KR20010032967A - Glycine transport inhibitors - Google Patents

Abstract

The present invention relates to the central and peripheral nervous system disorders of α, α-diphenyl-1-piperidinebutaneamide that inhibit glycine transport, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), seizures, head injury trauma), the use for the manufacture of a medicament for the treatment of multiple sclerosis and the like. The invention also includes novel compounds, methods for their preparation and pharmaceutical forms.

Description

Glycine transport inhibitors

N, N-dimethyl-α, α-diphenyl-1-piperidinebutaneamide, for example 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-di Phenyl-1-piperidine butaneamide (loperamide, Imodium ^™ ) is well known as a branch office. These compounds, their activities and methods of preparation are disclosed for the first time in US Pat. No. 3,714,159.

The present invention relates to the central and peripheral nervous system disorders of α, α-diphenyl-1-piperidinebutaneamide that inhibit glycine transport, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), seizures, head injury trauma), the use for the manufacture of a medicament for the treatment of multiple sclerosis and the like. The invention also includes novel compounds, methods for their preparation and pharmaceutical forms.

The present invention relates to the use of glycine transport inhibitor compounds for the manufacture of a medicament for the treatment of central and peripheral nervous system disorders, said compounds comprising the compounds of formula (1), their N-oxides, stereochemically isomeric forms and pharmaceutically acceptable additions It is a salt:

In the above formula,

R ¹ and R ² each independently represent hydrogen or C _1-4 alkyl;

X is a chemical formula

Represents a radical of:

From here,

The dotted line represents any bond;

Silver chemical formula

Represents the radical of

[From here,

R ⁶ and R ⁷ may each represent hydrogen or together may form a phenyl ring with two carbon atoms to which they are attached;

R ⁸ represents hydrogen or halo;

n is 1 or 2;

R ⁴ represents hydrogen, hydroxy, C _1-4 alkyloxy, C _1-4 alkyloxyC _1-4 alkyl, or arylC _1-4 alkyloxy;

R ⁵ is diarylmethyloxyC _1-4 alkyl or formula

Represents the radical of

[From here,

B ¹ represents —CH ₂ , —CH (OH) —, —NH—, —CH ₂ —NH— or a direct bond;

B ² represents -NH-, -CH ₂ -or a direct bond;

B ³ represents —NR ¹² —, —CH ₂ —, —C (═O) — or a direct bond;

B ⁷ represents —C _1-4 alkanediyl-NH— or —NH—C _1-4 alkyl-;

B ⁸ represents —NR ¹⁹ —, —CH ₂ — or —CH (aryl);

Each Y independently represents O or S;

-a ¹ = a ² -a ³ = a ⁴ -is a chemical formula

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

-N = CH-N = CH- (b-1-b)

Divalent radicals

Wherein the hydrogen atom of the radical (b-1-a) may be substituted with hydroxy);

R ⁹ is C _1-4 alkyl; Or aryl, thienyl, furanyl, furanyl substituted with hydroxyC _1-4 alkyl, or C _1-4 alkyl substituted with thiazolyl;

R ¹⁰ represents aryl, arylamino, C _1-4 alkylamino, C _1-4 alkylthio;

R ¹¹ represents hydrogen, C _1-4 alkyl, halo or trifluoromethyl;

R ¹² represents hydrogen or C _1-4 alkylcarbonyl;

R ¹³ represents hydrogen, C _1-4 alkyl or aryl;

R ¹⁴ represents hydrogen or halo;

R ¹⁵ and R ¹⁶ each independently represent hydrogen or aryl;

R ¹⁷ represents hydrogen or C _1-4 alkyl;

R ¹⁸ is optionally substituted with 1 or 2 substituents each independently selected from aryl, 10,11-dihydro-5H-dibenz [b, f] azin-5-yl or C _3-7 cycloalkyl and aryl C _1-4 alkyl;

R ¹⁹ represents hydrogen, C _1-4 alkylcarbonyl or diarylC _1-4 alkyl;

