SK13082000A3 - 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

Technical field

The present invention relates to the use of glycine transfer inhibitors, [4,4-bis (4-fluorophenyl) butyl] -1- (piperazines 1 and piperidinyl) derivatives for the preparation of medicaments for the treatment of disorders of the central and peripheral nervous system, in particular psychoses, pain conditions, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis, and others. The invention includes novel compounds, their preparation and pharmaceutical forms.

[4,4-Bis (4-fluorophenyl) butyl] -1- (piperazinyl and piperidinyl) derivatives are known antihistamines and antiserotonics. These compounds, their effects and preparation are described in patents EP-A-0,151,826 and GB-1,055,100.

The present invention provides glycine transfer inhibitors useful in the preparation of medicaments for the treatment of central and peripheral nervous system disorders. These compounds have the formula

(I)

It is the N-oxide, the stereochemically isomeric form, or a suitable addition salt for pharmaceutical purposes, wherein X is CH or N;

wherein n is 0 or 1;

m is 0 or 1;

Alk represents C _1-6 alkanediyl;

A is N or CH;

B ¹ represents CH ₂ or NH;

-a ¹ = a ² -a ³ = a ⁴ - represents a divalent substituent of the formula

-CH = CH-CH = CH- (α-1) or -N = CH-CH = CH- (α-2);

R ¹ is C ₁ _ ₄ 4 alkyl substituted Ci_4 be matched ^and lkoxylom, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo [l, 2-a] pyridinyl, thiazolyl;

R ² is hydrogen or aryl;

R ³ is hydrogen, C ₁ _ ₆ alkyl or C ₃ _ ₇ cycloalkyl; R ⁴ is thienyl, furanyl, arylamino or a substituent of the formula

wherein R ⁵ represents hydrogen or aryl;

aryl represents phenyl optionally substituted with one or two substituents selected from

C ₁ _ ₄ alkyl, halogen, hydroxy, C ₁ _ ₄ alkyloxy.

The present invention also relates to a method of treating warm-blooded animals suffering from central and peripheral nervous system disorders, in particular psychosis, pain conditions, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. Said method comprises listing a therapeutically effective amount of compound (I) or the oxid -oxide form and a pharmaceutically acceptable acid or base addition salt or stereoisomer thereof in combination with a pharmaceutical carrier.

In the above formulas and the following formulas, halogen is the generic term for fluorine, chlorine, bromine and iodine; C ₃ _ ₇ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C ₁ _ ₄ 4alkyl defines straight and branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the other; Part C ₁ _ ₆ alkyl includes the C ₁ _ ₄ alkyl and the higher homologs thereof having five or six carbon uhlíko4 oil change, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the other; C ₁ _ ₆ alkándienyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as 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 others.

Addition salts suitable for pharmaceutical purposes are the therapeutically active non-toxic forms of the basic and acid addition salts that the compounds of formula (I) may form. Compounds (I) occurring in free form as a base are converted to an acid addition salt by reacting the corresponding base with a suitable inorganic acid, for example, hydrohalic (hydrochloric or hydrobromic), sulfuric, nitric, or phosphoric, or organic, such as acetic, hydroxyacetic, propane, milky, pyruvic, oxalic, malaric, amber, maleic, fumaric, cider, tartar, lemon, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, N-cyclohexylsulfamic, and salycilic.

Compounds of formula (I) containing acidic protons are converted into therapeutically active non-toxic bases, i. metal or amine, by reaction with the corresponding organic and inorganic bases. Suitable base salts include, for example, ammonium salts of alkali and alkaline earth metals, i.e., lithium, sodium, potassium, magnesium, calcium salts and the like. Among the salts containing the organic base, mention may be made, for example, of benzatin, ZT-methyl D-glucosamine, amino acid hydrates and salts with amino acids such as arginine, lysine and the like.

Conversely, these salts are converted to the free form by reaction with the corresponding base or acid.

The term addition salt as used herein also includes solvates of compounds (I) and their salts, for example hydrates, alcoholates and others.

The designation of the oxid -oxide form of the compounds of formula (I) includes those compounds (I) in which one or more nitrogen atoms are oxidized to the so-called N-oxide.

