HRP20000523A2 - Glycine transport inhibitors - Google Patents

Description

The proposed 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 production of drugs for the treatment of central and peripheral nervous system disorders, especially psychosis, pain , epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The invention further encompasses new compounds, their production and their pharmaceutical forms.

[4,4-bis(4-fluorophenyl)butyl]-1-(piperazinyl and piperidinyl) derivatives are well-known histamine and serotonin antagonists. These compounds, their action and preparation are described in EP-A-0,151,826 and GB-1,055,100.

The proposed invention relates to the use of compounds that inhibit the transport of glycine for the production of drugs for the treatment of central and peripheral nervous system disorders, wherein said compounds have the formula

[image]

their N-oxides, stereochemically isomeric forms or their pharmaceutically acceptable addition salts, in which formula

X represents CH or N;

L represents the radical of the formula

[image]

where

n is 0 or 1;

m is 0 or 1;

Alk represents C1-6-alkanediyl;

A represents N or CH;

B1 represents CH2 or NH;

-al = a2 –a3 =a4- represents the divalent radical of the formula

-CH=CH-CH=CH- (a-1); or

-NH=CH-N=CH- (a-2);

R1 represents C1-4-alkyl optionally substituted with C1-4-alkyloxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo[1,2-a]pyridinyl, thiazolyl;

R 2 represents hydrogen or aryl;

R3 represents hydrogen, C1-6-alkyl or C3-7-cycloalkyl;

R4 represents thienyl, furanyl, arylamino or a radical of the formula

[image]

where

R 5 represents hydrogen or aryl; aryl represents phenyl optionally substituted with one or two substituents selected from C1-4-alkyl, halogen, hydroxy, C1-4-alkyloxy.

The proposed invention also relates to a method for treating warm-blooded animals suffering from disorders of the central and peripheral nervous system, especially psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. Said method involves administering a therapeutically effective amount of a compound of formula (I) or its N-oxide, a pharmaceutically acceptable acid or base addition salt thereof or a stereochemically isomeric form thereof with a pharmaceutical carrier.

As used in the definitions above and below, halogen refers to fluorine, chlorine, bromine and iodine; C3-7-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C1-4-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl-propyl, 2,2 -dimethylethyl and the like; C1-6-alkyl is considered to include C1-4-alkyl and its higher homologues having 5 or 6 carbon atoms, for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like. C1-6-alkanediyl defines divalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1, 4-butanediyl, 1,2-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2, 3-butanediyl and the like.

It is understood that the above-mentioned pharmaceutically acceptable addition salts include therapeutically active forms of non-toxic basic or acid addition salts which can be formed by the compounds of formula (I). The form of the acid addition salt of the compound of formula (I), which is formed in its free form as a base, can be obtained by treating said free base with a suitable acid, such as an inorganic acid, for example a hydrohalic acid, for example hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, and similar acids; or organic acids such as acetic, hydroxyacetic, propionic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclaminic, salicylic, p- aminosalicylic, pamoic and similar acids.

Compounds of formula (I) containing acidic protons can be converted into their therapeutically active non-toxic bases, i.e. forms of metal or amine addition salts, by treatment with appropriate organic or inorganic bases. Suitable base salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, e.g. salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, e.g. salts of benzathine, N-methyl-D- glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, the aforementioned salt forms can be converted into free forms by treatment with a suitable base or acid.

The term addition salt, as used above, also includes solvates which may be formed by the compounds of formula (I) as well as their salts. Such solvates are, for example, hydrates, alcoholates and the like.

N-oxides of compounds of formula (I) are considered to include those compounds of formula (I) in which one or more nitrogen atoms have been oxidized to a so-called N-oxide.

The term "stereochemically isomeric forms", as used herein, defines all possible stereoisomeric forms in which the compounds of formula (I) may occur. If not mentioned or stated otherwise, the chemical designation of the compound denotes a mixture, and in particular a racemic mixture of all possible stereochemically isomeric forms, wherein said mixture contains all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of compounds of formula (I) and mixtures of such forms are obviously encompassed by formula (I).

