Imidazo[1,2-b]pyridazine compounds (versions), method for preparing imidazo[1,2-b]pyridazine compounds (versions), pharmaceutical composition and drug preparation for treating and/or preventing diseases related to gaba receptor inhibition. RU patent 2486188.

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention provides new imidazo[1,2-b]pyridazine compounds covered by general structural formula (I) wherein the radicals and symbols have the values presented in the patent claim, and pharmaceutically acceptable salts thereof. The compounds of structural formula (I) are effective both for treating or preventing the diseases related to GABA receptor inhibition, anxiety, epilepsy, sleep disorders, including insomnia, and for inducing a sedative-hypnotic, anaesthetic effect, sleep and muscle relaxation.

EFFECT: there are presented methods for preparing the above compounds, and also intermediate compounds for preparing them.

21 cl, 4 tbl, 13 ex

The technical field to which the invention relates

The present invention relates to the agents with affinity to And GABA receptor, in particular compounds [1,2-b].

The level of technology

GABA A receptor (gamma-aminobutyric acid (A) is the protein that forms a membrane ion channel. GABA A receptor involved in the regulation of sedative effect, anxiety, muscle tone, activity epilepsy and memory functions. These effects are caused GABA A receptor, especially α 1 - and a 2-.

Sedative effect is modulated α 1-subunit. Zolpidem is characterized by a high affinity to α 2-receptors and its sedative pills and the modulated by these receptors in vivo. Similarly, somnifacient also indirectly α-1 receptors.

Neuroleptic action of diazepam mediated amplification GABA- migration in the population of neurons expressing α-2 receptors. This indicates that α 2-receptors are target for treatment of anxiety.

Miorelaxation, caused by diazepam, mainly mediated by the α 2-receptors, as the expression of these receptors is highly specific towards phosphates in the spinal cord.

Protivosudorozhny effect of diazepam partially mediated α-1 receptors. When taking diazepam, impaired memory, anterograde amnesia is mediated by the α-1 receptors.

GABA A receptor and its α 1 - and a 2-subunit have been described in detail Meller with employees (J. Pharmacol. Exp. Ther., 300, 2-8, 2002; Curr. Opin. Pharmacol., 22-25, 2001), Rudolf with employees (Nature, 401, 796-800, 1999) and with employees (Br. J. Psychiatry, 179, 390-396, 2001).

Diazepam and other classic benzodiazepines is used intensively as neuroleptics, tranquilizers, protivosudorozhnykh agents and miorelaksantov. Their side effects include amnesia, the weakening of motor activity and strengthening the effect of alcohol.

In this connection, proposed in the present invention are ligands α 1 - and a 2-GABA A receptor for the application of sleep disorders, primarily insomnia, anxiety and epilepsy. Insomnia is a common disease. The chronic form suffers 10% of the population and 30% short form. Insomnia is characterized by problems with falling asleep and waking and related to the lingering over the next day effects, such as fatigue, lack of energy, low concentration and irritability. Social significance of this disease and significant contribution to the health and leads to the obvious socio-economic consequences.

Treatment of insomnia drugs primarily includes barbiturates and hloralgidrat, but these drugs have many side effects, such as poisoning in overdose, induction of metabolism and the emergence of dependence and sustainability. In addition, they influence the structure of sleep by reducing the total duration and the number of stages of REM sleep. Later, benzodiazepines possess significant therapeutic advantage due to their low toxicity, but there is still a serious problem of addiction, myorelaxation, amnesia, and the resumption of insomnia after stopping treatment.

The newest famous therapeutic approach is the use of hypnotics nature, such as [3,4-b] (zopiclone), [1,2-a] () and pyrazolo[1,5-a]pyrimidines (). Later, they started the development of two new pyrazolo[1,5-a]pyrimidine, and , the latter has expressed neurotic action. All of these compounds cause a rapid fall asleep and have fewer effects observed in the course of the next day, less likely to misuse and reduced the risk of a resumption of insomnia is compared with benzodiazepines. Mechanism of action of these compounds is GABA receptor activation And after accession to the site linking benzodiazepine (C. F. P. Geroge, The Lancet, 358, 1623-1626, 2001). As benzodiazepines are non-specific ligand binding site of the GABA receptor , zolpidem and have greater selectivity to α 1-. Despite this, these drugs are still affect the structure of sleep and can be as addictive prolonged treatment.

Some N-[1,2-b]-3-yl- and N-[1,2-b]-3-yl- in which phenolic ring group can be replaced, were shown in the WO 89/01333.

Connection, presented in the present invention, structurally similar but differ detach N,N,6-trimethyl-2-R-[1,2-a]pyridine-3-, zolpidem, which is described in US 4382938, due to their superior properties, as shown in the section "making inventions".

The search for new active compounds for the treatment of insomnia meets the needs of health care because even recently issued antipsychotics affect the structure of sleep and can be as addictive prolonged treatment.

Therefore, it is desirable to focus on the development of new antipsychotic drugs with a lower risk for side effects.

