Oxadiazole derivatives and use thereof as metabotropic glutamate receptor potentiators 842

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 7-methyl-5-(3-piperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having potentiating activity on glutamate receptors, containing the compound described above; also described is use of the compound or a pharmaceutically acceptable salt in claim 1 in producing a medicinal agent for therapy of neurological and mental disorders associated with glutamate dysfunction.

EFFECT: novel compound which can be used in therapy of neurological and mental disorders is obtained and described.

5 cl, 4 ex

 

PRIOR art

The present invention relates to new compounds which function as potentiating funds in respect of glutamate receptors, methods for their preparation, containing their pharmaceutical compositions and their use in therapy.

Metabotropic glutamate receptors (mGluR) are a family of receptors coupled to GTP-binding protein (G protein), which are activated by glutamate and play an important role in synaptic activity in the Central nervous system, including the plasticity of the nervous system, the developing nervous system and neurodegeneration.

The mGluR activation in intact mammalian neurons causes one or more of the following reactions: activation of phospholipase C; the increase in hydrolysis of phosphoinositides (PI); intracellular calcium release; activation of phospholipase D; activation or inhibition of adenylcyclase; increase or decrease the formation of cyclic adenosine monophosphate (camp); activation guanililcyclase; increase education of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increased release of arachidonic acid and increase or decrease the activity of potential - and licenzawiki ion channels (Schoepp et al., 1993, Trends Pharmacol. Sci., 14:13; Schoepp, 1994, Neurochem. Int., 24:439; Pin et al., 1995, Neuropharmacology 34:1; Bordi & Ugolini, 1999, Prog. Neurobol. 59:55).

Identified eight mGluR subtypes, which are divided into three groups on the basis of similarity in primary sequence, connections for conducting signal and pharmacological profile. Group I includes mGluR1 and mGluR5, which activate phospholipase C and the generation of intracellular calcium signaling. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7 and mGluR8) mediates mGluR inhibition activity adenylylcyclase and levels of cyclic AMP. Overview see Pin et al., 1999, Eur. J. Pharmacol., 375:277-294.

Activity collection mGluR receptors are involved in many normal processes in the Central nervous system of mammals and is an important target for compounds used for the treatment of various neurological and psychiatric disorders. The mGluR activation is required for induction of long-term potentiation in the hippocampus and long-term depression in the cerebellum (Bashir et al., 1993, Nature, 363:347; Bortolotto et al., 1994, Nature, 368:740; Aiba et al., 1994, Cell, 79:365; Aiba et al., 1994, Cell, 79:377). It was also demonstrated the role of mGluR activation in nociception and analgesia (Meller et al., 1993, Neuroreport, 4: 879; Bordi & Ugolini, 1999, Brain Res., 871:223). In addition, suggested that mGluR activation plays a modulatory role in many other normal processes, including synaptic transmission, development of neuronal apoptotic death of neurons, synaptic plasticity, spatial learning, olfactory memory, Central the monitoring of cardiac activity, wakefulness, regulation of motility and regulation vestibuloocular reflex (Nakanishi, 1994, Neuron, 13:1031; Pin et al., 1995, Neuropharmacology, supra; Knopfel et al., 1995, J. Med. Chem., 38:1417).

Recent advances in the elucidation of the physiological role of mGluR identified these receptors as promising targets for drugs in therapy of acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders. Due to physiological and pathophysiological value mGluR there is a need for new drugs and compounds that can modulate mGluR function.

Description of the INVENTION

The inventors have identified a class of compounds that modulate mGluR function. In one aspect of the proposed invention the compounds of formula I, or their pharmaceutically acceptable salt, hydrate, MES, optical isomer, or combination thereof:

where:

R1represents halogeno or C1-3halogenoalkanes;

Q representsorand

R2represents hydrogen or C1-3alkyl, or a pharmaceutically acceptable salt, hydrate, MES, optical isomer, or combination thereof.

