Trisubstituted 1,2,4-triazoles

FIELD: chemistry.

SUBSTANCE: described are novel trisubstituted 1,2,4-triazoles of general formula (I) (values of radicals are given in the claim) or pharmaceutically acceptable salts or hydrates or solvates thereof and a pharmaceutical composition containing said compounds. The novel compounds relate to potential positive allosteric modulators of nicotinic acetylcholine receptors, which can be used in medicine to treat psychotic disorders, intellectual impairment disorders, inflammatory diseases or conditions.

EFFECT: capacity to increase efficiency of agonists of nicotinic receptors.

9 cl, 7 tbl, 9 ex

 

The present invention relates to substituted derivatives of 1-alkyl-3-aniline-5-arestrictly and to their pharmaceutically acceptable salts, processes for their preparation, containing their pharmaceutical compositions and to their use in therapy. The invention relates to selective positive allosteric to modulators of α7-nicotinic acetylcholine receptor possessing the ability to enhance the efficacy of agonists of nicotinic receptors.

Prior art in this field

European patent EP 1044970 describes 3-alkylamino-1,2,4-triazole as ligands of the receptor for neuropeptide Y.

The author Makara G.M. et al. (Organic Letters (2002) Vol. 4 (10); 1751-1754) describes a solid-phase synthesis of 3-alkylamino-1,2,4-triazoles and reports the unsuccessful synthesis of N-(4-methoxyphenyl)-1-methyl-5-(4-were)-1H-1,2,4-triazole-3-amine, and does not indicate about the possible therapeutic applications of the above compounds, in particular regarding its use as positive allosteric modulator of α7-nicotinic acetylcholine receptor.

Chen Chen et al. in Bioorganic & Medicinal Chemistry letters 11 (2001) 3165-3168 describes the synthesis of 1-alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles, in particular N-(2-methoxyphenyl)-1-methyl-5-(2,4-dichlorophenyl)-1H-1,2,4-triazole-3-amine, and their use as antagonists of the corticotropin-releasing factor-1 (CRF1).

Before the silky to create inventions

As a rule, cholinergic receptors are associated with the endogenous neurotransmitter acetylcholine (ACH, ACh), thereby stimulating the opening of ion channels. The AH receptor in the Central nervous system of mammals can be divided into muscarinic (machr, mAChR) and nicotinic (Nahr, nAChR) subtypes based on agonistic activities of muscarine and nicotine, respectively. Nicotinic acetylcholine receptors are ligand-controlled ion channels composed of five subunits. The members of the gene family subunits Nahr were divided into two groups on the basis of the coded amino acid sequences; one group containing the so-called β subunit, and the second group containing the α subunit. It was shown that three types of α subunits α7, α8 and α9, form functional receptors in the expression of only one type, and, accordingly, suggested that they form homopolyamide pentamers receptors.

Model n-Ahram allosteric transition state Nahr was developed that includes at least the rest state, an activated state and desensitization status closed ion channel, which is characterized by the fact that the receptors become insensitive to agonist. Various ligands Nahr can stabilize conformational state Rotz the Torah, with whom they preferred to be contacted. For example, agonists OH and (-)-nicotine stabilize the respectively active and desensitization state.

Changes in the activity of nicotinic receptors have been reported in a number of diseases. Some of them, such as myasthenia gravis and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with a decrease in the activity of signal transmission through nicotinic receptors, or due to the reduction in the number of receptors, or as a result of increased data demonstrate that differently modulated.

It is assumed that the reduction in the number of nicotinic receptors mediates cognitive deficits observed in diseases such as Alzheimer's disease and schizophrenia.

The effects of nicotine from tobacco is also mediated by nicotinic receptors, and because the effect of nicotine is to stabilize the receptor in desensitization condition, increased activity of nicotinic receptors may weaken the desire to smoke.

Compounds that bind to the Nahr have been proposed for the treatment of diseases associated with decreased cholinergic function, such as learning deficit, impaired cognitive ability, disorder of attention or memory loss. Modulation of the activity of α7-nicotinic receptors is believed to have a beneficial effect in some diseases the s, including Alzheimer's disease, dementia, when developing the disease diffuse Taurus Levi, hyperactivity, attention deficit, anxiety, schizophrenia, manic syndrome, bipolar depression, Parkinson's disease, Huntington's disease, the syndrome of Gilles de La Tourette, a brain injury or other neurological, degenerative or psychiatric disorder, in which there is loss of cholinergic synapses, including the syndrome, jet lag, addiction to nicotine, pain.

However, treatment with agonists of nicotinic receptors, which affect the same area, and OH, is problematic because AH not only enables, but also blocks the receptor activity through mechanisms involving desensitization and non-competitive lock. In addition, prolonged activation, apparently, causes long-term inactivation. Therefore, we can assume that agonists AH reduce the activity as well as enhance it.

In General, nicotinic receptors, and particularly the α7-nicotinic receptor desensitization limits the duration of action used agonist.

Description of the invention

Surprisingly, the inventors have found that some new connections can increase the efficacy of agonists at nikodinov the x acetylcholine receptors. Connection with the specified action type, referred to as “positive allosteric modulators”, and they probably suitable for treating conditions associated with reductions in signal transmission through nicotinic receptors. When therapeutic purpose such compounds can restore magnetronnoi communication without affecting temporary profile activation. In addition, positive allosteric modulators, as I believe, do not produce long-lasting inactivation of receptors, as can be seen after repeated or prolonged application of agonists.

Positive modulators Nahr according to the present invention is suitable for treatment or prevention of mental disorders, decrease or violations of intellectual activity or inflammatory diseases or conditions in which modulation of the α7-nicotinic receptor is beneficial.

The present invention relates to substituted derivatives of 1-alkyl-3-aniline-5-arestrictly showing the properties of positive allosteric modulators that increase the efficacy of agonists at the α7-nicotinic receptor. The invention also relates to methods for their preparation and pharmaceutical compositions containing these compounds. The invention also relates to compounds of formula (I) to use the education in the treatment or prevention of mental disorders, cuts or violations of intellectual activity, inflammatory diseases or conditions in which modulation of the α7-nicotinic receptor is beneficial. The invention also relates to the use of these derivatives for the production of a medicinal product for treatment or prevention of mental disorders, decrease or violations of intellectual activity, inflammatory diseases or conditions in which modulation of the α7-nicotinic receptor is beneficial.

Compounds according to the present invention differ in structure from the compounds of the preceding prior art in this field and pharmacologically by their activity as positive allosteric modulators of α7-nicotinic acetylcholine receptor.

The present invention relates to the compound of formula (I)

or its stereoisomeric form, where

R1means methyl, ethylamino or methoxyethylamine;

R2means hydrogen or methyl;

R3means fluorine, chlorine, trifluoromethyl or methyl;

R4means hydrogen or fluorine;

R5means hydrogen, fluorine, chlorine or methoxy;

R6means1-3alkyl;

or its pharmaceutically acceptable salt, or hydrate, or MES.

In the first Varian is the first implementation of the present invention the invention relates to the compound of formula (I-a)

or its stereoisomeric form, where

R1means methyl, ethylamino or methoxyethylamine;

R2means hydrogen or methyl;

R3means fluorine, chlorine, trifluoromethyl or methyl;

R4means hydrogen or fluorine;

R5means hydrogen, fluorine, chlorine or methoxy;

R6means1-3alkyl;

or its pharmaceutically acceptable salt, or hydrate, or MES.

In the second embodiment of the present invention the invention relates to the compound of formula (I-a)

or its stereoisomeric form, where

R1means methyl, ethylamino or methoxyethylamine;

R2means hydrogen or methyl;

R3means fluorine, chlorine, trifluoromethyl or methyl;

R4means hydrogen or fluorine;

R5means hydrogen, fluorine or methoxy;

R6means1-3alkyl;

or its pharmaceutically acceptable salt, or hydrate, or MES.

In the third embodiment of the present invention the invention relates to the compound of formula (I) or its stereoisomeric form, where

R1means 2-methyl, 2-ethylamino or 2-methoxyethylamine;

R2means hydrogen or 6-methyl;

R3means fluorine, chlorine, trifluoromethyl or methyl;

R4oznachaet is hydrogen or fluorine;

R5means hydrogen, fluorine, chlorine or methoxy;

R6means1-3alkyl;

or its pharmaceutically acceptable salt, or hydrate, or MES.

In the fourth embodiment of the present invention the invention relates to the compound of formula (I) or its stereoisomeric form, where

R1means 2-methyl, 2-ethylamino or 2-methoxyethylamine;

R2means hydrogen or 6-methyl;

R3means fluorine, chlorine, trifluoromethyl or methyl;

R4means hydrogen or fluorine;

R5means hydrogen, fluorine, chlorine or methoxy;

R6means methyl;

or its pharmaceutically acceptable salt, or hydrate, or MES.

In the fifth embodiment of the present invention the invention relates to the compound of formula (I), with a total R-configuration.

In the sixth embodiment of the present invention the invention relates to the compound of formula (I), with full S-configuration.

In the seventh embodiment of the present invention the invention relates to the compound of formula (I)with R3-substitution in the ortho-position of the phenyl ring.

In the eighth embodiment of the present invention the invention relates to a compound according to any of the previous options, where

R5means hydrogen, fluorine or IU is hydroxy.

In the ninth embodiment of the invention the compound of formula (I) are selected from the group consisting of

(S)-1-[3-(3,4-dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,

(R)-1-[3-(3-chlorpheniramine)-5-(2-ethylaminomethyl-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-5-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[3-(3-fluoro-5-methoxybenzylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,

(S)-1-[3-(3-fluoro-5-methoxybenzylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-fluoro-5-methoxybenzylamine)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,

(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-fluoro-5-methoxybenzylamine)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[3-(4-fluoro-3-methylphenylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,

including any stereochemical isomeric form,

and their pharmaceutically acceptable additive salts and solvate.

In the tenth embodiment of the invention the compound of formula (I) are selected from the group consisting of

(S)-1-[5-(2-methylpyridin-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,

(S)-1-[3-(3-chloro-2-ftoh is ylamino)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,

(S)-1-[3-(3-chloro-2-forgenerating)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,

including any stereochemical isomeric form,

and their pharmaceutically acceptable additive salts and solvate.

In another embodiment of the invention the present invention preferably relates to (S)-1-[3-(3,4-dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-Olu or (R)-1-[3-(3-chlorpheniramine)-5-(2-ethylaminomethyl-4-yl)-[1,2,4]triazole-1-yl]butane-2-Olu.

The compounds of formula (I) and their additive salt, hydrate and solvate contain one or more centers of chirality and exist in the form of stereochemical isomeric forms.

