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

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 agents that have affinity to the GABAAndthe receptor, in particular the compounds of imidazo[1,2-b]pyridazine.

The level of technology

GABAAndreceptor (γ-aminobutyric acid (A) is pentamers protein, which forms a membrane ion channel. GABAAndthe receptor involved in the regulation of sedation, anxiety, muscle tone, activity epilepsy and memory functions. These effects are caused by the subunits GABAAndreceptor, especially α1and α2-subunits.

Sedative effect is modulated α1-subunit. Zolpidem is characterized by high affinity to α2-receptors and sedative and hypnotic effect is modulated by these receptors in vivo. Similarly, widespread effects of zaleplon also mediated α1-receptors.

Neuroleptic effects of diazepam is mediated by increased GABA-ergicheskoe migration in a population of neurons expressing α2-receptors. This indicates that α2receptors are highly specific target for the treatment of anxiety.

Myorelaxation caused by diazepam, mainly mediated by α2receptors, because the expression of these receptors in vsokospecificno in the spinal cord.

1-receptors. When receiving diazepam, worsening memory, anterograde amnesia mediated α1-receptors.

GABAAndreceptor and α1and α2-subunit have been described in detail Meller with employees (J. Pharmacol. Exp. Ther., 300, 2-8, 2002; Curr. Opin. Pharmacol., 22-25, 2001), Rudolf employees (Nature, 401, 796-800, 1999) and Nottom with employees (Br. J. Psychiatry, 179, 390-396, 2001).

Diazepam and other classical benzodiazepines are intensively used as antipsychotic, hypnotic, anticonvulsant agents, and muscle relaxants. Their side effects include anterograde amnesia, the weakening of locomotor activity and enhanced activity of alcohol.

In this context, the compounds proposed in the present invention are ligands α1and α2-GABAAndreceptor for use in sleep disorders, primarily insomnia, anxiety and epilepsy. Insomnia is a common disease. The chronic form suffers 10% of the population and 30% of the short form. Insomnia is characterized by problems with falling asleep and awakening, and is associated with persisting into the next day effects such as fatigue, lack of strength, poor concentration and irritability. The social significance of this disease and contribute to significant health and prevadid obvious socio-economic consequences.

Treatment of insomnia drugs primarily includes barbiturates and chloral hydrate, but these medications have numerous side effects, such as poisoning, overdose, induction of metabolism and the appearance of dependence and sustainability. In addition, they affect the structure of sleep by reducing the total duration and the number of stages of REM sleep. Later, benzodiazepines began to have a significant therapeutic advantage because of their low toxicity, but there is still a serious problem of addiction, myorelaxation, amnesia and resume insomnia after stopping treatment.

The latest known therapeutic approach is the use of pills dibenzodiazepine nature, such as pyrrolo[3,4-b]pyrazine (zopiclone), imidazo[1,2-a]pyridine (zolpidem) and pyrazolo[1,5-a]pyrimidines (zaleplon). Later started the development of two new pyrazolo[1,5-a]pyrimidine, indiplon and ocinaplon, the latter has a strong neuroleptic action. All these compounds cause fast asleep and have fewer effects observed in the course of the next day, they are less likely to misuse and reduced the risk of a relapse of insomnia compared with benzodiazepines. The mechanism of action of these compounds lies what is in allosterically activation of GABA receptors Andby joining the binding site of the benzodiazepine (C. F. P. George, The Lancet, 358, 1623-1626, 2001). Because benzodiazepines are non-specific ligands binding site of the receptor GABAAnd, zolpidem and zaleplon have greater selectivity for α1the subunit. Despite this, these drugs still affect the structure of sleep and can cause addiction in long-term care.

Some N-imidazo[1,2-b]pyridazin-3-yl-methylalanine and N-imidazo[1,2-b]pyridazin-3-yl-methylbenzamide, in which the phenolic ring benzamide group may be substituted, have been shown in WO 89/01333.

The compounds presented in this invention, structurally related, but differ detach N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3-acetamide", she zolpidem, which is described in US 4382938, due to their superior properties, as shown in the section "implementation of the invention".