The invention also suggested methods for obtaining the compounds of formula I.

The AOC is e, in the proposed invention, a pharmaceutical composition comprising a compound of formula I together with a pharmaceutically acceptable carrier or excipient; in another aspect of the invention, a method of treating or preventing neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment. The method involves the step of introducing the animal a therapeutically effective amount of the compounds of formula I or pharmaceutical composition containing such a number.

The invention also suggested the use of the compounds of formula I or its pharmaceutically acceptable salt or MES in the manufacture of medicinal products for the treatment of the conditions referred to in this application.

In addition, in the proposed invention the compound of formula I or its pharmaceutically acceptable salt or MES for use in therapy.

Compounds described in this application demonstrate activity as modulators of metabotropic glutamate receptors and, more specifically, demonstrate activity as potentiate funds in respect of the mGluR2 receptor. It is assumed that the compounds are useful in therapy as medicines, in particular, for the treatment of neurological and psychiatric disorders associated with CH is tamanoi dysfunction.

Definition

Unless otherwise stated in the description of the invention, the nomenclature used in this description generally follows the examples and the rules accepted in the Nomenclature of Organic Chemistry, Sections a, b, C, D, E, F and H, Pergamon Press, Oxford, 1979, which is incorporated in this application by reference to the names of their typical chemical structures, and rules for the assignment of names to chemical structures. Perhaps the title compound can be formed using the names of chemical compounds: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

The term "C1-3alkyl," as used in this application means an unbranched, branched or cyclic hydrocarbon radical, having from one to three carbon atoms, and includes methyl, ethyl, propyl, isopropyl and cyclopropyl.

The term "C1-3halogenoalkanes", as used in this application, means an alkoxy radical with a straight or branched chain, having from one to three carbon atoms and at least one halogeno Deputy, and includes formatxml, trifloromethyl, foretoken, cryptosporidosis, fcarisoprodolono and the like.

The term "halogen", as used in this application means halogen and includes fluorescent, chloro, bromo and iodide, as in radioactive and non-radioactive forms.

The symbol Δ in the use of the AI in this application means the heating or the application of heat.

The term "pharmaceutically acceptable salt" means any salt accession acid or salt joining the Foundation, which is compatible with the introduction of the patients.

"Pharmaceutically acceptable salt accession acid" is any non-toxic salt of the accession of organic or inorganic acids of the compounds of formula I. Typical inorganic acids which form suitable salts include hydrochloric, Hydrobromic, sulfuric and phosphoric acid and acid metal salts such as monohydrogenphosphate sodium and potassium hydrosulfate. Typical organic acids which form suitable salts include mono-, di - and tricarboxylic acids. Examples of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleimide, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, para-toluensulfonate acid and other sulfonic acids, such as methanesulfonate and 2-hydroxyethanesulfonic acid. If possible from a chemical point of view, it can be formed by mono - or docile salts, and such salts may exist in hydrated, solvated, or essentially anhydrous form. In General, with whom and attach acids of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison with their form free grounds. Other pharmaceutically unacceptable salts, e.g. oxalates, may be used, for example, for the isolation of compounds of formula I for laboratory use or for subsequent transformation into a pharmaceutically acceptable salt accession acids.

"MES" means a compound of formula I or pharmaceutically acceptable salt of the compounds of formula I, in which molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically acceptable dose, administered as MES. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, then the molecule is called a hydrate.

The term "stereoisomers" is a General term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes a mirror isomers (enantiomers), geometric (CIS/TRANS) isomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers).

The term "treat" or "treatment" means the relief of symptoms, elimination of the causes of symptoms on a temporary or permanent basis, or prevent or slow the appearance of symptoms of the disorder or condition.

The term "t is repitions effective amount" means the amount of coupling, which is effective in the treatment of a specified disorder or condition.

