MXPA00008690A - Glycine transport inhibitors - Google Patents

Abstract

The present invention is concerned with the use of glycine transport inhibiting [4,4-bis(4-fluorophenyl)butyl]-1-(piperazinyl and piperidinyl) derivatives for the preparation of medicaments for treating disorders of the central and peripheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further comprises novel compounds, their preparation and their pharmaceutical forms.

Description

GLYCINE TRANSPORTATION INHIBITORS The present invention relates to the use of [4,4-bis- (4-fluorophenyl) butyl] -1- (piperazinyl and piperidinyl) derivatives which inhibit the transport of glycine for the preparation of medicaments for treating disorders of the central nervous system. and peripheral, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), cerebrovascular accidents, cranial trauma, multiple sclerosis and the like. Additionally, the invention comprises novel compounds, their preparation and their pharmaceutical forms. The derivatives of [4,4-bis (4-fluorophenyl) butyl] -1- (piperazinyl and piperidinyl) are already known histamine and serotonin agonists. These compounds, their activity and preparation were described in EP-A-0,151,826 and GB-, 055,100. The present invention relates to the use of compounds that inhibit the transport of glycine for the preparation of medicaments for treating disorders of the central and peripheral nervous system, said compounds having the formula the? / - oxides, the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof, wherein X represents CH or N; L represents a radical of formula where n is 0 or 1; m is 0 or 1 Alk represents alkenidiyl of C-i-β; A represents N or CH; B1 represents CH2 or NH; -a1 = a2-a3 = a4 -represents a bivalent radical of formula -CH = CH-CH = CH- (a-1); or -N = CH-CH = CH- (a-2); R 1 represents a C?-Alkyl optionally substituted with C 1-pyridinyl alkyloxy, aryl, arylcarbonyl, thienyl, furanyl, imidazo [1,2-a] pyridinyl, thiazolyl; R 2 represents hydrogen or aryl; R3 represents hydrogen, C-? -6 alkyl or C3.7 cycloalkyl; R4 represents thienyl, furanyl, arylamino or a radical of formula where R 5 is hydrogen or aryl: aryl represents phenyl optionally substituted with one or two substituents selected from C 1-4 alkyl, halo, hydroxy, C 1-4 alkyloxy. The present invention also relates to a method for treating hot-blooded animals exhibiting such disorders of the central and peripheral nervous system, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's), carotid accident, cranial trauma, multiple sclerosis and similar. Said method comprises the administration of a therapeutically effective amount of a compound of formula (1) or an? -oxide form, an isomeric form stereochemically or an acid addition salt or pharmaceutically acceptable base thereof in a mixture with a pharmaceutical carrier. As used in the definitions herein, halo is a generic for fluorine, chlorine, bromine and iodine; C3-7 cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1.4alkyl defines straight or branched chain saturated hydrocarbon radicals having from one to four carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2- dimethylethyl and the like; C? -6 alkyl means that it includes C-? alkyl and higher homologs thereof having 5 or 6 carbon atoms, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C-α-C6-alkynediyl defines straight-chain or branched-bivalent saturated hydrocarbon radicals having from one to 6 carbon atoms, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl and the like The pharmaceutically acceptable addition salts as recited herein means that they comprise the non-toxic active therapeutically active base or acid forms which can form the compounds of formula (I). The acid addition salt form of a compound of formula (I) which is presented in free form as a base obtainable by treatment of said free base form with a suitable acid such as an inorganic acid, for example, hydrohalic acid, example, hydrochloric or hydrobromic, sulfuric, nitric, phosphoric acids and the like; or an organic acid, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p -aminosalicylic, pamoic and the like. The compounds of formula (I) containing acidic protons can be converted to their therapeutically active non-toxic base, i.e. metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkaline earth metal and alkali metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example, benzathine salts, n-methyl-D-glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine and the like. On the contrary, said salt forms can be converted to free forms by treatment with a suitable base or acid. The term "addition salt" as used herein also encompasses the solvates that the compounds of formula (I), as well as the salts thereof, can form. Such solvates are, for example, hydrates, alcoholates and the like. The? / -oxide forms of the compounds of formula (I) mean that they comprise those compounds of formula (I) wherein 1 or various nitrogen atoms are oxidized to form the known? / - oxide.