R ²⁰ , R ²¹ , R ²² , and R ²³ each independently represent hydrogen, C _1-4 alkyl or aryl;

R ²⁴ represents hydrogen or trifluoromethyl;

R ²⁵ represents hydrogen or halo;

When R ⁵ represents a radical of formula (b-3), R ⁴ may also be phenyl-C _1-4 alkylaminocarbonyl;

R ⁴ and R ⁵ together are

Spiro radicals can form

Wherein R ²⁶ and R ²⁷ each independently represent hydrogen, C _1-4 alkyl, aryl or arylC _1-4 alkyl;

Aryl represents phenyl or phenyl substituted with 1 or 2 substituents independently selected from C _1-4 alkyl, halo, trifluoromethyl, hydroxy and C _1-4 alkyloxy.

The present invention also relates to methods of treating warm-blooded animals with central and peripheral nervous system disorders, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), seizures, head injury, multiple sclerosis, and the like. The method comprises administering a therapeutically effective amount of a compound of formula (I) or an N-oxide form thereof, a pharmaceutically acceptable acid or base addition salt or stereochemically isomeric form in a mixture with a pharmaceutical carrier.

Halo as used above and below is a generic name for fluoro, chloro, bromo and iodo; C _3-7 cycloalkyl is the generic name of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C _1-4 alkyl is a straight and branched chain saturated hydrocarbon radical having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethyl Ethyl and the like; C _1-4 alkanediyl is a divalent straight and branched chain saturated hydrocarbon radical having 1 to 4 carbon atoms, for example 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl and the like.

The pharmaceutically acceptable addition salts mentioned above include the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) can form. Acid addition salt forms of the compounds of formula (I), which are present in free form as bases, include suitable acids, such as inorganic acids, such as hydrochloric acid, such as hydrochloric acid or hydrobromic acid; Sulfuric acid; nitric acid; Phosphoric acid and the like; Or organic acids such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p It can be obtained by treating the free base form with toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like.

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

In contrast, the salt form may be converted to the free form by treatment with a suitable base or acid.

The term addition salt as used above also includes solvates that the salts of the compounds of formula (I) as well as their salts can form. Such solvates are, for example, hydrates, alcoholates and the like.

N-oxide forms of compounds of formula I include compounds of formula I in which the piperidine nitrogen atom is oxidized to N-oxide.

The term "stereochemically isomeric form" as used herein is defined as all possible stereoisomeric forms of the compounds of formula (I). Unless stated or otherwise stated, the chemical names of compounds denote mixtures of all possible stereochemically isomeric forms, in particular racemic mixtures, which mixtures represent all diastereomers and enantiomers of the basic molecular structure. It includes. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of these forms are expressly included by formula (I).

In particular, the compounds of formula (I) and some intermediates thereof may have at least one stereogenic center in the structural formula. Such stereocenters can exist in an R or S configuration and the R and S symbols are described in Pure Appl. Chem., 1976, 45, 11-30.

Some of the compounds of formula (I) may also exist in their tautomer form. Such forms are included within the scope of the present invention, although not explicitly indicated in the above formula.

Whenever used, the term compound of formula (I) also includes N-oxides, pharmaceutically acceptable addition salts and all stereochemically isomeric forms.

The compounds of formula (I) are considered novel. Provided that when R ⁴ is hydrogen and R ⁵ is a radical of formula (b-1) wherein B ¹ is -CH ₂ -and R ⁹ is 4-fluorobenzyl, then -a ¹ = a ² -a ³ = a ⁴ -is not -CH = CH-CH = CH-; When R ⁴ is hydrogen and R ⁵ is a radical of the formula (b-1) wherein B ¹ is -NH- and R ⁹ is 4-methoxybenzyl) -a ¹ = a ² -a ³ = a ⁴ -is not -CH = N-CH = N-. The invention also relates to the novel compounds of formula (I) above for use as medicaments.