The term “stereochemical isomeric forms”as used in the description, defines all the possible stereoisomeric forms which the compounds of formula (I) and their additive salts can exist. Unless otherwise stated, the chemical designation of compounds shows a mixture of all possible stereochemical isomeric forms, where these mixes contain all diastereomers and enantiomers of basic molecular structure as well as each of the individual isomeric forms of formula (I) and their salts, solvate, mostly free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2%, and most preferably less than 1% of other isomers. Obviously, with Erewhonese isomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.

For therapeutic use, salts of the compounds of formula (I) are salts in which the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are not pharmaceutically acceptable may also find use, for example, in obtaining or purification of pharmaceutically acceptable compounds. All salts, whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Pharmaceutically acceptable additive salts of acids and bases presented in the description, are intended to include the types of therapeutically active non-toxic additive salts of acids and bases, which are the compounds of formula (I) can form. Pharmaceutically acceptable acid additive salts can be obtained in a suitable manner by processing the basic form of the corresponding acid. Appropriate acids comprise, for example, inorganic acid, such as halogen acids, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic (i.e. o), malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric,methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acids. In turn, these salt forms can be converted by treatment of the corresponding base in the free basic form.

The term "solvate" refers to hydrate and alcoholate, which can form compounds of formula (I)and their salts.

Some of the compounds of formula (I) can also exist in their tautomeric form. Although such shape is not explicitly stated in the above formula, they are intended to be included within the scope of the present invention.

Obtaining compounds

The connection according to the invention can usually be obtained through the implementation of a number of successive stages, each of which is known to the person skilled in the art. In particular, the compounds in this patent application can be obtained according to one or more of the following methods of obtaining. In the following schemes, unless otherwise indicated, all variables items use, as defined in the formula (I). L' represents a radical of the formula

oror

and Q represents

where R3, R4and R5are as defined in the above.

Compounds according to this invention can be obtained by any of several standard methods of synthesis that are frequently used by specialists in the field of organic chemistry.

Scheme 1

Important intermediate compounds of formula (VIII) can usually be obtained according to scheme 1 by conversion of N-acyl of carbamodithioate derived methyl ester of General formula (V), 1,2,4-triazole of the formula (VIII)using the appropriate hydrazine (VI), known in the field conditions. This transformation is usually carried out in a protonic solvent, such as methanol or higher alcohol, such as, for example, 2-methyl-2-propanol (t-BuOH), and the reaction requires temperatures between room temperature and 150°C. In a separate embodiment of the invention, the higher alcohol is tertiary butyl alcohol and the reaction temperature is between 70°C and 120°C, most preferably 100°C. To the above reaction, where hydrazine (VI) use as HCl-salt, adding a stoichiometric amount of base is preferred. The specified base can be an inorganic base such as potassium acetate or potassium carbonate, most preferably, however, the specified base is a tertiary amine, such as diisopropylethylamine or the like (scheme 1). the CE variable elements in figure 1 are such as specified above.

Optional free hydroxyl group in the intermediate compounds of formula (VIII) may be protected by a conventional protecting group (PG)is outlined in the description (VIII-1), such as, for example, acetyl group. The specified type of interaction can be carried out in the presence of ethyl acetate. Typically, the catalyst, such as, for example, N,N-dimethyl-4-pyridylamine (DMAP), add. The interaction is carried out at elevated temperature, such as, for example, the boiling temperature under reflux.

Scheme 2

Total intermediate compound (V) in the synthesis trisemester triazoles according to the present invention is usually obtained in the Protocol, consisting of 3 synthetic transformations (scheme 2), the reference compound is acylchlorides General formula (II).

In the first stage allerease reagent, such as acylchlorides (II), mixed or symmetrical anhydride, allford or the like, communicates with the thiocyanate monovalent metal cation (MNCS in scheme 2), such as, for example, potassium thiocyanate or ammonium thiocyanate, to obtain the corresponding arylisocyanate. This interaction is usually carried out using acetone as solvent and at a temperature between 0°C and 70°C, predpochtite is) at room temperature.

The intermediate connection utilizationand do not produce, and processed in the same reaction medium corresponding aniline (III) to obtain N-ulltimately General formula (IV). The specified transformation is usually carried out at a temperature between 0°C and 70°C, preferably at room temperature.

At the last stage of the S-methylation of N-ulltimately (IV) leads to N-arylcarbamoyl derived methyl ether of General formula (V). For this final transformation requires the presence of a base, preferably a strong inorganic base, such as NaH or potassium carbonate, and the reaction is carried out in an aprotic solvent such as, for example, DMF, THF (tetrahydrofuran), or the like, at temperatures ranging from -70°C. to room temperature, preferably 0°C (scheme 2).

Scheme 3

Alcohols-hydrazines of General formula VI can be obtained from monosubstituted of oxirane General formula (VII) when heated in excess of hydrazine hydrate (scheme 3). Preferably the reaction temperature is 40 to 70°C. and the reaction time is 2 hours. If oxiran (VII) available in optically pure form, resulting alcohol-hydrazine (VI) are obtained from the corresponding stereochemical identity and purity, such as, for example, when R6 =methyl. In other examples, the present invention above oxiran (VII) is available as a racemic mixture, and therefore the corresponding intermediate compounds and final products are obtained as racemic mixtures. In this case, the final products can be obtained in enantiomerically pure form by separation of the racemic mixture using chiral chromatography. In a separate embodiment, the invention specified chiral chromatography is carried out with supercritical CO2as the mobile phase.

Scheme 4

2-Ethylaminoethanol General formula (Ic) can be obtained by treating the corresponding chloropyridine predecessor (VIIIa) ethylamine in an alcohol solvent such as methanol or 1-butanol or the like, optionally in the presence of co-solvent, such as THF or the like, and when heated at high temperatures, preferably between 140°C and 160°C in a microwave oven or at 160°C-180°C in an autoclave (scheme 4). The specified transformation can be carried out under mild conditions (low temperature, such as between 100°C and 130°C) using as a starting compound dichloropyridine compound (VIIId) to obtain the intermediate compounds of General formula (VIIIb). Ostasis is in (VIIIb), a chlorine atom can be removed catalytically, in an atmosphere of hydrogen using Pd/C as catalyst, in the presence of inorganic bases such as potassium acetate, or an amine base such as triethylamine, or the like (scheme 4). Alternatively, when the Deputy Q contains functionality that are incompatible with the conditions of catalytic hydrogenation, a specific connection of General formula (Ic) can be obtained from chloropyridine General formula (VIIIb) by processing carbenoxolone catalyst, such as Pd-catalyst is [1,3-bis[2,6-bis(1-methylethyl)phenyl]-2-imidazolidinone]chlorine(η3-2-propenyl)palladium (CAS [478980-01-7]), in the presence of a strong base, such as sodium methylate, in proton solvent such as methanol or 2-propanol, or the like. The above reaction can be performed at elevated temperatures, such as 100-120°C. in a microwave oven (scheme 4).

Scheme 5

Monomethylarsonic peridotite General formula (Ie) can be obtained by treating 2-chloropyridine predecessor (VIIIa) excess (3-15 EQ.) the Grignard reagent MeMgBr in the presence of catalytic amounts of iron acetylacetonate(III) in an organic solvent or solvent system consisting of various solvents, such as, for example, a mixture of THF/NMP. The usual mixture of THF/NMP (1-methyl-2-pyrrolidinone) with the, may contain from 75% to 99% THF and from 1% to 25% NMP by volume. The specified transformation can be performed at temperatures between 0°C and 50°C, most preferably between 0°C and 25°C (scheme 5).

Scheme 6

Dimethylselenide peridotite General formula (If) can be obtained by treating 2,6-dichloropyridine predecessor (VIIId) excess (10-15 EQ.) the Grignard reagent MeMgBr in the presence of catalytic amounts of iron acetylacetonate(III) in an organic solvent or solvent system consisting of various solvents such as a mixture of THF/NMP. The usual mixture of THF/NMP (1-methyl-2-pyrrolidinone) contain from 75% to 99% THF and from 1% to 25% NMP by volume. The specified transformation can be performed at temperatures between 0°C and 50°C, most preferably between 0°C and 25°C (scheme 6).

Scheme 7

Alternatively, monomethylarsonic peridotite General formula (Ie) and dimethylselenide peridotite General formula (If) can be obtained through a common intermediate compound (VIIIg) (scheme 7). The reaction with the Grignard reagent MeMgBr, acetylacetonate catalyzed by iron(III), when using the above conditions leads to end connection (If) (scheme 7). When the catalytic hydrogenation of an intermediate compound (VIIIg) using known in the field conditions described above, obrazu the Xia target compound (Ie). Alternatively, when the Deputy Q contains functionality that are incompatible with the conditions of catalytic hydrogenation, a specific connection of General formula (Ie) can be obtained from chloropyridine General formula (VIIIg) by processing carbenoxolone catalyst, such as Pd-catalyst is [1,3-bis[2,6-bis(1-methylethyl)phenyl]-2-imidazolidinone]chlorine(η3-2-propenyl)palladium (CAS [478980-01-7]), in the presence of a strong base, such as sodium methylate, in proton solvent such as methanol or 2-propanol, or the like. The above reaction can be performed at elevated temperatures, such as 100-120°C. in a microwave oven.

In the case when the intermediate connection (VIIIg) has a protected hydroxyl group, such as, for example, the acetate, the compound of General formula (If) can be obtained by reacting with a Grignard reagent MeMgBr, acetylacetonate catalyzed by iron(III), in the presence of an organic solvent or mixture of organic solvents, such as, for example, a mixture of NMP and THF. To facilitate removal of the protective group (such as, for example, acetyl group), to the reaction mixture optionally you can add a base, such as, for example, NaOH.

Pharmacology

Compounds according to the present invention, as has been discovered, are positive allosteric modulate the Rami of α7-nicotinic receptor. Nicotinic α7 receptor (α7-Nahr) belongs to the superfamily “cys-loop”, ionotropic, ligand-gated ion channels, which includes family receptors 5-HT3GABAAand glycine. Nicotinic α7 receptor is activated by acetylcholine and its cleavage product choline, and the main characteristic of α7-Nahr is rapid desensitization with the constant presence of the agonist. He is the second most common subtype receptor in the brain and an important regulator of the release of many neurotransmitters. It has a discrete distribution in some brain structures important for the processes of attention and cognition, such as the hippocampus and prefrontal cortex, and associated with a number of mental and neurological disorders in humans. He is also involved in inflammatory cholinergic path.

Genetic evidence linking it with schizophrenia are presented in the form of a solid connection between the sign of schizophrenia (violation touch regulation) and the locus of α7 on 15q13-14 and polymorphisms in the core promoter region of the gene α7.

Evidence of pathological conditions is the loss of α7 immunoreactivity and α-Btx binding in the hippocampus, frontal and cingulate cortex in schizophrenia, Parkinson's disease and diseases of al the gamer and in paraventrikulyarnoe the core and connecting the nucleus reuniens) in autism.

