CZ20003146A3 - Inhibitors of glycine transfer - Google Patents

Abstract

Use of glycine transfer inhibitors, [4,4-bis (4- fluorophenyl) butyl] -1- (piperazinyl and piperidinyl) derivatives for the preparation of medicines for the treatment of central and peripheral disorders nervous system, especially psychoses, painful conditions, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and others. The solution involves completely novel compounds of formula I, their preparation and pharmaceutical forms

Description

GLYCIN TRANSMISSION INHIBITORS

Technical field

The present invention relates to the use of glycine transfer inhibitors, [4,4-bis (4-fluorophenyl) butyl] -1- (piperazinyl and piperidinyl) derivatives for the preparation of medicaments for the treatment of central and peripheral nervous system disorders, particularly 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.

h

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

—L (I) (01-1507.doc)

-2 ·· φ · η • φ • • · φ φ φ φ φ · · φ φ φ • φ φ φ φ φ φ φ φ φ • φ • » φφ φ «

It is a ο 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 1-6 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- (a-1) or -N = CH-CH = CH- (a-2);

R ¹ represents C _1-4 alkyl optionally substituted with C _1-4 alkoxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo [1,2-a] pyridinyl, thiazolyl;

R ² is hydrogen or aryl;

R ³ represents hydrogen, C ₆ alkyl or C ₃ _ ₇ cycloalkyl;

R ⁴ is thienyl, furanyl, arylamino or a substituent of formula (01-1507.doc) • • · ·

- 3 · · · · · · · · · · · · · · · · ·

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 disorders of the central and peripheral nervous system, particularly psychosis, pain conditions, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. (I) or the Noxide forms and pharmaceutically acceptable acid or base addition salts or stereoisomers thereof in combination with a pharmaceutical carrier.

In the above and subsequent formulas, halogen is generic to fluoro, chloro, bromo and iodo; C ₃ _7cykloalkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C 1-4 alkyl defines straight and branched chains of saturated hydrocarbon radicals having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl,

2-methylpropyl, 2,2-dimethylethyl and others; the term C _1-6 alkyl includes C 1-4 alkyl and higher homologues with five or six carbon atoms, for example pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and others; C _1-6 alkanedienyl defines divalent straight and branched chains of saturated hydrocarbon residues that (01-1507.doc)

-4 have 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) present 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, optionally phosphoric, or organic, such as acetic, hydroxyacetic, propane, lactic, pyruvic, oxalic, malonic, amber, maleic, fumaric, cider, tartaric, lemon, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, N-cyclohexylsulfamic, salycilic, p-aminosalycil.

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

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

(01-1507.doc) 4 4 4 4 4 4

44444 44444. · 4 4 4 4 4 -4445 44 44 44 44 44

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

The designation of the N-oxide form of the compounds of formula (I) includes those compounds (I) in which one or more nitrogen atoms are oxidized to a 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 intermediates thereof have at least one stereogenic center in their structure.

This center is referred to as the R or S configuration, in accordance with 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 includes N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms. A new composition of compounds (I) is contemplated in the following cases;

- if X is CH, L is a substituent of formula (a), wherein B ¹ is 16 (01-1507.doc)

4 ·· 4 4 99

4 4 4 4 9 9

445 4 · · '· «»

4 4 4

4 4 4

CH ₂ - and R ¹ is pyridin-2-ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then -a ^{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 phenylamino.

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

An interesting group are those compounds (I) wherein in formula n is 0, m is 1, R ¹ is C _1-4 alkyl optionally substituted with C _1-4 alkoxy, arylcarbonyl or imidazo [1,2a] pyridinyl and R ⁴ is thienyl, furanylzl 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, the compounds of formula (I) are prepared by the reaction processes described in patents EP-A-0,151,826 and GB1,055,100, in particular by reacting an intermediate of formula (II) wherein W ¹ is a corresponding tear-off reaction group (e.g. halogen) with an intermediate of formula (III).