Suitably R ⁵ is diarylmethyloxyC _1-4 alkyl or formulas (b-2), (b-3), (b-4), (b-5), (b-6), (b- 7), (b-8), (b-9), (b-10), (b-11), (b-12), or (b-13) radicals; R ⁵ together with R ⁴ may form a spiro radical of formula (b-14).

Interesting groups of compounds are compounds of formula I, wherein R ¹ and R ² are methyl.

Particular compounds are those of the formula I in which X represents a radical of formula (a), more particularly a radical of formula (a) in which R ⁶ and R ⁷ together with the two carbon atoms to which they are attached form a phenyl ring.

Other particular compounds are those in which X represents a radical of formula (b), wherein R ⁵ is a radical of formula (b-1), preferably R ⁹ represents C _1-4 alkyl substituted with aryl, in particular R ⁹ Is 4-fluorobenzyl).

Another particular compound is a compound of Formula I, wherein X is a radical of formula (b), wherein R ⁵ is a radical of formula (b-2), preferably Y is S.

Preferred compounds are as follows:

4- (11,12-Dihydro-6H-benzimidazo [2,1-b] [3] benzazin-6-yl) -N, N-dimethyl-α, α-diphenyl-1-pi Ferridine butaneamide;

4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazol-2-yl] hydroxymethyl] -N, N-dimethyl-α, α-diphenyl-1-piperidine Butaneamide; And N-oxides, stereochemically isomeric forms and pharmaceutically acceptable addition salts thereof.

In general, the compounds of formula (I) are prepared according to the reaction methods described in US Pat. No. 3,714,159, US Pat. No. 4,695,575, and US Pat. No. 5,008,268, and more particularly, the intermediate of formula (II) or a functional derivative thereof with Can be prepared by reaction:

Wherein W is a suitable counter ion, for example halogen.

The reaction is carried out in a reaction-inert solvent, for example methylisobutyl ketone, N, N-dimethylacetamide or N, N-dimethylformamide, with a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine In the presence of water, optionally in the presence of potassium iodide.

In this preparation method and the following preparation method, the reaction product can be separated from the reaction medium and, if necessary, in a method generally known in the art, for example, extraction, crystallization, distillation, trituration and chromatography. It can be further purified accordingly.

The compounds of formula I can also be converted to one another according to functional group transformation schemes known in the art.

The compounds of formula (I) can also be converted to the corresponding N-oxide form according to known methods for converting trivalent nitrogen to its N-oxide form. The 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 peroxide or alkaline earth metals such as sodium peroxide, potassium peroxide; Suitable organic peroxides are peroxy acids, for example benzenecarboperoxo acid or benzenecarboperoxo acid substituted with halo, for example 3-chlorobenzenecarboperoxo acid, peroxoalkanoic acid, for example per Oxoacetic acid, alkylhydroperoxides such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, for example ethanol, and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and Mixture of solvents.

Some compounds of formula (I) and some intermediates of the present invention may include asymmetric carbon atoms. Pure stereochemically isomeric forms of the compounds and the intermediates can be obtained by applying known methods. For example, diastereomers can be separated by physical methods such as selective crystallization or chromatography techniques, such as counter-current distribution, liquid chromatography, and the like. Enantiomers initially convert the racemic mixture into a diastereomeric salt or mixture of compounds with a suitable resolving agent such as chiral acid; Then physically separating the diastereomeric salts or mixture of compounds by, for example, selective crystallization or chromatography techniques such as liquid chromatography and the like; Finally, the isolated diastereomeric salts or compounds can be obtained from the racemic mixture by conversion to the corresponding enantiomers. Pure stereochemically isomeric forms can also be obtained from pure stereochemically isomeric forms of suitable intermediates and starting materials when the intervening reaction occurs stereospecifically.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using chiral stationary phases.

Some intermediates and starting materials are known compounds and are either commercially available or can be prepared according to known methods.