Pharmacological data, such as a pronounced habit of Smoking in patients with schizophrenia compared with normal people, was interpreted as an attempt patients through medication to achieve failure nicotinergic transmission of the α7 receptor. Transient normalization of sensory regulation (compulsive suppression PPI) in both animal model and human model, with the introduction of nicotine and temporary restoration of normal sensory regulation in schizophrenics, when cholinergic activity forebrain low (for example, stage 2 sleep), was interpreted as the result of a transient activation of α7-nicotinic receptor after data demonstrate that differently modulated.

Thus, there are grounds to assume that activation of α7-Nahr will have therapeutically beneficial effects in a number of disorders of the Central nervous system (mental and neurological).

As already mentioned, α7-Nahr quickly reduces its sensitivity at constant presence of natural transmitter acetylcholine, and exogenous ligands, such as nicotine. In desensitization state, the receptor remains bound to the ligand, but functionally inactive. This condition does not represent a problem for the natural transmitters, such as acetylcholine and choline, as they are the subst is Atami for effective mechanisms of splitting (acetylcholinesterase) and excretion (kalinovy conveyor). These mechanisms splitting/removing transmitters will likely allow you to maintain the balance between activated and desensitization α7-Nahr in a physiologically effective area. However, synthetic agonists, which are not substrates for natural mechanisms of splitting and removal, are considered as showing the potential for increased stimulation and guides the equilibrium population of α7-Nahr towards permanent desensitizing state, which is undesirable for violations, where the lack of expression and function of α7-Nahr plays a role. Agonists by their nature should target binding pocket AH, which is highly conserved among different subtypes of nicotinic receptors, leading to possible adverse reactions as a result of non-specific activation of other subtypes of nicotinic receptors. Therefore, to avoid these potential drawbacks, an alternative therapeutic strategy for agonism α7 is the increased reactivity of the receptor in relation to natural agonists using positive allosteric modulators (PAM). FRAMES defined as an agent that binds to a site other than the binding site agonist, and therefore should not be expected that he will show what waista agonist or data demonstrate that differently modulated, but it enhances the reactivity 7α-Nahr in relation to the natural transmitter. The value of this strategy is that for a given number of unit magnitude response of α7-Nahr is increased in the presence of FRAMES relative to the level of transmission, possible in its absence. As for disorders in which there is a lack of protein α7-Nahr, RUM-induced increase transmission nicotinic cholinergic receptor α7 may be favorable. Because FRAMES depends on the presence of natural transmitter, the possibility of increased stimulation is limited by the mechanisms of splitting/removing natural transmitter.

Compounds according to the present invention are classified as type 1 through 4 on the basis of qualitative kinetic characteristics that define a method for fixing a voltage of the cell. This classification is based on the effects of FRAME connection of the α7 receptor, as described above, in the signal caused by the agonist. In particular, the above agonist is choline at a concentration of 1 mm. In the preferred experimental conditions mentioned above RAM connection of the α7 receptor and choline simultaneously applied to the cell, as presented in the description below. The desensitization is defined as the closure of the receptor when activated during the term and is onista used in electrophysiology method of fixing the voltage of a cell, as evidenced by the decrease of the level of the output current after initial activation by the agonist.

Definition of types of FRAMES 1-4 are described below:

Type 1compounds enhance the dimensional effect of the current induced by 1 mm choline, but minimally alter the kinetics of the receptor. In particular, the rate and extent data demonstrate that differently modulated caused by the agonist, does not change. A compound that modulates the response to 1 mm choline, therefore, is close to a linear change in response to 1 mm choline in the absence of a FRAME connection of the α7 receptor.
Type 2compounds enhance the dimensional effect of the current induced by 1 mm choline, at the same time, reduce speed and/or degree data demonstrate that differently modulated.
Type 3compounds enhance the dimensional effect of the current induced by 1 mm choline. When the compounds are tested at higher concentrations up to 10 μm, they completely inhibit the desensitization, in particular when using 1 mm choline within 250 milliseconds.
Type 4compounds contribute original data demonstrate that differently modulated receptor with subsequent re-opening of the receptor during agonis the and. At concentrations of connection FRAMES receptor α7 low potential induced by agonist activation, followed by desensitization, can be separated from the induced connection is re-opening as the initial input current is maximum. When more high-grade concentrations FRAMES-link receptor α7 re-opening is faster than closing due to data demonstrate that differently modulated, so that the initial current-maximum disappears.

Thus, the aim of the present invention is to provide methods of treatment, which include the introduction of either a positive allosteric modulator as the only active substance, modulating the activity of endogenous agonists of nicotinic receptor, such as acetylcholine or choline, or the introduction of a positive allosteric modulator with an agonist of nicotinic receptor. In a separate form of this aspect of the invention, the method of treatment includes the treatment of the positive allosteric modulator of nicotinic receptor α7, as presented in the description, and an agonist of nicotinic α7 receptor or partial agonist. Examples of suitable compounds with agonistic activity of nicotinic receptor α7 include, but are not limited to:

- 1,4-diazabicyclo[3.2.2]nonan-4-carboxylic acid 4-Romanovy ether monohydrochloride (SSR180711A);

- (-)-Spiro[1-azabicyclo[2.2.2]Octan-3,5'-oxazolidin]-2'-he;

- 3-[(2,4-dimethoxy)benzylidene]anabaseine the dihydrochloride (GTS-21);

- [N-[(3R)-1-azabicyclo[2.2.2]Oct-3-yl]-4-chlorobenzamide hydrochloride] (PNU-282987).

Positive modulators Nahr according to the present invention is suitable for treatment or prevention of mental disorders, disorders of mental abilities or diseases or conditions in which modulation of the activity of the nicotinic α7 receptor is beneficial. Another aspect of the method of the invention is a method of treating deficiency learning, disorders cognitive disorders, attention or memory loss, modulation of the activity of nicotinic receptor α7 expected to have a positive effect in a number of diseases, including Alzheimer's disease, dementia, when developing the disease diffuse Taurus Levi, hyperactivity, attention deficit, anxiety, schizophrenia, manic syndrome, bipolar depression, Parkinson's disease, Huntington's disease, the syndrome of Gilles de La Tourette, a brain injury or other neurological, degenerative or mental disorder in which there is loss of cholinergic synapses, including the syndrome shift time belts, addiction to nicotine, pain.

The connection can also find therapeutic and the use as anti-inflammatory drugs, because subunit of nicotinic acetylcholine α7 receptor is essential for inhibition of cytokine synthesis in cholinergic inflammatory pathway. Examples of medical conditions that can be treated by the compounds, are groove toxins, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, inflammatory bowel disease, an inflammatory disease of the gall bladder, Crohn's disease, pancreatitis, heart failure and rejection of the allograft.

On the basis of the above described pharmacological properties, the compounds of formula (I) or any subgroup, their pharmaceutically acceptable salt additive and stereochemical isomeric form can be used as a medicine.

On the basis of the above described pharmacological properties, the compounds of formula (I) or any subgroup, their pharmaceutically acceptable salt additive and stereochemical isomeric form can be used in the treatment or prevention of mental disorders, disorders of mental abilities, inflammatory diseases or conditions in which modulation of the nicotinic α7 receptor has a beneficial effect.

On the basis of the above described pharmacological properties, the compounds according to the present invention can be used in the us for the manufacture of a medicinal product for the treatment or prevention of mental disorders, disorders mental abilities, inflammatory diseases or conditions in which modulation of the nicotinic α7 receptor has a beneficial effect.

With regard to the usefulness of the compounds of formula (I) is provided a method of treating warm-blooded animals, including man, suffering from disease, or a method of preventing warm-blooded animals, including man, from diseases in which modulation of the nicotinic α7 receptor has a beneficial effect, such diseases as schizophrenia, manic syndrome and bipolar depression, anxiety, Alzheimer's disease, learning deficit, impaired cognitive ability, impairment of attention, memory loss, dementia, when developing the disease diffuse Taurus Levi, hyperactivity, attention deficit, Parkinson's disease, Huntington's disease, the syndrome of Gilles de La Tourette, traumatic brain injury, syndrome, jet lag, addiction to nicotine and pain. The above methods include the introduction, i.e. the systemic or local injection, preferably oral administration, of an effective amount of the compounds of formula (I), including all stereochemical isomeric forms, its pharmaceutically acceptable additive salt, MES or hydrate, warm-blooded animals, including humans.

Specialist in this field on what should be recognized, that is therapeutically effective amount of FRAMES according to the present invention is the amount sufficient to modulate the activity of nicotinic α7 receptor, and that this amount varies inter alia depending on the type of disease, the concentration of the compound in therapeutic drug and the patient. In most cases, the number of FRAMES that must be entered as a therapeutic agent for treating diseases in which modulation of the nicotinic α7 receptor has a beneficial effect, such as schizophrenia, manic syndrome and bipolar depression, anxiety, Alzheimer's disease, learning deficit, impaired cognitive ability, impairment of attention, memory loss, dementia, when developing the disease diffuse Taurus Levi, hyperactivity, attention deficit, Parkinson's disease, Huntington's disease, the syndrome of Gilles de La Tourette's, traumatic brain injury, syndrome, jet lag, addiction to nicotine and the pain will be determined by the attending physician for each case separately.

In General, a suitable dose is the dose, which leads to a concentration of RAM in the place of influence in the region from 0.5 nm to 200 μm and more preferably from 5 nm to 50 μm. To achieve such influencing concentrations, the patient in need of treatment, the probability is about, will enter from 0.005 mg/kg to 10 mg/kg of body weight, in particular from 0.1 mg/kg to 0.50 mg/kg of body weight. The number of compounds according to the present invention, also referred to in the description as the active ingredient required for a therapeutic effect, as it is known, will vary from case to case, may vary depending on individual compounds, method of administration, the age and condition of the recipient and a separate disorders or disease being treated. The treatment method may also include the introduction of the active ingredient according to the scheme between one and four injections a day. In the above methods of treatment of the compounds according to the invention preferably is prepared to receive. As described below, suitable pharmaceutical preparations are prepared by known methods, using well known and readily available ingredients.

The present invention also provides compounds for preventing or treating diseases in which modulation of the nicotinic α7 receptor has a beneficial effect, such as schizophrenia, manic syndrome and bipolar depression, anxiety, Alzheimer's disease, learning deficit, impaired cognitive ability, impairment of attention, memory loss, dementia, when developing the disease diffuse Taurus Levi, sink the m hyperactivity with attention deficit, Parkinson's disease, Huntington's disease, the syndrome of Gilles de La Tourette's, traumatic brain injury, syndrome, jet lag, addiction to nicotine and pain. These compounds containing a therapeutically effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier or diluent.

Although it is possible to introduce the active ingredient separately, it is preferable to present it as a pharmaceutical composition. Thus, the present invention also provides a pharmaceutical composition comprising the compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable”in the sense of being compatible with other ingredients of the composition and do not adversely affect the recipient.