The search for new active compounds for the treatment of insomnia meets the needs of health care because even the recently released neuroleptics affect the structure of sleep and can cause addiction in long-term care.

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

Disclosure of inventions

The present invention relates to but is haunted by the compounds of imidazo[1,2-b]pyridazine, which is active with respect to GABAAndespecially to its α1and α2-subunits. Therefore, the compounds presented in this invention is effective for the treatment and prevention of all diseases related to GABAAndreceptor and α1and α2-subunits. Non-limiting examples of such diseases are sleep disorders, primarily insomnia, anxiety and epilepsy. Non-limiting examples of the characteristic indications for the compounds presented in this invention, are all diseases or conditions, such as insomnia or lack of sensitivity, requiring the induction of sleep, sedation or myorelaxation.

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

and their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers,

where R1-R4and Y, defined below, are ligands of the receptor for GABAAnd.

On the other hand, the present invention provides methods of synthesis of compounds covered by the General formula (I), some of their intermediate products, as well as intermediate products. New ways of treating or preventing diseases associated with module what their receptors GABA Andsuch as anxiety, epilepsy and sleep disorders, including insomnia, and for inducing sedative neuroleptic, anesthetic, hypnotic effect and myorelaxation using the introduction of therapeutically effective doses of these compounds are also included within the scope of the present invention.

The implementation of the invention

The present invention relates to new compounds of imidazo[1,2-b]pyridazine covered by the General structural formula (I):

where R1and R2independently selected from the group comprising hydrogen,

linear or branched alkyl (C1-C6), alkenyl (C2-C6), quinil (C2-C6), cycloalkyl (C3-C6), halogenated (C2-C6), -O-alkyl (C1-C6), fenoxaprop, -S-alkyl (C1-C6), phenylthiourea, halogen, the nitro-group, a cyano, an amino group, alkylamino (C1-C6), dialkylamino (C1-C6), pyrrolidinyl, morpholinyl, N-alkyl(C1-C6)piperazinil, phenyl, optionally substituted by one to five Z groups and heteroaryl, optionally substituted by one to five Z groups; R3and R4independently selected from the group comprising hydrogen, linear or branched alkyl (C1-C6), alkenyl (C2-C6), quinil (C2-C 6), cycloalkyl (C3-C6), hydroxyalkyl (C1-C6), an amino group, -NH-alkyl (C1-C6), -N-dialkyl (C1-C6), pyrrolidinyl, morpholinyl, piperidinyl, -N-alkyl(C1-C6)piperazinil, phenyl, optionally substituted by one to five Z groups, or both R3and R4may form together with the nitrogen atom to which they are attached, 5-6-membered heterocycle, optionally substituted with one to five Z groups, provided that R3and R4are not simultaneously be hydrogen atoms; X is selected from CO and CO2;

Z is selected from the group including linear or branched alkyl (C1-C6), alkenyl (C2-C6), quinil (C2-C6), cycloalkyl (C3-C6), halogenated (C2-C6), a hydroxy-group, -O-alkyl (C1-C6), fenoxaprop, -S-alkyl (C1-C6), phenylthiourea, halogen, the nitro-group, a cyano, an amino group, alkylamino (C1-C6), dialkylamino (C1-C6); and

their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers.

Preferably, R1selected from the group including methyl-, chlorine-, methoxy-, ethoxy, phenylthio - or 1-pyrrolidinium, a R2represents a phenyl group or a phenyl group substituted in the para-p is the situation of the stands, halogen, a methoxy group, a nitro-group or trifluoromethyl.

Preferably, X represents CO; R3selected from the group comprising hydrogen, linear or branched alkyl (C1-C6), phenyl, optionally substituted by one to five Z groups, the amino group, -NH-alkyl(C1-C6), -N-dialkyl (C1-C6), 1-pyrrolidinyl, 4-morpholinyl; and R4selected from the group comprising hydrogen, linear alkyl (C1-C6), phenyl, optionally substituted by one to five Z groups and heteroaryl, optionally substituted by one to five Z groups; or both R3and R4may form together with the nitrogen atom to which they are attached, 5-6 - membered heterocycle, optionally substituted with one to five Z groups; and Z is selected from methyl and metoxygroup.