The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersing agent, excipient, adjuvant or other substance that is mixed with the active ingredient with the aim of providing education to pharmaceutical compositions, that is, the dosage form suitable for administration to a patient. One example of such a carrier is a pharmaceutically acceptable oil, commonly used for parenteral administration.

Connection

Described compounds generally correspond to the formula I:

where:

R1represents halogeno or1-3halogenoalkanes;

Q representsorand

R2represents hydrogen or C1-3alkyl, or their pharmaceutically acceptable salt, hydrate, MES, optical isomer, or combination thereof.

In a specific embodiment R1represents chloro or trifloromethyl.

In another embodiment R1is triptoreline.

In one embodiment Q represents.

In one embodiment Q representswhere R2represents N.

1represents chloro or trifloromethyl, Q represents.

In another embodiment R1is triptoreline, and Q represents.

In another embodiment R1represents chloro or trifloromethyl, and Q representswhere R2represents N.

In another embodiment R1represents chloro or trifloromethyl, and Q represents.

Believe pharmaceutically acceptable salt, hydrate, MES, optical isomer, or combination thereof for each of the above embodiments included in the scope of the invention.

Specialists in the art it will be clear that, when the compounds of the present invention contain one or more chiral centers, the compounds according to the invention can exist and can be isolated in the form of enantiomeric or diasteriomeric forms or as racemic mixtures. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof of compounds of formula I. the Optically active forms of the compounds according to the invention can be obtained, for example, by chiral chromatography separation of a racemate, by synthesis from optically active source is x materials or by asymmetric synthesis-based methods, described below.

Specialists in the art will also understand that some compounds of the present invention may exist in solvated, for example hydrated, as well as resolutional forms. Also it will be clear that the present invention encompasses all such solvated forms of the compounds of formula I.

In the scope of the invention also includes salts of compounds of formula I. Typically, pharmaceutically acceptable salts of the compounds of the present invention is obtained using standard methods, well known in this technical field.

In one embodiment of the present invention the compound of formula I can be converted into its pharmaceutically acceptable salt or MES, in particular, in salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or para-toluensulfonate.

The way to obtain

The compounds of formula I can be obtained by various synthesis methods, as shown in this application. Therefore, the choice of specific structural features and/or substituents can influence the choice of one method relative to another.

Within these General principles, the methods described in this application can be used to obtain typical of the subgroups of compounds on this izobreteniya not specified, the variables described in the schemes and methods have the same definition as in the above formula I.

Thus, the average person skilled in the art will understand that changes and additions applied to one or more methods disclosed in this application will allow you to synthesize other compounds of formula I.

The invention is additionally illustrated by the following examples, in which are described some embodiments of the invention. The scheme of synthesis and the synthesis procedure proposed for Examples 1, 2 and 4, is provided for illustration and should not be construed as limiting the invention. Specialists in the art will understand that other illustrated compounds may be obtained by methods similar to those described.

Scheme of synthesis:

Reagents and conditions used in a typical procedure: (a) SOCl2, Δ; (b) 2-chloro-N-hydroxyacetamido, K2CO3, MeCN, then DMF, Δ; (b) QH, K2CO3, MeCN, Δ.

(a) In a typical procedure, 100 mmol 7-methyl-1-oxo-2-(substituted-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid was dissolved in the excess of thionyl chloride and heated at a temperature of flavobacteria within 30 minutes the Reaction mixture was cooled to room temperature and concentrated to obtain 7-methyl-1-oxo-2-(zames the config-benzyl)-2,3-dihydro-1H-isoindole-5-carbonylchloride.

(b) To a solution of 7-methyl-1-oxo-2-(substituted-benzyl)-2,3-dihydro-1H-isoindole-5-carbonylchloride (100 mmol) in MeCN (50 ml) was added 2-chloro-N-hydroxyacetamido (110 mmol) and K2CO3(200 mmol). The mixture was stirred overnight, then was diluted with water and was extracted with tO. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in DMF (50 ml) and was heated at a temperature of flavobacteria for 3.5 hours, the Cooled solution was diluted with water and was extracted with tO. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. In the result column chromatography on silica gel (10-35% tO/hexane) received a 2-substituted-benzyl-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-isoindole-dihydro-1-it.