Disclosure of the invention

The present invention relates to new connections [1,2-b] that are active in relation to the GABA And , particularly its α 1 - and a 2-subunits. Therefore, connection, presented in the present invention are effective for the treatment and prevention of all related diseases And GABA receptor, and C 1 - and a 2-. examples of such diseases are disorders of sleep, primarily insomnia, anxiety and epilepsy. examples of typical indications for compounds given in the present invention are all diseases or conditions such as insomnia or lack of sensitivity that require induction of sleep, sedation or miorelaxation.

Thus, in the present invention described a new class of compounds covered by the General structural formula (I):

and pharmaceutically acceptable salts, , hydrates, , and ,

where R 1-R 4 and Y defined below are of the GABA receptor ligands And .

On the other hand the present the invention provides methods for the synthesis of compounds covered by the General formula (I), some their intermediate products and intermediate products. A new method of treatment or prevention of diseases associated with modulation of the GABA receptors , such as anxiety, epilepsy and sleep disorders, including insomnia, and for the induction of sedative-neuroleptic, , hypnotic effect and miorelaxation by administering a therapeutically effective doses of these compounds also included in the scope of the present invention.

Realization of the invention

Present the invention relates to new connections [1,2-b] covered by the General structural formula (I):

where R 1 and R 2 independently selected from the group consisting of hydrogen,

linear or branched alkyl (C 1-C 6 ), (C 2 C 6 ), (C 2 C 6 ), cycloalkyl (With 3-C 6 ), (C 2 C 6 ), -O-alkyl (C 1-C 6 ), , -S-alkyl (C 1-C 6 ), , halogen, , , amino, (C 1-C 6 ), (C 1-C 6 ), pyrrolidinyl, , N-alkyl(C 1-C 6 )piperazinil, phenyl, optionally substituted from one to five groups and Z , optionally substituted one-to five-Z group; R3 and R4 independently selected from the group consisting of hydrogen, linear or branched alkyl (C 1-C 6 ), (C 2 C 6 ), (C 2 C 6 ), cycloalkyl (With 3-C 6 ), (C 1-C 6 ), amino, -NH-alkyl (C 1-C 6 ), -N-dialkyl (C 1-C 6 ), pyrrolidinyl, , , -N-alkyl(C 1-C 6 )piperazinil, phenyl, optionally substituted one-to five-Z groups, or both R 3 and R 4 may form together with the nitrogen atom to which they are attached, 5-6-membered ring heterocycle, optionally substituted one-to five-Z groups, provided that R 3 and R 4 are not simultaneously serve on hydrogen atoms; X is selected from CO and CO 2 ;

Z is selected from the group consisting of linear or branched alkyl (C 1-C 6 ), (C 2 C 6 ), (C 2 C 6 ), cycloalkyl (C 3-C 6 ), (C 2 C 6 ), , -O-alkyl (C 1-C 6 ), , -S-alkyl (C 1-C 6 ), , halogen, , , amino, (C 1-C 6 ), (C 1-C 6 ); and

their pharmaceutically acceptable salt, polymorphs, hydrates, , and stereoisomers.

Preferably, R 1 is selected from the group consisting of methyl-, chloro-, methyl-, -, - or 1-, a R 2 is a phenyl group or phenyl group, substituted in para-position bromide, halogen, by methoxy group, or .

Preferably, X is a; R 3 is selected from the group consisting of hydrogen, linear or branched alkyl (C 1-C 6 ), phenyl, optionally substituted one-to five-Z groups, amino, -NH-alkyl(C 1-C 6 ), -N-dialkyl (C 1-C 6 ), 1-pyrrolidinyl, 4-; and R 4 is selected from the group consisting of hydrogen, linear alkyl (C 1-C 6 ), phenyl, optionally substituted from one to five groups and Z , optionally substituted one-to five-Z groups; or both R 3 and R 4 may form together with the nitrogen atom to which they are attached, 5-6 - membered heterocycle, optional substituted one-to five-Z groups; and Z is selected from bromide and derivatives of the methoxy group.

The term "pharmaceutically acceptable salt" is used here to refer to any of the salts formed from organic and inorganic acids, such as , , phosphoric acid, nitric acid, sulfuric acid, acetic acid, adipic, aspartic acid, , benzoic acid, citric acid, , formic acid, fumaric, glutamic acid, lactic, maleic, malic acid, malonic, almond, , 1,5-, oxalic, , propionic, R-, amber, tartaric acid, and others.

Preferred connection covered by the General structural formula (I) include:

2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-N,N-diethyl-;

2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-N,N--;

N,N--2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6-chloro-2-p-tolyl-[1,2-b]-3-yl)-1-pyrrolidine-1-Il-;

N,N-diethyl-2-(6-pyrrolidine-1-Il-2-p-tolyl-[1,2-b]-3-yl)-;

N,N-diethyl-2-(6-methoxy-1-Il-2-p-tolyl-[1,2-b]-3-yl)-;

2-[2-(4-)-6--2-R--[1,2-b]-3-yl]-1-morpholine-4-yl-;

2-[2-(4-)-6--[1,2-b]-3-yl]-1-piperidine-1-yl-;

2-[2-(4-)-6--[1,2-b]-3-yl]-N,N--;

2-[2-(4-)-6--[1,2-b]-3-yl]-N,N--;