The term "pharmaceutically acceptable salt" is used here to denote any salts formed from organic and inorganic acids, such as Hydrobromic, chloromethane, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, Benzenesulfonic, benzoic, citric, econsultancy, formic, fumaric, glutamic, lactic, maleic, malic, malonic, almond, methansulfonate, 1,5-naphthalenedisulfonate, oxalic acid, trimethylarsine, propionic, R-toluensulfonate, amber, the other acid, and others.

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

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

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

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

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

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

2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;

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

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

2-[2-(4-bromophenyl)-6-ethoxy-2-p-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;

2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;

2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutil-ndimethylacetamide;

2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;

2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;

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

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

2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutil-ndimethylacetamide;

2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-is ypropyl-ndimethylacetamide;

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

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

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

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

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

2-[2-(4-chlorophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-[2-(4-chlorophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;

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

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

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

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

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

2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;

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

2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;

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

2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-dipropyl-acetamide;

N,N-dibutil-2-(6-methyl-2-fennel-imidazo[1,2-b]p is ridazin-3-yl)-ndimethylacetamide;

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

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

2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;

2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;

2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-[6-ethoxy-2-(forfinal)-imidazo[1,2-b]pyridazin-3-yl]-acetone;

2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;

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

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

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

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

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

2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;

N,N-dibutil-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;

2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;

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

2-(6-ethoxy-2-R-is oil-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;

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

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

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

2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;

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

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

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

2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;

N,N-diethyl-2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;

2-[2-(4-forfinal)-6-metoxy-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;

2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;

2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-athinon;

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

2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;

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

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

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

2-[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-Pipa is one-1-yl-Etalon;

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

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

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

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

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

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

Ester

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

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

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

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

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

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

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

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

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

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

N-(3,5-dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]peridas the n-3-yl)-ndimethylacetamide;

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

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

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

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

N-(5-methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;

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

N-(3-methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;

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

[2-(4-forfinal)-6-pyrrolidin-1-yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;

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

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

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

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

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

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

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

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

<> In accordance with another aspect of the present invention, it is proposed a method of obtaining compounds covered by the General structural formula (I), and intermediates of imidazo[1,2-b]pyridazine covered by the General structural formula (II):

where R represents methyl, R1is methyl, chlorine, methoxy, ethoxy, thiophenoxy or 1-pyrrolidinyl, a R2means phenyl or phenyl substituted in the para-position of the stands, a halogen, a methoxy group, a nitro-group or trifluoromethyl.

Compounds of General formula (I), when X is CO, can be obtained in accordance with the synthesis technique presented in figure 1.

Figure 1

From ketoacids (III) the standard conditions for the reaction of the compound can be obtained ketoamide (IV). These ketoamide (IV) can be bronirovat in α-position with an active carbonyl group, owned by acetic acid, to obtain bracketology (V). Finally, cyclization of aminopyridazine (VI) in acetonitrile under heating leads to the formation of imidazopyridines (1, X=CO).

On the other hand, if R3or R4optional substituted amino groups, the resulting molecule is not amidon, and hydrazide. The scheme of synthesis must be slightly modified, as proposed below (Scheme 2).

Scheme 2

The esterification according to the method of Fischer same ketoacid (III), conducted with alcohol ROH allows to obtain the corresponding ester (VII). This ester pomeroys in the same conditions as for the amide (IV)described above, to obtain bracketeer (VIII). Cyclization with aminopyridazine (VI) to receive imidazopyridine (II)containing an ester group. Finally, the acyl substitution involving substituted hydrazine in a suitable solvent under heating leads to the formation of the corresponding hydrazides (1, X=CO, R3or R4optional substituted amino groups). Suitable solvents that can be used in this reaction, preferably selected among linear or branched alkanols (C1-C6), it is preferable to use methanol or containing mixtures.