The term "stereochemically isomeric forms" as used herein defines all possible stereoisomeric forms in which the compounds of formula (I) may be present. Unless otherwise mentioned or indicated, the chemical designation of the chemical compounds denotes the mixture and in particular the racemic mixture of all isomeric forms stereochemically, said mixtures contain all the diastereomers and enantiomers of basic molecular structure. Stereochemically isomeric forms of the compound of formula (I) and mixtures of such forms have obviously been created to be included in formula (I). In particular, the compounds of formula (I) and some of the intermediates herein have at least one stereogenic center in their structure. This stereogenic center can be present in an R and S configuration, said notation R and S is used in correspondence with rules described in Appl. Chem., 1976, 45. 11-30. Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, were created with the intention of being included within the scope of the present invention. When used herein, the term compounds of formula (I) means that it also includes the forms of N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms.

The present compounds of formula (I) are considered novel since - when X is CH; L is a radical of formula (a) wherein B1 is -CH2- and R1 is pyridin-2-ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then -a1 = a2-a3 = a4- is different from -N = CH-CH = CH-; and - when X is CH; L is a radical of formula (a) wherein B1 is -CH2- and R1 is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -a1 = a2-a3 = a4- is different from -CH = CH-CH = CH -; and - when X is N; L is a radical of formula (d) wherein Alk is 1,3-propanediol, then R 4 is different from phenylamino. The present invention also relates to the novel compounds of the formula (I) as defined herein for use as a medicine. An interesting group of compounds are the compounds of formula (I) wherein n is 0, m is 1; R1 is C1-4alkyl optionally substituted by C- [alpha] - [alpha] alkyloxy, arylcarbonyl or imidazo [1,2, a] pyridinyl and R4 is thienyl, furanyl or a radical of formula (d-1). they prefer are the compounds of formula (I) wherein L is a radical of formula (a) or (b). In general, the compounds of formula (I) can be prepared according to the reaction methods described in the documents EP-A-0,151, 826 and GB-1, 055,100, in particular by reacting an intermediate of formula (II) wherein W 1 is a suitable leaving group, such as, for example, a halogen, with an intermediate of formula (III).

F (CH2) 3-W1 +? ~? H-N X- L (O \ / (") (III) Said reaction may be carried out in an inert reaction solvent, for example, methyl isobutyl ketone, V, / Vdimethylacetamide or N, N-dimethylformamide, in the presence of a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine, and optionally in the presence of potassium iodide. In this and the following preparations, the reaction products can be isolated from a reaction medium and, if necessary, further purified according to the methodologies generally known in the art for example extraction, crystallization, distillation, trituration and chromatography Alternatively, the compounds of formula (I) can be prepared by reductive alkylation. An intermediate of formula (IV) is subsequently reacted with an intermediate of formula (III) in an inert reaction solvent, for example, methanol, in the presence of a reducing agent such as, for example, hydrogen in the presence of a suitable catalyst, for example , palladium on activated carbon. Conveniently, thiophene is added to the reaction mixture.

(IV) (III) The compounds of formula (I) wherein X is N, said compounds being represented by formula (Ia), can be prepared by reaction of an intermediate of formula (V) with an intermediate of formula (VI) wherein W1 is a group Suitable protrusion, such as halogen.

(V) (VI) (r-a) Said reaction can be carried out in an inert reaction solvent, for example, methyl isobutyl ketone, V, V-dimethylacetamide or N, N-dimethylformamide, in the presence of a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine, and optionally in presence of potassium iodide.