The term stereochemical isomers defines all possible stereoisomeric forms in which Compound (I) may exist. Unless otherwise indicated, the chemical name of a compound refers to mixtures, especially racemic mixtures, in all possible stereochemical forms, in other words, mixtures containing all diastereomers and enantiomers of the basic molecular structure. Thus, it will be understood that formula (I) includes all stereoisomers of compound (I) and mixtures thereof.

The compounds of formula (I) and some of their intermediates have at least one stereogenic center in their structure. This center is referred to as the R or S configuration, according to the rules described in Pure Appl. Chem., 1976, 45, 11-30.

Some of the compounds of formula (I) may exist in tautomeric forms. Although these forms do not correspond exactly to formula (I), they are included in the field of the present invention.

As already mentioned, the term compound of formula (I) also refers to N -oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms. A new composition of compounds (I) is contemplated in the following cases:

- when X is CH, L is a substituent of formula (a) wherein B ¹ is -CH ₂ - and R ¹ is pyridin-2-ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then - and ¹ = a ² -a ³ = a ⁴ is other than -N = CH-CH = CH-; and

- when X is CH, L is a substituent of formula (a) wherein B ¹ is -CH ₂ - and R ¹ is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -a ^{1 =} a ² -a ³ = a ⁴ - is other than -CH-CH-CH = CH-; and

when X is N, L is a substituent of formula (d) wherein Alk is 1,3-propanediyl, then R ⁴ is other than a phenylamino group.

The invention also relates to the use of the compounds of formula (I) as defined above for the preparation of medicaments.

An interesting group are those compounds (I), wherein in the formula n is 0, m is 1, R ¹ is C ₁ _ ₄ alkyl optionally substituted with C ₁ _ ₄ alkoxy, arylcarbonyl or imidazo [l, 2-a] pyridinyl and ^R4 is thienyl, furanyl or a substituent of formula (d-1).

Preferred compounds of formula (I) are those wherein L is a substituent of formula (a) or (b).

BACKGROUND OF THE INVENTION

In general, compounds of formula (I) are prepared by the reaction processes described in patents EP-A-0,151,826 and GB-1,055,100, in particular by reacting an intermediate of formula (II) wherein W ¹ is the corresponding tear-off reaction group (e.g. halogen) with an intermediate of formula (III).

/ ~ Λ <l>

(II)

The reaction may be carried out in an inert solvent such as methyl isobutyl ketone, N, N-dimethylacetamide or N, N-dimethylformamide in the presence of a suitable base, for example sodium carbonate, sodium bicarbonate, trimethylamine or even in the presence of potassium iodide.

In this and the following preparations, the reaction products are isolated from the reaction medium and, if necessary, purified by conventional methods, for example, extraction, crystallization, distillation, comminution and chromatography.

An alternative method of preparing compounds of formula (I) is by reductive alkylation. The intermediate of formula (IV) is reacted with intermediate (III) in an inert solvent, for example methanol, in the presence of a reducing agent, for example hydrogen, in the presence of a suitable catalyst such as palladium on charcoal. Thiophene can optionally be added to the reaction mixture.

(IV) (D

Compounds of formula (I) wherein X is N depicts formula (Ia) and can be prepared by reacting an intermediate of formula (V) with an intermediate of formula (VI) wherein W ¹ is a suitable reaction group which is removed by reaction, for example halogen.

The reaction is carried out in an inert solvent, for example methyl isobutyl ketone, N, N-dimethylacetamide or N, N-dimethylformamide, in the presence of a suitable base, for example sodium carbonate, sodium bicarbonate or triethylamine. Potassium iodide may also optionally be added.

Compounds of formula (I) wherein L is a substituent of formula (b), depicting formula (I-b), may be prepared by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VII).

^O-C-N-R3 (VIII)

(I-b)

This reaction takes place in an inert solvent such as diisopropyl ether.

The compounds of formula (I) may cross each other by simple transformation of functional groups.

Compounds (I) can be converted to the corresponding N-oxide forms by a conventional process of transitioning a trivalent nitrogen atom to an N-oxide; in general, oxidation occurs by reaction of the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine, optionally with a suitable organic or inorganic peroxide. Suitable inorganic peroxides are, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides and others; suitable organic peroxides are, in particular, peracids, for example benzenecarboperoxide acid or its halogen derivatives, such as 3-chlorobenzenecarboperoxide acid, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides, for example t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbon derivatives such as dichloromethane and mixtures of these solvents.