(C) To a solution of 2-(substituted-benzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-isoindole-dihydro-1-it (100 mmol) in MeCN was added K2CO3(200-300 mmol) and appropriate amine (QH, 150-200 mmol). The mixture was heated to give the desired isoindole, which was purified column chromatography on silica gel (1-5% 2 M NH3in MeOH/CH2Cl2).

Example 1: 7-Methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-cryptomaterial)-2,3-dihydroindol-1-he

To a solution of 5-(3-chloromethyl-[1,2,4,]-oxadiazol-5-yl)-7-IU the Il-2-(4-cryptomaterial)-2,3-dihydroindol-1-she (3.25 g, the 7.43 mmol) in MeCN (50 ml) was added piperazine-1-carboxylic acid tert-butyl ether (2,77 g, 14.9 mmol) and K2CO3(to 2.57 g of 18.6 mmol). The mixture was heated to 40°C for 24 h, then cooled to room temperature and diluted with water. The mixture was extracted with tO and the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue is triturated with hexane and filtered. In the result column chromatography on silica gel (40-80% tO/hexane) followed by rubbing with 1% MeOH//Et2O received the BOC-protected intermediate compound (4,78 g) as a colourless solid.

The BOC-protected intermediate compound was dissolved in CH2Cl2(15 ml) was added in 1:1 TFA/CH2Cl2(40 ml). After 45 min the reaction mixture was concentrated and podslushivaet aqueous NaHCO3to pH 9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. In the result column chromatography on silica gel (1-5% 2 M NH3in the Meon/CH2CL2) received 7-methyl-5-(5-piperazine-1-ylmethyl-[1,2,4,]oxadiazol-3-yl)-2-(4-cryptomaterial)-2,3-dihydroindol-1-he (3,79 g) as a colourless foam.1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 8.00 (s, 1H), 7.36 (d, 2H), 7.20 (d, 2H), 4.81 (s, 2H), 4.33 (s, 2H), 3.77 (s, 2H), 2.94-3.05 (m, 4H), 2.84 (s, 3H),2.61 (brs, 4H).

Example 2: 2-(4-Chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroindol-1-he

To a solution of 2-(4-Chlorobenzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroindol-1-it (40 mg, 0,103 mmol) in MeCN (4 ml) was added K2CO3(0,309 mmol) and (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (31 mg, 0,154 mmol). The mixture was heated at 60°C over night. The reaction mixture was cooled and was diluted with water, then was extracted with tO. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. In the result column chromatography on silica gel (1% to 2 M NH3in MeOH/CH2Cl2) received 2-(4-Chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroindol-1-it is in the form of a brown solid (27 mg).1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s, 1H), 7.37 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.30 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.26 (d, 1H), 3.11 (d, 1H), 2.89 (d, 1H), 2.84 (s, 3H), 2.63 (d, 1H), 1.88 (d, 1H), 1.66 (d, 1H).

Example 4: 2-(4-Chlorobenzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2,3-dihydroindol-1-he