The compounds of formula (I) wherein L is a radical of formula (b), said compounds being represented by formula (lb), can be prepared by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII) ). (l-b) Said reaction can be carried out in an inert reaction solvent such as diisopropyl ether. The compounds of formula (I) can also be converted into each of the processes known in the art of transforming the functional group. The compounds of formula (I) can also be converted to the corresponding / V-oxide forms following art-known procedures for converting triva nitrogen into its / V-oxide form. Said? -oxidation reaction can generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxazidine or with a suitable organic or inorganic peroxide. Inorganic peroxides 1 suitable include, for example, hydrogen peroxide, alkaline earth metal peroxides or alkali metals, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxyacids, for example, benzecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkylhydroperoxides, for example, t-butylhydroperoxide. Suitable solvents are for example, water, lower alkanols, for example, ethanol and the like; hydrocarbons, for example, toluene; ketones, for example 2-butanone; halogenated hydrocarbons, for example, dichloromethane and mixtures of such solvents. Some of the compounds of formula (I) and some of the intermediates of the present invention may contain an asymmetric carbon atom. The stereochemically pure isomeric forms of said compounds and said intermediates can be obtained by the application of procedures known in the art. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatography techniques, for example countercurrent distribution, liquid chromatography and similar methods. The enenatiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as chiral acids, to mixtures of salts or diastereomeric compounds; then physically separating said mixtures of diastereomeric salts or compounds, for example by selective crystallization or chromatographic techniques, for example liquid chromatography and similar methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Stereochemically isomeric forms can also be obtained from stereochemically isomeric forms of the suitable intermediates and starting materials, since the intervening reactions occur stereospecifically. An alternative way to separate the enantiomeric forms of the compounds of formula (I) and the intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared in accordance with procedures known in the art. Glycine is a neurotransmitter of amino acids in the central and peripheral nervous system, in synapses of inhibition and excitation. These different functions of glycine are mediated by two types of receptors, each of which is associated with a different class of glycine transporter. The actions of glycine inhibition are mediated by glycine receptors that are sensitive to the alkaloid convulsant strychnine, and are therefore referred to as strychnine sensitive. Glycine receptors sensitive to strychnine are found predominantly in the brainstem and spinal cord. Glycine functions in excitatory transmission by modulating the actions of glutamate, the main excitatory neurotransmitter in the nervous system (Johnson and Ascher, Nature, 325, 529-531 (1987)).; Fletcher et al., Glycine Transmission, (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219). Specifically, glycine is a mandatory co-agonist in the class of glutamate receptor called N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are widely distributed throughout the brain, with high density particularly in the cerebral cortex in the hippocampal formation. The transporters take the neurotransmitter from the synapse, thereby regulating the concentration and terminus of the neurotransmitter at the synapse, which determines the magnitude of the synaptic transmission. By preventing the diffusion of the neurotransmitter to nearby synapses, transporters maintain their fidelity in synaptic transmission. Finally, by means of the reabsorption of the transmitter released in the presynaptic terminal, the conveyors allow the reuse of the transmitter. The neurotransmitter transport depends on the extracellular sodium and the voltage difference in the membrane. Under specific conditions, for example during an attack, the transporters can function in reverse, releasing the neurotransmitter in a non-exocytotic manner independent of calcium (Attwell et al., Neuron, H, 401-407 (1993)). The modulation of neurotransmitter transporters in this way provides a means to modify synaptic activity, which provides a useful therapy for the treatment of central and peripheral nervous system disorders. Molecular cloning has revealed the existence of two types of glycine transporters, called GlyT-1 and GlyT-2. Glyt-1 is predominantly found in the forebrain, and its distribution corresponds to the glutamatergic trajectories and NMDA receptors (Smith, et al., Neuron, 8, 927-935 (1992)). At least three splice variants of GlyT-1 are known, called GlyT-1a, GlyT-1 by GlyT-1c (Kim, et al., Molecular Pharmacoloqv., 45, 608-617 (1994)), each of the which shows a unique distribution in brain and peripheral tissues. In contrast, GlyT-2 is found predominantly in the brainstem and spinal cord, and its distribution corresponds closely to that of strychnine responsive glycine receptors (Liu et al., J Biological Chemistry., 268 ,. 