(01-1507.doc) • 4 • 4 '444 4 4' «

4. 4 «

I · 4 · 4 ·

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 subsequent preparations, the reaction products are isolated from the reaction medium and, if necessary, further purified by conventional methods, for example, extraction, crystallization, distillation, trituration 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 such as methanol in the presence of a reducing agent such as hydrogen in the presence of a suitable catalyst such as palladium on activated carbon. Thiophene may optionally be added to the reaction mixture.

(01-1507.doc)

- 8 • 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · 9 '· 9 9 9 9 9 9 9 9 9

9999 99 99 99 99 99

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 detached by the reaction, for example halogen.

The reaction is carried out in an inert solvent, for example methyl isobutyl ketone, Ν, Ν-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) depicts formula (I-b) and may be prepared by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII).

(01-1507.doc) •

(l-b)

This reaction takes place in an inert solvent, for example diisopropyl ether.

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

Compounds (I) can be converted to the corresponding Noxide forms by a conventional transition process of 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 halogenated derivatives, such as 3-chlorobenzenecarboperoperoxide acid, peroxoalkanoic acids such as peroxoacetic acid, alkyl hydroperoxides, (01-1507.doc) «4 • 9

-10 8 8

Eg 9 t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol, hydrocarbons, for example toluene ketones, for example 2-butanone halogenated hydrocarbons, such as dichloromethane, and mixtures of these solvents.

Some of the compounds (I) and intermediates of this invention may contain asymmetric carbon. 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, then separating these mixtures or compounds, for example, by selective crystallization or chromatography (liquid chromatography and other methods), and finally converting the individual diastereomeric 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 chiral stationary phase method.

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

(01-1507.doc)

-11 ♦ fcfc • fcfc c fcfc c fcfc f fcfc f fcfc f fc fcfc

Glycine is an amino acid that causes both inhibitory and excitatory transmission at the nerve endings of the central and peripheral nervous system. This different function is due to two types of receptors that act as glycine transporters. The inhibitory effects of glycine are due to 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 StormMathisen nakl. (1990), pp. 193-219]. Glycine, by its nature, is one of the so-called NMDA glycine receptors (N-methyl-D-aspartate), which are found to a large extent in the brain, particularly in the cortex and hippocampus.

Glycine transporters regulate the concentration and duration of neurotransmitter activity in the nerve endings (synapses), or regulate the intensity of synaptic transmission. In addition, they also maintain the accuracy of synaptic transmission so that neurotransmitters do not spread to adjacent synapses. Finally, after transmission of excitement, the synapses released by the transmiters store at the presynaptic end and are ready for further use. The transmission of neurotransmitters depends on the amount of extracellular sodium and the membrane voltage gradient. For example, in reverse, neurotransmitters in calcium-induced channels [Attwell et al: Neuron, 11 (1993), 401-407]. Changing carriers thus allows to modify specific conditions, carriers function seizure, they can release neurotransmitters synaptic (01-1507.doc)

99 * 9 9 9

-12 • 9 • 999 99 «9 9 · 99 99 • 9 9 ·« * 9 9 • 9 99 9 9 9

99 9 9 99 9 · 9 99 99 activity, which is successfully used in the treatment of central and peripheral nervous system disorders.

Molecular cloning revealed the existence of two classes of glycine transporters, called GlyT-1 and GlyT-2. GlyT-1 is found predominantly in the forebrain and its distribution corresponds to the pathways of glutamate and NMDA receptors [Smith et al: Neuron, 8 (1992), 927-935]. Three highly interrelated 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 of them shows a unique distribution in the brain and peripheral tissues. In contrast to these substances, 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]. Lye can therefore be expected to selectively alter the activity of NMDA receptors and strychnine-sensitive receptors, respectively, when regulating the synaptic glycine levels of GlyT-1 and GlyT-2.