Glycine is an amino acid neurotransmitter in both inhibitory and excitatory synapses of the central and peripheral nervous systems. This distinct action of glycine is mediated by two types of receptors, each associated with a different kind of glycine transporter. The inhibitory action of glycine is mediated by glycine receptors that are sensitive to convulsive alkaloid strychnine and are therefore called 'strikine-sensitive'. Strycnin-sensitive glycine receptors are found primarily in the spinal cord and brainstem.

Glycine acts on excitatory delivery by modulating the action of glutamate, a major excitatory neurotransmitter in the nervous system [Johnson and Ascher, Nature, 325, 529-531 (1987); Fletcher et al., Glycine Transmission, (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219). In particular, glycine is an essential co-agonist in the glutamate receptor class named N-methyl-D-aspartate (NMDA). NMDA receptors are widely distributed throughout the brain, especially at high density in the cerebral cortex and hippocampal formation.

The transporter absorbs neurotransmitters from the synapse, thereby controlling the concentration and term of the neurotransmitter at the synapse to determine the magnitude of synaptic transmission together. By preventing neurotransmitters from spreading to adjacent synapses, the transporter maintains fidelity of synaptic transmission. Finally, by re-absorbing the released transporter to the presynaptic end, the transporter enables reuse of the transporter. Neurotransmitter transport depends on the potential difference between both the extracellular sodium and the membrane. Under specific conditions, for example, during seizure, the transporter can work backwards by releasing neurotransmitters in a calcium-independent non-exocytotic method (Attwell et al., Neuron, 11, 401-407 (1993). Thus, modulation of neurotransmitter transporters provides a means of modifying synaptic activity, which provides useful therapies for the treatment of central and peripheral nervous system disorders.

Molecular cloning revealed the presence of two types of glycine transporters and named them GlyT-1 and GlyT-2. GlyT-1 is mainly found in the whole brain and its distribution corresponds to that of the glutamate pathway and NMDA receptors (Smith, et al., Neuron, 8, 927-935 (1992)). GlyT-1 is known to have at least three splice variants, GlyT-1a, GlyT-1b and GlyT-1c (Kim, et al., Molecular Pharmacology, 45, 608-617 (1994). )), Each with a unique distribution in brain and peripheral tissues. In contrast, GlyT-2 is found primarily in the brainstem and spinal cord, and its distribution closely corresponds to that of the strychnine-sensitive glycine receptor (Liu et al., J Biological Chemistry., 268 ,. 22802-22808 (1993); Jursky and Nelson, Neurochemistry, 64, 1026-1033 (1995). Thus, by regulating the synaptic concentration of glycine, it is expected that GlyT-1 and GlyT-2 selectively regulate the activity of the NMDA receptor and the strynnin-sensitive glycine receptor, respectively.

Compounds that inhibit or activate glycine transporters are therefore expected to alter receptor action and provide therapeutic benefit in various disease states. Thus, GlyT-2 inhibition increases the synaptic concentration of glycine, reducing the activity of neurons with strikin-sensitive glycine receptors, and pain-related (ie nociceptive) in the spinal cord known to be mediated by these receptors. It can be used to reduce the transfer of information (Yaksh, Pain, 37, 111-123 (1989)). In addition, an increase in inhibitory glycine delivery through the striknin-sensitive glycine receptor in the spinal cord can be used to reduce muscle hyperactivity, which is associated with increased muscle contraction, eg, spasms, myoclonus, and diseases related to epilepsy. Or in the treatment of conditions (Truong et al., Movement Disorders, 3, 77-87 (1988); Becker, FASEB J, 4 2767-2774 (1990)). Spasms that can be treated with modulation of glycine receptors are associated with epilepsy, seizures, head injury, multiple sclerosis, spinal cord injury, dysonia, and other disease states and damage of the nervous system.