In particular, compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in the R or S configuration, with the designations S and R being used according to the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Some compounds of formula (I) may also exist in their tautomeric forms. Although not specifically mentioned in the above formula, such forms are considered to be included within the scope of the meaning of the proposed invention.

When the term compounds of formula (I) is used below, it is intended that the N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms are also included.

The proposed compounds of formula (I) are considered novel provided that

- when X represents CH; L is a radical of formula (a) in which B1 represents -CH2-, and R1 is pyridin-2-ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then -al=a2-a3 =a4- different from -N=CH-CH=CH-; and

- when X represents CH; L is a radical of formula (a) in which B1 represents -CH2- and R1 is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -al=a2-a3=a4- is different from -CH=CH-CH=CH- ; and

- when X represents N; L is a radical of formula (d) in which Alk represents 1,3-propanediyl, then R4 is different from phenylamino.

The proposed invention also relates to the use of the mentioned new compounds of formula (I) as medicine.

An interesting group of compounds are those compounds of formula (I) in which

n is 0;

m is 1;

R1 is C1-4-alkyl, optionally substituted with C1-4-alkyloxy, arylcarbonyl or imidazo[1,2-a]pyridinyl and

R4 is thienyl, furanyl or a radical of formula (d-1).

Preferred compounds are those compounds of formula (I), in which L represents a radical of formula (a) or (b).

In general, compounds of formula (I) can be prepared according to the reaction procedures described in EP-A-0,151,826 and GB-1,055,100, in more detail, by reacting intermediates of formula (II), in which W1 represents a suitable leaving group such as, on example, halogen, with an intermediate of formula (III).

[image]

Said reaction can be carried out in a reaction-inert solvent, such as, for example, methylisobutyl ketone, N,N-dimethylacetamide or N,N-dimethylformamide, in the presence of a suitable base, such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and if necessary in the presence of potassium iodide.

In this and subsequent preparations, the reaction products can be isolated from the reaction medium and, if necessary, can be further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.

Alternatively, compounds of formula (I) can be prepared by reductive alkylation. Intermediate (IV) is then reacted with an intermediate of formula (III) in a reaction-inert solvent, such as for example methanol, in the presence of a reducing agent such as for example hydrogen in the presence of a suitable catalyst, eg palladium on activated carbon. Thiophene is usually added to the reaction mixture.

[image]

Compounds of formula (I), wherein X represents N, and shown by formula (Ia), can be produced by reacting an intermediate of formula (V) with an intermediate of formula (VI), wherein W1 represents a suitable leaving group, such as, for example , halogen.

[image]

Said reaction can be carried out in a reaction-inert solvent, such as, for example, methylisobutyl ketone, N,N-dimethylacetamide or N,N-dimethylformamide, in the presence of a suitable base, such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and if necessary in the presence of potassium iodide.

Compounds of formula (I), in which L represents a radical of formula (b), and which are represented by formula (I-b), can be produced by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII).

[image]

Said reaction can be carried out in a reaction-inert solvent, such as, for example, diisopropylether.

Compounds of formula (I) can also be converted into each other by functional group transformation procedures, which procedures are known in the art.

Compounds of formula (I) can also be converted into the corresponding N-oxide forms by methods known in the art for converting trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, eg sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as, for example, benzenecarboperoxy acid or halogen substituted benzenecarboperoxy acid, eg 3-chloro-benzenecarboperoxy acid, peroxyalkanoic acids, eg peroxyacetic acid, alkyl hydroperoxides, eg t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, eg ethanol and the like, hydrocarbons, eg toluene, ketones, eg 2-butanone, halogenated hydrocarbons, eg dichloromethane, and mixtures of such solvents.