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 receptors. This reduces 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 (1988), 77 - 87; Becker: FASEB J., (01-1507.doc)

-13 * * fr fr * * ft .. ft · ft ft ft ft ft ft ft ft ft ft ft ft ft ft fr fr fr fr fr fr fr fr (1990), 2767 - 2774], Convulsive conditions that are treated with glycine receptor alteration are associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord trauma, dystonia, possibly 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]. Decreased function of these receptors leads to symptoms of schyzophrenia [Olney and Farber: Archives General Psychiatry, 52 (1996), 998-1007]. Therefore, agents that inhibit GlyT-1 and thereby increase NMDA receptor activity are used as a modern psychopharmaceutical to affect psychoses and dementia in the treatment of diseases, including attention deficit disorders and organic brain disease. Conversely, increased NMDA receptor activity is used in the treatment of a number of diseases related to nerve death, including stroke, head trauma, or neurogenerative diseases such as Alzheimer's disease, dementia due to heart attack or AIDS, Huntington's disease, Parkinson's disease, and amiotrophic 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.

(01-1507.doc)

-14 · »14 * 4 4 4 4 4 4 4 4 4 9 4

4 4 4 4 44

443 4 4 4 4 4 4 4 4 4 4

4 4 4 4 4 4 4 4

4444 44 44

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 of a variety of pharmaceutical composites. These are prepared by intimately mixing an effective amount of the compound (I) in the form of an acidic or basic addition salt (active ingredient) with a suitable carrier selected according to the route of administration (oral, percutaneous, parenteral injection), drugs for oral administration of media such as water, glycols, the resulting products in this are syrups, elixirs and drops, or solids

For the manufacture of pharmaceutical alcohols suspension, use conventional liquid oils, if worn, prepare and form. For example, starch, sugars, kaolin, lubricants, binders, comminuted substances, from which powders, capsule pills and tablets are then prepared. For oral administration, tablets and capsules are most commonly used. Parenteral compositions contain 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.

If these solutions contain compounds (I), for example, pine oil, sesame oil, cottonseed oil, cereal oil, soybean oil, synthetic esters of glycerol and higher fatty acids, or mixtures, of these substances. Injectable solutions may also be in the form of 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 possibly also facilitate the subcutaneous application of the composition. Percutaneous (subcutaneous) mixtures are applied differently - form (01-1507.doc) φ

-15ΦΦ φ φ · · - * * * φ φ φ Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φφ φφ patches, spot 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 uniformity of description, it is preferable to list the amount of pharmaceutical compositions in dosage units, each unit containing a predetermined amount 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 packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons 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 with stirring for 2 days. After cooling, water (250 mL) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was recrystallized from methylisobutyl ketone (80 mL) to give 3 g

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] 16 (01-1507.doc)

44

4 <4

4 4 4

4 4 4 4

4 4 4

44

-164 * ·· 44

4 4 • 4 4

444 4

4

4445 44 <4

4

4 4

4 4

44

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-benzimidazole-2-amine; mp 160.1 ° C (compound 3).

2 - [[4- [4,4-bis (4-fluorophenyl) butyl] -1-piperazinyl] methyl] -3 (2-ethoxyethyl) -3 H -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-dihydro-pyrido [2,3-d] -2 (1H) -pyrimidinone dihydrochloride; mp 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 monohydrate of dihydrobromide (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 50 ° C, using 10% palladium on catalyst activated carbon (2 g). After addition of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. Water was added to the oily residue and the mixture was basified with ammonium hydroxide. The resulting product was extracted

4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The oily residue is converted to the ethanedioate salt in acetonitrile and 4-methyl-2-pentanone as it can crystallize in the salt form. The crystallization product was filtered and dried to give 5 g (63.3%).

3- [2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -1H-benzimidazol-1-yl] -1- (4-fluorophenyl) -1-propanone ethanedioate (1: 2); mp 156.4 ° C (Compound No. 6).

(01-1507.doc)

φ * φ φφ

Example Α.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 several crystals of potassium iodide in

4-Methyl-2-pentanone (200 mL) was refluxed for 24 hours. Then a second portion was added

Of 4-chloro-1- (2-thienyl) butanone (4.1 g) and the whole was stirred and refluxed for an additional 36 hours. After cooling, water (100 mL) was added. 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 was filtered and hydrogen chloride gas was introduced into the filtrate. A salt precipitated, which was 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 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) are added dropwise with stirring

2-isocyanatpropane (1.36 g) in 2,2'-oxybis (propane) (35 mL). After addition of the entire batch, 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) -1 '- (1-methylethyl) urea (4.8 g, 59%); mp 170.9 ° C (compound 8).

