; CDCl 3) d: 1.42 (6H, s), 2.61 (3H, s), 2.76 (2H, s), 3.78 (2H, s), 7.20 (1 H, m), 7.50-8.65 ( 7H, m), 7.95 (1 H, d, J = 2 Hz), 8.46 (1 H, s), 8.72 (1 H, s), 8.72 (1 H, d, J = 2 Hz); m / z (API +): 346.1 (MH +, 70%).

EXAMPLE 21 N-.5,6,7,8-Tetrahydro-6,8,8-trimethylH, 6, naphthyridin-3-yl) -3- cyano-4-iso-propyloxybenzamide hydrochloride 1 H NMR [free base] (250 MHz: CD 3 OD) d: 1.24 (6H, s), 1.32 (6H, d, J = 6 Hz), 2.34 (3H, s), 2.48 (2H, s), 3.49 (2H , s), 4.74 - 4.84 (1 H, m), 7.21 (1 H, d, J = 9 Hz), 7.81 (1 H, d, J = 2 Hz), 8.10 (1 H, dd, J = 9.2 Hz), 8.14 (1 H, d, J = 2 Hz) , 8.57 (1 H, d, J = 2 Hz); m / z (API +): 379.2 (MH +).

EXAMPLE 22 N-.5,6,7,8-Tetrahydro-6,8,8-trimethylH -61-naphthyridin-3-yl) -3-acetyl-4-ethylbenzamide hydrochloride 1H NMR [free base] (260 MHz, CD3OD) d: 0.98 (3H, t, J = 7 Hz), 1.11 (6H, s), 2.20 (3H, s), 2.34 (2H, s), 2.41 (3H , s), 2.67 (2H, q, J = 7 Hz), 3.34 (2H, s), 7.22 (1 H, brd, J = 8 Hz), 7.70 (1 H, brs), 7.78 (1 H, brd , J = 8 Hz), 8.08 (1 H, brs), 8.47 (1 H, brs); m / z (API +): 366.2 (MH +).

EXAMPLE 23 N-.5.6 Hydrochloride, 8-tetrahydro-6,8,8-trimethyl-l, 6-naphthyridin-3-yl) -2,3-dihydrobenzofuran-5-carboxamide 1 H NMR [free base] (250 MHz; CD 3 OD) d: 1.35 (6H, s), 2.44 (3H, s), 2.58 (2H, s), 3.26 (2H, t J = 9 Hz), 3.58 (2H, s), 4.64 (2H, t, J = 9 Hz), 6.81 (1 H, d, J = 8 Hz), 7.76 (1 H, dd, J = 8.2 Hz), 7.83 (1 H, brs), 7.89 (1 H, d, J = 2 Hz), 8.67 (1 H, d, J = 2 Hz): m / z (API +): 338.2 (MH +).

EXAMPLE 24 N-.5,6,7,8-Tetrahydro-6,8,8-trimetiip. 61-naphthyridin-3-yl) -3- / 7-butyroyl-4-methoxybenzamide hydrochloride 1 H NMR [free base] (250 MHz; CD 3 OD) d: 0.71 (3H, t, J = 7 Hz),, 08 (6H, s), 1.42 (2H, m), 2.17 (3H, s), 2.31 ( 2H, s), 2.72 (2H, t, J = 7 Hz), .32 (2H, s), 3.74 (3H, s), 7.00 (1 H, d, J = 9 Hz), 7.64 (1 H, m), 7.86 (1 H, dd J = .2 Hz), 7.95 (1 H, d, J = 2 Hz), 8.41 (1 H, d, J = 2 Hz); m / z (API +): 396.2 (MH +), 18.2 (M + Na +).

EXAMPLE 25 N- (5,6,7,8-Tetrahydro-6,8,8-trimetipropyl) -61-naphthyridin-3-yl) -4-methoxy-3-n-propionylbenzamide hydrochloride 1H NMR [free base] (250 MHz; CD3OD) d: 1.12 (3H, t, J = 7 Hz), .31 (6H, s), 2.41 (3H, s), 2.54 (2H, s), 3.00 ( 2H, q, J = 7 Hz), 3.56 (2H, s), .97 (3H, s), 7.24 (1 H, d, J = 9 Hz), 7.88 (1 H, d, J = 2 Hz) , 8.10 (1 H, dd, J = .2 Hz), 8.21 (1 H, d, J = 2 Hz), 8.64 (1 H, d, J = 2 Hz); m / z (APf): 382.2 (MH +).