The pharmaceutical compositions according to this invention can be prepared by any means well known in the field of pharmacy, such methods, which are described in the publication Gennaro et al., Remington''s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of individual compounds in the form of a base or addition salt as an active ingredient together in the form of a homogeneous mixture with a pharmaceutically p is memlimit media which can be in various forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in a standard dosage forms, preferably for system administration, such as oral, percutaneous or parenteral administration; or local injection, such as by inhalation, nasal spray, eye drops, or by means of a cream, gel, shampoo or the like. For example, when preparing the compositions in oral dosage form, any of the pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja tools and the like in the case of powders, pills, capsules and tablets. Because of the ease of introduction of tablets and capsules represent the most effective standard oral dosage form, in which case, of course, use solid pharmaceutical carriers. For parenteral compositions, the carrier will typically include sterilized water, at least for the most part, though other ingredients, for example contributing to the solubility, can b shall be included. For example, can be prepared injectable solutions, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can be prepared injectable suspension, in which case can be used appropriate liquid carriers, suspendresume tools and the like. In the compositions suitable for percutaneous administration, the carrier optionally includes enhancing the penetration of the tool and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small proportions, and supplements do not cause any significant adverse effects on the skin. The above additives can facilitate an introduction to the skin and/or may be useful for the preparation of the desired compositions. These compositions can be introduced in various ways, for example in the form of a transdermal patch, in the form of getting to the point of the tool or in the form of ointment.

Particularly beneficial preparation of pharmaceutical compositions in a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, as used in the description and the claims refers to physically discrete units suitable as single doses, each unit is and contains a predetermined amount of the active ingredient, designed to achieve the desired therapeutic effect, in Association with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored or coated tablets), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, teaspoons (any liquid or solid substance), tablespoons (any liquid or solid substance) and the like and their individual multiples of units.

Compounds according to the present invention can be used for system administration, such as oral, percutaneous or parenteral administration; or local injection, such as by inhalation, nasal spray, eye drops, or by means of a cream, gel, shampoo or the like. The compounds are preferably administered orally. The exact dosage and frequency of injection depends on the individual used the compounds of formula (I), a separate condition being treated, the severity of the condition being treated, age, weight, sex, extent of disturbance, and General physical condition of the individual patient, as well as another drug, well known to the person skilled in the art that the individual can take. Moreover, it is clear that the effective day the number may be increased or decreased depending on the receptivity of the subject, being treated, and/or depending on the evaluation of the physician prescribing the compounds according to the present invention.

The compounds of formula (I) can also be used in combination with other conventional agonists nicotinic α7 receptor, such as, for example, 1,4-diazabicyclo[3.2.2]nonan-4-carboxylic acid 4-brompheniramine ether monohydrochloride (SSR180711A); (-)-Spiro[1-azabicyclo[2.2.2]Octan-3,5'-oxazolidin]-2'-Oh; 3-[(2,4-dimethoxy)benzylidene]anabaseine the dihydrochloride (GTS-21) or [N-[(3R)-1-azabicyclo[2.2.2]Oct-3-yl]-4-chlorobenzamide hydrochloride] (PNU-282987). Thus, the present invention also relates to combinations of compounds of formula (I) and agonist of nicotinic receptor α7. This combination can be used as a drug. The present invention also relates to a product comprising (a) compound of formula (I) and (b) an agonist of nicotinic receptor α7, as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases, where the modulation of the nicotinic α7 receptor has a beneficial effect. Various drugs can be combined in one preparation together with pharmaceutically acceptable carriers.

Experimental part

Chemistry

Some ways of getting connected is th according to this invention is illustrated in the following examples. Unless otherwise stated, all raw materials are received from private suppliers and used without further purification.

In the description before and after “THF” means tetrahydrofuran; “EtOAc” means ethyl acetate; “DIPE” means diisopropyl ether; “DMF” means N,N-dimethylformamide; “NPM” means 1-methyl-2-pyrrolidinone; “q.s.” means “as needed”, “I.D.” means the internal diameter and t-BuOH” means 2-methyl-2-propanol.

The reaction, carried out under the action of microwave radiation, conducted in a single reactor: InitiatorTMSixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).

Analytical data are presented in part C.

A. Obtaining intermediates

Description 1

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3,4-differenl)thiourea (D1)

Ammonium salt titanoboa acid (10.6 g) was added to a mixture of 2-chloro-6-methyl-4-pyridinecarboxamide (22,04 g, 116 mmol) and acetone (400 ml). The reaction mixture was stirred for 30 minutes and then 3,4-diferently (14,98 g, 116 mmol) was slowly added via an additional funnel. The resulting solution was stirred for 2 hours, the reaction extinguished with water (100 ml) and then the reaction mixture was extracted with CH2Cl2(3×100 ml). The combined organic phase sushi is whether over MgSO 4was filtered and the solvent was evaporated in vacuum. Output: 38,1 g of intermediate compound D1.

Description 2

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3,4-differenl)-2-methylisothiazoline (D2)

Was carefully added to a mixture of intermediate compound D1 (38 g; byr111.4 mmol) in THF (400 ml), cooled to 0°C and NaH (60% purity) (6.7 g; 167 mmol). The reaction mixture was stirred for 15 minutes and then added CH3I (14.2 g; 100 mmol). Then the mixture was heated to room temperature and was stirred for 2 hours. The reaction was suppressed by the addition of water and then the mixture was extracted with CH2Cl2(3×100 ml). The combined organic solution was washed with saturated salt solution, dried over MgSO4was filtered and the solvent was evaporated in vacuum. The residue was purified column chromatography on silica gel (gradient: heptane/EtOAc from 80/20 to 50/50). Output: 22,2 g of intermediate compound D2.

Description 3

(S)-1-Hydrazinolysis-2-ol (D3)

(2-S) 2-heteroxylan (15 g, 208 mmol) was dissolved in hydrazine, 64% (42 g; 832 mmol). The reaction mixture was stirred at 50°C for 2 hours and then was evaporated in a fume hood in a water bath at 50°C. Xylene was added (×2)to remove by evaporation of the excess amount of hydrazine from a crude reaction mixture. Output: 18,9 g PR is an interstitial compound D3 (white solid; S-enantiomer).

Description 4

(S)-1-[5-(2-Chloro-6-methylpyridin-4-yl)-3-(3,4-dipertanyakan)-[1,2,4]triazole-1-yl]butane-2-ol (D4)

Intermediate compound D2 (1 g; of 2.81 mmol) was dissolved in t-BuOH (40 ml) and then added intermediate compound D3 (0,44 g; 4,22 mmol). The reaction mixture was stirred and boiled under reflux for 4 hours and then the solvent was evaporated. The residue was purified column chromatography on silica gel (gradient: CH2Cl2/10% CH3OH in CH2Cl2from 100/0 to 0/100). Yield: 1.1 g of intermediate compound D4 (S-enantiomer).

Description 5

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3-methoxy-5-triptoreline)thiourea (D5)

The sodium thiocyanate (6,998 g, 0,08632 mol) was added to a solution of 2-chloro-6-methyl-4-pyridinecarboxamide (14,912 g, 0,078472 mol) in acetone (2 l). The resulting mixture was stirred for 1 hour at room temperature (formation of brown precipitate). Next, 3-methoxy-5-triftorperasin (15 g, 0,078472 mol) was added dropwise and the reaction mixture was stirred for 2 hours at room temperature (brown precipitate). The mixture was dissolved in CH2Cl2(1.5 l) and then washed with 2×250 ml of water and saturated salt solution. The separated organic layer was evaporated and the residue races is Irali over night in a mixture of DIPE/heptane. The product was filtered and dried in vacuum. Output: one-21.32 g of intermediate compound D5 (67%).

Description 6

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3-methoxy-5-triptoreline)-2-methylisothiazoline (D6)

(The reaction was carried out in an atmosphere of N2)

NaH (1,267 g, 0,05279 mol) was added in portions to a cooled on ice to a solution of intermediate compound D5 (one-21.32 g, 0,05279 mol) in THF (480 ml) and the resulting mixture was stirred for 15 minutes at 0°C. was Further added dropwise a solution of CH3I (7,493 g, 0,05279 mol) in THF (40 ml) and the mixture was stirred for 2 hours at room temperature. Then the reaction extinguished H2Oh and the mixture was extracted with CH2Cl2(3×500 ml). The organic layers were separated, combined, washed with a saturated solution of salt, dried (MgSO4), filtered and the solvent was evaporated in vacuum. The crude product is triturated in a mixture of DIPE/heptane. Not quite white solid was filtered and dried to obtain 16,203 g of intermediate compound D6 (73,5%). Heptane and H2O was added to the filtrate and the resulting mixture was stirred over night at room temperature. The precipitate is not quite white was filtered and dried to obtain additional quantities (1,957 g) intermediate compound D6 (9%).

Description 7

(S)-1-[5-(2-Chloro-6-methylpyridin the-4-yl)-3-(3-methoxy-5-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (D7 )

A mixture of intermediate compound D6 (8,356 g, at 0.020 mol) and intermediate compound D3 (2,083 g, at 0.020 mol) in ethanol (200 ml) was stirred over night while boiling under reflux. Next, the solvent was evaporated to obtain intermediate compound D7 (S-enantiomer) as a yellow oil, which was used as such for the next reaction stage.

Description 8

(S)-1-[5-(2-chloro-6-methylpyridin-4-yl)-3-(3-methoxy-5-triptoreline)-[1,2,4]triazole-1-ylmethyl]propyl ester acetic acid (D8)

N,N-Dimethyl-4-pyridylamine (0,1222 g, 0.001 mol) was added to a solution of intermediate compound D7 (9,117 g, at 0.020 mol) in ethyl acetate (378 ml). The reaction mixture was stirred at the boil under reflux for 30 minutes. Next, the mixture was cooled to room temperature and the solvent was evaporated in vacuum. The residue was dissolved in CH2Cl2. The resulting organic solution was washed with a saturated solution of sodium bicarbonate, washed with saturated salt solution and then dried (MgSO4), filtered and the solvent was evaporated in vacuum. The obtained yellow oil was purified by high-performance liquid chromatography with reversed phase (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). The gradient with 3 mobile phases ispolzovaniya: 0.25% solution of NH 4HCO3in water; phase B: methanol; phase C: CH3CN). The desired fractions were collected. The solvent was evaporated and was co-evaporated with methanol. The product was led from a mixture of DIPE/heptane. White crystals were filtered and dried in vacuum. Output: 3,677 g of intermediate compound D8 (37%; the S-enantiomer).