2-[2-(4-)-6--[1,2-b]-3-yl]-N,N-diethyl-;

2-[2-(4-)-6-methyl-[1,2-b]-3-yl]-1-morpholine-4-yl-;

2-[2-(4-)-6-methyl-[1,2-b]-3-yl]-1-morpholine-4-yl-;

2-[2-(4-)-6-methyl-[1,2-b]-3-yl]-N,N--;

2-[2-(4-)-6-methyl-[1,2-b]-3-yl]-N,N--;

2-[2-(4-)-6-methyl-[1,2-b]-3-yl]-N,N-diethyl-;

2-[2-(4-chlorophenyl)-6-methyl-[1,2-b]-3-yl]-N,N-diethyl-;

2-[2-(4-chlorophenyl)-6--[1,2-b]-3-yl]-N,N-diethyl-;

2-[2-(4-chlorophenyl)-6-methyl-[1,2-b]-3-yl]-N,N--;

N,N--2-[2-(4-chlorophenyl)-6-methyl-[1,2-b]-3-yl]-;

2-[2-(4-chlorophenyl)-6--[1,2-b]-3-yl]-N,N--;

N,N--2-[2-(4-chlorophenyl)-6--[1,2-b]-3-yl]-;

N,N-diethyl-2-(6-methoxy-2-phenyl-[1,2-b]-3-yl]-;

2-(6-methoxy-2-phenyl-[1,2-b]-3-yl)-N,N--;

N,N--2-(6--2-phenyl-[1,2-b]-3-yl)-;

2-(6-methoxy-2-phenyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6--2-phenyl-[1,2-b]-3-yl)-N,N-diethyl-;

2-(6--2-phenyl-[1,2-b]-3-yl)-N,N--;

N,N--2-(6--2-phenyl-[1,2-b]-3-yl)-;

2-(6--2-phenyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6--2-phenyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

N,N-diethyl-2-(6-methyl-2-phenyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-phenyl-[1,2-b]-3-yl)--;

N,N--2-(6-methyl-2--[1,2-b]-3-yl)-;

2-(6-methyl-2-phenyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6-methyl-2-phenyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

2-[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-N,N--;

N,N--2-[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-;

2-[2-(4-fluorophenyl)-6-methoxy-[1,2-b]-3-yl]-N,N--;

N,N--2-[2-(4-fluorophenyl)-6-methoxy-[1,2-b]-3-yl]-;

2-[6--2-(4-fluorophenyl)-[1,2-b]-3-yl]-N,N--;

N,N--2-[6--2-(4)-[1,2-b]-3-yl]-;

2-[6--2-(4-fluorophenyl)-[1,2-b]-3-yl]-1-morpholine-4-yl-;

N,N-diethyl-2-(6-methoxy-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methoxy-2-p-tolyl-[1,2-b]-3-yl)-N,N-diethyl-;

N,N--2-(6-methoxy-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methoxy-2-p-tolyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

2-(6--2-p-tolyl-[1,2-b]-3-yl)-N,N-diethyl-;

2-(6--2-p-tolyl-[1,2-b]-3-yl)-N,N--;

N,N--2-(6--2-p-tolyl-[1,2-b]-3-yl)-;

2-(6--2-p-tolyl-[1,2-b]-3-yl)-1-pyrrolidine-1-Il-;

2-(6--2-p-tolyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6--2-p-tolyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

N,N-diethyl-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N,N--;

N,N--2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-1-pyrrolidine-1-Il-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-1-morpholine-4-yl-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-1-piperidine-1-yl-;

N,N-diethyl-2-[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-;

2-[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-1-piperidine-1-Il-;

N,N-diethyl-2-[2-(4-fluorophenyl)-6-methoxy-[1,2-b]-3-yl]-;

2-[2-(4-fluorophenyl)-6--[1,2-b]-3-yl]-1-piperidine-1-yl-;

2-[6--2-(4-fluorophenyl)-[1,2-b]-3-yl]-N,N-diethyl-;

2-[6--2-(4-fluorophenyl)-[1,2-b]-3-yl]-1-piperidine-1-yl-;

2-[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-1-morpholine-4-yl-;

2-[2-(4-fluorophenyl)-6-methoxy-[1,2-b]-3-yl]-1-morpholine-4-yl-;

N,N-diethyl-2-[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-yl]-;

2-[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-yl]-N,N--;

N,N--2-[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-yl]-;

2-[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-yl]-1-piperidine-1-yl-;

2-[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-Il]-1-morpholine-4-yl-;

N,N-diethyl-2-[6-methoxy-2-(4-methoxyphenyl)-[1,2-b]-3-yl]-;

2-[6-methoxy-2-(4-methoxyphenyl)-[1,2-b]-3-yl]-N,N--;

N,N--2-[6-methoxy-2-(4-methoxyphenyl)-[1,2-b]-3-yl]-;

2-[6-methoxy-2-(4-methoxyphenyl)-[1,2-b]-3-yl]-1-piperidine-1-yl-;

2-[6-methoxy-2-(4-methoxyphenyl)-[1,2-b]-3-yl]-1-morpholine-4-yl-;

2-{[2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl]-acetyl-propyl-amino} and acetic acid;