EXAMPLE 26 N- (5,6,7,8-tetrahydro-6,8,8-trimetiiri .61naphyridin-3-yl) - / so-butyroyl-4-methoxybenzamide hydrochloride 1 H NMR [free base] (2dOMHz; CD3OD) d: 1.04 (6H, d, 7 Hz), 1. 26 (6H, s), 2.36 (3H, s), 2.76 (2H, s), 3.40 (1 H, m), 3.61 (2H, s), 3.88 (3H, s), 7.16 (1 H, d, J = 8 Hz), 7.82 (1 H, d, J = 2 Hz), 8.02 (2 H, m), 8.68 (1 H, d, J = 2 Hz): m / z (API +): 396.3 (MH +) .

EXAMPLE 27 N-.8,8-dimethyl-5,6,7,8-tetrahydro, 1, 6-naphthyridin-3-yl) -4-ethoxy-3-trifluoromethylbenzamide hydrochloride 1 H NMR [HCl salt] (250MHz; CD3OD) d: 1.53 (3H, t, J = 7 Hz), 1.69 (6H, s), 3.64 (2H, s), 4.35 (2H, q, J = 7 Hz) , 4.71 (2H, s), 7.41 (1 H, d, J = 9 Hz), 8.38 (2H, m), 8.70 (1 H, d, J = 2 Hz), 9.38 (1 H, d, J = 2 Hz); m / z (API "): 364.1 [M-Et].

EXAMPLE 28 N- (8,8-Dimethyl-5,6,7,8-tetrahydro-M-61-naphthyridin-3-yl) -3-acetyl-4- / so-propyloxybenzamide hydrochloride 1 H NMR [free base] (260 MHz: CD3OD) d: 1.22 (6H, s), 1.34 (6H, d, J = 6 Hz), 2.63 (3H, s), 2.84 (2H, s), 3.78 (2H , s), 4.76 - 4.86 (1 H, m), 7.16 (1 H, d, J = g Hz), 7.79 (1 H, d, J = 2 Hz), 7.9 g (1 H, dd, J = 9.2 Hz), 8.18 (1 H, d, J = 2 Hz), 8.67 (1 H, d, J = 2 Hz); m / z (API +): 382.2 (MH +).

EXAMPLE 29 N- (8,8-Dimethyl-5,6,8-tetrahydroH, 61naphthyridin-3-yl) -3-bromo-4-methoxybenzamide hydrochloride 1 H NMR [HCl salt] (260 MHz; (CD 3) 2 SO) d: 1.27 (6H, s), 3.19 (2H, brs), 3.81 (3H, s), 4.22 (2H, brs), 7.14 (1 H, d, J = 8 Hz), 7.94 (1 H, brd), 8.08 (1 H, brd), 8.14 (1 H, d, J = 2 Hz), 8.73 (1 H, brd), 9.45 - g.70 (2 H, brs, interchangeable), 10.53 (1 H, brs, interchangeable) : m / z (API "): 38g.8, 387.9 (M-H).

EXAMPLE 30 N-, 8,8-Dimethyl-5,6,7,8-tetrahydro-1,6,6-naphthyridin-3-in-3-chloro-4-methoxybenzamide hydrochloride 1 H NMR [HCl salt] (260 MHz: (CD 3) 2 SO) d: 1.40 (6H, s), 3.30 (2H, brs), 3.91 (3H, s), 4.33 (2H, brs), 7.28 (1H, d, J = 8 Hz), 8.02 (1 H, dd, J = 9.2 Hz), 8.11 (1 H, d, J = 2 Hz), 8.2d (1 H, d, J = 2 Hz), 8.88 ( 1 H, d, J = 2 Hz), 9.86 (2H, brs, exchangeable), 10.73 (1 H, s, exchangeable): m / z (API +): 346.1, 347.2 (MH +: 100%).