NMDA receptors are associated with memory and learning (Rison and Stanton, Neurosci. Biobehav. Rev., 19, 533 552 (1995); Danysz et al., Behavioral Pharmacol., 6, 455-474 (1995)); Reduction of NMDA-mediated neurotransmitter activity appears to contribute to schizophrenia (Olney and Farber, Archives General Psychiatry, 52, 998-1007 (1996). Thus, it inhibits GlyT-1, thereby activating glycine of NMDA receptors). Drugs that increase the levels of can be used as novel antipsychotic and anti-dementia drugs and can be used to treat other diseases with impaired cognitive processes, such as attention deficit disorder and organic brain syndrome. Activation is associated with numerous disease states, particularly seizures, head injury, and neurodegenerative diseases such as Alzheimer's disease, multiple-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis or neuronal cell death Associated with the death of neurons, possibly related to other conditions (Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton and Rosenberg, New Engl. J. of Medicine, 33 0, 613-622 (1993), Choi, Neuron 1, 623-634 (1988)), therefore, pharmacological agents that increase the activity of GlyT-1 result in a decrease in glycine-activation of NMDA receptors and their associated Similarly, drugs that directly block the glycine site on the NMDA receptor can be used to treat these and related disease states.

For administration purposes, the subject compounds may be formulated into a variety of pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a novel compound of formula (I) as a main component. Complete preparations with a pharmaceutically acceptable carrier which can take various forms depending on the formulation intended for administration of an effective amount of a particular compound as an active salt, as an active ingredient, as an active ingredient, to prepare a pharmaceutical composition of the invention. Blend into mixture. These pharmaceutical compositions are preferably in unit dosage forms suitable for oral, transdermal or parenteral injection. For example, when preparing compositions in oral dosage forms, for example, oral liquid preparations such as suspending agents, syrups, elixirs and solutions, water, glycols, oils, alcohols and the like; Or in the case of powders, pills, capsules and tablets, conventional pharmaceutical media such as solid carriers such as starch, sugar, kaolin, glidants, binders, disintegrating agents and the like can be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are explicitly used. In the case of parenteral compositions, the carrier may, for example, contain other ingredients that aid in solubility, but will generally contain at least mostly sterile water. Injectable solutions, for example, can be prepared using a carrier comprising saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions comprising a compound of formula (I) may be formulated in oils for sustainability. Oils suitable for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration accelerator and / or a suitable wetting agent, optionally in combination with a small amount of suitable additives having certain properties that do not have a very harmful effect on the skin. Such additives may facilitate administration to the skin and / or may be helpful for preparing the desired compositions. Such compositions can be administered in a variety of ways, for example as a transdermal patch, as a drop or as an ointment. Addition salts of formula (I) are obviously more suitable for preparing aqueous compositions because they have higher water solubility than the corresponding free base or free acid forms.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein and in the claims refers to physically discrete units suitable as unit dosages, each unit comprising a predetermined amount of active ingredient calculated to produce the desired therapeutic effect with respect to the required pharmaceutical carrier. do. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoon preparations, large spoon preparations, and the like, and their divided portions. There are segregated multiples.

The following examples are intended to illustrate the invention.

Experiment part

Example A.1

Dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide (0.01 mol), prepared as described in US Pat. No. 3,714,159 in methyl isobutyl ketone (200 mL) (±)- 4- (11,12-Dihydro-6H-benzimidazo [2,1-b] [3] benzazin-6-yl) -piperidine (0.01 mol), Na ₂ CO ₃ (0.01 mol) And the KI (10 mg) mixture was stirred and refluxed overnight. The solvent was evaporated and the residue dissolved in water / CH ₂ Cl ₂ . The organic layer was separated and the aqueous layer was extracted again with CH ₂ Cl ₂ . The combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by silica gel on a glass filter (eluent: CH ₂ Cl ₂ / CH ₃ OH 95/5 to 90/10). Pure fractions were combined and evaporated. The residue was crystallized from CH ₃ CN to yield 0.88 g (15%) of (±) -4- (11,12-dihydro-6H-benzimida [2,1-b] [3] benzazin-6- Il) -N, N-dimethyl-α, α-diphenyl-1-piperidinebutaneamide (Compound 1; melting point 255.3 ° C.) was obtained.