Connections proposed in the present invention, or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers can be used to prepare a medicinal product for the treatment or prevention of diseases associated with modulation of receptor GABAAndin humans or other mammals. More specifically, diseases associated with modulation of receptor GABAAndinclude diseases associated with modulation Rotz is tori α 1-GABAAndand/or α2-GABAAnd. Specialists in this field is well known, what diseases associated with modulation of receptor GABAAnd(cf. Kaufmann, W.A. et al., "Compartmentation of alpha 1 and alpha 2 GABAA receptor subunits within the 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 list of such diseases include anxiety, epilepsy, sleep disorders, including insomnia and similar diseases.

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

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

In accordance with another embodiment of the invention, it is proposed the use of compounds of General formula (I) or their pharmaceutically acceptable salts, Paul the morphs, hydrates, tautomers, solvate or stereoisomer to obtain drugs for the treatment and prevention of sleep disorders in humans or other mammals.

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

In accordance with another embodiment of the invention, it is proposed the use of compounds of General formula (I) or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate or stereoisomer to obtain drugs for the induction of sedative neuroleptic effect in humans and mammals, if necessary.

In accordance with another embodiment of the invention, it is proposed the use of compounds of General formula (I) or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate or stereoisomer to obtain drugs for the induction of an anesthetic effect in humans and mammals, if necessary.

In accordance with another embodiment of the invention, it is proposed the use of the joining of General formula (I) or their pharmaceutically acceptable salts, of polymorphs, hydrates, tautomers, solvate or stereoisomer to obtain drugs to modulate the time required for sleep and duration of sleep in humans and mammals, if necessary.

In accordance with another embodiment of the invention, it is proposed the use of compounds of General formula (I) or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate or stereoisomer to obtain drugs for the induction of myorelaxation in humans and mammals, if necessary.

The present invention also relates to a method of treatment or prevention in humans and other mammalian diseases associated with modulation of receptor GABAAndin which these people or other mammals when necessary is administered a therapeutically effective amount of compounds of General formula (I) or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate or stereoisomer with pharmaceutically acceptable diluents or carriers. More specifically, diseases associated with modulation of receptor GABAAndinclude diseases associated with changes in receptor α1-GABAAndand/or α2-GABAAnd. Unlimited list of such diseases is the BOJ anxiety, epilepsy, sleep disorders, including insomnia and similar diseases.

The term "mammal" is used here to denote the higher vertebrate animal of the class of Mammals. The term "mammal" includes, but is not limited to only human.

In accordance with another embodiment of the invention the present invention relates to pharmaceutical compositions comprising compounds of General formula (I) or their pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvate and stereoisomers, in conjunction with a therapeutically inert carrier.

These compositions are suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous), although the most suitable method depends on the nature and severity of the condition that should be treated. These compositions can be presented in unit dosage form and prepared by any of the methods described in the literature on pharmaceutical science.

The active compound can be mixed with a pharmaceutical carrier according to conventional pharmaceutical methods of mixing. The media can be a number of forms depending on the form of preparation desired for introduction into an organism, for example, oral or parenteral (including the Isla intravenous injection or infusion). In the preparation of compositions for oral administration can be used any pharmaceutical environment. Traditional pharmaceutical environment include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and other in the case of cooking liquid form for oral use (for example, suspensions, solutions, emulsions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, solvent, granulating agents, moving components, binding agents, dezintegriruetsja agents and others in the case of preparation of solid preparations for oral administration (such as, for example, powders, capsules and tablets), with the solid oral preparations are preferable to liquid oral drugs.

Due to the simple ingestion of tablets and capsules represent the most convenient unit dosage form oral drug, used in this case solid pharmaceutical carriers. If desired, tablets may be coated by standard aqueous or anhydrous method.

An acceptable interval of dosage for use is from about 0.01 mg to about 100,00 mg total daily dose given once a day to receive shares or, if necessary, on the dose. The connection made is certain in this invention, Vysocany with respect to α1and α2-GABAAndthe receptors. These results obtained in vitro are consistent with results obtained in vivo when conducting sedative neuroleptic research.

In accordance with the obtained results, for some of the compounds presented in this invention, has been shown pharmacological activity both in vitro and in vivo, which was equal or higher than the activity of the compounds of the predecessor zolpidem. All these results indicate that the claimed compounds can be used in the treatment of diseases or conditions caused by α1and α2-GABAAndreceptors, such as insomnia or loss of sensitivity, which requires the induction of sleep, sedation or induction of myorelaxation.