EXAMPLE 31 N-f8,8-Dimethyl-5,6,7,8-tetrahydrof1.61naphthyridin-3-yl) -4-methoxy-3-pentafluoroethylbenzamide 1 H NMR (400 MHz. CDCl 3) d: 1.32 (6H, s), 2.96 (2H, s), 3.96 (3H, s), 4.05 (2H, s), 7.13 (1 H, d), 7.93 (1 H , s), 8.04 (1 H, s), 8.06 (1 H, s), 8.44 (1 H, d); m / z (API +): 430 (M + H) +.

EXAMPLE 32 N- (8.8-Dimethyl-5,6,7,8-tetrahydrori.61naphthyridin-3-yl) -4- / so-propoxy-3-trifluoromethylbenzamide 1 H NMR (400 MHz, CD 3 OD) d: 1.41 (6 H, d, J = 6 Hz), 1.70 (6 H, s), 3.63 (2 H, s), 4.71 (2 H, s), 4.96 (1 H, m - overlapped per solvent), 7.40 (1 H, d), 8.32 (1 H, s), 8.34 (1 H, d), 8.73 (1 H, s), 9.46 (1 H, s); m / z (API +): 408 (M + H) +.

EXAMPLE 33 N- (8.8-Dimethyl-5,6,7,8-tetrahydrop.61naphthyridin-3-yl) -4-etl-3-trifluoromethylbenzamide 1 H NMR (400 MHz, CD 3 OD) d: 1.36 (3 H, t, J = 7 Hz), 1.62 (6 H, s), 2.96 (2 H, q), 3.57 (2 H, s), 4.63 (2 H, s), 7.68 (1 H, d), 8.25 (1 H, d), 8.33 (1 H, s), 8.57 (1 H, s), 9.21 (1 H, s); m / z (API +): 378 (M + H) +.

EXAMPLE 34 N-f8.8-Dimethyl-5,6,8-tetrahydrop.61naphthyridin-3-yl) -3-bromo-4- / so-propylbenzamide 1 H NMR (400 MHz: CD3OD) d: 1.32 (6H, d, J = 6 Hz), 1.65 (6H, s), 3.58 (2H, s), 4.67 (2H, s), 7.58 (1 H, d) , 8.02 (1 H, d), 8.26 (1 H, s), 8.63 (1 H, s), 9.32 (1 H, s); m / z (API +): 402, 404 (M + H) +.

EXAMPLE 35 N- (5,6, 8-Tetrahydro-6,8,8-trimetiip.61-naphthyridin-3-yl) -3-chloro-4-ethoxybenzamide 1 H NMR (250 MHz: CDCl 3) d: 1.36 (6H, s), 1.52 (3H, t, J = 7 Hz), 2. 45 (3H, s), 2.53 (2H, s), 3.59 (2H, s), 4.19 (2H, q, J = 7 Hz), 7.00 (1 H, d, J = 7 Hz), 7.64 (1 H , brs), 7.76 (1 H, dd, J = 7.2 Hz), 7.90 (1 H, d, J = 2 Hz), 7.08 (1 H, d, J = 2 Hz), 8.42 (1 H, d, J = 2 Hz); m / z (API +): 3g6.2 (M + Na \ 100%), 374. 2 (MH +: 33%).

EXAMPLE 36 N- (5,6,7,8-Tetrahydro-6,8,8-trimethyl, 61naphyridin-3-yl) -3-fluoro-4-methoxybenzamide 1 H NMR (400 MHz; CDCl 3) d: 1.35 (6H, s), 2.44 (3H, s), 2.50 (2H, s), 3.56 (2H, s), 3.99 (3H, s), 7.03 (1H, t, J = 7 Hz), 7.62 (1 H, d), 7.72 (1 H, s), 7.95 (1 H, d, J = 2 Hz), 8.40 (1 H, d, J = 2 Hz); m / z (API +): 344.2 (MH +; 03%).

EXAMPLE 37 N- (5,6,7,8-Tetrahydro-6,8,8-tritytiri, 61-naphthyridin-3-yl) -4-methoxy-3-pentafluoroethylbenzamide 1 H NMR (400 MHz; CDCl 3) d: 1.35 (6H, s), 2.46 (3H, s), 2.51 (2H, s), 3.57 (2H, s), 3.06 (3H, s), 7.10 (1H, d, J = 7 Hz), 7.71 (1 H, s) 7.03 (1 H, d J = 2 Hz), 8.04 (1 H, d), 8.06 (1 H, d), 8.44 (1 H, d, J = 2 Hz); m / z (API +): 444 (MH +; 00%).