Certain compounds (I) and intermediates of this invention may contain asymmetric carbon, the pure stereoisomers of said compounds and intermediates are obtained by conventional methods; for example, diastereoisomers are isolated by physical methods such as selective crystallization or chromatographic methods such as countercurrent resolution, liquid chromatography, and the like. Enantiomers are obtained from racemic mixtures by first converting them with suitable solvents, such as chiral acids, into mixtures of diastereoisomeric salts or compounds, followed by resolution of the mixtures or compounds by, for example, selective crystallization or chromatography (liquid chromatography and other methods), and finally transforming them. diastereoisomeric salts or other compounds to the corresponding enantiomers. Pure stereochemical isomers may also be obtained directly from the pure stereoisomeric forms of the appropriate intermediates and starting materials so that the respective reactions proceed stereospecifically.

Alternative methods for resolving enantiomeric forms of compounds (I) and intermediates include liquid chromatography, in particular a method employing chiral stationary phases.

Some intermediates and starting materials are known, often commercially available or readily prepared substances.

Glycine is an amino acid that causes both inhibitory and excitatory transmission at the nerve endings of the central and peripheral nervous systems. This different function is due to two types of receptors that act as glycine transporters. The inhibitory effects of glycine are caused by strychnine-sensitive receptors (alkaloid-inducing convulsions) and are therefore called strychnine-sensitive. Strychnine-sensitive glycine receptors are found primarily in the spinal cord and brainstem.

In excitatory transfer, glycine functions as a regulator of glutamate, a major neurotransmitter in the nervous system [John and Ascher: Nature, 325 (1987), 521-531; Fletcher et al. Glycine Transmission, Otterson and Storm-Matisen (1990) p. 193-219]. Glycine, by its nature, ranks among the so-called NMDA glycine receptors (N-methyl-D-aspartate), which are extensively found in the brain, particularly in the cerebral cortex and hippocampus.

Glycine transporters regulate the concentration and time of neurotransmitter action in the nerve endings (synapses), thus regulating the intensity of synaptic transmission. In addition, they also maintain the accuracy of synaptic transmission so as to prevent neurotransxnitors from spreading to adjacent synapses. Finally, after transmission of excitement, the synapse-released transmitters are stored at the presynaptic end and are ready for further use. Transmission of neurotransmitters depends on the amount of extracellular sodium and the voltage gradient on the membrane. Under specific conditions, such as seizure, the transporters may function inversely to release neurotransmitters in calcium-dependent channels [Attwell et al: Neuron, 11 (1993), 401-407]. Thus, changing neurotransmitter transporters makes it possible to modulate synaptic activity, which is successfully used in the treatment of central and peripheral nervous system disorders.

Molecular cloning revealed the existence of two groups of glycine transporters, called GlyT-1 and GlyT-2. GlyT-1 is mainly found in the forebrain and its distribution corresponds to glutamate and NMDA receptor pathways [Smith et al: Neuron, 8 (1992), 927-935]. Three highly linked variants of GlyT-1, known as GlyT-1α, GlyT-1b and GlyT-1c, are known today [Kim et al: Molecular Pharmacology, 45 (1994), 608-617]. Each exhibits a unique distribution in the brain and peripheral tissues. In contrast, GlyT-2 is found primarily in the brainstem and spinal cord, and its distribution is associated with strychnine-sensitive receptors [Liu et al: J. Biological Chemistry, 268 (1993), 22802-22808; Jursky and Nelson: Neurochemistry, 64 (1995), 1026-1033]. It is therefore expected that, in regulating the synaptic levels of glycine, GlyT-1 and GlyT-2 selectively alter the activity of NMDA receptors and strychnine-sensitive receptors, respectively.

Compounds inhibiting or activating glycine transporters are believed to modulate receptor function and are thus useful in the treatment of various diseases. For example, suppression of GlyT-2 function by decreasing synaptic glycine levels results in decreased activity of neurons with strychnine-sensitive rece12 receptors. This inhibits the transmission of painful information in the spinal cord, which has been shown to be mediated by these receptors [Yaksh: Pain, 37 (1989), 111-123].