To a solution of 2-(4-Chlorobenzyl)-5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-7-methyl-2,3-dihydroindol-1-it (40 mg, 0,103 mmol) in MeCN (4 ml) was added To a2CO3(3.0 EQ.) piperazine-1-to benovoy acid tert-butyl ester (29 mg, 0,154 mmol). The mixture was incubated at 70°C for 1 week. The reaction mixture was cooled and was diluted with water, then was extracted with tO. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. In the result column chromatography on silica gel (10-50% tO/hexane) received the BOC-protected intermediate compound in the form of oil. This residue was dissolved in 1:1 TFA/CH2Cl2for 30 min, then the reaction mixture was concentrated and podslushivaet water Panso3to pH 9-10. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was dissolved in tO and was extracted with 1 M HCl. The aqueous phase was podslushivaet 6 M NaOH and was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated to obtain 2-(4-Chlorobenzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2,3-dihydroindol-1-it is in the form of a colorless oil (29 mg).1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.99 (s, 1H), 7.34 (d, 2H), 7.26 (d, 2H), 4.77 (s, 2H), 4.31 (s, 2H), 3.77 (s, 2H), 2.97 (br s, 4H), 2.84 (s, 3H), 2.62 (br s, 4H).

The compounds shown in the following table illustrate the invention:

No. AveStructure Name1H NMR
17-Methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-Cryptor-methoxybenzyl)-2,3-dihydroindol-1-heδ 8.05 (s, 1H), 8.00 (s, 1H), 7.36 (d, 2H), 7.20 (d, 2H), 4.81 (s, 2H), 4.33 (s, 2H), 3.77 (s, 2H), 2.94-3.05 (m, 4H), 2.84 (s, 3H), 2.61 (br s, 4H).
22-(4-Chlorobenzyl)-5-[3-(2,5-diazabicyclo[2.2.1]
hept-2-ylmethyl-[1,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydroindol-1-he
δ 8.04 (s, 1H), 7.99 (s, 1H), 7.26-7.35 (m, 4H), 4.83 (s, 2H), 4.00 (s, 2H), 3.94 (dd, 2H), 3.58 (d, 2H), 3.18 (d, 1H), 3.11 (dd, 1H), 2.89 (d, 1H), 2.78 (s, 3H), 2.64 (d, 1H), 1.64-1.92 (m, 6H).
32-(4-Chlorobenzyl)-7-methyl-5-[3-(3-methylpiperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl]-2,3-dihydroindol-1-heδ 8.04 (s, 1H), 7.99 (s, 1H), 7.25-7.35 (m, 4H), 4.77 (s, 2H), 4.30 (s, 2H), 3.72 (s, 3H), 2.84-3.01 (m, 5H), 2.84 (s, 3H), 2.25 (ddd, 1H), 1.89 (t, 1H), 1.26 (dd, 1H), 1.04 (d, 3H).
42-(4-Chlorobenzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2,3-dihydro-isoindole-1-heδ 8.05 (s, 1H), .99 (s, 1H), 7.26-7.35 (m, 4H), 4.77 (s, 2H), 4.31 (s, 2H), 3.77 (s, 2H), 2.97 (br s, 4H), 2.84 (s, 3H), 2.62 (br s, 4H).
52-(4-Chlorobenzyl)-7-methyl-5-[3-(2-methylpiperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl]-2,3-dihydroindol-1-heδ 8.02 (s, 1H), 7.97 (s, 1H), 7.26-7.35 (m, 4H), 4.81 (s, 2H), 4.31 (s, 2H), 3.98 (d, 2H), 2.85-2.96 (m, 4H), 2.85 (s, 3H), 2.51-2.64 (m, 3H), 1.22 (d, 3H).
62-(4-Chlorobenzyl)-7-methyl-5-[3-(2-methylpiperazin-1-ylmethyl-[1,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindole-1-heδ 8.02 (s, 1H), 7.97 (s, 1H), 7.26-7.35 (m, 4H), 4.81 (s, 2H), 4.31 (s, 2H), 3.98 (d, 2H), 2.85-2.96 (m, 4H), 2.85 (s, 3H), 2.51-2.64 (m, 3H), 1.22 (d, 3H).

The pharmaceutical composition

Compounds described in this application can be prepared, usually in the form of pharmaceutical compositions containing a compound of formula I or its pharmaceutically acceptable salt or MES together with a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid form include, but are not limited to, powders, tablets, dispersible granules, capsules, pills and suppositories.