EXAMPLE 38 N- (8,8-Dimethyl-5,6,7,8-tetrahydron-6-naphthyridin-3-n-3-fluoro-4-methoxybenzamide hydrochloride 1 H NMR (250 MHz, CDCl 3) [free base] d: 1.32 (6H, s), 2.20 (2H, s), 3.07 (2H, s), 3.96 (3H, s), 4.04 (2H, s), 7.02 (1 H, t, J = 7 Hz), 7.62 (1 H, d), 7. 64 (1 H, d), 7.95 (1 H, d, J = 2 Hz), 8.44 (1 H, d, J = 2 Hz); m / z (API +): 330 (MH +, 100%).

EXAMPLE 39 N- (8,8-Dimethyl-5,6,8-tetrahydro-6,6-naphthyridin-3-yl) -4-methoxy-3-propionylbenzamide 1 H NMR (250 MHz; CDCl 3) d: 1.18 (3 H, t, J = 7 Hz), 1.32 (6 H, s), 2.96 (2 H, s), 3.05 (2 H, q, J = 7 Hz), 3.9 g (3H, s), 4.05 (2H, s), 7.11 (1 H, d, J = 7 Hz), 7.07 (1 H, d J = 2 Hz), 8.11 (2H, d), 8.16 (1 H, d), 8.45 (1 H, d); m / z (API +): 3g? (MNa +, 03%), 368 (MH + 80%).

EXAMPLE 40 N- (5,6,7,8-Tetrahydro-6,8,8-trimethylM, 61-naphthyridin-3-yl) indole-2-carboxamide 1 H NMR (250 MHz: CDCl 3 + CD 3 OD) d: 1.34 (6H, s), 2.46 (3H, s), 2.56 (2H, s), 3.60 (2H, s), 7.20-7.00 (6H, m), 8.12 (1 H, d, J = 2 Hz), 8.40 (1 H, d, J = 2 Hz), 8.60 (1 H, brd, J = 8 Hz); m / z (API +): 335.2 (MH +, 100%).