Some compounds of formula (I) and some intermediates in the proposed invention may have an asymmetric carbon atom. Stereochemically pure isomeric forms of the mentioned compounds and intermediates can be obtained using known procedures. For example, diastereoisomers can be separated by physical methods, such as selective crystallization, or by chromatographic methods, eg, countercurrent separation, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures by first converting the racemic mixtures with suitable redissolving agents, such as, for example, chiral acids, to obtain mixtures of diastereomeric salts or compounds; then by physically separating said mixture of diastereomeric salts or compounds, for example by selective crystallization or chromatographic methods, for example liquid chromatography and similar methods; and finally, by converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms can also be obtained from pure stereochemically isomeric forms of the corresponding intermediates and starting materials, provided that the reactions between them proceed stereospecifically.

An alternative way of separating enantiomeric forms of compounds of formula (I) and intermediates involves liquid chromatography, especially liquid chromatography using a chiral stationary phase.

Some intermediates and starting materials are known compounds and can be obtained commercially or can be produced according to known procedures.

Glycine is an amino acid neurotransmitter in the central and peripheral nervous system, in both cases at inhibitory and excitatory synapses. These special functions of glycine are mediated by two types of receptors, each associated with a different class of glycine transporters. The inhibitory effects of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are therefore referred to as "strychnine-sensitive." Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brain stem.

Glycine acts in excitatory transmission by modulating the action of glutamate, the main excitatory neurotransmitter in the nervous system (Johnson and Ascher, Nature, 325, 529-531 (1987); Fletscher et al., Glycine Transmission, (Otterson and Strom-Mathisen, ed., 1990 , pp. 193-219). Specifically, glycine is an obligate co-agonist in a class of glutamine receptors called the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are widely distributed in the brain, with a particularly high density in the cerebral cortex. in the hippocampal formation.

Transporters take the neurotransmitter from the synapse, thereby regulating the concentration and time of the neurotransmitter in the synapse, which together determines the magnitude of synaptic transmission. By preventing the spread of neurotransmitters to neighboring synapses, transporters maintain the accuracy of synaptic transmission. Finally, by reuptake of the released transmitter into the presynaptic terminal, transporters allow the transmitter to be reused. Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane. Under specific conditions, for example during seizures, the transporters can function in the opposite direction, releasing the neurotransmitter outside the cell in a calcium-dependent manner (Attwell et al., Neuron, 11, 401-407 (1993)). Modulation of neurotransmitter transporters therefore provides a means of modifying synaptic activity, which provides a useful therapy for the treatment of central and peripheral nervous system disorders.

Molecular cloning revealed the existence of two classes of glycine transporters, named GlyT-1 and GlyT-2. GlyT-1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 927-935 (1992)). At least three related variants of GlyT-1 are known, namely GlyT-1a, GlyT-1b and GlyT-1c (Kim, et al., Molecular Pharmacology, 45, 608-617 (1994)), each of which exhibits a unique distribution in the brain and in peripheral tissue. In contrast, GlyT-2 is found predominantly in the brain stem and spinal cord, and its distribution matches that of strychnine-sensitive glycine receptors (Liu, et al., J. Biological Chemistry, 268, 22802-22808 (1993); Jursky and Nelson , Neurochemistry, 64, 1026-1033 (1995)). Therefore, it can be expected that by regulating the synaptic levels of glycine, GlyT-1 and GlyT-2, the action of NMDA receptors, i.e. glycine receptors sensitive to strychnine, can be selectively modulated.

Compounds that inhibit or activate glycine transporters can therefore be expected to alter receptor function and thereby provide therapeutic benefits in a range of disease states. Therefore, inhibition of GlyT-2 can be used to attenuate the action of neurons that have strychnine-sensitive glycine receptors by increasing synaptic levels of glycine and thus attenuate the transmission of pain-related (ie, nociceptive) information in the spinal cord, which has been shown to mediated by these receptors. Yaksh, Pain, 37, 111-123 (1989). In addition, enhancement of inhibitory glycinergic transmission with strychnine-sensitive glycine receptors in the spinal cord can be used to reduce muscle hyperactivity, which is useful in the treatment of diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Troung et al. al., Movement Disorders, 3, 77-87 (1988); FASEB J, 4, 2767-2774 (1990)). Spasticity, which can be treated by glycine receptor modulation, is associated with epilepsy, strokes, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other disease states or injuries to the nervous system.