(01-1507.doc)

-18 • Φ φφ φφ φφ φφ φφ

Φ ΦΦ Φ Φ ΦΦ Φ Φ * 4 • • Φ φ φ φφ φ φφ 4

4 ΦΦ Φ φ φφφ 4 · φ • Φ · ΦΦΦ φ 4φ φ

4444 4 «ΦΦ φφ φφ φφ

Similarly prepared:

[- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N ’-butyl-N (4-methoxyphenyl) urea; mp 101.9 ° C (Compound No. 9),

N- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -N- (4-methoxyphenyl) -N'-propylurea; mp 124.1 ° C (Compound No. 10),

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

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

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

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

Pharmacological examples

Example B.l: Analysis of Transport of GlyT-1 Carrier

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 of DMEM medium (Dulbeccos Modified Eagle Medium saturated with 10% fetal bovine serum, 1 mM sodium pyruvate, 100 U 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 the third day, the cells were washed in a microprocessor-controlled Tecan PW96 washer capable of washing all 96 cells (01-1507.doc)

-19 * «» * ·· 44 ·· 44 • 44 · · 44 4 4 44 4

444444 44 444 44 ·

4 4 4 4 4 4 4 4

4 444 4 "44 44 44 44 one tray simultaneously with uptake buffer (25 mM Hepes, 5.4 mM potassium gluconate, 1.8 mM calcium gluconate, 0.8 mM MgSO _4, 140 mM NaCl, 5 mM glucose, 5 mM alanine, where The pH of the solution was adjusted to 7.5 with 2M Tris. Tecan PW96 was programmed to wash the cells five times, adding 75 μ 75 of solution to each cell. Test substances were dissolved in micromoles of DMSO at various concentrations. 1 μΐ of test solution was added to each cell and the cells were aged for 5-10 minutes at room temperature. Then, 25 μΐ 30 μΜ [U ¹⁴ C] glycine dissolved in 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 with a TopCount (Packard microplate scitillation counter) scintillation tube. From the results obtained for the various concentrations of test substances, the concentration at which glycine absorption is inhibited by 50% (IC ₅₀ ) was calculated. Calculated concentration values for the compounds described in the present invention are summarized in Table 1 (Data expressed pIC50 -log _IC50).

Further tested were:

Compound No. 15: 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-pyridinylmethyl) -3 H -imidazo [4,5- b] pyridine ethanedioate (1: 2); Compound No. 16: 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3 - [(4-fluorophenyl) methyl] -32'-imidazo [4,5-b] ] pyridine ethanedioate (1: 2);

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

compound 18 which is 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-thienylmethyl) 16 (01-1507.doc)

-20 • 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 9 9 9 9

9,999 9 9 9 9 9 9 9 9

9,999 9,999

9999 99

3 H -imidazo [4,5- b] pyridine ethanedioate (1: 1);

Compound No. 19: 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (2-furanylmethyl) 3 H -imidazo [4,5- b] pyridine ethanedioate (1: 2); Compound No. 20: 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3 - [(4-methoxyphenyl) methyl] -1H-benzimidazole ethanedioate (1: 2) ; Compound No. 21: 2 - [[1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] methyl] -3- (4-thiazolylmethyl) -1H-benzimidazole ethanedioate (1: 2) as described EP-A-0,151,826 and Compound No. 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

Compound No. PIC ₅₀ Compound No. PIC ₅₀ Compound 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 Dec 6.15 4 6.81 12 6.02 20 May 6.09 5 6.26 13 6.18 21 6.07 6 6.44 14 6.18 22nd 6.33 7 6.29 15 Dec 6.65 8 6.51 16 6.55

Examples of composition

The following example characterizes the typical composition (01-1507.doc) • 4

4

4

4

4

-21 • 4 '· *' 44 '4 • * · 4 4 4 4 4 • · · 4 4 44

944 '4 4 - 4 4 4 •' 4 4 4 4 4

4444 44 44 44 pharmaceutical substances suitable for regular administration to animals and humans. The active ingredient (A.I.) represents a compound (I) or, for pharmaceutical purposes, a more suitable addition salt of the compound.