1-(3,5-dimethyl-piperidine-1-yl)-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N--2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-propyl-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N--2-Il-;

N,N-aminobutiramida 2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N-cyclohexyl-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-phenyl-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-p-tolyl-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-pyridine-2-Il-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-pyridine-2-Il-methyl-;

N-(3,5-dimethyl-isoxazole-4-yl)-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N--2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N,N-diallyl-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N--2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N--2-Il-;

N-(5-methyl-isoxazole-3-yl)-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N-(4-methoxyphenyl)-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

N-(3-methyl-isoxazole-5-yl)-2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-[1,3,4]thiadiazole-2-Il-;

[2-(4-fluorophenyl)-6-pyrrolidine-1-Il-[1,2-b]-3-yl]-acetic acid hydrazide;

[2-(4-)-6-methyl-[1,2-b]-3-yl]-acetic acid hydrazide;

[2-(4-methoxyphenyl)-6-methyl-[1,2-b]-3-yl]-acetic acid hydrazide;

[2-(4-chlorophenyl)-6-methyl-[1,2-b]-3-yl]-acetic acid hydrazide;

[2-(4-fluorophenyl)-6-methyl-[1,2-b]-3-yl]-acetic acid hydrazide;

(6-methyl-2-phenyl-[1,2-b]-3-yl)-acetic acid hydrazide;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-morpholine-4-yl-;

2-(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-N-piperidine-1-yl-;

(6-methyl-2-p-tolyl-[1,2-b]-3-yl)-acetic acid N',N'-dimethyl hydrazide.

In accordance with another aspect of this invention provides a method of obtaining compounds covered by the General structural formula (I)and interim connections [1,2-b] covered by the General structural formula (II):

where R is a methyl -, R-1 - methyl, chlorine, methoxy, , or 1-pyrrolidinyl, a R 2 means phenyl or phenyl, substituted in para-position bromide, halogen, by methoxy group, or .

Compounds of General formula (I)when the X means WITH, can be obtained in accordance with the methodology of synthesis presented in figure 1.

From (III) the standard conditions for the reaction of compound can be obtained (IV). These (IV) can be in α-active position of the carbonyl group, owned by acetic acid to get (V). Finally, the cyclization of (VI) in acetonitrile at heating leads to the formation of (1, X=CO).

On the other hand, if R 3, R 4 optionally substituted amino groups, resulting molecule is not amide, and hydrazide. The scheme of synthesis must be slightly modified as proposed below (Diagram 2).

Etherification by Fisher method of the same (III), conducted with alcohol ROH allows you to get the appropriate ester (VII). This ester in the same conditions as for the Amidah (IV)above, to get (VIII). Cyclization with (VI) to get the (II)containing group. Finally, replacement with the participation of the substituted hydrazine in a suitable solvent when the heating leads to the formation of the respective hydrazides (1, X=CO, R 3, R 4 optionally substituted amino groups). Suitable solvents that can be used in this reaction, chosen preferably among linear or branched alkanols (C 1-C 6 ), it is more preferable to use methanol or containing mixtures.

Connection, proposed in the present invention, or pharmaceutically acceptable salt, polymorphs, hydrates, , and stereoisomers used for the preparation of a medicament for the treatment or prevention of diseases associated with modulation of the GABA receptor And humans or other mammals. More specifically, diseases associated with modulation of the GABA receptor And include diseases associated with modulation receptors α 1-GABA-A and/or α 2-And GABA . Experts in the given area is well known, what diseases are associated with modulation of the GABA receptor A (cf. Kaufmann W.A. et al., "Compartmentation of alpha 1 and alpha 2 GABAA receptor subunits within rat extended amygdala: implications for benzodiazepine action, Science 2003, vol.964 p.91-99; Mohler H. et al., "GABAA-receptor subtypes: a new pharmacology", Current Opinion in Pharmacology, 2001, vol.1:22-25). A non-limiting the list of such diseases include anxiety, epilepsy, sleep disorders, including insomnia and similar diseases.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for the treatment and prevention of anxiety in humans or other mammals.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for the treatment and prevention of epilepsy in humans or other mammals.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain medicines for treatment and prevention of sleep disorders in humans or other mammals.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for the treatment and prevention of insomnia in humans or other mammals.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for induction of sedative-neurotic effect in humans and mammals, if necessary.

In accordance with another embodiment, offered the use of compounds total formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for induction of anaesthetic effect in humans and mammals, if necessary.

In accordance with another embodiment, proposed use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs to modulate the time needed to fall asleep, and duration of sleep in humans and mammals in if necessary.

In accordance with another embodiment, offered the use of compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers to obtain drugs for induction miorelaxation in humans and mammals, if necessary.

The present invention also relates to a method of treatment or prevention in humans and other mammals diseases associated with modulation of the GABA receptors , which specified humans or other mammals if necessary, enter therapeutically effective amount compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers with a pharmaceutically acceptable solvents or carriers. More specifically, diseases associated with modulation of the GABA receptor And include diseases associated with changes in the receptor α 1-GABA-A and/or α 2-And GABA . Unlimited list of such diseases includes anxiety, epilepsy, sleep disorders, including insomnia and similar diseases.