22802-22808 (1993); Jursky and Nelson Neurochemistry, 64, 10261033 (1995)). In this way, it can be expected that by regulating the synaptic levels of glycine, GlyT-1 and GlytT-2 the activity of NMDA receptors and strychnine responsive glycine receptors, respectively, is selectively modulated. In this way it would be expected that compounds that inhibit or activate glycine transporters will alter the receptor function, and provide therapeutic benefits in a variety of disease states. In this way, inhibition of GlyT-2 could be used to decrease the activity of neurons having strychnine-sensitive glycine receptors by increasing synaptic levels of glycine, and to decrease the transmission of pain-related (ie nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 37, 111-123 (1989). In addition, by improving inhibitory glucyrenergic transmission through strychnine responsive strychnine receptors in the spinal cord, they can be used to decrease muscle hyperactivity, which is useful in the treatment of disorders or conditions associated with increased muscle contraction, such as spasticity, myoclonus and epilepsy (Truong et al., Movement Disorders, 3, 77-87 (1988); Becker, FASEB J, 4 2767-2774 (1990)). Spasticity that can be treated by modulating glycine receptors is associated with epilepsy, stroke, cranial trauma, multiple sclerosis, spinal cord damage, dystonia and other conditions of disease and nervous system damage. NMDA receptors are involved in memory and learning processes (Rison and Stanton, Neurosci, Biobehav, Rev., 19, 533 552 (1995); Danysz et al., Behavioral Pharmacol .. 6, 455-474 (1995)); and apparently a decreased function of NMDA-mediated neurotransmission contributes to the symptoms of schizophrenia (Olnay and Farber, Archives General Psychiatry, 52, 998-1007 (1996).) Thus, agents that inhibit GlyT-1 and increase this Thus, glycine activation of NMDA receptors can be used as novel antipsychotic and anti-dementia agents and to treat other disorders where cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. NMDA receptors have been implicated in a number of disease states, in particular neuronal death associated with stroke, cranial trauma and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, dementia caused by AIDS, Huntington, Parkinson's disease, amyotrophic lateral sclerosis or other conditions where the death of neuronal cells occurs. Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton and Rosenberg, New Enal. i. of Medicine. 330, 613-622 (1993); Choi, Neuron i, 623-634 (1988). In this manner, pharmacological agents that increase the activity of Gly-T-1 will result in decreased glycine activation of NMDA receptors, whose activity can be used to treat these and related disease states. Similarly, drugs that directly block the glycine site at NMDA receptors can be used to treat these and other related disease states. For administration purposes, subject compounds can be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a novel compound of formula (I). To prepare the pharmaceutical compositions of the present invention, an effective amount of the particular compound in addition salt or in free acid or in base form, as the active ingredient is combined in a mixture with a pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in a suitable unit dosage form, preferably for oral, percutaneous or parenteral injection. For example, in the preparation of oral dosage form compositions, any of the pharmaceutical media, for example water, glycols, oils, alcohols and the like may be used in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, capsules, pills and tablets. Due to the ease of administration, tablets and capsules represent the oral unit dosage form that has the most advantages, where solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients may also be included, for example to aid in solubility. For example, injectable solutions can be prepared wherein the vehicle comprises a saline solution, glucose solution or a mixture of saline and glucose. Injectable solutions containing the compounds of the formula (I) can be formulated in an oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids and mixtures thereof, as well as other oils. Injectable suspensions can also be prepared, in which case suitable liquid carriers may be employed as suspending agents and the like. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant damaging effects on the skin. Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, for example, as a transdermal patch or as an ointment. The addition salts of the formula (I) due to their increased solubility in water over the corresponding free acid form or free base, are obviously more suitable in the preparation of aqueous compositions. It is especially useful to formulate the aforementioned pharmaceutical compositions in dosage unit forms for ease of administration and uniformity of dosage. The dosage unit form as used in this description and claims herein refers to units physically suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier . Examples of such dosage unit forms are tablets (including coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, scoops and the like, and segregated multiples thereof. The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART EXAMPLE A.1 A mixture of 1-chloro-4,4-bis (4-fluorophenyl) butane (5.6 g), 4- (1, 2,3,4-tetrahydro-2-oxo-3-quinazolinyl) piperidine (3.5 g), Sodium carbonate (6.36 g), some Kl crystals in methyl isobutyl ketone (160 ml) was stirred and refluxed for 2 days. After cooling, water (250 ml) was added.