A solid carrier can be one or more substances, to the which also can act as solvents, flavors, solubilization, lubricating agents, suspendida agents, binding agents or leavening agents. A solid carrier can also be an encapsulating material.

In powders, the carrier is a finely dispersed solid material, which is mixed with fine coupling of the active component. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in the appropriate proportions, and pressed into the desired shape and size.

To prepare suppozitornyj compositions of low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active ingredient distributed therein, for example, by stirring. The molten homogeneous mass is then poured into molds of suitable size and leave to cool and harden.

Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like.

The term "composition" is also intended to enable the preparation of the active ingredient with encapsulating material as a carrier, forming a capsule in which the active component (with different n is Cetelem or without it) is surrounded by carrier, which thus is in Association with him. Similarly included the wafer.

Tablets, powders, pills and capsules can be manufactured as solid dosage forms suitable for oral administration.

Compositions in liquid form include solutions, suspensions and emulsions. For example, solutions of the active compounds in sterile water or aqueous propylene glycol can be a liquid preparations suitable for parenteral administration. Liquid compositions can also be prepared in solution in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be obtained by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners, if desired. Aqueous suspensions for oral administration can be produced by dispersing finely dispersed active component in water together with a viscous substance, such as natural synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspendresume agents known in the field of preparation of pharmaceutical preparations. Typical compositions intended for oral use may contain one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

Could be the value from the method of administration, the pharmaceutical composition will include from approximately 0.05 wt.% (percent by weight) to about 99 wt.%, more specifically from about 0.10 wt.% up to 50 wt.% compounds according to the invention, all percentages by weight based on the total weight of the composition.

A therapeutically effective amount for the implementation of the present invention can be determined by the average expert in the art using known criteria, including the age, weight and response of the particular patient, and interpreted depending on the disease being treated or which warn.

Medical use

Compounds described in this application demonstrate activity as modulators of metabotropic glutamate receptors and, more specifically, demonstrate activity as potentiate funds in respect of mGluR2 receptor. It is assumed that the compounds are useful in therapy as medicines, in particular, for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in an animal and especially of a person.

More specifically, neurological and mental disorders include, but are not limited to such disorders as cerebral insufficiency after bypass surgery on the heart and transplantation, Insa is before, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, horey's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral insufficiency, secondary to prolonged epileptic status, migraine (including migraine headache), urinary incontinence, tolerance to the substance, withdrawal of substances (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleep AIDS, and so on), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder and post-traumatic stress disorder (PTSD), mood disorders (including depression, mania, bipolar disorders), disorders of the circadian rhythm (including jet lag, shift working schedule), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eyes is a, emesis, brain edema, pain (including acute and chronic pain States, severe pain, nekupiruemy pain, neuropathic pain, inflammatory pain, and post-traumatic pain), late dyskinesia, sleep disorders (including narcolepsy), disorder attention deficit/hyperactivity disorder and conduct disorder.

Thus, in the invention it is proposed to use any of the compounds of formula I or its pharmaceutically acceptable salt or MES for the manufacture of a medicinal product for the treatment of any of the conditions described above.

In addition, in the invention, a method of treatment of a subject suffering from any of the States described above, wherein the effective amount of the compounds of formula I or its pharmaceutically acceptable salt or MES is administered to a patient in need of such treatment. The invention also suggested that the compound of formula I or its pharmaceutically acceptable salt or MES, as defined in this application above for use in therapy.

The term "therapy" in the context of the present invention also includes "prevention", unless otherwise noted. The term "therapeutic" and "therapeutically" should be interpreted accordingly. The term "therapy" in the context of the present invention additionally encompasses the introduction of an effective amount connected the I of the present invention to mitigate or existing painful conditions, acute or chronic, or to mitigate recurrent state. It also covers preventive therapy for prevention of recurrent States and long-term therapy for chronic disorders.