The term "mammal" is used here to denote higher spinal animal class of Mammals. The term "mammals" includes, but is not limited to only man.

In accordance with another option for carrying out the invention the present invention relates to pharmaceutical compositions, including compounds of General formula (I) or pharmaceutically acceptable salts, polymorphs, hydrates, , and stereoisomers, together with therapeutically inert carrier.

These songs are suitable for receiving orally, rectally or parenteral (including subcutaneous, intramuscular and intravenous), although the most suitable method depends on the nature and severity of condition that should be treated. These songs can be easily presented in the form of single metered dosage forms and prepared using any of the methods described in the literature for the pharmaceutical industry.

Because of the simplicity of introduction into the organism tablets and capsules are most comfortable single dosage of oral dosage form of the drug, in this case, use solid pharmaceutical carriers. If desired, the tablets can be covered by a standard water or waterless methodology.

An acceptable interval dosage for use is approximately 0.01 mg about to 100.00 mg total daily dose given once a day for the reception or shares, if necessary, the dose. Connection, presented in the present invention towards α 1 - and a 2-GABA-A receptors. These results obtained in vitro coincide with the results obtained in vivo when conducting a sedative-neuroleptic research.

In accordance with the results obtained, for some compounds given in the present invention, was shown the pharmacological activity both in vitro and in vivo, which was the same or higher activity of the connection of the predecessor zolpidem. These results prove that the claimed compounds may be used in the treatment of diseases or conditions caused by α 1 - and a 2-GABA-A receptors, such as insomnia or loss of sensation, which requires induction of sleep, sedation or induction).

Pharmacological activity of the compounds given in the present invention was determined as described below.

a) Analysis of ligand binding. Determination of affinity of the studied compounds α 1 - and a 2-GABA A receptor

In the experiment were used rat line Sprague-Dawley weighing 200-250 g After animal selected cerebellum (cloth, mainly containing α 1-GABA A receptor) and the spinal cord (cloth, mainly containing α 2-GABA A receptor). Membranes were prepared in accordance with the methodology suggested by J.Lameh et al. (Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 24, 979-991, 2000) and .Noguchi et al. (Eur. J. Pharm., 434, 21-28, 2002) with slight modifications. After weighing fabric suspended in 50 mm Tris-HCl (pH 7.4), 1:40 (volume/volume), or 0.32 M sucrose when working with the spinal cord, homogenized and then centrifuged at 20000 g for 10 minutes at 7 degrees C. the Resulting sediment resuspended as described above and centrifuged. Precipitate is then resuspended in a minimum volume and stored at -80 OC for the night. Changes in methodology were working with the spinal cord at the first stage of centrifugation. Speed centrifugation was 1000 g, and selected , and no residue, as in the case of work with . Then was centrifuged at 20000 g and resuspended twice as described above for the cerebellum. The next day the procedure was repeated until the sediment not be diluted in the ratio 1:10 (volume/volume) for the cerebellum and the ratio 1:5 (volume/volume) for the spinal cord.

Affinity determined using the competitive analysis using radioactively labeled flumazenila as a ligand. Analysis was carried out in accordance with the method described S.Arbilla et al. (Eur. J. Pharmacol., 130, 257-263, 1986); and Y.Wu et al. (Eur. J. Pharmacol., 278, 125-132, 1995) 96-well plates tablets for . Incubated membrane containing studied receptors flumazenil (final concentration of radioactive label was 1 nm) and the connection in increasing concentrations (in total 230 mm at 50 mm [pH 7.4] Tris-HCl buffer). Simultaneously incubated with the membrane only marked with a radioactive label (General binding, 100%) and in the presence of flumazenila without a radioactive label in increasing concentrations (non-specific binding,%, determined by the ligand to a radioactive label). Reaction started addition of a ligand to a radioactive label and then incubated at 4 C for 60 minutes. At the end of the incubation period and 200 ul of the reaction mixture was transferred to the tablet for multiple screening (Millipore) and filtered using a vacuum collector and then washed three times cold buffer. Tablets for multiple screening supplied GF/B filters, which detained membrane containing receptors, and acceded to the receptor ligand with a radioactive label. After washing tablets left till the moment of drying. After drying, the added liquid scintillator and incubated at constant shaking during the night. The next day produced records of the results of using counter Perkin-Elmer Microbeta.

For the analysis of the results percentage of specific binding for each of the analyzed connection calculated by the following formula:

% specific binding = (X-N/T-N)*100

X - the amount of bound peroxidase ligand each concentration connection,

T - total linking, the maximum amount of bound peroxidase ligand with a radioactive label,

N - nonspecific binding, number of ligand with a radioactive label, nespecificski regardless of what receptor was used.

Each concentration of the compound was analyzed in three times and the average values were used to determine the experimental values % specific binding, depending on the concentration of the compound. Data on the affinity expressed in % inhibition at concentration of 10-5 M and 10-7 M The results are presented in Tables 1 and 2.