Example A.2

Stirred mixture of 4- (3-bromo-2-oxopropyl) -N, N-dimethyl-α, α-diphenyl-1-piperidinebutaneamide monohydrobromide (13 g) in methanol (80 mL) To (2,6-dimethylphenyl) thiourea (4.1 g) was added at 70 ° C. Stirring was continued for 1 hour at reflux temperature. The solvent was evaporated and the residue dissolved in water. Potassium carbonate was added to bring the pH to about 9, and the mixture was extracted with ethyl acetate. The organic phase was purified by acid base extraction, dried, filtered and the solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off, washed and dried to give 6.7 g (52%) of 4-[[2-[[2,6-dimethylphenyl) amino] -4-thiazolyl] methyl] -N, N-dimethyl-α , α-diphenyl-1-piperidinebutaneamide (Compound 47; melting point 210.5 ° C.) was obtained.

In a similar manner the following was prepared:

4-[[2-[[2,6-dichlorophenyl) amino] -4-thiazolyl] methyl] -N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (Compound 48; Melting point 207.0 ℃)

N, N-dimethyl-4-[[2- (methylamino) -4-thiazolyl] methyl] -α, α-diphenyl-1-piperidinebutaneamide (Compound 49; Melting point 188.3 ° C.).

Example A.3

To a stirred mixture of NaH (78% dispersion; 0.55 g) in 1,4-dioxane (50 mL) 1- (4-fluorophenyl) -N, N-dimethyl-4-oxo-α, α-di Phenyl-1,3,8-triazaspiro [4,5] -decane-8-butaneamide (7.7 g) was added. After stirring for 1 hour at room temperature, the mixture was heated to 60 ° C. and (chloromethyl) benzene (2.3 g) was added. Stirring was continued at 60 ° C. overnight. The reaction mixture was poured into water and the mixture was extracted with CHCl ₃ . The extract was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography using a mixture of 3% methanol and CHCl ₃ saturated with gaseous ammonia as eluent. Pure fractions were combined and the solvent was evaporated. The residue was triturated with n-hexane. The precipitate was filtered off and dried to give 2 g of 1- (4-fluorophenyl) -N, N-dimethyl-4-oxo-α, α-diphenyl-3-phenylmethyl-1,3,8-triazaspiro [4,5] decane-8-butaneamide (Compound 50; melting point 139.8 ° C.) was obtained.

Tables 1 and 2 list the compounds prepared according to Example A.1. Some compounds were prepared using bases and / or solvents different from those used in Example A.1. In addition, some compounds were prepared without using KI. Reaction conditions are mentioned in the “Reaction Conditions” column of Tables 1 and 2. In this column, MIK represents methylisobutyl ketone, DMA represents N, N-dimethylacetamide, and DMF represents N, N-dimethylformamide.

TABLE 1

TABLE 2

Also according to Example A.1 but without using KI 1- (5-chloro-2-methyl-phenyl) -N, N-dimethyl-4-oxo-α, α-diphenyl-1,3,8- Triazaspiro [4,5] decane-8-butaneamide (Compound 46; melting point 175.7 ° C.) was prepared.

Pharmacological Examples

Example B.1 Transport Analysis of GlyT 1 Transporters

100 µl DMEM medium (10% fetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine, 100 U penicillin / Seed at a concentration of 50,000 cells per well in Cytostar-T plates in Dulbecco's Modified Eagle Medium supplemented with ml and 0.1 mg / ml stereptomycin. Cells were incubated for 48 hours at 37 ° C., 5% CO ₂ , 95% humidity.