In addition, by increasing the inhibitory transmission of strychnine-sensitive receptors in the spinal cord, it is used to reduce muscle hyperactivity in the treatment of diseases and conditions where muscle contraction is increased, for example, in convulsions, myoclonia and epilepsy [Truong et al: Movement Disorders, 3 - 87; Becker: FASEB J., 4 (1990), 2767-2774]. Convulsive conditions that are treated by altering glycine receptors are associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord trauma, dystonia, or other diseases and injuries of the nervous system.

NMDA receptors are important for memory function and ability to learn [Rison and Stanton: Neurosci. Biobehav. Rev. 19 (1995), 533-552; Danysz et al., Behavioral. Pharmacol., 6 (1995),

455-474]. Impaired function of these receptors leads to symptoms of schizophrenia [Olney and Parber: Archives General Psychiatry, 52 (1996), 998-1007]. Therefore, agents that inhibit GlyT-1 and thereby increase NMDA receptor activity are used as modern psychopharmaceuticals to affect psychoses and dementia in the treatment of diseases in which attention disorders and organic brain disease occur. Conversely, increased NMDA receptor activity is used in the treatment of a variety of diseases related to nerve death, such as stroke, head trauma, or neurogenerative diseases such as Alzheimer's disease, dementia due to heart attack or AIDS, Huntington's disease, Parkinson's disease, andmiotrophic lateral sclerosis and other diseases in which nerve cells die [Coyle and Puttfarcken: Science, 262 (1993),

689 - 695; Lipton and Rosenberg: New Eng. J. of Medicine, 330 (1993), 613-622; Choi: Neuron, 1 (1988), 623-634]. Thus, drugs that increase the activity of GlyT-1 and thereby reduce the activity of NMDA receptors are useful in the treatment of these diseases. Basically, they are drugs that immediately block glycine binding at NMDA receptors.

SUMMARY OF THE INVENTION

The compounds of formula (I) of the present invention are present in addition to a suitable carrier as an active ingredient in a variety of pharmaceutical compositions. These are prepared by intimately mixing an effective amount of the respective compound (I) in the form of an acid or base addition salt (active ingredient) with a suitable carrier selected according to the route of administration (oral, percutaneous, parenteral injection). Oral pharmaceuticals are prepared using conventional liquid pharmaceutical media such as water, glycols, oils, alcohols - the resulting products are suspensions, syrups, elixirs and drops, or solid carriers such as starch, sugars, kaolin, lubricants, binders, comminuted substances from which powders, pills, capsules and tablets are then prepared. Tablets and capsules are most commonly used for oral administration. Parenteral compositions comprise predominantly water, optionally supplemented with another component, for example, to aid solubility. Injectable solutions are generally prepared as saline solutions, glucose solutions or mixtures thereof. When these solutions contain compounds (I), they are also formulated in oily form to enhance their effectiveness. Suitable for this purpose are, for example, pine oil, sesame oil, cottonseed oil, cereal oil, soybean oil, synthetic esters of glycerol and higher fatty acids, or mixtures thereof. Injectable solutions may also be a suspension. In formulations suitable for percutaneous administration, the carrier generally comprises a wetting agent, and optionally an absorption aid, usually in admixture with a small amount of a natural substance that does not adversely affect the skin. Said additives help to achieve an optimum composition of the composition and optionally also facilitate the subcutaneous application of the composition. Percutaneous (subcutaneous) mixtures are applied differently - in the form of patches, point-to-point with very precise localization or as ointments. For the preparation of aqueous solutions, the compounds (I) are used predominantly in the form of addition salts which are more soluble in water than the corresponding free bases or acids.

For the sake of simplicity and consistency of the description, it is preferable to indicate the amounts of the pharmaceutical compositions in dosage units, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier. Examples of such units are, for example, tablets (both base and coated), capsules, pills, powder sachets, cachets, injectable solutions or suspensions, teaspoon, tablespoon and others, or a proportional amount thereof.