Affinity to α 1- GABA A receptor

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 17

Example 20

Example 22

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 24

Example 26

Example 40

Example 41

Example 42

Example 43

Example 65

Example 66

Example 67

Example 70

Example 71

Example 72

Example 73

Example 75

Example 77

Example 78

Example 80

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 81

Example 82

Example 83

Example 84

Example 86

Example 87

Example 88

Example 91

Example 93

Example 94

Example 100

Example 102

Example 105

Example 106

Affinity to α 2- GABA A receptor

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 17

Example 20

Example 22

Example 24

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 26

Example 40

Example 41

Example 42

Example 43

Example 65

Example 66

Example 67

Example 70

Example 71

Example 72

Example 73

Example 75

Example 77

Example 80

Example 83

Example 84

Connection

% inhibition of 10 -5 M

% inhibition of 10 -7 M

Example 86

Example 100

Example 102

b) the perceived sedative-neurotic activity in vivo

Activity compounds in vivo evaluated using predictive Analytics sedative-neurotic activity in experiments with mice (D.J.Sanger et al., Eur. J. Pharmacol., 313, 35-42, 1996; and G.Griebel et al., Psychopharmacology, 146. 205-213, 1999).

In the experiment we used a group of male mice line CD1 5-8 animals weighing 22-26, The compounds were injected at a concentration of 98 µmol/kg by injection. Compounds dissolved in the 0.25% agarose, for one group was made additive Tween concentration of 10 ml/kg of the Control animals were treated only media. Using the Smart System (Panlab, S.L. Spain) recorded the distribution of the drug in centimeters for each mouse with a five-minute intervals intervals within 30 minutes after a dose. Expected percentage of inhibition during distribution in mice receiving treatment compared with the control group of animals (first 5 minutes were dropped). Some compounds are also examined in smaller doses of 0,98 micrometers/kg to determine the possibility of the development of neurotic disorders. The results are presented in Tables 3 and 4.

The definition of a sedative-neurotic activity in mice when 98,0 µmol/kg

Connection

% inhibition of motor activity

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 17

Example 20

Connection

% inhibition of motor activity

Example 22

Example 24

Example 26

Example 40

Example 41

Example 42

Example 43

Example 65

Example 66

95.95 the

Example 67

Example 70

Example 71

Example 72

Example 73

Example 75

Example 77

Connection

% inhibition of motor activity

Example 78

Example 80

Example 81

Example 82

Example 83

Example 84

Example 86

Example 87

Example 88

Example 91

Example 93

Example 94

Example 100

Example 102

Example 105

Example 106

Definition sedative-neurotic activity in mice when 0,98 µmol/kg

Connection

% inhibition of motor activity

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 17

Example 22

Example 24

Connection

% inhibition of motor activity

Example 26

Example 41

15.73 vertical

C) specification of the anticipated anaesthetic activity in vivo

Activity compounds in vivo evaluated using predictive Analytics anaesthetic activity in experiments with mice to oppression installation reflex (Kralic et al., Neuropharmacology, 43 (4), 685-6892002; Accumulate et al., Neuropharmacology, 45, 57-71, 2003).

In the experiment we used a group of male mice line CD1 5-8 animals weighing 22-26, the compounds were injected at a concentration of 98 µmol/kg by injection. Compounds dissolved in the 0.25% agarose, for one group was made additive Tween concentration of 10 ml/kg. Expected percentage of mice treated connection, which happened oppression installation reflex.

It is interesting that the compound in Examples 2, 3 and 82 caused 90%, 100% and 30% of the animals oppression installation reflex respectively. In contrast, zolpidem, connection predecessor, has lower anesthetic effect, which causes the necessity to use a double dose compared with the compounds, proposed in the present invention to 80% of animals happened oppression installation reflex.

d) Comparative analysis

To show that connection, proposed in the present invention, greater than the known, particularly described in Annex PCT to WO 89/01333, calculated the value of the IC 50 for connections 22, 26, 88, 95, 96, 97 and 98 and compared with structurally close connections described in the Annex of the PCT, i.e. connections 317 and 318. All of these compounds are in the third position [1,2-b] ring . Other connections as described in the WO 89/01333, have no structural similarity with connections proposed in the present invention.

Values IC 50 were determined using the equation Cheng-Prusoff (Cheng Y.C. and Prusoff W.H.; Biochem. Pharmacol. 22, 3099-3108, 1973)

Ki is determined for each of the connections, proposed in the present invention, as described above (section (a)).

[RL*] is the concentration of the ligand, a radioactive label (1 nm).

Kd - constant affinity of (cerebellum 1,34 nm/spinal cord 1,19 nm).

Table 5 shows the values of the IC 50 obtained for compounds proposed in the present invention, as well as the values of IC 50 for connections, 317 and 318 of the PCT application KWO 89/01333:

Comparing values IC 50

Connection of the invention

Number example

IC 50 (nM)

Connection of WO 89/01333

As can be seen from the obtained results, IC 50 for connections proposed in the present invention, lower than the value of IC 50 for connections from WO 89/01333, that means that to achieve the same therapeutic effect require a lower dose of compounds according to the present invention.

The following examples are provided for illustration only and do not limit the scope of the claims stated in the present invention.