To use for therapy in a warm-blooded animal, such as man, the compounds of the present invention can be introduced in the form of a standard pharmaceutical composition by any route including oral, intramuscular, subcutaneous, local, intranasal, intraperitoneally, intracoronary, intravenous, epidural, intrathecal, intracerebroventricularly way, and by injection into the joints. In preferred embodiments of the invention, the route of administration is oral, intravenous or intramuscular.

The dosage will depend on the method of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician that defines the individual and the level of dosage for a particular patient.

As mentioned above, the compounds described in this application may be offered or delivered in a form suitable for oral administration, for example, tablet, toffee, hard and soft capsule, aqueous solution, oily solution, emulsion and suspension. Alternatively, the joint may be prepared for topical administration, for example, in the form of a cream, ointment, gel, spray or aqueous solution, an oil solution, emulsion or suspension. Compounds described in this application can also be offered in a form that is suitable for intranasal, for example, as a nasal spray, nose drops or as a dry powder. Connections can be inserted into the vagina or rectum in the form of a suppository. Compounds described in this application, you can also enter parenterally, e.g. by intravenous, intravascular, subcutaneous or intramuscular injection or infusion. Connections can be entered by insufflation (for example, in the form of a fine powder). Connections can also be entered transdermal or sublingual.

In addition to their use in therapeutic medicine, the compounds of formula I or their salts are useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors mGluR-related activity in laboratory animals as part of the search for new therapeutic agents. Such animals include, for example, cats, dogs, rabbits, monkeys, rats and mice.

General methods

Source materials are commercially available or previously described in the literature.

1H and13With NMR spectra were recorded either on a Bruker 300, Bruker DPX400 or Varin +400 spectrophotometers, operating at 300, 400 and 400 MHz for1H NMR, respectively, using the signal of TMS (tetramethylsilane was) or residual solvent as a reference, in deuterated chloroform as solvent unless otherwise stated. All the obtained chemical shifts are given in million-1on a scale Delta and with fine splitting of signals in the registered spectra (s: singlet, br s: broad singlet, d: doublet, t: triplet, q: Quartet, m: multiplet).

Analytical sequential separation by liquid chromatography followed by detection of the mass spectra were recorded on a Waters LCMS (liquid chromatograph with a mass spectrometer), consisting of an Alliance 2795 (LC) and odnokletochnogo mass spectrometer ZQ. Mass spectrometer equipped with a source of ionization elektrorazpredelenie working in a positive and/or negative ions. The voltage of the sputtering ions were ±3 kV and the mass spectrometer was scanned in the range m/z 100-700 when the scan time of 0.8 C. For column X-Terra MS, Waters, C8, and 2.1×50 mm, 3.5 mm, used a linear gradient from 5% to 100% acetonitrile in 10 mm ammonium acetate (aq.) or in 0.1% TFA (aq.).

Preparative chromatography with reversed phase was performed on an automated preparative high performance liquid chromatograph (HPLC) with Gilson detector diode matrix using XTerra S C8, 19×300 mm, 7 mm, as a column.

Purification by Chromatotron using carried on a rotating glass plates coated with silica gel/gypsum (Merck, 60 PF-254 with calcium sulfate), with a covering layer 1, 2 or 4 mm, using TC Research T Chromatotron.

Purification of products was also carried out using columns for extraction Chem Elut (Varian, cat. #1219-8002), columns Mega BE-SI (Bond Elut Silica) SPE (Varian, cat. # 12256018; 12256026; 12256034) or flash chromatography glass columns Packed with silica gel.

Microwave heating was carried out in a Smith synthesizer with single-mode microwave cavity producing continuous irradiation at 2450 MHz (Personal Chemistry AB, Uppsala, Sweden).