NMDA receptors are involved in memory and learning (Rison and Stanton, Neurosci. Biobehev. Rev., 19, 533-552 (1995);

Danysz et al., Behavioral Pharmacol., 6, 455-474 (1995)); and reduced function of NMDA-mediated transmission appears to contribute to the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996). Therefore, agents that inhibit GlyT-1 and thereby increase glycine activation of NMDA receptors, may be used as novel antipsychotic and antidementia agents, and for the treatment of other diseases in which cognitive processes are impaired, such as attention deficit disorder and organic brain syndromes.Conversely, overactivation of NMDA receptors has been implicated in a number of disease states, especially neuronal death associated with stroke, head trauma and possibly in neurodegenerative diseases such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs. Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton and Rosenberg, New Engl. J. of Medicine, 330, 613-622 (1993); Choi, Neuron 1, 623-634 (1988). Therefore, pharmacological agents that increase the action of GlyT-1 will result in a reduction of glycine activation of the NMDA receptor, whose action can be used to treat these and related disease states. Similarly, drugs that directly block the glycine side of the NMDA receptor can be used to treat these and related disease states.

For application purposes, the compounds in question can be formulated into various pharmacological compositions that include a pharmacologically acceptable carrier, and contain as an active ingredient a therapeutically effective amount of the new compound of formula (I). For the preparation of pharmaceutical compositions according to the invention, an effective amount of the compound in question, additionally as a salt or in the form of a free base, as an active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier, which can have very different forms depending on the form of the preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage form, preferably for oral, percutaneous or parenteral injection administration. For example, in the case of liquid preparations such as suspensions, syrups, elixirs and solutions, any conventional pharmaceutical vehicle can be used, such as water, glycols, oils, alcohols and the like, to prepare compositions for oral dosage form; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like can be used. Due to their easy administration, tablets and capsules represent the most convenient form of oral dosage unit, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier usually includes sterile water, at least in large part, although other ingredients may be included, for example to aid solubility. Injectable solutions can be prepared in which, for example, the carrier includes a saline solution, a glucose solution, or a mixture of a saline solution and glucose. Injection solutions containing compounds of formula (I) can be formulated in oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic long chain fatty acid glycerol esters and mixtures thereof, and other oils. Injectable suspensions can also be produced, in which case suitable liquid carriers, suspending agents and the like can be used. In compositions suitable for percutaneous administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally combined with small amounts of suitable additives of any nature, which additives do not cause any adverse effects on the skin. The mentioned additives can facilitate administration through the skin and/or can help in the preparation of the desired compositions. These compositions can be administered by various routes, eg as a transdermal patch, as a poultice or as an ointment. The addition salts of the compounds (I), due to their increased solubility in water compared to the corresponding free bases or the free acid form, are obviously more suitable for the preparation of aqueous compositions.

It is particularly useful to formulate the above-mentioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form, as used herein in the specification and claims, refers to physically separate units as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with a desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, soup spoons, and the like, and separate multipacks thereof.

The following examples are provided to illustrate the proposed 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), a few crystals of KJ in methyl isobutyl ketone (160 ml) are stirred and refluxed for 2 days. When it cools down, add water (250 ml). The separated organic layer is dried, filtered and the solvent is evaporated. The residue is recrystallized from methylisobutyl ketone (80 ml), which gives 3 g of 3-[1-[4,4-bis (4-fluoromethyl)butyl]-4-piperidinyl]-3,4-dihydro-2(1H) -quinazolinone; melting point 199-200.5°C (compound 1).