Example A: a Common way to obtain amides (IV)

To a solution of acid (III) (1 EQ.) in dichloromethane solution would flow of water-soluble carbodiimide (1,5 EQ.) in dihlormetane. The mixture was incubated for 30 minutes at room temperature, stirring constantly. After that, the solution was added to 0.5 EQ. 4-dimethylamino-pyridine and 1.5 EQ. the corresponding Amin and the mixture was incubated for 30 minutes, stirring constantly. Crude connection washed twice 1N HCl, organic layer is dried with the help of Na 2 SO 4 , filtered, and carried in vacuum (IV).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ 7,80-7,15 m, 4H, Ar), 3,30 (t, 4H, CH 2 (N), of 2.87 (t, 2H, CH 2 CO), 2,74 (t, 2H, H 2 CON), 1,58-0,93 (m, 14H, CH 2 CH 2 CH 3 ). MS (ES) m/z=308 (MH + )

HPLC =100%

Output =80%

Example: a Common way to obtain (V, X=CO)

To a solution of the compound (IV) (1 EQ.) in acetic acid was added dropwise solution of bromine (2,2 EQ.) acetic acid. The mixture was incubated at room temperature for 24 hours at constant stirring. Solvent selected in vacuo and the residue of the extract with a mixture of dichloromethane/1N NaOH and with a mixture of dichloromethane/water.

The organic layer was dried over Na 2 SO 4 and filtered, solvent selected in vacuo, thus received (V).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ of 7.97-7,23 (m, 4H, Ar), 5,20 (t, 2H, CHBr), 3,24 (t, 4H, CH 2 (N), of 2.87 (t, 2H, CH 2 CON), a 1.75-0,76 (m, 14H, CH 2 CH 2 CH 3 ).

MS (ES) m/z=380 (M), 382 (M + 2H)

HPLC =95%

Output =34%

Example: a Common way to obtain (I, X=CO)

To a solution of compound (V) (1 EQ.) in acetonitrile solution was added compounds (VI) (1,2 EQ.) in acetonitrile. The mixture was incubated for 2 hours at heating and stirring. Solvent selected in vacuo and the residue of the extract with a mixture of dichloromethane/1 N HCl and with a mixture of DMC/water. The organic layer was dried over Na 2 SO 4 and filtered, solvent selected in vacuo, thus received (1).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ 7,30-7.03 is (m, 6N, Ar), 3,48 (s, 2H, CH 2 ), 2,32 (s, 3H, CH 3 ), 3,21-0,96 (m, 18H, CH 2 CH 2 CH 2 CH 3 ).

MS (ES) m/z=397 (MH + )

HPLC =89%

Output =60%

Connection 1-98 were obtained by this method.

Example D: Common way of obtaining complex keto (VII)

1 H NMR (400 MHz, DMSO-d 6 ): δ 7,89-6,88 (m, 4H, Ar), to 3.75 (s, 3H, OCH 3 ), of 3.77 (s, 3H, OCH 3 ), 2,65 (t, 2H, CH 2 CO)by 2.25 (t, 2H, CH 2 COO).

MS (ES) m/z=223 (MH + )

HPLC =95%

Output =93%

Example F: a Common way to obtain (VIII)

To a solution of the compound (VII) in acetic acid dropwise solution of bromine (2,2 EQ.) acetic acid. The mixture was incubated at room temperature at constant stirring within 24 hours. Solvent selected in vacuo and the residue of the extract with a mixture of dichloromethane/NaOH 1 N with a mixture of dichloromethane/water. The organic layer was dried over Na 2 SO 4 and filtered, solvent selected in vacuo, thus gained the complex (VIII).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ of 7.98-PC 6.82 (m, 4H, Ar), 5,38 (t, 1H, CHBr), 3,98 (s, 3N, cos 3 ), 3,54 (s, 3N, OCH 3 ), 2,75 (t, 2H, CH 2 COO).

MS (ES) m/z=301 (M), 303 (M + 2H)

HPLC =95%

Output =35%

Example F: a Common way to obtain (II)

To a solution of compounds (VIII) (1 EQ.) in acetonitrile solution was added compounds (VI) (1,2 EQ.) in acetonitrile. The mixture was incubated for 2 hours at heating and stirring. Solvent selected in vacuo and the residue of the extract with a mixture of dichloromethane/1N HCl and with a mixture of dichloromethane/water. The organic layer was dried over Na 2 SO 4 and filtered, solvent selected in vacuo, thus received (II).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ 7,69-6,79 (m, 6N, Ar), to 3.75 (s, 3H, OCH 3 ), to 3.67 (s, 3H, OCH 3 ), 3,35 (s, 2H, CH 2 ), 2,17 (s, 3H, CH 3 ).

MS (ES) m/z=312 (M + )

HPLC =90%

Output =60%

Example G: General method of obtaining (I, X=CO, R 3, R 4 substituted amino groups)

To a solution of the compound (II) (1 EQ.) in methanol solution was added (substituted) hydrazine (5 EQ.) in methanol. The mixture was incubated for 24 hours at heating and stirring. Solvent selected in vacuo and the residue of the extract with a mixture of dichloromethane/1N HCl and with a mixture of dichloromethane/water. The organic layer was dried over Na 2 SO 4 and filtered, solvent selected in vacuo, thus received (I).