The separated organic layer was dried, filtered and the solvent was evaporated. The residue was recrystallized from methyl isobutyl ketone (80 ml), yielding 3 g of 3- [1- [4,4-bis (4-fluoromethyl) butyl] -4-piperidinyl] -3,4-dihydro-2 (1 H) -quinazolinone; pf. 199-200.5 ° C (compound 1). In an analogous way, it was prepared: Etandioate of 4- [2- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] acetyl] -3,4-dihydro-3-phenyl-2 (1H) -quinolone ( 1: 1); pf. 190.8 ° C (compound 2); Y- [1 - [4,4-bis (fluorophenyl) butyl] -4-piperidinyl] -1 - (imidazo [1,2- a] pyridin-2-methyl) - 1-benzimidazol-2-amine; pf. 160.1 ° C (compound 3); Etandioate of 2 - [[4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinylmethyl] -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] pyridine (1 :2); pf. 173.2 ° C (compound 4); 3- [1 - [4,4-bis (4-fluoromethyl) butyl] -4-p-peridinyl] -3,4-dihydro-pyrid [2,3-d] -2-hydrochloride (1 / - y) -pyrimidonone; pf. 220-222 ° C (compound 5).

EXAMPLE A.2 A mixture of 4-fluoro-? - (4-fluorophenyl) benzenebutanal (2.6 g), 1- (4-fluorophenyl) -3- [2- (4-piperidinylmethyl) -l? -benzimidazole-1-diborohydride -l] -1-propanone monohydrate (5.5 g), a solution of thiophene in 3% ethanol (1 g), potassium acetate (3 g) and methanol (200 ml) was hydrogenated at normal pressure and at 50 ° C with a 10% palladium on carbon catalyst (2 g). After the calculated amount of hydrogen was absorbed, the catalyst was filtered and the filtrate was evaporated. Water was added to the oily residue and the whole was made alkaline with ammonium hydroxide. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The oily residue was converted to the ethanedioate salt in acetonitrile and 4-methyl-2-pentanone. The salt was allowed to crystallize. The product was filtered and dried yielding 5 g (63.3%) of 3- [2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl ethanedioate] -1 - / -benzimidazol-1-yl] -1- (4-fluorophenyl) -1-propanone (1: 2); mp 156.4 ° C (compound 6).

EXAMPLE A.3 A mixture of 1- [4,4-bis (4-fluorophenyl) butyl] piperazine (6.9 g), 4-chloro-1- (2-thienyl) -butanone (4.1 g), sodium carbonate (3.18 g), some crystals of potassium iodide in 4-methyl-2-pentanone (200 ml) were refluxed for 24 hours. Subsequently a second portion of 4-chloro-1- (2-thienyl) butanone (4.1 g) was added and the whole was stirred and refluxed for 36 more hours After cooling, water (100 ml) was added. The organic layer was separated, dried over potassium carbonate, filtered and evaporated. The oily residue was dissolved in anhydrous ether (480 ml). The solution was filtered and gaseous hydrogen chloride was introduced into the filtrate. The salt of the precipitate was filtered and crystallized from 2-propanol (320 ml), yielding 4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinyl] -1- (2-thienyl) butanone; pf. 227.5-230 ° C (compound 7).

EXAMPLE A.4 To a stirred solution of 1- [4,4-bis (4-fluorophenyl) butyl] - / V- (4-methoxyphenyl) -4-piperidinamine (6.75 g) in 2,2'-oxybispropane (105 ml) and tetrahydrofuran. (45 ml) was added dropwise a solution of 2-isocyanatopropane (1.36 g) in 2,2'-oxybispropane (35 ml). At the end, stirring was continued, first for 1 day at room temperature and then for 1 hour at about 50 ° C. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding / V- [1- [4,4-bis (4-fluorophenyl) but! l] -4-piperidinyl] -? / - (4-methoxyphenyl) -? and '- (1-methylol) urea (4.8 g, 59%); pf. 170.9 ° C (compound 8). The following was prepared analogously:? _!; [4j4_b¡s (4-fluorophenyl) butl] -4-piperidinyl] - / V'-butyl- / V- (4-methoxyphenyl) urea; pf. 101.9 ° C (compound 9); ? / - [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -? / - (4-methoxy-phenyl) -? / - propyl-urea; pf. 124.1 ° C (compound 10); ? / - [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -? And'-cyclohexyl- / V- (4-methoxyphenyl) urea; pf. 128.2 ° C (compound 11); ? - [1- [4,4-bis (4-fluorophenyl] butyl] -4-piperidinyl] - / V'-ethyl-? / - (4-methylphenyl) urea; pf. 129.1 ° C (compound 12); V- [1- [4,4-bis (4-fluorophenyl) butyl] -4-p-peridinyl] -? / '- (1-methylethyl) - / V- (4-methylphenyl) urea; pf. 167.2 ° C (compound 13); and 3 ? / - [1- [4I4-bis (4-fluorophenyl] butyl] -4-piperidinyl] -? / '- (4-chlorophenyl) - / V' - (1-methylethyl) urea; pf. 157.4 ° C (compound 14).