DETAILED DESCRIPTION OF THE INVENTION

Example A1

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) and several KI crystals in methyl isobutyl ketone (160 ml) were heated under reflux for 2 days with stirring. After cooling, water (250 mL) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was recrystallized from methyl isobutyl ketone (80 mL) to give 3 g of 3- [1- [4,4-bis (4-fluoromethyl) butyl] -4-piperidinyl] -3,4-dihydro-2 (1H) -quinazolinone; mp 199-200.5 ° C (compound 1).

Similarly prepared:

4- [2- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] acetyl] -3,4-dihydro-3-phenyl-2 (1H) -quinoxalinone ethanedioate (1: 1) ); mp 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, 1C (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); mp 173.2 ° C (compound 4).

3- [1- [4,4-bis (4-fluoromethyl) butyl] -4-piperidinyl] -3,4-dihydropyrido [2,3-d] -2 (1H) -pyrimidinone dihydrochloride; mp 220-222 ° C (compound 5).

Example A.2

A mixture of 4-fluoro-T- (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 3% ethanol (1 g), potassium acetate (3 g) and methanol (200 ml) was hydrogenated under normal pressure and 50 ° C, using 10% palladium on charcoal as catalyst (2 g) After addition of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated, water is added to the oily residue and the mixture is basified with ammonium hydroxide and extracted with 4-methyl-2-pentanone. The oily residue is purified on a chromatography column over silica gel, eluting with a mixture of trichloromethane and methanol (95: 5 by volume), and the oily residue is converted into the ethanedioate salt in acetonitrile and 4-methyl-2-pentanone as The salt may be crystallized ea dried to give 5 g (63.3%) of 3- [2 - [[1- [4,4-bis (4-fluorophenyl) butyl] 4-piperidinyl] methyl] -1H-benzimidazol-1-yl] - 1- (4-fluorophenyl) 1-propanone ethanedioate (1: 2); melting point 156.4 ° C (Compound No. 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) and a few crystals of potassium iodide in 4-methyl-2-pentanone (200 ml) were refluxed for 24 hours, then a second portion of 4-chloro-1- (2-thienyl) butanone (4.1 g) and the whole were added. The mixture was stirred and refluxed for an additional 36 hours, water (100 mL) was added after cooling, the organic layer was separated, dried over potassium carbonate, then filtered and evaporated The oily residue was dissolved in anhydrous ether (480 mL). The solution is filtered and hydrogen chloride gas is introduced into the filtrate, and a salt is precipitated, which is filtered and crystallized from 2-propanol (320 ml) to give 4 - [[4,4-bis (4-fluorophenyl) butyl] - 1-piperazinyl] -1 (2-thienyl) butanone, mp 227.5-230 ° C (Compound No. 7).

Example A.4

To a solution of 1- [4,4-bis (4-fluorophenyl) butyl] -N- (4-methoxyphenyl) -4-piperidinamine (6.75 g) in 2,2'-oxybis (propane) (105 mL) and tetrahydrofuran (45 mL) was added dropwise with stirring with a solution of 2-isocyanate propane (1.36 g) in 2,2'-oxybis (propane) (35 mL). After the addition is complete, stirring is continued for 1 day at room temperature and then for one hour at 50 ° C. The reaction mixture was then evaporated and the residue was crystallized from a mixture of 2,2'-oxybis (propane) and 2-propanol to give N- [1- [4,4-bis (4-fluorophenyl) butyl] -1-piperidinyl]. N- (4-methoxyphenyl) -N '- (1-methylethyl) urea (4.8 g, 59%); melting point 170.9 'C (compound 8).

Similarly prepared:

N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N'-butyl-N- (4-methoxyphenyl) urea; Melting point 101.9'C (Compound No. 9)

N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N- (4-methoxyphenyl) -N-propylurea; Melting point 124, 1C (Compound No. 10)

N - [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N'-cyclohexyl-N- (4-methoxyphenyl) urea; Melting point 128.2'C (Compound No. 11)

N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N'-ethyl-N- (4-methylphenyl) urea; Melting point 129, l 'C (Compound No. 12)

N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N '- (1-methylethyl) -N- (4-methylphenyl) urea; melting point 167.2 'C (Compound No. 13) a

N - [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N '- (4-chlorophenyl) -N' - (1-methylethyl) urea; mp 157.4 'C (Compound No. 14).