Description 9

1-(2,6-Dichloropyridine-4-carbonyl)-3-(2,3,4-tryptophanyl)thiourea (D9)

Isothiocyanate ammonium (7,726 g, 0,1015 mol) was added to a solution of 2,6-dichloro-4-pyridinecarboxamide (17.8 g, 0,0846 mol) in acetone (300 ml). The mixture was stirred for 30 minutes and then slowly added 2,3,4-triptorelin hydrochloride (.HCl). The reaction mixture was stirred at room temperature for 2 hours and then the reaction extinguished H2O (100 ml). The mixture was extracted with CH2Cl2(3×80 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified flash chromatography (eluent: a mixture of heptane/EtOAc, 80/20 to 50/50). The desired fractions were collected and the solvent was evaporated in vacuum. Output: 22,2 g of intermediate compound D9 (69%).

Description 10

1-(2,6-Dichloropyridine-4-carbonyl)-2-methyl-3-(2,3,4-tryptophanyl)estimacion (D10)

NaH (2.70 g, 0,06747 mol) was carefully added to the cooled solution is (0°C) intermediate D9 (28.5 g, 0,04498 mol) in THF (200 ml). The mixture was stirred for 15 minutes and then added CH3I (6,38 g, 0,04498 mol). Bath ice was put aside and the reaction mixture was stirred for 2 hours at room temperature. Next, the reaction extinguished H2Oh and the reaction mixture was extracted with CH2Cl2(3×100 ml). The combined organic layers were washed (saturated salt solution), dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified flash chromatography (eluent: a mixture of heptane/EtOAc, gradient from 80/20 to 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 5.7 g of the intermediate compound D10 (32%).

Description 11

(S)-1-[5-(2,6-Dichloropyridine-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (D11)

Intermediate compound D3 (0,143 g, 0,00137 mol) was added to a solution of intermediate compound D10 (0.3 g, 0,000457 mol) in t-BuOH (40 ml). The reaction mixture was stirred over night while boiling under reflux. The solvent was evaporated in vacuum and the residue was purified flash chromatography on silica gel (eluent a mixture of EtOAc/heptane, gradient from 20/80 to 50/50). The desired fractions were collected and the solvent was evaporated. Output: 0,160 g of intermediate compound D11 (81%; the S-enantiomer).

Description 12

(S)-1-[3-(3-Chloro-2-forgenerating)-5-(2,6-dichloropyridine-4-yl)-[1,2,]triazole-1-yl]butane-2-ol (D12)

The intermediate connection D12 was obtained according to the procedure similar to that used for the synthesis of D11. Output: intermediate connection D12 (79%; the S-enantiomer).

Description 13

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3-fluoro-5-methoxyphenyl)thiourea (D13)

2-Chloro-6-methyl-4-pyridinecarboxamide (44,087 g, 0,232 mol) in acetone (1 l) was treated with isothiocyanates ammonium (21,192 g, 0,278 mol) and the mixture was stirred for 1 hour at room temperature. Next, a solution of 3-fluoro-5-methoxybenzamide (36,02 g, 0,255 mol) in acetone (200 ml) was added dropwise and the reaction mixture was stirred for 4 hours at room temperature. The solvent was evaporated in vacuum and the residue was dissolved in CH2Cl2(1 liter). The resulting organic solution was washed (H2O), dried (MgSO4), filtered and the solvent was evaporated in vacuum to obtain a brown solid. The brown solid is triturated in acetonitrile (0.8 l), stirred overnight and the solid was filtered and dried (vacuum drying Cabinet, 4 hours at 65°C). Output: 59,69 g of intermediate compound D13 (73%).

Description 14

1-(2-Chloro-6-methylpyridin-4-carbonyl)-3-(3-fluoro-5-methoxyphenyl)-2-methylisothiazoline (D14)

3I (15,651 ml), dissolved in THF (200 ml). The reaction mixture was stirred over night at room temperature and then the reaction extinguished H2O (25 ml). After treatment and evaporation of the solvent, the solid is triturated in a mixture of DIPE (0.5 l) and CH3CN (50 ml). The reaction mixture was stirred for 3 hours and then the product was filtered and dissolved in CH2Cl2(1.5 liters). The organic solution was washed N2(0.8 l), dried (MgSO4), filtered and the solvent was evaporated in vacuum. Output: 52,3 g of intermediate connections D14 (84.3 percent).

Description 15

(S)-1-[5-(2-Chloro-6-methylpyridin-4-yl)-3-(3-fluoro-5-methoxybenzylamine)-[1,2,4]triazole-1-yl]butane-2-ol (D15)

A mixture of intermediate compound D3 (22,213 g, 0,213 mol), intermediate connections D14 (52,3 g, 0,142 mol) and ethanol (500 ml) was boiled under reflux for 16 hours, at the same time, the mixture was purged with N2. The reaction was suppressed by a solution of NaOCl. Next, the solvent was evaporated in vacuum and the residue was led from DIPE (400 ml). The light yellow solid was filtered and used as such for the next reaction stage. Output: 33,124 g of intermediate compound D15 (574%; S-enantiomer).

C. Obtaining connections

Example B1

(S)-1-[3-(3,4-Dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol (E1)

Intermediate compound D4 (1.1 g, 2,80 mmol) was dissolved in THF (15 ml) was added iron acetylacetonate(III) (0,099 g, 0.28 mmol) and NMP (1 ml). Then the reaction mixture was cooled to 0°C. Under the protection of N2(gas) was slowly added a 3 M solution of CH3MgBr in Et2O (4 ml, 12 mmol). The reaction mixture was heated to room temperature and was stirred for one hour before until the reaction has ended. Then the reaction was suppressed with saturated solution of NH4Cl and the reaction mixture was extracted with CH2Cl2(3×30 ml). The combined organic phase was washed with saturated salt solution, dried over MgSO4was filtered and the solvent was evaporated in vacuum. The residue was purified by high-performance liquid chromatography with reversed phase (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). The gradient with 2 or 3 mobile phases used (phase A: a 0.25% solution of NH4HCO3in water; phase B: CH3OH (optional); phase C: CH3CN). Output: 0.152 g of compound E1 (S-enantiomer).

Example B2

(S)-1-[3-(3-Chlorpheniramine)-5-(2-ethylaminomethyl-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol (E2)

Intermediate compound 1-[3-(3-chlorpheniramine)-5-(2-chloropyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol (obtained as described 4) (1,15 g; totaling 3.04 mmol) was dissolved in CH3HE (20 ml) and then was added ethylamine (3 g). The reaction mixture was stirred for 16 hours at 160°C under pressure (up until the reaction was not finished). Then the solvent was evaporated in vacuum. The residue was purified by high-performance liquid chromatography with reversed phase (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). Used a gradient with 2 mobile phases (phase A: a 0.25% solution of NH4HCO3in water; phase B: CH3CN). The desired fractions were collected, processed and, finally, the residue was led from diisopropyl ether. Output: 0,1595 g of compound E2 (S-enantiomer).

Example B3

1-[3-(3,4-Dipertanyakan)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]hexane-2-ol (E3)

A mixture of intermediate compound, 1-[5-(2-chloro-6-methylpyridin-4-yl)-3-(3,4-dipertanyakan)-[1,2,4]triazole-1-yl]hexane-2-ol (obtained according to the procedure for obtaining compounds D4) (1.5 g, 3.5 mmol) and Et3N (2 ml) in THF (40 ml) was subjected to hydrogenation with Pd/C 10% (at 0.020 g) as a catalyst in the presence of a solution of thiophene (0.1 ml; 4% in DIPE). After the absorption of H2(1 EQ.) ceased, the catalyst was filtered and the filtrate was evaporated in vacuum. The residue is suspended in DIPE and filtered. The crystals were dried in a vacuum drying Cabinet at 70°C during the night.

Output: 876 mg is soedineniya E3 (65%).

Example B4

(-)-1-[3-(3,4-Dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]hexane-2-ol (E4) and (+)-1-[3-(3,4-dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]hexane-2-ol (E5)

Connection E7 (564 mg; 1.4 mmol) was separated into the enantiomers by supercritical fluid chromatography (SFC) on a column Chiralpak AD-H (30×250 mm) with a flow rate of 50 ml/min a Mixture of 30% CH3OH (+ 0,2% 2-Propylamine)/70% CO2used as eluent. The column heater was set at a temperature of 40°C and the pressure in the nozzle was set at 100 bar.

First eluruumis isomer, peak “A”, was collected and concentrated, the oily residue is triturated in a mixture of DIPE and heptane. A white solid was collected by filtration, washed with heptane and dried in a vacuum drying Cabinet. Output: 200 mg of compound E4 in the form of a white powder (crystalline).

Second eluruumis isomer, the peak “B”, were collected and concentrated, the oily residue is triturated in a mixture of DIPE and heptane. A white solid was collected by filtration, washed with heptane and dried in a vacuum drying Cabinet. Output: 212 mg of compound E5 in the form of a white powder (crystalline).

Example B5

(S)-1-[5-(2,6-Dimethylpyridin-4-yl)-3-(3-methoxy-5-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (E30)

NMP (1 ml, anhydrous) and acetylacetonate Fe(III) (35,33 g, 0.0001 mol) was added to a solution of intermediate compound D8 (498,08 g, 0.001 mol) in THF (10 ml, anhydrous) and the mixture was cooled to 0°C. was Slowly added methylmagnesium (1,67 ml of 0.005 mol) and the reaction mixture was stirred for 5 minutes at 0°C. Then reaction was suppressed with saturated solution of NH4Cl and the reaction mixture was extracted with CH2Cl2(3×50 ml). The combined organic layers were washed with a saturated solution of salt, dried (MgSO4), filtered and the solvent was evaporated. The residue was dissolved in methanol and was added NaOH (800 mg, at 0.020 mol). The resulting mixture was stirred for 1 hour at room temperature. Was added a saturated solution of NH4Cl and the mixture was extracted with CH2Cl2(3×50 ml). The combined organic layers were washed (saturated salt solution), dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel (eluent: (7 N NH3/MeOH)/CH2Cl2the gradient from 0/100 to 10/90). Fractions of product were collected and the solvent was evaporated in vacuum. The residue was treated with heptane, getting white crystals. The obtained white crystals were filtered and dried in vacuum. Output: 0,632 g of compound E30 (83%; the S-enantiomer).

Example B6

(S)-1-[5-(2,6-Dimethylpyridin-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (E32) and (S)-1-[5-(2-chloro-6-methylpyridin-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (D16)

A mixture of intermediate compound D11 (0,47 g, 0,0011 mol), iron acetylacetonate(III) (0,0383 g, 0,00011 mol), NMP (1 ml) and THF (25 ml) was stirred at 0°C. 3 M solution of CH3MgBr in Et2O (2,9 ml, 0,0087 mol) was added. The reaction mixture was stirred for 2 hours at room temperature. The reaction was suppressed with saturated solution of NH4Cl and the reaction mixture was extracted with CH2Cl2(3×30 ml). The combined organic layer was washed (saturated salt solution), dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified by high-performance liquid chromatography with reversed phase (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). The gradient with 3 mobile phases used. Phase A: a 0.25% solution of NH4HCO3in water; phase B: methanol; phase: CH3CN). Two different fractions of product were collected and processed. Output: 0,077 g of intermediate compound D16 (17%). Output: 0,183 g of compound e (43%; the S-enantiomer).