On day 3, cells were simultaneously cultured in all 96 wells of the microplates in buffer (25 mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate, 0.8 mM MgSO ₄ , 140 mM NaCl, 5 mM glucose, 5 mM alanine, 2M Tris). Washing with a Tecan PW96 microprocessor controlled washer designed for washing with pH 7.5). Tecan PW96 is programmed to wash cells five times and leave 75 μl in each well. Test compounds were dissolved in DMSO at different concentrations in the micromolar range. 1 μl test solution was added to each well and the cells were incubated at ambient temperature of 5-10 ° C. Then 25 μl 30 μM [U ¹⁴ C] glycine diluted with buffer was added. Cells were incubated for 1 hour at ambient temperature. The plate was sealed and [U ¹⁴ C] glycine uptake was measured with a Packard microplate scintillation counter (TopCount). Glycine uptake 50% inhibitory concentration (IC ₅₀ ) was calculated from the results obtained for each test drug at various concentrations. The calculated data for the test compounds according to the invention are shown in Table 3 as pIC ₅₀ values (negative log values of IC ₅₀ ).

4-[[1-[(4-fluorophenyl) methyl] -1 H-benzimidazol-2-yl] methyl] -N, N-dimethyl-α, α- of compound 51 disclosed in US Pat. No. 4,695,575 4-[[9-[(4-methoxyphenyl) methyl] -9H-purin-8-yl] amino] -N of diphenyl-1-piperidinebutaneamide and compound 52 disclosed in US Pat. No. 5,008,268 , N-dimethyl-α, α-diphenyl-1-piperidinebutaneamide (E) -2-butenedioate (2: 5) was also tested.

TABLE 3

C. Composition Examples

The following formulations illustrate typical pharmaceutical compositions suitable for systemic administration to animal and human subjects in accordance with the present invention. "Active ingredient" (A.I.) relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example C.1 Film-Coated Tablets

Nuclear tablet

A.I. A mixture of 100 g, 570 g lactose and 200 g starch was mixed well and then wet with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml water. The wet powder mixture was quadranted, dried and requated. 100 g of microcrystalline cellulose and 15 g of cured vegetable oil were added. The whole was mixed well and compressed to give 10,000 tablets each containing 10 mg of active ingredient.

coating

To a solution of 10 g of methyl cellulose in 75 ml of modified ethanol, a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane was added. 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were then added. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former, 2.5 g of magnesium octadecanoate, 5 g of polyvinyl-pyrrolidone and 30 ml of a concentrated colored suspension were added to homogenize the whole. The core tablets were coated with the mixture obtained above in a coating apparatus.

Claims (10)