Pharmacological properties of the compounds according to the invention can be analyzed using standard analysis of functional activity. Examples of analyses of glutamate receptors are well known in the art, as described, for example, Aramori et al., 1992, Neuron, 8:757; Tanabe et al., 1992, Neuron, 8:169; Miller et al., 1995, J. Neuroscience, 15:6103; Balazs, et al., 1997, J. Neurochemistry, 1997, 69:151. The methodology described in these publications included in this application by reference. Usually the compounds according to the invention can be investigated using analysis, which measure the mobilization of intracellular calcium [Ca2+]iin cells expressing mGluR2.

The hERG activity was determined using STRs is both described in Bridgland-Taylor, M.N., et al, J. Pharm. Tox. Methods 54 (2006) 189-199.

Solubility was determined in phosphate buffer with a pH of 7.4 after equilibration for 24 h at 25°C, and HPLC-UV (HPLC with UV detector) and LC-MSMS (liquid chromatograph-mass spectrometer-mass spectrometer) was used for quantitative determination.

Analysis of the binding of [35S]-GTPγS was used for functional analysis of activation of mGluR2 receptor. Allosteric activator activity of compounds against the human mGluR2 receptor was measured by analysis of the binding of [35S]-GTPγS membranes derived from cells of Cho, which stably Express human mGluR2. The analysis is based on the principle that agonists bind G-protein-coupled receptors to stimulate GDP-GTP exchange of G-protein. Because of [35S]-GTPγS is neytralizuya analogue of GTP, it can be used as an indicator GDP-GTP exchange and, consequently, activation of the receptor. Therefore, the analysis of the binding of GTPγS provides a quantitative measure of the activation of the receptor.

Membranes obtained from cells SNO, stably transfected with the human mGluR2. Membranes (30 μg protein) were incubated with the test compound (from 3 nm to 300 μm) for 15 minutes at room temperature, then added 1 μm glutamate, and incubated for 30 min at 30°C in 500 µl of buffer DL the analysis (20 mm HEPES, 100 mm NaCl, 10 mm MgCl2)containing 30 μm GDP, and 0.1 nm [35S]-GTPγS (1250 CI/mmol). The reaction was repeated three times in 2 ml polypropylene 96-well plates. Reactions were stopped by vacuum filtration using 96-well manifold Packard Unifilter-96, GF/B filter microplate. Filter-the plates were washed in ice-cold buffer for washing 4×1.5 ml (10 mm sodium phosphate buffer, pH 7,4). Filter the tablets were dried and to each well was added 35 μl of scintillation fluid (Microscint 20). The amount of bound peroxidase radioactivity was determined by counting the radioactivity in the tablets on the Packard TopCount. Data were analyzed using GraphPad Prism, and values of the EU50and Emax(relative to the maximum effect of glutamate) was calculated using nonlinear regression.

As shown in the Table below, the compounds described in this application, as a rule, have a suitable solubility, low ability to activate an ion channel hERG and are highly active in the analyses described in this application with respect modulatory activity of mGluR2, having values EU50shown below.

hERG, mcm
Table
Example No.GTPgS EU50mcmSolubility in water, mcm
10,23144,911,0
20,206336,533,0
30,154396,1to 12.0
40,378>50025,0
50,352383,912,6
6MX 0.317>50018,7

1. The Union, representing 7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4]oxadiazol-5-yl)-2-(4-cryptomaterial)-2,3-dihydroindol-1-it, or its pharmaceutically acceptable salt.

2. The compound or pharmaceutically acceptable salt according to claim 1 for use in the treatment of schizophrenia, anxiety, or generalized anxiety disorder in an animal in need of such treatment.

3. Pharmaceutical composition having potentiating activity against glutamate receptors containing the compound or pharmaceutically acceptable salt is .1 and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 3 for use in the treatment of schizophrenia, anxiety, or generalized anxiety disorder in an animal in need of such treatment.

5. The use of compound or pharmaceutically acceptable salt according to claim 1 in the manufacture of a medicine for therapy of neurological and psychiatric disorders associated with glutamate dysfunction.



 

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