The connection part a was converted into HCl-salt by conventional means, well known to the experts in this field, getting a connection A (HCl-salt; S-enantiomer).

Example B7

(S)-1-[5-(2-Methylpyridin-4-yl)-3-(2,3,4-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol (E31)

A mixture of intermediate compound D16 (0,13 g, 0,000316 supposedly is), [1,3-bis[2,6-bis(1-methylethyl)phenyl]-2-imidazolidinone]chlorine(η3-2-propenyl)palladium (CAS [478980-01-7]; catalyst) (0,01814 g, 0,0000316 mol) and NaOCH3(0.5 M in methanol) (1 ml) in 2-propanol (4 ml) was stirred under microwave irradiation for 10 minutes at 120°C. the Solvent was evaporated and the concentrate was washed N2O and was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified by high-performance liquid chromatography with reversed phase (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). Used a gradient with 3 mobile phases. Phase A: a 0.25% solution of NH4HCO3in water; phase B: methanol; phase: CH3CN. The desired fractions were collected and processed. Output: 0,0519 g of compound e (43,5%; the S-enantiomer).

Example B8

(S)-1-[3-(3-Chloro-2-forgenerating)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt (E35)

A mixture of intermediate compound D12 (2.6 g, 0,00604 mol), iron acetylacetonate(III) (0,427 g, 0,00121 mol), THF (150 ml) and NMP (35 ml) was stirred at 0°C. was Added a 3 M solution of CH3MgBr in Et2O (10 ml) and the mixture was stirred for 1 hour at room temperature. Added an additional amount of 3 M solution of CH3MgBr in Et2O (10 ml) and methanol. The solvent was evaporated and to the residue was added CH2Cl 2and H2O (a few ml). The mixture was filtered through diatomaceous earth. The filtrate was evaporated and the residue was dissolved in DIPE. The solution was washed (H2On) and the organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was dissolved in 2-propanol and the solution was added a mixture of HCl/2-propanol when cooled in a bath with ice. Next, the solvent was evaporated and the residue was stirred in acetone. The crystals were filtered off and dried. Yield: 0.96 g connection E (37%; the S-enantiomer; HCl-salt). Additional number of connections I could be extracted from the filtrate to obtain the total yield of 63%.

Example B9

(S)-1-[3-(3-Fluoro-5-methoxybenzylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt (E36) and (E38) (free base E36)

A mixture of intermediate compound D15 (0,406 g, 0.001 mol), [1,3-bis[2,6-bis(1-methylethyl)phenyl]-2-imidazolidinone]chlorine(η3-2-propenyl)palladium (CAS [478980-01-7]; catalyst) (by 0.055 g, 0,0000957 mol) and NaOMe (0.2 ml 5,33 M solution in MeOH, 0,001066 mol) in 2-propanol (10 ml) was heated in a microwave oven for 10 minutes at 120°C. Then the reaction mixture was concentrated in vacuum, diluted with CH2Cl2and washed with N2O. the Organic layer was dried (MgSO4), filtered and the solvent was evaporated in vacuum. The residue was purified column chromatography (e is UNT: CH 2Cl2/MeOH, 100/0-95/5). The desired fractions were collected and the solvent was evaporated to obtain 0,300 g colorless oil (compound E38, which is a free base of compound E36). Connection E38 (S-enantiomer) was converted into its HCl-salt: the oil was dissolved in DIPE and processed 6 N. HCl in 2-propanol and the resulting mixture was stirred for 5 hours. The yellow precipitate was filtered and dried (vacuum drying Cabinet, 65°C, 3 days). Output: 0,237 g of compound E36 (58%; the S-enantiomer; HCl-salt).

In tables 1 and 2 lists the compounds of formula (I), which were obtained similar to one of the above examples (No. of example).

Table 1

Table 2

Table 3

C. the Analytical part

IHMS

The General procedure And

Quantitative determination by HPLC was performed using the systems Alliance HT 2790 (Waters), including a pump for four-component mixtures with degasser, auto pump, column thermostat (set at 40°C, unless otherwise noted), the detector diode array (DAD) and a column as described in the respective methods below. Flow from the column is allocated to the MS-spectra is Romero. The MS detector was installed with an electrospray ionization source. Mass spectra were obtained by scanning from 100 to 1000 in 1 second with a time delay of 0.1 seconds. The voltage of the capillary needle was 3 kV and the source temperature was maintained at 140°C. Nitrogen was used as the gas for sputtering. Data collection was performed using a data processing system Waters-Micromass MassLynx-Openlynx.

The General procedure In

Quantification by LC was performed using the system Acquity UPLC (Waters), including a pump for a binary mixture, the device for sample, a column heater (set at 55°C), the detector diode array (DAD) and a column as described in the respective methods below. Flow from the column is allocated to the MS-spectrometer. The MS detector was installed with an electrospray ionization source. Mass spectra were obtained by scanning from 100 to 1000 in 0.18 seconds to the delay time of 0.02 seconds. The voltage of the capillary needle was 3.5 kV and the source temperature was maintained at 140°C. Nitrogen was used as the gas for sputtering. Data collection was performed using a data processing system Waters-Micromass MassLynx-Openlynx.

IHMS - Procedure 1

In addition to General procedure A: HPLC with reversed-phase was performed on column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Three under ignie phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase b: acetonitrile; mobile phase C: methanol) were used to run programs in a gradient from 100% a to 1% A, 49% and 50% for 6.5 minutes, to 1% and 99% In 1 minute and maintained these conditions for 1 minute and re-balanced 100% And within 1.5 minutes. The volume of the injectable solution was 10 µl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

IHMS - Procedure 2

In addition to General procedure a: column heater set at 60°C. HPLC with reversed-phase was performed on column Xterra MS C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase b: acetonitrile; mobile phase C: methanol) were used to run programs in a gradient from 100% a to 50% b and 50% for 6.5 minutes, to 100% b for 0.5 minutes and maintained these conditions for 1 minute and re-balanced 100% And within 1.5 minutes. The volume of the injectable solution was 10 µl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

IHMS - Procedure 3

In addition to General procedure A: HPLC with reversed phase was carried out on a column of Atlantis C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Two mobile phases (mobile phase A: 70% methanol + 3% N 2About; mobile phase b: 0.1% of formic acid in a mixture of N2O/methanol 95/5) was used to run programs in a gradient from 100% to 5% B + 95% And 12 minutes. The volume of the injectable solution was 10 µl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

IHMS - Procedure 4 (used only for intermediates D1, D2 and D4)

In addition to General procedure A: HPLC with reversed-phase was performed on column Chromolith (4,6×25 mm) with a flow rate of 3 ml/min. Three mobile phases (mobile phase A: 95% 25 mm ammonium acetate + 5% acetonitrile; mobile phase b: acetonitrile; mobile phase C: methanol) were used to run programs in a gradient from 96% a, 2% and 2%, 49% and 49% for 0.9 min, 100% b for 0.3 minutes, and these conditions kept within 0.2 minutes. The volume of the injectable solution was 2 µl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

IHMS - Procedure 5

In addition to General procedure a: column heater set at 45°C. HPLC with reversed phase was carried out on a column of Atlantis C18 (3.5 µm, a 4.6×100 mm) with a flow rate of 1.6 ml/min Two mobile phases (mobile phase A: 70% methanol + 30% N2About; mobile phase b: 0.1% of formic acid in a mixture of N2O/methanol 95/5) use the Wali to run the program in a gradient from 100% to 5% B + 95% And for 9 minutes and these conditions were maintained for 3 minutes. The volume of the injectable solution was 10 µl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

IHMS - Procedure 6

In addition to General procedure B: UPLC with inverted phase (- efficient liquid chromatography) was performed on a column with composite material etisalats/silica, United bridge connection (VEINS) C18 (1.7 mm, and 2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min Two mobile phases (mobile phase A: 0.1% of formic acid in a mixture of N2O/methanol 95/5; mobile phase b: methanol) used for program execution in a gradient from 95% a and 5% up to 5% a and 95% b for 1.3 minutes, and these conditions were maintained for 0.2 minutes. The volume of the injectable solution was 0.5 μl. The voltage at the cone was 10 type positive ionization and 20 In the type of negative ionization.

The melting point

For a number of compounds, melting points (TPL, m.p.) was determined using a calorimeter DSC823e (Mettler-Toledo). The melting point was measured with a temperature gradient of 30°C/min. The maximum temperature was 400°C.

Values were obtained from experimental errors commonly associated with this analytical method.

Table 4
Analytical data - retention Time (Rtin minutes, the peak of [M-H]-and procedure IHMS. In the case when the compound is a mixture of isomers, which give different peaks in the way IHMS, only the retention time of the main component are presented in table IHMS
No. of connectionsRt[M-H]-Procedure IHMS
D11,073404
D20,973924

8,04 5,34
Table 5
Analytical data - retention Time (Rtin minutes, the peak of [M-H]+the procedure IHMS and the melting point (TPL defined as the melting point). In the case when the compound is a mixture of isomers, which give different peaks in the way IHMS, only the retention time of the main component are presented in table IHMS.
No. of connectionsRt[M+H]+ Procedure IHMSTPL (°C)
D21,043564not defined
E65,333601142,72
E15,513741166,04
E9of 5.404191137,06
E155,643741133,10
E16the 5.653741134,82
E57,664023135,00
E47,684023134,60
E123883120,50
E118,033883121,64
E25,673871161,99
E17the 5.453581144,31
E135,803881141,14
E14of 5.813881139,48
E187,263723inconclusive result
E19are 5.363561133,85
E205,764221 120,54
E217,273723inconclusive result
E35,953881137,96
E226,013861not defined
E235,693862127,44
E245,703862inconclusive result
E76,094021158,22
E85,803881152,48
E105,643741161,40
E263601145,29
E255,513891156,18
E275,473741inconclusive result
E288,294225117,16
E296,833875158,66
E305,964361166,05
E315,463781inconclusive result
E32lower than the 5.373922inconclusive result
E335,38 3922237,44
E345,563902inconclusive result
E356,033901inconclusive result
E361,203726inconclusive result
E37of 6.683865inconclusive result
E38not definednot defined-not defined
E39not definednot defined-not defined

Optical rotation:

Optical rotation was measured by a Perkin Elmer polarimeter 341. [α]D20indicates the optical rotation, change the i.i.d. with light with a wavelength of D-line of sodium (589 nm) at 20°C. The path length of the cell was 1 inch Below the actual value of the concentration and the solvent used for the measurement of optical rotation.