Analogously, they were produced:

4-[2-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-acetyl]-3,4-dihydro-3-phenyl-2(1H)-quinoxalinone ethanedioate (1: 1); melting point 190.8°C (compound 2);

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-benzimidazol-2-amine; melting point 160.1°C (compound 3);

2-[[4-[4,4-bis(4-fluorophenyl)butyl]-1-piperazinyl]methyl]-3-(2-ethoxyethyl)-3H-(imidazo[4,5-b]pyridine ethanedioate (1 :2); melting point 173.2°C (compound 4);

3-[1-[4,4-bis(4-fluoromethyl)butyl]-4-piperidinyl]-3,4-dihydro-pyrido[2,3-d]-2(1H)-pyrimidinone; melting point 220-222°C (compound 5).

Example A.2

A mixture of 4-fluoro-γ-(4-fluorophenyl)benzenebutanal (2.6 g), 1-(4-fluorophenyl)-3-[2-(4-piperidinylmethyl)-1H-benzimidazol-1-yl]-1- propanone dihydrobromide monohydrate (5.5 g), a solution of thiophene in ethanol 3% (1 g), potassium acetate (3 g) and methanol (200 ml) is hydrogenated under normal pressure and at 50°C with palladium on charcoal (10% , 2 g) as a catalyst. After stopping the intake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. Water is added to the oily residue and everything is made alkaline with ammonium hydroxide. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The oily residue was converted to the ethanedioate salt in acetonitrile and 4-methyl-2-pentanone. The salt is allowed to crystallize. The product is filtered off and dried, yielding 5 g (63.3%) of 3-[2-[[1-[4,4-bis(4-fluoro-phenyl)butyl]-4-piperidinyl]methyl]-1H -benzimidazol-1-yl]-1-(4-fluorophenyl)-1-propanone ethanedioate (1:2); melting point 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), several crystals of potassium iodide in 4-methyl-2-pentanone (200 ml) are refluxed for 24 hours. Then a second portion of 4-chloro-1-(2-thienyl)butanone (4.1 g) was added and everything was stirred and refluxed for another 36 hours. When it cools down, add water (100 ml). The organic layer is separated, dried over potassium carbonate, filtered and evaporated. The oily residue was dissolved in anhydrous ether (480 ml). The solution is filtered and gaseous hydrogen chloride is introduced into the filtrate. The precipitate is filtered off and crystallized from 2-propanol (320 ml), which gives 4-[4,4-bis(4-fluoromethyl)butyl]-1-piperazinyl]-1-(2-thienyl)-butanone; melting point 227.5-230°C (compound 7).

Example A.4

To a mixed solution of 1-[4,4-bis(4-fluoromethyl)butyl]-N-(4-methoxyphenyl)-4-piperidinamine (6.75 g) in 2,2'-oxybispropane (105 ml) and tetrahydrofuran ( 45 ml) was added dropwise to a solution of 2-isocyanatopropane (1.36 g) in 2,2'-oxybispropane (3.5 ml). After the addition is complete, the mixing is continued for another 1 day at room temperature and another 1 hour at approx. 50°C. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N-( 4-Methoxyphenyl)-N'-(1-methylethyl)urea (4.8 g, 59%); melting point 170.9°C (compound 8).

The following were produced in an analogous way:

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N'-butyl-N-(4-methoxyphenyl)urea; melting point 101.9°C (compound 9);

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N-(4-methoxyphenyl)-N'-propylurea; melting point 124.1°C (compound 10);

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N'-cyclohexyl-N-(4-methoxyphenyl)urea; melting point 128.2°C (compound 11);

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N'-ethyl-N-(4-methylphenyl)urea; melting point 129.1°C (compound 12);

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N'-(1-methylethyl)-N-(4-methylphenyl)urea; melting point 167.2°C (compound 13); and

N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N'-(4-chlorophenyl)-N'-(1-methylethyl)urea; melting point 157.4°C (compound 14).