Pharmacological examples

Example B. I Analysis of GlyT-1 transport by transporters

Subconfluent HEK 293-GlyT1 cells (a series of cells that are stable transporters of human glycine 1) are seeded on Cytostar-T plates at 50,000 cells per well in 100 μΐ DMEM medium (Dulbecco Modified Eagle Medium Medium saturated with 10% fetal bovine serum, 1 mM sodium pyruvate, 100 U units of penicillin / ml and 0.1 mg / ml streptomycin). The cells were aged at 37 ° C, 5% CO ₂ and 95% humidity for 48 hours.

On day 3, the cells were washed in a microprocessor-controlled Tecan PW96 washer capable of washing all 96 wells of a single plate simultaneously with absorption buffer (25 mM).

Hepes, 5.4 mM potassium gluconate, 1.8 mM calcium gluconate,

0.8 mM MgSO4, 140 mM NaCl, 5 mM glucose and 5 mM alanine, the pH of the solution was adjusted to 7.5 with 2M Tris). Tecan PW96 was programmed to wash the cells five times, dispensing 75 μΐ of solution into each well. Test substances were dissolved in micromoles of DMSO at various concentrations. 1 μΐ of test solution was added to each well and the cells were aged for 5 to 10 minutes at room temperature. Then 25 μΐ 30 M [U ¹⁴ C] glycine dissolved in the absorption buffer was added and the cells were aged at room temperature for an hour. Finally, the plates were sealed and the [U ¹⁴ C] glycine uptake was measured by TopCount (Packard microplate scintillation counter scintillation tube). ). From the results obtained for various concentrations of test substances, the concentration at which glycine absorption is inhibited by 50% (IC ₅₀ ) was calculated. The calculated concentrations for the compounds described in the invention set forth in Table 1 (entry ₅₀ PIC negative log IC _50).

The following were also tested:

Compound No. 15 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-pyridinylmethyl) -3Himidazo [4,5-b] pyridine ethanedioate ( 1: 2);

compound no. 16 which is 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 no. 17 - 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (phenylmethyl) -3H-imidazo [4,5-b] ] pyridine ethanedioate (1: 2);

compound no. 18 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-thienylmethyl) -3H-imidazo [4,5-b] ] pyridine ethanedioate (1: 1);

compound no. 19 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-furanylmethyl) -3-imidazo [4,5- b] pyridine ethanedioate (1: 2);

compound no. 20 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl) methyl] -3 - [(4-methoxyphenyl) methyl] -1H-benzimidazole ethanedioate (1: 2);

compound no. 21 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (4-thiazolylmethyl) -1H-benzimidazole ethanedioate (1: 2) as discloses EP-A-0,151,826 ' 22, which is 1- [4,4-di (4-fluorophenyl) butyl] 4- [3- (anilinecarbonyl) -propyl] -piperazine dihydrochloride, as described in GB -1,055,100.

Table 1

Bile. no. ^PIC 50 Bile. no. ^PIC 50 Bile. No. PIC ₅₀ 1 6.61 9 6.15 17 6.42 2 6.34 10 6.12 18 6.26 3 6.14 11 6.28 19 6.15 4 6.81 12 6.02 20 6.09 5 6.26 13 6.18 21 6.07 6 6.44 14 6.18 22 6.33 7 6.29 15 6.65 8 6.51 16 6.55 Examples composition

The following example characterizes a typical pharmaceutical composition suitable for regular administration to animals and humans. The active ingredient ”(A.I.) represents compound (I) or a more suitable addition salt of the compound for pharmaceutical purposes.

Example C1 Film-coated tablets

Preparation of the base tablet

A mixture of 100 g of A.I., 570 g of lactose and 200 g of starch is mixed well and moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil are then added. The whole mixture is mixed well and compressed into tablets; from this amount, 10,000 tablets are prepared, each containing 10 mg of the active ingredient.

coating

To a solution of 10 g methylcellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. In addition, 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The first and second solutions are mixed, 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension are added. Everything is homogenized. The base tablets are coated with the mixture thus obtained in the corresponding apparatus.