PHARMACOLOGICAL DATA 1. Binding test method WO 92 / 222g3 (SmithKine Beecham) describes compounds having anticonvulsant activity, including, among others, the compound frans (+) - 6-acetyl-4S- (4-fluorobenzoylamino) -3,4- dihydro-2,2-d-methyl-2H-1-benzopyran-3R-ol (hereinafter referred to as compound A). It has been found that WO g2 / 22293 compounds bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18660 (SmithKine Beecham). The affinity of the test compounds for the novel receptor site is determined in the following manner. Method Complete rat forebrain tissue is obtained. First, the tissue is homogenized in buffer solution (usually Tris / 50 mM HCl, pH 7.4). The homogenized fabric is washed by centrifugation and resuspension in the same buffer solution; then store at -70 ° C until use. To carry out the radioligand binding test, aliquots of the tissue prepared above (usually at a concentration of 1-2 mg protein / ml) are mixed with aliquots of [3H] -Compound A dissolved in buffer solution. In general, the final concentration of [3H] -Compound A in the mixture is 20 nM. The mixture is incubated room temperature for 1 hour. The [3H] -Compound A bound to the tissue of the unbound [3H] -Compound A is then separated by means of filtration through Whatman GF / B glass fiber filters. The filters are then washed quickly with ice-cold buffer. The amount of radioactivity bound to the tissue trapped on the filter is measured by the addition of a liquid scintillation cocktail to the filters, followed by counting in a liquid scintillation counter. To determine the "specific" binding amount of [3 H] -Compound A, parallel tests are carried out as described above, in which [3 H] -Compound A and tissue are incubated together in the presence of unlabeled Compound A ( usually 3 M). The amount of binding of [3H] -Compound A remaining in the presence of this unlabeled compound, is defined as "non-specific" binding. This amount is subtracted from the total amount of binding of [3H] -Compound A (ie, which is present in the absence of the unlabeled compound), to obtain the "specific" binding amount 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 the [3 H] -Compound A and tissue, in the presence of a range of concentrations of the compound to be tested. The reduction of the specific binding level of [3 H ] -Composed A as a result of competition when increasing the concentrations of the compound under test, and non-linear regression analysis of the resulting curve is used to give an estimate of the affinity of the compound in terms of the value of pKi. Results The compounds of were active in this test with pK1 > 6. For example, the compounds of Examples 2-11 and 26-34 gave pKi values greater than 8. 2. MEST test The maximum electroshock seizure threshold test (MEST) in rodents is particularly sensitive to detect potential anticonvulsant properties1. In this model, anticonvulsant agents raise the threshold for electrically induced seizures, while proconvulsants reduce the seizure threshold. Method for mouse model Randomly assigned mice (male, intact, Charles River ,. United Kingdom, strain CD-1, 25-30 g) in groups of 10-20, and dosed orally or intraperitoneally at a volume dose of 10 ml / kg with various amounts of compound (0.3-300 mg / kg) or vehicle. The mice are then subjected, 30 or 60 minutes after the dose, to a simple electro-shock (0.1 sec, 50 Hz, sinusoidal waveform) administered by means of horn electrodes. The common mean and the standard error required to induce a tonic seizure in 60% of the mice (CC5o) in a particular treatment group, are determined by the method of "up to below "by Dixon and Mood (1948) 2. Statistical comparisons are made between vehicle-treated and drug-treated groups using the Litchfield and Wilcoxon method (ig4g) .3 In control animals, the CC50 is usually 14-18 mA. Therefore, the first animal in the control group is subjected to a current of 16 mA.If a tonic seizure does not occur, the current is increased for a subsequent mouse.If a tonic seizure occurs, then the current is reduced, and so on, until all the animals in the group have been tested.? 10 Studies are carried out using a Hugo Sachs Electronik constant current shock generator with fully variable shock level control from 0 to 300 mA, and commonly used 2 mA steps Method for rat model 15 The threshold for maximum convulsion (tonic extension of the hind paw) was determined by electric shock in male rats (Sprague Dawley, w 80-150 g, 6 weeks old) by means of of an est Hugo Sachs Electronik imulator, which supplied a constant current (0.3 sec. of duration; of 1- 300 mA in steps of 5-20 mA). The procedure is similar to the one described above for mouse, and full details are like those that / publish Upton and others4.

The percent increase or reduction of CC50 is calculated for each group compared to the control. The drugs were suspended in 1% methylcellulose. Results At a dose of 2 mg / kg orally, in 2 hours, the compounds of examples 3 and d showed increases in the rat model of 314% and 360%, respectively.

REFERENCES 1. - Loscher, W. and Schmidt, D. (1088), Epilepsy Res. 2, 146-181. 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), ß. J. Pharmacol, 121, 1679-1686.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: (l) wherein R 1 is hydrogen, C 1-6 alkyl (optionally substituted with hydroxy or C 1-4 alkoxy), phenyl (C? -) alkyl, C? -6 alkenyl or Ci-β alkynyl; R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3SO2-, CF3CO-, C1-6 alkyl, C? -6 alkenyl of C? -6 alkynyl, perfluoroalkyl of C? -6, cycloalkyl of JC3.6, cycloalkyl Cs-eJ-alkylCi ^) -, alkyl (C? -6) -O-, alkyl (C1-6) -CO-, cycloalkyl (C3-6) -0 -, (C3-6) cycloalkyl-CO-, cycloalkyl Cs-dJ-alkyl / Ci.-O-, cycloalkyl-.Cs.e) -alkyl (C? -4) -C0-, phenyl, phenoxy, benzyloxy , benzoyl, phenyl (C 1-4 alkyl) -, alkyl (C? -6) -S-, (C 1-6) -SO 2 - alkyl, (C 1-4 alkyl-NSO 2 -, alkyl (C? -4 ) NHSQ2-, (C? -4.2-NCO- alkyl, (C? 4) alkyl -NHCO- or CONH2; or -NR5R6, wherein R5 is hydrogen or C? -4 alkyl, and R6 is hydrogen, C 1-4 alkyl, formyl, -CO-C 1-4 alkyl, or C 1-4 -CO-alkyl, or two R 2 groups together form a carbocyclic ring that is saturated or unsaturated, optionally interrupted by O or NH; the groups R3 and R4 are each independently hydrogen or C1-6alkyl, and / or the two groups R3 and / or the two groups R4, together form a spiroalkyl ring of C3-6; with the proviso that at least one group R3 or R4 is not hydrogen; and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy. 2. A compound according to claim 1, further characterized in that it has the formula (IA):