Pharmacological example

Example B.1

Transport experiment via GlyT1 transporter.

Subconfluent HEK 293-GlyT1 cells (ie, 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 DMEM medium (Dulbecco's modified Eagle medium 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 and 95% humidity.

On day 3, cells were washed using a microprocessor-controlled Tecan PW96 washer designed to wash all 96 wells of a microtiter plate simultaneously with buffer (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). The Tecan PW 96 was programmed to wash the cells five times leaving 75 µl in each well. The test compounds were dissolved in DMSO in different concentrations in the micromolar range. 1 µl of test solution was added to each well and the cells were incubated for 5' to 10' at room temperature. 25 µl of 30 µM [U14C] glycine diluted in flow buffer was added. The cells were incubated for 1 hour at room temperature. The plates were then stoppered and the [U14C] glycine collected was determined on a Packard microtiter plate scintillation counter (TopCount). From the results obtained for different concentrations, the concentration that gives 50% inhibition (IC50) of glycine reuptake was calculated for each tested drug. The calculated data for the test compounds according to the invention are presented in Table 1 as pIC50 values (values of the negative logarithm of IC50).

They were also examined:

compound 15, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(2-pyridinylmethyl)-3H-imidazo-[4,5- b]-pyridine ethanedioate (1:2);

compound 16, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-[(4-fluorophenyl)methyl]-3H-imidazo[4, 5-b] pyridine ethanedioate (1:2);

compound 17, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(phenylmethyl)-3H-imidazo[4,5-b]pyridine ethanedioate (1:2);

compound 18, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(2-thienylmethyl)-3H-imidazo[4,5-b ]-pyridine ethanedioate (1:1);

compound 19, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(2-furanylmethyl)-3H-imidazo[4,5-b ]-pyridine ethanedioate (1:2);

compound 20 , which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-[(4-methoxyphenyl)methyl]-1H-benzimidazole ethanedioate ( 1 :2);

compound 21, which was 2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(4-thiazolylmethyl)-1H-benzimidazole ethanedioate (1:2) , as described in EP-A-0,151,826; and

compound 22, which was 1-[4,4-di(4-fluorophenyl)butyl]-4-[3-(anilinocarbonyl)propyl]piperazine dihydrochloride, as described in GB-1,055,100.

Table 1

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C. Composition examples

The following formulation is an example of a typical pharmaceutical composition suitable for systemic administration to animals and humans in accordance with the present invention.

"Active ingredient" (A.I.) refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example C.1: film-coated tablets

Preparation of tablet core:

A mixture of 100 g of A.I., 570 g of lactose and 200 g of starch is mixed well and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in approx. 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are added. Everything is mixed well together and pressed into tablets, whereby 10,000 tablets are obtained, each of which contains 10 mg of the active ingredient.

Coating

A solution of 5 g of ethyl cellulose in 150 ml of dichloromethane is added to a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol. Then 75 ml of dichloroethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then 2.5 mg of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated dye suspension are added and everything is homogenized. The tablet cores are coated with the resulting mixture in a tablet coating device.

Claims (10)