Table 6
Analytical data - Optical rotation
No. of connections[α]D20ConcentrationSolvent
E6+47,42°0,4660% wt./about.MeOH
E2+51,10°0,4286% wt./about.MeOH
E1+45,63°0,4624% wt./about.MeOH
E15-41,99°0,3882% wt./about.MeOH
E16+41,69°0,5494% wt./about.MeOH
E17+49,47°0,2850% wt./about. MeOH
E18-46,63°0,4396% wt./about.MeOH
E19+44,52°0,4358% wt./about.MeOH
E5+36,74°0,3402% wt./about.MeOH
E9+41,82°0,3826% wt./about.MeOH
E4-36,39°0,3188% wt./about.MeOH
E12+37,42°0,3474% wt./about.MeOH
E11-38,53°0,3348% wt./about.MeOH
E13-40,97°0,2880% wt./about.MeOH
E26-46,37°0,3860% wt./about.MeOH
E25-42,42° 0,4856% wt./about.MeOH
E14+38,69°0,3076% wt./about.MeOH
E20+42,58°0,4674% wt./about.MeOH
E21+47,41°0,4134% wt./about.MeOH
E23-44,30°0,4740% wt./about.MeOH
E24+44,62°0,4370% wt./about.MeOH
E27-46,37°0,4982% wt./about.MeOH
E28-42,10°0,4822% wt./about.MeOH
E29-50,75°0,3448% wt./about.MeOH
E30+41,04°0,2924% wt./about.MeOH
E37 +24,34°0,3944% wt./about.MeOH

The drugs examples

Example D.1: flow Visualization CA2+(FDSS)

Materials

a) a Buffer for analysis

Balanced salt Hanks solution (HBSS, Invitrogen, Belgium)with 10 mm HEPES (Invitrogen, Belgium), CaCl2to a final concentration of 5 mm, with 0.1% bovine serum albumin (Sigma-Aldrich NV, Belgium).

b) Calcium-sensitive dye Fluo-4AM

Fluo-4AM (molecular probes, USA) was dissolved in DMSO containing 10% pluranguloj acid (molecular probes, USA), to obtain the initial solution, which was diluted with buffer for analysis, equipped with a 5 mm probenecid (Sigma, Aldrich NV, Belgium)to obtain a final concentration of 2 μm.

(C) 384-well tablets

Black 384-well plate, black/clear plates, pre-coated with PDL (Corning Incorporated, USA)

d) measuring the flow of calcium ions

Functional screening system of medicines (FDSS, Hamamatsu) was used to measure intracellular signals flow of free calcium.

Way

Monolayers of GH4C1 cells expressing receptors hα7-wt Nahr, were grown in advance tablets, in particular in 384-well tablets with black wall and clear bottom, coated with poly-D-lysine, within 24 hours before making flu is rescenter indicator of calcium ions, in a separate embodiment of the invention, the introduction of fluo-4AM up to 120 minutes.

The activity of FRAMES determined in real time by making connections subjected to testing, to cells with an agonist of nicotinic receptor α7 in terms of ongoing monitoring of cellular calcium mobilization through registration of fluorescence in the FDSS system. Compounds that produce responses in the form of peaks of fluorescence greater than the response produced only agonist, was seen as modulators FRAMES receptor α7-Nahr. In a separate embodiment, the invention is an agonist of nicotinic receptor α7 was choline, in the preferred embodiment of the invention choline used a submaximal concentration, 100 μm. In another embodiment of the present invention the compounds under test were made to agonist nicotinic receptor α7, in a separate embodiment of the invention, up to 10 minutes before making agonist.

The control response to choline counted on each plate based on the difference between the peaks of fluorescence in the wells with either choline or only buffer for analysis. Compounds according to the present invention was tested at a concentration in the area of from 0.01 μm to 30 μm. Compounds were considered as showing interest is aktivnosti, when they increased the signal of the choline, at least 200% when tested at a concentration of 30 μm (efficiency 100 μm choline was determined as 100% in the absence of FRAMES).

Size EU50(activity), the maximum effect (% efficiency) and the slope of the curve of the hill was evaluated by aligning the equations describing a sigmoidal curve, with the data obtained using the program GraphPad Prism (GraphPad Software, Inc., San Diego, CA). An EC50(or RES50) was defined as the concentration producing half maximal effect, when observed a clear sigmoidal curve with the top of the plateau.

Compounds according to the present invention also showed potentiate the effect on the response to choline in the measurement of electrophysiological method of fixing the voltage of a cell in GH4C1 cells stably expressing elevated levels of the receptor α7 wild-type person, as described below.

Example D.2: the Method of fixing the voltage of a cell

The method of fixing the voltage of a cell used for mammalian cells, provides a credible means of assessing the function of membrane proteins, which are considered to be a subunit of a ligand-gated ion channels. Activation of such proteins endogenous or exogenous ligands causes the opening of pores associated with PE is atoron, through which ions move according to their electrochemical gradient. In the case of a recombinant cell line GH4C1 expressing hα7-wt Nahr, selective permeability with respect to ions of calcium for this receptor means that calcium ions move into the cell when activated AH, choline and other nicotinic ligands, causing calcium current. Because the specified receptor rapidly undergoes data demonstrate that differently modulated in the presence of agonist, it is important to use a software system that allows you to very quickly change the solutions of (<100 MS) to prevent partial or complete loss of receptor sensitivity, adequate duration of agonist. So the second way is appropriate for evaluation of increasing nicotine efficiency is a method of fixing a voltage of the cells used for GH4C1 cells expressing hα7-wt Nahr, in combination with accelerated software system.

Materials

a) Buffers for analysis

External fixative consisted of 152 mm NaCl, 5 mm KCl, 1 mm MgCl2, 1 mm calcium, 10 mm HEPES, pH 7.3. Internal fixing solution consisted of 140 mm CsCl, 10 mm HEPES, 10 mm EGTA, 1 mm MgCl2, pH 7.3.

b) Method of fixation potential (patch-clamp) was performed using the amp patch-clamp (Multiclamp 700A compound, Axon Instruments, CA, USA). The membrane potential of GH4C1 cells, Express arousih hα7-wt Nahr, was fixed in the configuration of the whole cells (Hamill et. al., 1981) using borosilicate glass electrodes with a resistance at the end of 1.5 to 5 Mω when filled his inner fixing solution. Registrations were made on cells with the membrane resistance of >500 MW and more preferably 1 gigaom and resistance in series <15 MOhm, at least 60% of compensation series resistance. Membrane potential was recorded at -70 mV.

C) Agonists

OH, choline were purchased from Sigma-Aldrich NV, Belgium.

d) Complex application

16-channel Dynflow model DF-16 microhydrodynamics system (Cellectricon, Sweden) for quick replacement solutions (allowing time to replace the <100 MS) was used to make control of agonist and FRAMES-connection to the GH4C1 cells expressing hα7-wt Nahr.

Way

GH4C1 cells expressing hα7-wt Nahr, were sown on plates in the outer fixing solution in the chamber system for perfusion Dynaflow and left to stabilize up to 20 minutes. Individual cells used for the method of the patch-clamp in the configuration of the whole cells and their carefully torn from the bottom of the camera, the patch-pipette in an ongoing perfusion flow (of 0.75 μl/min) external locking solution. The activity of FRAMES determined in real time by pre-making the connection is s, subjected to testing, to cells, with subsequent submission of agonist nicotinic receptor α7 while controlling the current through the cell membrane. Compounds that produce responses in the form of electricity, exceeding the answers only on the action of the agonist, was seen as modulators FRAMES receptor α7 Nahr. In a separate embodiment of the invention, the agonist of nicotinic receptor α7 activated non-selective nicotinic agonist, in a more specific embodiment of the invention agonist was choline, and even in a more specific embodiment of the invention choline was used by a submaximal concentration of 1 mm. In another embodiment of the present invention the compounds under test were made to agonist nicotinic receptor α7, in a more specific embodiment of the invention for 30 seconds prior to the agonist. The control response was calculated based on the area under the curve of the current induced in each cell under the action of a submaximal concentration of choline within 250 MS. The area under the curve is the total integration of the current over time and is the usual representation of the total ion flow through the channel. Increase the efficiency of the agonist, caused a positive allosteric modulator, was calculated as the potentiation “square crooked under the (AUC) of the response of the agonist, expressed in procentah. Potentiation was higher than than AUC in control caused by the compounds according to the invention, indicates that they, as expected, show a suitable therapeutic activity.

Table 7
Activity (RES50and % efficiency for a number of connections
Connection # pEC50% EfficiencyThe type of RAM
E156,1715801
E17of 5.9240402
E26,4511502
E66,0222002
E16,2316802
E96,0310002
E146,5014002
E166,3845802
E116,4511501
E12to 6.5821602
E4of 6.681010not defined
E56,6919202
E136,614901
E18of 5.8912601
E195,7124602
E20to 6.6746604
E21between 6.08 35002
E256,1613901
E266,115801
E236,0516401
E246,0745702
E276,0012702
E28of 5.7552102
E295,9920101
E306,7039402
E316,2630502
E326,2926002
E336,6 1560not defined
E346,5025202
E356,3319002
E36of 5.6842602
E375,8014202
E38not specifiednot specifiednot defined
E39not specifiednot specifiednot defined

Type 1connections enhance the dimensional effect of the current induced by 1 mm choline, but minimally alter the kinetics of the receptor. In particular, the rate and extent data demonstrate that differently modulated caused by the agonist, does not change. Therefore, the compound modulates the response to 1 mm choline, is close to a linear scale of the response to 1 mm choline in the absence of a connection of α7-FRAMES.

Type 2connections enhance the dimensional effect of the current induced by 1 m is choline, at the same time, reduce speed and/or degree data demonstrate that differently modulated.

Type 3connections enhance the dimensional effect of the current induced by 1 mm choline. When tested at higher concentrations up to 10 μm, they completely inhibit the desensitization, in particular under the action of 1 mm choline within 250 milliseconds.

Type 4connections contribute original data demonstrate that differently modulated receptor with subsequent re-opening of the receptor for the agonist actions. At low concentrations of the compounds of α7-FRAMES induced by agonist activation, followed by desensitization, can be separated from the induced connection is re-opening as the original incoming current is maximum. When more high-grade concentrations of the compounds of α7-RAM re-opening is faster than closing due to data demonstrate that differently modulated, so that the initial current-maximum disappears.

Surprisingly, the absolute stereochemistry has an impact on the type of modulation: in almost all cases levogyrate compounds that are believed to all have an absolute R-configuration, are modulators of type 1, while the corresponding programada compounds that are believed to all have the S absolute configuration, are modulators of the type 2. Neozed the NGOs, however, levogyrate connection E28 is a modulator of type 2, while the corresponding programame connection E20 is a modulator of the type 4.

Example D.3: hERG

The binding affinity of all of the tested compounds according to the present invention the potassium channel hERG is above 10 μm (pIC50<5).