For example, for

1 H NMR (400 MHz, DMSO-d 6 ): δ 8,00 (bs, 1 H, NH), 7,50-6,93 (m, 6H, Ar), 3,78 (s, 3H, OCH 3 ), 3,96 (s, 3H, OCH 3 ), 3,28 (s, 2H, CH 2 ), 2,12 (bs, 2H, NH 2 ).

MS(ES) m/z=312 (MH + )

HPLC =93%

Output =65%

Connection 99-107 were also received by the above method.

Example song 1: 5 mg tablets

The active ingredient

Colloidal silicon dioxide

Croskar sodium

Magnesium stearate

Polysorbate 80

Hydroxypropylmethylcellulose

Polyethylene glycol 4000

Titanium dioxide E171

Microcrystalline cellulose to

Example 2 composition: capsules 10 mg

The active ingredient

Colloidal silicon dioxide

Crospovidone

Magnesium stearate

Sodium lauryl sulfate

Dioxide titanium E171

Indigotin 132

Microcrystalline cellulose to

An example of songs 3: oral drops

The active ingredient

Propylene glycol

Sodium saccharin

Polysorbate 80

Lemon flavor

Purified water to

An example of songs 4: tablets 2.5 mg

The active ingredient

Colloidal silicon dioxide

Croskar sodium

Magnesium stearate

Polysorbate 80

Hydroxypropyl methylcellulose

Polyethylene glycol 4000

Titanium dioxide E171

Microcrystalline cellulose to

An example of songs 5: 5 mg capsules

The active ingredient

Colloidal silicon dioxide

Crospovidone

Magnesium stearate

Sodium lauryl sulfate

Titanium dioxide E171

Indigotin 132

Microcrystalline cellulose to

An example of songs 6: oral drops

The active ingredient

Propylene glycol

Sodium saccharin

Polysorbate 80

Lemon flavor

Purified water to

1. Connection [1,2-b] covered by the General structural formula (I)

where R 1 is selected from the group consisting of linear or branched alkyl(1-6 ), -O-alkyl(1-6 ), 1-pyrrolidinyl, halogen; R 2 is a phenyl group or phenyl group substituted in para-position of the group Z; R3 and R4 independently selected from the group consisting of hydrogen, linear or branched alkyl(1-6 ), (2-6 ), (2-6 ), cycloalkyl(With 3-6 ), amino, -NH-alkyl(1-6 ), -N-dialkyl(1-6 ), pyrrolidinyl, , , pyridine-2-, CH 2 CH 2-O-C(O)-CH 3 CH 2 3 cycloalkyl, phenyl, optionally substituted (1-6), or-O-(1-6 ), and selected from the group , including thiazolyl, pyridinyl, , substituted one or two (1-6 ), and 1,3,4-, or both R 3 and R 4 may form together with the nitrogen atom to which they are attached, 5-6-membered heterocycle selected from the group , including pyrrolidinyl, , , optionally substituted two groups alkyl(1-6 ) provided that R 3 and R 4 cannot mean the hydrogen atom, pyridine-2-, CH 2 CH 2-O-C(O)-CH 3 CH 2 3 cycloalkyl; X means; Z is selected from the group consisting of linear or branched alkyl(1-6 ), -O-alkyl(1-6), and halogen, if one of the R 3 and 4 R is a pyridine-2-, other R 3 and R 4 represents hydrogen, R 1 is a 1 alkyl, R 2 is a phenyl group, substituted in para-position of the group Z, Z is a 1 alkyl, if one of the R 3 and R 4 is a CH 2 CH 2-O-C(O)-SN 3 , other R 3 and R 4 represents a linear 3-alkyl -, R-1 is a 1 alkyl, R 2 is a phenyl group, substituted in para-position of the group Z, Z is a 1 alkyl, if one of the R 3 and R 4 is a CH 2 3 cycloalkyl, other R 3 and 4 R it represents a linear 3-alkyl -, R-1 is a 1 alkyl, R 2 is a phenyl group, substituted in para-position of the group Z, Z is a 1 alkyl, or pharmaceutically acceptable salts.

2. Connection according to claim 1, where R 1 is selected from the group consisting of methyl chloride, , or 1-pyrrolidinyl, a R 2 is a phenyl group or phenyl group, substituted in para-position bromide, halogen, by methoxy group.

3. Connection according to claim 1, where X is a, R 3 is selected from the group consisting of hydrogen, linear alkyl(1-6 ), phenyl, optionally substituted (1-6), or-O-(1-6 ), selected from the group , including thiazolyl, pyridinyl, , substituted one or two (1-6 ), and 1,3,4-, amino, -NH-alkyl(C 1-6 ), -N-dialkyl(1-6 ), 1-pyrrolidinyl, 4- and 1-; R 4 is selected from the group consisting of hydrogen, linear alkyl(C 1-6 ), phenyl, optionally substituted (1-6), or-O-(1-6 ), , selected from the group , including thiazolyl, pyridinyl, , substituted one or two (1-6 ), and 1,3,4-, or both R 3 and R 4 may form together with the nitrogen atom to which they are attached, 5-6 membered heterocycle selected from the group , including pyrrolidinyl, , optional substituted two groups alkyl(1-6 ), provided that R 3 and R 4 cannot mean the hydrogen atom.