1. Use of a compound that inhibits glycine transport for the manufacture of a medicament for the treatment of central and peripheral nervous system disorders, wherein said compound has the formula [image] of its N-oxide, stereochemically isomeric form or its pharmaceutically acceptable addition salt, indicated that X represents CH or N; L represents the radical of the formula [image] where n is 0 or 1; m is 0 or 1; Alk represents C1-6-alkanediyl; A represents N or CH; B1 represents CH2 or NH; -al=a2-a3=a4- represents the divalent radical of the formula -CH=CH-CH=CH- (a-1); or -NH=CH-N=CH- (a-2); R1 represents C1-4-alkyl optionally substituted with C1-4-alkyloxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo[1,2-a]pyridinyl, thiazolyl; R 2 represents hydrogen or aryl; R3 represents hydrogen, C1-6-alkyl or C3-7-cycloalkyl; R4 represents thienyl, furanyl, arylamino or a radical of the formula [image] where R 5 represents hydrogen or aryl; aryl represents phenyl optionally substituted with one or two substituents selected from C1-4-alkyl, halogen, hydroxy, C1-4-alkyloxy. 2. Use according to claim 1, characterized in that L represents a radical of formula (a) or (b). 3. Use according to claim 1, characterized in that the disorder is psychosis, pain, epilepsy, neurodegenerative diseases, stroke, head trauma or multiple sclerosis. 4. The compound of formula (I) defined as in claims 1 or 2, indicated that under the condition - when X represents CH; L is a radical of formula (a) in which B1 represents -CH2-, and R1 is pyridin-2-ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then -al=a2-a3 =a4- different from -N=CH-CH=CH-; and - when X represents CH; L is a radical of formula (a) in which B1 represents -CH2- and R1 is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -al=a2-a3=a4- is different from -CH=CH-CH=CH- ; and - when X represents N; L is a radical of formula (d) in which Alk represents 1,3-propanediyl, then R is different from phenylamino. 5. Compound according to claim 4, characterized in that n is 0; m is 1; R1 is C1-4-alkyl, optionally substituted with C1-4-alkyloxy, arylcarbonyl or imidazo[1,2-a]pyridinyl and R4 is thienyl, furanyl or a radical of formula (d-1). 6. A compound according to claim 4, characterized in that it 3-[1-[4,4-bis(4-fluoromethyl)butyl]-4-piperidinyl]-3,4-dihydro-2(1H)-quinazolinone; 4-[2-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-acetyl]-3,4-dihydro-3-phenyl-2(1H)-quinoxalinone; N-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-benzimidazol-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-piperidinyl]-3,4-dihydro-pyrido[2,3-d]-2(1H)-pyrimidinone; 3-[2-[[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-methyl]-1H-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-methoxyphenyl)-N'-(1-methylethyl)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-piperidinyl]-N-(4-methoxyphenyl)-N'-propylurea; 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-methylphenyl)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; its N-oxide, its stereochemically isomeric form or its pharmaceutically acceptable addition salt. 7. A pharmaceutical composition characterized in that it contains a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of the compound described in any of claims 4 to 6. 8. A method for producing a pharmaceutical composition according to claim 7, characterized in that a therapeutically effective amount of the compound described in any of claims 4 to 6 is thoroughly mixed with a pharmaceutical carrier. 9. The compound described in any of claims 4 to 6, for use as a medicine. 10. The process for the production of the compound described in claim 4, characterized in that it is carried out a) reaction of the intermediate of formula (II), in which W represents a suitable leaving group, with the intermediate of formula (III), in a reaction-inert solvent, in the presence of a suitable base and, if necessary, in the presence of potassium iodide; [image] b) reductive alkylation of the intermediate of formula (III) with the intermediate of formula (IV) in a reaction-inert solvent and in the presence of a reducing agent as needed in the presence of a suitable catalyst; [image] c) reaction of an intermediate of formula (V) with an intermediate of formula (VI), in which W1 represents a suitable leaving group; thereby, in a reaction-inert solvent and in the presence of a suitable base, and if necessary in the presence of potassium iodide, a compound of formula (Ia) is obtained; [image] d) reaction of the intermediate of formula (VII) with the isocyanate derivative of formula (VIII), in a reaction-inert solvent; this gives the compound of formula (I-b) [image] and, optionally, the compound of formula (I) is converted to an acid addition salt by treatment with an acid, or is converted to a base addition salt by treatment with a base, or vice versa, the acid addition salt is converted to a free base by treatment with an alkali, or the base addition salt is convert the salt into a free acid by treating with acid; and, optionally, its N-oxide and/or its stereochemically isomeric form is produced.