PHARMACOLOGICAL EXAMPLE EXAMPLE B.1 Transport analysis using GlyT1 conveyors Subconfluent HEK 293 -GlyT1 cells (i.e., a cell line stably expressing human glycine transporter 1) were seeded in Cytostar-T plates at a concentration of 50,000 cells per well in 100 μl of DMEM medium. Dulbecco's Eagle supplemented with 10% fetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine, 100 U penicillin / ml and 0.1 mg / ml streptomycin). The cells were incubated for 48 hours at 37 ° C, 5% CO2, 95% humidity. On day 3, the cells were washed using a Tecan PW96 microprocessor controlled scrubber designed to simultaneously wash the 96 wells of a microplate with an absorption pH regulator (25 mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate , 0.8 mM MgSO4, 140 mM NaCl, 5 mM glucose, 5 mM alanine, adjusted to pH 7.5 with 2M Tris). Tecan PW96 was programmed to wash the cells five times, leaving 75 μl in each well. The test compounds were dissolved at different concentrations in the micromolar range in DMSO. 1 μl of test solution was added to each well and the cells were incubated for 5 to 10 minutes at room temperature. Subsequently, 25 μl 30 μM [U14 Cjglicina diluted in absorption pH regulator was added. The cells were incubated for 1 hour at room temperature. The plates were subsequently sealed and the absorption of [U14C] glycine was determined in a Packard microplate scintillation counter (TopCount). From the results obtained for various concentrations of each test drug, the concentration giving 50% inhibition (IC5o) of glycine absorption was calculated. The data calculated for the test compounds according to the present invention are shown in table 1 as plC50 values (negative record values of IC5o). Compound 15 being ethanedioate of 2 - [[1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-pyridinylmethyl) -3- -imidazole [4,5 -b] pyridine (1: 2); Compound 16 being ethanedioate of 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3 - [(4-fluorophenyl) methyl) -3 and- imidazole [4,5-bjpyridine (1: 2); Compound 17 being ethanedioate of 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-p-peridinyl-3-methyl] -3- (phenylmethyl) -3-imidazo [4,5-b] pyridine compound 18 being ethanedioate of 2 - [[1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-thienylmethyl) -3 - / - imidazole [4, 5-b] pyridine (1: 1); Compound 19 being ethanedioate of 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-furanylmethyl) -3- -imidazole [4,5-b ] pyridine (1: 2); Compound 20 being ethanedioate of 2 - [[1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3 - [(4-methoxy-phenyl) -methyl] -1f-benzimidazole ( 1: 2); Compound 21 being 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (4-thiazolyl-methyl) -1H-benzimidazole ethanedioate (1 :2); as described in EP-A-0,151,826; And compound 22 being 1- [4,4-di (4-fluorophenyl) butyl] -4- [3-anilinocarbonyl] -propyl] -piperazine dihydrochloride as described in GB-1, 055,100 were also tested.

TABLE 1 C. EXAMPLES PE COMPOSITION The following formulations exemplify typical pharmaceutical compositions suitable for systemic administration to animal and human subjects in accordance with the present invention. "Active ingredient" (A.l.) as used in these examples refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

EXAMPLE C.1 Film-coated tablets Preparation of the center of the tablet A mixture of 100 g of AI, 570 g of lactose and 200 g of starch were mixed well and subsequently humidified with a solution of 5 g of dodecyl sodium sulfate and 10 g of polyvinyl pyrrolidone in approximately 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Subsequently, 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole was mixed well and compressed into tablets, giving 10,000 tablets, each comprising 100 mg of the active ingredient.

Coating: To a solution of 10 g of methylcellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Subsequently, 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. 10 g of polyethylene glycol was ground and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and subsequently 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated color suspension were added and the whole was homogenized. The centers of the tablets were coated with the result of this procedure obtaining a mixture in a coating apparatus.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a glycine transport inhibiting compound for the preparation of a medicament for the treatment of disorders of the central and peripheral nervous system, said compound has the formula a? / -oxide, an isomeric form stereochemically or a pharmaceutically acceptable addition salt thereof, wherein X represents CH or N; L represents a radical of formula where n is 0 or 1; m is 0 or 1; Alk represents Ci-β alkanediyl; A represents N or CH; B1 represents CH2 or NH; -a1 = a2-a3 = a4- represents a bivalent radical of formula -CH = CH-CH = CH- (a-1); or -N = CH-CH = CH- (a-2); R 1 represents C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo [1,2-a] pyridinyl, thiazolyl; R 2 represents hydrogen or aryl; R3 represents hydrogen, C-? 6 alkyl or C3-7 cycloalkyl; R4 represents thienyl, furanyl, arylamino or a radical of formula wherein R5 is hydrogen or aryl; aryl represents phenyl optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl, halo, hydroxy, C- alkyloxy.