Example C1: Film-coated tablets

Preparation of 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; 10,000 tablets are prepared, each containing 10 mg of 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 REQUIREMENTS • * * * 4 4 4 4 4 4 4 4 4 44 · '999 9' 9 4 4 9 4 5 9883 94 94 89 9 4 9 4 9 4 4 4 4 9 4 4 9 4 8 5 44 44 Glycine transfer inhibiting compound for use in 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 a oxid-oxide, stereochemically isomeric form, or a pharmaceutically acceptable addition salt thereof, wherein X is CH or N; L represents a substituent of formula (a)? ² ? N — C — N R ³ H (b 16 (01-1507.doc) 03 09 0 0 · 0 0 0 0 «0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9 0 0 0 0 0 0 0 9 0 0 0 00 90 00 90 9 0 0 9 0 0 0 9,000 0 0 0 9 0 «« < 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- (a-1) or -N = CH-CH = CH- (α-2); R ₁ represents C _1-4 alkyl optionally substituted by C _1-4 alkoxy, pyridinyl, aryl, arylcarbonyl, thienyl, furanyl, imidazo [1,2-a] pyridinyl, thiazolyl; R ² is hydrogen or aryl; R ³ represents hydrogen, Ci_6alkyl or C3 _'7 cycloalkyl; R ⁴ is thienyl, furanyl, arylamino or a substituent of the formula wherein R ⁵ is hydrogen or aryl; aryl represents phenyl optionally substituted by 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). A compound according to claim 1 wherein the disorder is psychosis, a painful condition, epilepsy, neurodegenerative diseases, stroke, head trauma or 16 (01-1507.doc) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · · ···· ·· ·· ·· ·· ·· multiple sclerosis. Compound of formula (I) according to claim 1 or 2, characterized in that 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; = a ² -a ³ = a ⁴ - is different from -N = CH-CH = CH-, and further characterized in 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 different from -CH = CH-CH = CH-, and further characterized in that if X is N and L is a substituent of formula (d), wherein Alk is 1,3-propanediyl, then R ⁴ is a substituent other than phenylamino. 5. A compound according to claim 4, characterized in that n is 0, m is 1, R ¹ is C ₄ alkyl, optionally substituted C ₄ alkoxy, arylcarbonyl or imidazo [1,2-a] pyridinyl and ^R4 is thienyl, furanyl or a substituent of formula (d-1). 6. 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 (1H) 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 - [[1- [4,4-bis (4-fluorophenyl) butyl] -416 (01-1507.doc)] 25 ······· ··· «•« '··' '. »:. ·. · · · · · · · · · · · · · · · · · · · · · · [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) -1 '- (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 preparing a pharmaceutical composition according to claim 7, wherein the therapeutically effective amount of the compound of one of claims 4 to 6 is intimately admixed with the pharmaceutical carrier. Compound according to one of Claims 4 to 6, characterized in that it is used as a medicament. A process for the preparation of a compound according to claim 4, characterized in that a) the compound is formed by reacting an intermediate of formula (II) wherein W ¹ is a corresponding reaction group which is peeled off with an intermediate of formula (III) in an inert solvent, in the presence of a suitable base and optionally in the presence of potassium iodide; 16 (01-1508.doc) • e b) the compound is formed by 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 a suitable catalyst; c) the compound of formula (Ia) is formed by reacting an intermediate of formula (V) with an intermediate of formula (VI), wherein W ¹ is a suitable reaction group; in an inert solvent, in the presence of a suitable base and optionally in the presence of potassium iodide; 16 (01-1507.doc) d) the compound of formula (Ib) is formed by reacting an intermediate of formula (VII) with an isocyanate derivative of formula (VIII) in an inert solvent and further characterized in that, if necessary, the compounds of formula (I) are converted to acid addition salts by reaction with an acid or to base addition salts by reaction with a base; or vice versa, acid addition salts are converted to the free base by treatment with an alkali, and base addition salts are converted to the free acids by treatment with an acid; and further, if desired, the compound is prepared in the form of N16 (01-1507.doc)