Use for the manufacture of a medicament for treating central and peripheral nervous system disorders of glycine transport inhibitory compounds of Formula 1, their N-oxides, stereochemically isomeric forms or pharmaceutically acceptable addition salts: [Formula 1] In the above formula, R ¹ and R ² each independently represent hydrogen or C _1-4 alkyl; X is a chemical formula Represents a radical of: From here, The dotted line represents any bond; Silver chemical formula Represents the radical of [From here, R ⁶ and R ⁷ may each represent hydrogen or together may form a phenyl ring with two carbon atoms to which they are attached; R ⁸ represents hydrogen or halo; n is 1 or 2; R ⁴ represents hydrogen, hydroxy, C _1-4 alkyloxy, C _1-4 alkyloxyC _1-4 alkyl, or arylC _1-4 alkyloxy; R ⁵ is diarylmethyloxyC _1-4 alkyl or formula Represents the radical of [From here, B ¹ represents —CH ₂ , —CH (OH) —, —NH—, —CH ₂ —NH— or a direct bond; B ² represents -NH-, -CH ₂ -or a direct bond; B ³ represents —NR ¹² —, —CH ₂ —, —C (═O) — or a direct bond; B ⁷ represents —C _1-4 alkanediyl-NH— or —NH—C _1-4 alkyl-; B ⁸ represents —NR ¹⁹ —, —CH ₂ — or —CH (aryl); Each Y independently represents O or S; -a ¹ = a ² -a ³ = a ⁴ -is a chemical formula -CH = CH-CH = CH- (b-1-a) or -N = CH-N = CH- (b-1-b) Divalent radicals Wherein the hydrogen atom of the radical (b-1-a) may be substituted with hydroxy); R ⁹ is C _1-4 alkyl; Or aryl, thienyl, furanyl, furanyl substituted with hydroxyC _1-4 alkyl, or C _1-4 alkyl substituted with thiazolyl; R ¹⁰ represents aryl, arylamino, C _1-4 alkylamino, C _1-4 alkylthio; R ¹¹ represents hydrogen, C _1-4 alkyl, halo or trifluoromethyl; R ¹² represents hydrogen or C _1-4 alkylcarbonyl; R ¹³ represents hydrogen, C _1-4 alkyl or aryl; R ¹⁴ represents hydrogen or halo; R ¹⁵ and R ¹⁶ each independently represent hydrogen or aryl; R ¹⁷ represents hydrogen or C _1-4 alkyl; R ¹⁸ is optionally substituted with 1 or 2 substituents each independently selected from aryl, 10,11-dihydro-5H-dibenz [b, f] azin-5-yl or C _3-7 cycloalkyl and aryl C _1-4 alkyl; R ¹⁹ represents hydrogen, C _1-4 alkylcarbonyl or diarylC _1-4 alkyl; R ²⁰ , R ²¹ , R ²² , and R ²³ each independently represent hydrogen, C _1-4 alkyl or aryl; R ²⁴ represents hydrogen or trifluoromethyl; R ²⁵ represents hydrogen or halo; When R ⁵ represents a radical of formula (b-3), R ⁴ may also be phenyl-C _1-4 alkylaminocarbonyl; R ⁴ and R ⁵ together are Spiro radicals can form Wherein R ²⁶ and R ²⁷ each independently represent hydrogen, C _1-4 alkyl, aryl or arylC _1-4 alkyl; Aryl represents phenyl or phenyl substituted with 1 or 2 substituents independently selected from C _1-4 alkyl, halo, trifluoromethyl, hydroxy and C _1-4 alkyloxy. 2. Use according to claim 1, wherein R ¹ and R ² are methyl. 3. Use according to claim 1 or 2, wherein X is of formula (a) or (b). Use according to claim 1, wherein the disorder is psychosis, pain, epilepsy, neurodegenerative disease, seizures, head trauma or multiple sclerosis. A compound of formula (I) according to any one of claims 1 to 3 Provided that when R ⁴ is hydrogen and R ⁵ is a radical of formula (b-1) wherein B ¹ is -CH ₂ -and R ⁹ is 4-fluorobenzyl, then -a ¹ = a ² -a ³ = a ⁴ -is not -CH = CH-CH = CH-; When R ⁴ is hydrogen and R ⁵ is a radical of the formula (b-1) wherein B ¹ is -NH- and R ⁹ is 4-methoxybenzyl) -a ¹ = a ² -a ³ = a ⁴ -is not -CH = N-CH = N-. The compound of claim 5, wherein R ⁵ is diarylmethyloxyC _1-4 alkyl or formulas (b-2), (b-3), (b-4), (b-5), (b-6), or a radical of (b-7), (b-8), (b-9), (b-10), (b-11), (b-12), or (b-13); R ⁵ may form together with R ⁴ a spiro radical of formula (b-14). A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 5 as an active ingredient. A method for preparing a pharmaceutical composition according to claim 7, characterized in that a therapeutically effective amount of a compound according to claim 5 or 6 is intimately mixed with a pharmaceutical carrier. The compound according to claim 5 or 6, for use as a medicament. Reacting the intermediate of formula (II) or a functional derivative thereof with the intermediate of formula (III) in a reaction-inert solvent in the presence of a suitable base, optionally in the presence of potassium iodide; If desired, the compounds of formula (I) are converted to acid addition salts by treatment with acids, or base addition salts by treatment with bases, or conversely, the acid addition salt forms are converted to free base by treatment with alkalis, or base additions. Conversion of the salt to the free acid by treatment with an acid; A process for preparing a compound according to claim 5, characterized in that if desired, the N-oxide and / or stereochemically isomeric forms thereof are prepared: Wherein W is a suitable counter ion.