(IA)

3. - A compound according to claim 1, further characterized in that it has the formula (IB): (IB)

4. A compound selected from the group consisting of: N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) benzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-cyano-4- / so-propylbenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -4-methoxy-3-trifluoromethyl-benzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1) 6] naphthyridin-3-yl) -3-bromo-4-ethylbenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimetyl [1,6] naphthyridin-3-yl) -3-bromo-4-ethoxybenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] naphthyridin-3-yl) -3-chloro-d-4- / so-propyloxybenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-bromo-4- / so-propyloxybenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] -naphthyridin-3-yl) -3-acetyl-4- / so-propyloxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridi-3-yl) -4-ethoxy-3-trifluoromethylbenzamide; N- (8,8-dimethyl-5,6,7,8-tetrahydro [1,6] naphthyridin-3-yl) -4-methoxy-3-trifluoromethylbenzamide; N-0 (d, 6,7,8-tetrahydro-6,8,8-trimetyl [1,6] naphthyridin-3-yl) -3-bromo-4-methoxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-chloro-4-methoxy-benzamide; N-5,6,7,8-tetrahydro-6,8,8-trimetyl [1,6] naphthyridin-3-yl) -3-cyano-4-methoxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3- cyano-4-ethylbenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] naphthyridin-3-yl) -3-d bromo-4-methylbenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthridin-3-yl) -3-pivaloylbenzamide; N-ßS.βJ.β-tetrahydro-ß.β.β-trimethylthl.β-naphthyridin-S-ylJ-d-chloro-2-methoxy-4- / so-propyloxybenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] naphthyridin-3-yl) -3-cyano-4-ethoxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -4-methoxy-3-trifluoroacetylbenzamide; N- (5,6,7,8-0-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) naphthalene-2-carboxamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthridin-3-yl) -3-cyano-4- / so-propyloxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-acetyl-4-ethylbenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -2,3-dihydrobenzofuran-5- carboxamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -3-n-butyroyl-4-methoxybenzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -4-methoxy-3-n-propionylbenzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] -naphthyridin-3-yl- / so-butyroyl-4-methoxy-benzamide; N- (8, 8-dimethyl-5,6,7,8-tetrahydro-d [1,6] naphthyridin-3-yl) -4-ethoxy-3-trifluoromethylbenzamide; N- (8,8-dimethyl-d, 6, 7,8-tetrahydro [1, 6] naphthyridin-3-yl) -3-acetyl-4- / so-propyloxybenzamide; N- (8,8-dimethyl-6,7,8-tetrahydro [1,6] ] naphthyridin-3-yl) -3-bromo-4-methoxybenzamide; N- (8,8-dimethyl-d, 6,7,8-tetrahydro [1,6] naphthyridin-3-yl) -3-chloro- 4-methoxybenzamide; N- (8,8-dimethyl-5,6,7,8-tetrahydro [1,6] naphthyridin-3-yl) -4-methoxy-3-pentafluoroethyl-0-benzamide; N- ( 8,8-dimethyl-d, 6,7,8-tetrahydro [1, 6] naphthyridin-3-yl) -4- / so-propoxy-3-trifluoromethylbenzamide; N- (8,8-dimethyl-d, 6) 7,8-tetrahydro [1,6] naphthyridin-3-yl) -4-ethyl-3-trifluoromethylbenzamide; N- (8,8-dimethyl-5,6,7,8-tetrahydro [1,6] ] naphthyridin-3-yl) -3-bromo-4- / so-propyl benzamide; N- (d, 6,7,8-tetrahydro-6,8,8-trimethyl [1, 6] - naphthyridin-3 il) -3-chloro-4-ethoxy-benzamide; N- (5,6,7,8-tetrahydro-6,8,8-trimethyl-d [1,6] naphthyridin-3-yl) -3- fluoro-4-methoxybenz amide; N- (d, 6,7,8-tetrahydro-6,8,8-tr'methyl [1,6] naphthyridin-3-yl) -4-methoxy-3-pentafluoroethylbenzamide; N- (8,8-dimethyl-d, 6,7,8-tetrahydro [1,6] naphthridin-3-yl) -3-fluoro-4-methoxybenzamide; N- (8,8- d -methyl-d, 6,7,8-tetrahydro [1,6] naphthyridin-3-yl) -4-methoxy-3-propionylbenzamide, and N- ( d, 6,7,8-tetrahydro-6,8,8-trimethyl [1,6] naphthyridin-3-yl) -indole-2-carboxamide. 