2. The use as claimed in claim 1, wherein L is a radical of formula (a) or (b).

3. The use as claimed in claim 1, wherein the disorder is psychosis, pain, epilepsy, neurodegenerative diseases, cerebrovascular accidents, cranial trauma or multiple sclerosis.

4. A compound of formula (1) as defined in claims 1 or 2 provided that when X is CH, L is a radical of formula (a) wherein B1 is -CH2- and R1 is pyridin-2-ylmethyl , thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then -a1 = a2-a3 = a4- is different from -N = CH-CH = CH-; and when X is CH; L is a radical of formula (a) wherein B1 is -CH2- and R1 is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -a1 = a2-a3 = a4-is different from -CH = CH-CH = CH -; and when X is N; L is a radical of formula (d) wherein Alk is 1,3-propanediyl, then R4 is different from phenylamino.

5. A compound according to claim 4, further characterized in that n is 0, m is 1; R1 is C1-4alkyl optionally substituted with C1-4alkyloxy, arylcarbonyl or imidazo [1,2-ajpyridinyl and R4 is thienyl, furanyl or a radical of formula (d-1).

6. A compound according to claim 4, further characterized in that the compound is 3- [1 - [4,4-bis (4-fluoromethyl) butyl] -4-piperidinyl] -3,4-dihydro-2 ( 1 H) -quinazolinone; 4- [2- [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] acetyl] -3,4-dihydro-3-phenyl-2 (1H) -quinaxolinone; N- [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -1 - (imidazo [1,2- a] pyridin-2-yl-methyl) -1 H -benzimidazole-2 -amine; 2 - [[4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinyl] methyl] -3- (2-ethoxyethyl) -3H-imidazo [4,5-b] ] pyridine; 3- [1 - [4,4-bis (4-fluoromethyl) butyl] -4-p, pperidyl] -3,4-d, pyridyl [2,3- d] -2 (1 H) -pyrmidinone; 3- [2 - [[1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -1 H -benzimidazol-1 -yl] -1 - (4-fluorophenyl) - 1 -propanone; 4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinyl] -1 - (2-thienyl) butanone; N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N- (4-methoxy-phenyl) -N- (1-methyl-ethyl) -urea; N- [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N, -butyl-N- (4-methoxyphenyl) urea; N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-pperidinyl] -N- (4-methoxy-phenol) -N'-propyl-urea; N- [1- [4) 4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N'-cyclohexyl-N- (4-methoxyphenyl) urea; N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N'-ethyl-N- (4-methylene) urea; N- [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N '- (1 -methylethyl) -N- (4-methylphenyl) urea; or N- [1 - [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N '- (4-chlorophenyl) -N' - (1-methylethyl) urea; an N-oxide, an isomeric form stereochemically or a pharmaceutically acceptable addition salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound according to any of claims 4 to 6.

8. A process for preparing a pharmaceutical composition in accordance with claim 7, further characterized in that a therapeutically effective amount of a compound as claimed in any of claims 4 to 6 is intimately mixed with a pharmaceutical carrier.

9. The compound as described in any of claims 4 to 6 for use as a medicine.

10. The process for the preparation of a compound as described in claim 4, further characterized by a) reacting an intermediate of formula (II), wherein W1 is a suitable leaving group with an intermediate of formula (III) in an inert reaction solvent, in the presence of a suitable base and optionally in the presence of potassium iodide; (") (Neither) b) reductive alkylation of an intermediate of formula (III) with an intermediate of formula (IV) in an inert reaction solvent, in the presence of a reducing agent optionally in the presence of a suitable catalyst; c) reacting an intermediate of formula (V) by an intermediate of formula (VI) wherein W1 is a suitable leaving group; thereby forming a compound of formula (I-a), in an inert reaction solvent, in the presence of a suitable base and optionally in the presence of potassium iodide; (IV) (III) d) reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII) in an inert reaction solvent; thereby forming a compound of formula (I-b) and, if desired, converting the compounds of formula (I) to an acid addition salt by treatment with an acid or in a base addition salt by treatment with a base, or conversely, converting the salt form of acid addition in the free base by treatment with alkali or converting the base addition salt into the free acid by acid treatment; and, if desired, preparing N-oxide and / or stereochemically isomeric forms thereof.