Claims (10)

PATENT CLAIMS A compound which inhibits glycine transfer, for the preparation of a medicament for the treatment of disorders of the central and peripheral nervous system, characterized in that it has the formula: It is an N-oxide, stereochemically isomeric form, or a pharmaceutically acceptable addition salt thereof, wherein X is CH or N; L represents a substituent of the formula wherein n is 0 or 1; m is 0 or 1; Alk represents C 1-4 alkanediyl; A is N or CH; B ¹ represents CH ₂ or NH; -a ^{1 =} a ² -a ³ = a ⁴ - represents a divalent substituent of formula -CH = CH-CH = CH- (a-1) or -N = CH-CH = CH- (a-2); R ¹ is C ₁ _ 4 alkyl optionally substituted by ₄ C ₁ _ ₄ alkoxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo [l, 2-a] pyridinyl, thiazolyl? R ² is hydrogen or aryl? R ³ is hydrogen, C ^ alkyl or C ₃ _ ₇ cycloalkyl; R ⁴ is thienyl, furanyl, arylamino or a substituent of formula (d -1) wherein R ⁵ is hydrogen or aryl; aryl represents phenyl optionally substituted with one or two substituents selected from C ₁ _ ₄ alkyl, halogen, hydroxy, C ₁ _ ₄ alkyloxy. A compound according to claim 1, wherein L is a substituent of formula (a) or (b). I 3. A compound according to claim 1, wherein the disorder is psychosis, pain, epilepsy, neurodegenerative diseases, stroke, head trauma or multiple sclerosis. A compound of formula (I) according to claim 1 or 2, wherein when X is CH, L is a substituent of formula (a) wherein B ¹ is -CH 2 - and R ¹ is pyridin-2-ylmethyl, thien -2-methyl, furan-2-methyl, benzyl or 4-fluorobenzyl, then -a ^{1 =} and ² -a ³ = and ⁴ - is different from -N = CH-CH = CH-, and further characterized by: that when X is CH, L is a substituent of formula (a), wherein B ¹ is -CH 2 - and R ¹ is 4-methoxyphenylmethyl or thiazol-4-ylmethyl, then -a ¹ = a ² -a ³ = a ⁴ - is other than -CH = CH-CH = CH-, and further characterized in that when X is N and L is a substituent of formula (d) wherein Alk is 1,3-propanediyl, then R ⁴ is another substituent as phenylamino. 5. The compound according to claim 4, characterized in that n is 0, m is 1, R is a C - ^ _ ₄ alkyl optionally substituted with C ₁ _ ₄ alkoxy, arylcarbonyl or imidazo [1,2-a] pyridinyl and R ⁴ is thienyl, furanyl or a substituent of formula (d-1). The compound of claim 4, wherein the compound is 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 (177) quinoxalinone; N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] (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-C [1- C 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; A pharmaceutical composition comprising a suitable pharmaceutical carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 4 to 6. A process for the preparation of a pharmaceutical composition according to claim 7, wherein the therapeutically effective amount of the compound of one of claims 4 to 6 is intimately mixed with the pharmaceutical carrier. Compound according to one of Claims 4 to 6, characterized in that it is used as a medicament. 10. A process for the preparation of a compound according to claim 4, wherein: (a) the compound is formed by reacting an intermediate of formula (II) wherein W ¹ is the corresponding reaction group which is removed by reaction with an intermediate of formula (III) in an inert solvent in the presence of a suitable base and optionally also in the presence of potassium iodide; (H) (III) b) the compound is formed by the reductive alkylation of an intermediate of formula (III) with an intermediate of formula (IV) in an inert solvent, in the presence of a reducing agent and optionally also a suitable catalyst; (III) (III) c) the compound of formula (I-a) is formed by reacting an intermediate of formula (V) with an intermediate of formula (VI), wherein W * is a suitable reaction group; in an inert solvent, in the presence of a suitable base and, optionally, in the presence of potassium iodide; l d) the compound of formula (I-b) is formed by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII) in an inert solvent O = “C = N — R ´ (VIII) and further characterized, if necessary, by converting the compounds of formula (I) into acid addition salts by reaction with an acid or into basic addition salts by reaction with a base; or vice versa, the acid addition salts are converted to the free base by reaction with an alkali, and the base addition salts are converted to the free acids by reaction with an acid; and further, if necessary, preparing the compound in the form Oxidu-oxide and / or in the form of stereochemical isomers