1. The compound of formula (I)

or its stereoisomeric form,
where R1means methyl, ethylamino or methoxyethylamine;
R2means hydrogen or methyl;
R3means fluorine, chlorine, trifluoromethyl or methyl;
R4means hydrogen or fluorine;
R5means hydrogen, fluorine, chlorine or methoxy;
R6means C1-3alkyl;
or its pharmaceutically acceptable salt, or hydrate, or MES.

2. The compound according to claim 1 of formula (I-a)

or its stereoisomeric form,
where R1means methyl, ethylamino or methoxyethylamine;
R2means hydrogen or methyl;
R3means fluorine, chlorine, trifluoromethyl or methyl;
R4means hydrogen or fluorine;
R5means hydrogen, fluorine or methoxy;
R6means1-3alkyl;
or its pharmaceutically acceptable salt, or hydrate, or MES.

3. The compound according to claim 1 or its stereoisomeric form, where
R1means 2-methyl, 2-ethyl is Ino or 2-methoxyethylamine;
R2means hydrogen or 6-methyl;
R3means fluorine, chlorine, trifluoromethyl or methyl;
R4means hydrogen or fluorine;
R5means hydrogen, fluorine, chlorine or methoxy;
R6means C1-3alkyl;
or its pharmaceutically acceptable salt, or hydrate, or MES.

4. The compound according to claim 1 or its stereoisomeric form, where
R1means 2-methyl, 2-ethylamino or 2-methoxyethylamine;
R2means hydrogen or 6-methyl;
R2means fluorine, chlorine, trifluoromethyl or methyl;
R4means hydrogen or fluorine;
R5means hydrogen, fluorine, chlorine or methoxy;
R6means methyl;
or its pharmaceutically acceptable salt, or hydrate, or MES.

5. The compound according to claim 1, where the connection is
(S)-1-[3-(3,4-dipertanyakan)-5-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,
(R)-1-[3-(3-chlorpheniramine)-5-(2-ethylaminomethyl-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,
(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-5-triptoreline)-[1,2,4]triazole-1-yl]butane-2-ol,
(S)-1-[3-(3-fluoro-5-methoxybenzylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,
(S)-1-[3-(3-fluoro-5-methoxybenzylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,
(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-fluoro-5-methoxybenzylamine)-[1,2,4]triazole-1-yl]butane-2-ol HCl salt,
(S)-1-[5-(2,6-dimethylpyridin-4-yl)-3-(3-fluoro-5-netoxygen the laminitis)-[1,2,4]triazole-1-yl]butane-2-ol or
(S)-1-[3-(4-fluoro-3-methylphenylamine)-5-(2-methylpyridin-4-yl)-[1,2,4]triazole-1-yl]butane-2-ol,
including any stereoisomeric form, or a pharmaceutically acceptable additive salt, or MES.

6. The compound according to any one of claims 1 to 5 for use as a medicine.

7. The compound according to any one of claims 1 to 5 for use in the treatment or prevention of a disease or condition selected from mental disorders, decrease or violations of intellectual activity, inflammatory diseases or conditions.

8. The connection according to claim 6 for use in the treatment or prevention of a disease or condition selected from mental disorders, decrease or violations of intellectual activity, inflammatory diseases or conditions.

9. Pharmaceutical composition having the ability to enhance the efficacy of agonists alpha-nicotinic receptor containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 5.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns novel aryl pyrrolidines of formula I:

, where X, which can be identical or different, denote halogen, halogen-C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen-C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, OH, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl-amino, C1-6alkoxycarbonyl amino groups, halogen-C1-6alkoxycarbonylamino; Y, which can be identical or different, denote halogen, halogen- C1-6alkyl, NO2, C1-6alkyl, C1-6alkoxy, CN, halogen- C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl, halogen- C1-6alkylthio, halogen- C1-6alkylthionyl, halogen- C1-6alkylsulphonyl, hydroxyl groups, mercapto groups, NH2, C1-6alkylcarbonyl amino groups, halogen- C1-6alkylcarbonyl amino, C1-6alkoxycarbonyl amino groups, halogen- C1-6alkoxycarbonyl amino; R denotes halogen- C1-6alkyl; m equals 0, 1, 2, 3, 4, 5; n equals 1, 2, 3, 4; G denotes a group: , where R1 and R2 each independently denotes H, unsubstituted C1-6alkyl, halogen- C1-6alkyl, -CH2R7;R3, R4 each independently denotes H; I equals 1, 2, 3; R5 denotes H; R6 denotes C1-6alkylcarbonyl, a group: G6 - G8:

b where k3 equals 0; k4 equals 0; R7 denotes an unsubstituted 6-member heteroaryl with one N; A denotes C, N.

EFFECT: compounds exhibit insecticidal activity, which enables use thereof in insect and/or tick control method.

7 cl, 13 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel biaryl carboxyaryl amide derivatives of general formula , where: A is N; Z is a phenyl ring substituted with a group R selected from a halogen atom. The invention also relates to use of the compound of formula (I) and to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel biaryl carboxyaryl amide derivatives, which are useful as type 1 vanilloid receptor modulators, are obtained.

9 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,3-disubstituted indoles of general formula (I): , where the method involves the following steps: a) reaction of bromine diol (i): with dialkoxyborane in the presence of a ligand, a palladium catalyst, preferably selected from Pd(OAc)2, PdCl2, PdBr2, Pd2(dba)3, Pd2(dba)3.CHCl3, [Pd(ally)Cl]2,- Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, Pd/C and encapsulated Pd and a base to obtain a compound of general formula or, alternatively, reaction of compound (i) with a magnesium compound containing 3 alkyl groups, with subsequent treatment with a borate to obtain a compound of general formula ii given above; b) reaction of the product from step (a) with R2-Hal to obtain a compound of general formula I; where: R denotes (C1-C6)alkyl; R2 denotes: , , , , ,

, , , , ;

R3 denotes cyclopentyl: X denotes carboxymethyl; Hal denotes Br or I; or pharmaceutically acceptable salt thereof.

EFFECT: higher efficiency.

12 cl, 4 dwg, 2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered 5-substituted quinazolinone compounds having general structural formulas (II), (III) and (IV) or their pharmaceutically acceptable salts and stereomers. The radicals and symbols in the structural formulas presented below are designated as shown in the patent claim.

EFFECT: there are disclosed the methods for using and the pharmaceutical compositions of quinazolinone compounds.

16 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: in general formula 1 , a cyclic ring can be selectively formed; each of R1 and R2 is independently selected from a group consisting of hydrogen, with a straight or branched alkyl chain having 1-6 carbon atoms and phenetyl or R1 and R2 together form a 5- or 6-member heterocyclic ring or R1 and R2 together with Ar1 form a bicyclic ring; Ar1 is selected from a group consisting of furanyl, thionyl, methylene dioxyphenyl and phenyl, which can be substituted with at least one identical or different substitutes selected from a group consisting of hydrogen, with a straight or branched alkyl chain having 1-6 carbon atoms, a halogen such as F, O and Br, with a straight or branched alkoxy chain, having 1-6 carbon atoms, nitro and trifluoromethyl; Z is hydrogen or fluorine, or taken together with Ar1 forms a bicyclic ring; Ar2 is selected from a group consisting of phenyl, methylene dioxyphenyl, pyridine pyrimidine, naphthyl, bis(fluorophenyl)methyl and quinoxaline, which can be substituted with at least one identical or different substitutes selected from a group consisting of hydrogen, with a straight or branched alkyl chain, having 1-6 carbon atoms, hydroxy, halogen, with a straight or branched alkoxy chain having 1-6 carbon atoms, nitro, acetyl, tert-butyl acetate, trifluoromethyl, amino and acetate; n is equal to 1 or 2; m is an integer from 0 to 2.

EFFECT: improved method.

26 cl, 2 dwg, 2 tbl, 87 ex

FIELD: medicine.

SUBSTANCE: invention refers to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (formula I), pharmaceutical compositions and dosage forms containing these crystalline forms, as well as to methods for preparing such crystalline forms and methods for using them for treating, preventing a disease or a disorder associated with premature terminating codon. There are prepared new crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid which are non-absorbent and which can find application in medicine for treating or preventing such diseases or disorders as type III mucopolysaccharidosis, hemophilia A, hemophilia B, neurofibromatosis 1, neurofibromatosis 2, Parkinson's disease, cystic fibrosis, macular degeneration, cephalooculocutaneous telangiectasis, retinitis pigmentosa, tuberous sclerosis, Duchenne muscular dystrophy and Marfan's syndrome, cancer.

EFFECT: higher effectiveness of using the compounds and a method of treating.

46 cl, 11 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biochemistry and concerns an agent possessing neuroprotective action representing prostamide of formula (1) which can find application in medicine in therapy of ischemic cerebral damages and neurodegenerative diseases.

EFFECT: composition shows high efficacy.

16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to nicotinic acetylcholine receptor blocking biologically active peptides which can find application in biochemistry, biotechnology and medicine. The peptide azemyopsin has an amino acid sequence: H2N-Asp1-Asn2-Trp3-Trp4-Pro5-Lys6-Pro7-Pro8-His9-Gln10-Gly11 Pro12-Arg13-Pro14-Pro15-Arg16-Pro17-Arg18-Pro19-Lys20-Pro21-COX wherein X is a group OH or NH2, and has an ability to react selectively with nicotine muscarinic receptors. The peptide may be used an a base for preparing myorelaxants selectively blocking muscarinic receptors.

EFFECT: invention presents a new type of natural toxins reacting with nicotine receptors and containing no disulphide bonds.

2 cl, 5 dwg, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely psychiatry, and may be used for treating subacute reactive depressive psychosis. That is ensured by prescribing a drug-induced therapy consisting of Paroxetin in a double daily dose of 25-50 mg per os for 30 days. Diazepam 20-22 mg is intramuscularly introduced twice a day for 30 days. Mexidol in a daily dose 400-450 mg is introduced intravenously drop-by-drop for the first 20 days, and than 450-500 mg per os in tablets for the following 10 days. 0.01% Timogen 1.2-1.3 ml is introduced intramuscularly once a day for 10 days. The drug-induced therapy is combined with a hyperbaric oxygenation therapy with overpressure 0.8-1.0 atmospheres at compression rate and decompression 0.1 atmospheres a minute. An isopression period makes 40 minutes 2 times a day for the first 10 days, and then once a day for the following 10 days.

EFFECT: invention enables achieving a manifested clinical effect ensured by the use of the given therapeutic scheme.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds.

EFFECT: novel compounds can be used in medicine as antidepressant and antianxiety agents.

6 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds.

EFFECT: novel compounds can be used in medicine as antidepressant and antianxiety agents.

6 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and aims at treating Alzheimer's disease. What is used is S-adenosylmethionine (SAM) combined with superoxide dismutase (SOD). SAM and SOD may be applied either in a combination, or separately or sequentially.

EFFECT: group of inventions allows decreasing amyloid production in neuroblastoma cells and reducing an oxidation lever in cerebral tissues and erythrocytes.

5 cl, 3 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

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