0 d.- 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, effects associated with abstinence from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 deficits associated with AIDS, sleep disorders (including heart rhythm disorders, insomnia and / or narcolepsy), tics (for example, Giles de la Tourette syndrome) , traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease, ataxia, rigidity muscle (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS); comprising a compound as claimed in any of the preceding claims, and a pharmaceutically acceptable carrier. 6. The use of a compound claimed in any of claims 1-4, for the manufacture of a medicament for the treatment and / or prophylaxis of anxiety, mania, depression, panic disorders and / or aggression, associated disorders with a subarachnoid hemorrhage or neural shock, effects associated with abstinence from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders that can be treated and / or prevented with anticonvulsant 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 deficits associated with AIDS, sleep disorders ( including heart rhythm disorders, insomnia and / or narcolepsy), tics (for example, Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, activity inappropriate neuron that causes neurodistheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disease, ataxia, muscle stiffness (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS). 7. A process for the preparation of the compounds claimed in any of claims 1 to 4, which comprises reacting a compound of formula (II) (II) wherein R1A, R3A, R4A, X, are R1, R3 and R4, X, as defined for formula (I), or a group or groups convertible into R1, R3 and R4, X; with a compound of formula (III) (III) wherein Y is a leaving group, and groups R2A are independently R2 as defined for formula (I), or a group or groups convertible to R2, and wherein it is required to convert a group R1A, R2A, R3A, R4A, X in a group R1, R2, R3, R4, X, convert a group R1, R2, R3, R4, X, into another group R1, R2, R3, R4, X, or convert a salt product into the free base or another pharmaceutically acceptable salt, or separating any enantiomer, or converting a free base product to a pharmaceutically acceptable salt. SUMMARY OF THE INVENTION Compounds of formula (I) and their pharmaceutically acceptable salts and solvates, wherein R 1 is hydrogen, C 1-6 alkyl (optionally substituted with hydroxy or C 1-4 alkoxy), phenyl (C 1-4 alkyl) -, C? -6 alkenyl or Ci-β alkynyl; R 2 is hydrogen or up to three substituents selected from halogen, N 0 2, CN, N 3, CF 3 O-, CF 3 S-, CF 3 SO 2 -, CF 3 CO-, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, perfluoroalkyl -6, cycloalkyl of. C3-6, O-, (C 3-6) cycloalkyl-CO-, (C 3-6) cycloalkyl- (C 1-4) -0- alkyl, (C 3-6) cycloalkyl- (C 1-4) -CO- alkyl, phenyl , phenoxy, benzyloxy, benzoyl, phenyl (C? -4 alkyl) -, alkyl (C? -6) -S-, alkyl (C? -6) -S02-, (C1-4 alkyl) 2-NS02 -, alkyl (C? -4) NHS02-, (C 1-4 alkyl-NCO-, alkyl (C? -4) -NHCO- or CONH; or -NR5R6, wherein R5 is hydrogen or d- alkyl, and Rd is hydrogen, C1-4alkyl, formyl, -CO2-C4-4alkyl, or -CO-C1-4alkyl; or two R2 groups together form a carbocyclic ring that is saturated or unsaturated, optionally interrupted by O or NH; the groups R3 and R4 are each independently hydrogen or C1-6alkyl, and / or the two groups R3 and / or the two groups R4, together form a Spiroalkyl ring of O. ^; with the proviso that at least one group R3 or R4 is not hydrogen; and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy; They are useful in the treatment and prophylaxis of epilepsy, migraine and other disorders. d 0 5 EA / cgt P00 / 1794F