The pharmacological activity of the compounds presented in this invention was determined as described below.

a) Analysis of binding ligands. Determination of affinity of these compounds to α1and α2-GABAAndreceptor

In the experiment used rats line Sprague-Dawley weighing 200-250 g After decapitate animal were taken and cerebellum (fabric, mainly containing α1-GABAAndreceptor) and spinal cord (fabric, mainly containing α2-GABAAndthe receptor). The membrane is hotovely in accordance with the methodology proposed 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 the tissue suspended in 50 mm Tris-HCl (pH 7.4), 1:40 (vol/vol), or of 0.32 M sucrose when working with the spinal cord, homogenized and then centrifuged at 20000 g for 10 minutes at 7°C. the Formed precipitate resuspendable as described above and centrifuged. The precipitate is then resuspendable a minimum and kept at -80°C over night. The change in methodology was related to the work with the spinal cord at the first stage centrifugation. Speed centrifugation was 1000 g, and the supernatant was collected, and not the sediment, as in the case of the cerebellum. Then the supernatant was centrifuged at 20000 g and resuspendable twice as described above for the cerebellum. The next day the procedure was repeated up until the precipitate did not dissolve in the ratio of 1:10 (volume/volume) for cerebellum and in the ratio of 1:5 (volume/volume) to the spinal cord.

The affinity was determined by using a competitive analysis using radioactively labeled flumazenil as a ligand. The 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) on 96-well tablets for micrometrology. Incubated the membrane containing the target recipe is ture, flumazenil (final concentration of radioactive label was 1 nm) and analyzed the connection in increasing concentrations (total volume of 230 μl of 50 mm [pH 7.4] Tris-HCl buffer). Simultaneously incubated membrane only labeled with a radioactive label by flumazenil (total binding, 100%) and in the presence of flumazenil without radioactive label in increasing concentrations (nonspecific binding, % determined by the ligand with a radioactive label). The reaction was started by addition of a ligand with a radioactive label and then incubated at 4°C for 60 minutes. At the end of the incubation period, 200 μl of the reaction mixture was transferred to a tablet for multiple screening (Millipore) and filtered using a vacuum manifold and then washed three times with cold buffer. Tablets for multiple screening supplied GF/B filters, which were detained membranes containing receptors and joined the receptor ligand with a radioactive label. After washing tablets left until dry. After drying were added to scintillation fluid and incubated with constant shaking overnight. The next day was counting results by means of a counter Perkin-Elmer Microbeta.

For analysis of results the percentage of specific binding for each concentration of the analyzed compounds is podschitivala by the following formula:

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

where

X - the amount of bound peroxidase ligand for each concentration of the compound,

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

N - non-specific binding amount of the ligand with a radioactive label, who contacted nonspecific regardless of which receptor was used.

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

Table 1
The affinity for α1the subunit of the GABAAndreceptor
Connection% inhibition of 10-5M% inhibition of 10-7M
Example 1100,1of 98.2
Example 2100,399,6
P the emer 3 100,299,4
Example 499,998,3
Example 5100,397,5
Example 6100,097,4
Example 996,811,4
Example 10of 99.139,3
Example 1196,022,0
Example 1296,934,6
Example 1399,758,3
Example 1499,580,6
Example 1799,5to 97.1
Example 2099,673,7
Example 22100,097,6
Example 23 of 99.161,7

Connection% inhibition of 10-5M% inhibition of 10-7M
Example 2498,457,7
Example 26100,073,5
Example 35100,297,5
Example 40100,398,0
Example 4199,875,4
Example 4299,762,2
Example 4399,5to 49.9
Example 6599,558,5
Example 6698,350,4
Example 67the 98.942,2
Example 709,9 84,5
Example 71100,295,0
Example 72to 100.491,5
Example 7399,976,5
Example 7599,452,1
Example 77100,142,2
Example 7898,326,5
Example 8099,7to 85.2

Connection% inhibition of 10-5M% inhibition of 10-7M
Example 81100,198,5
Example 82100,199,2
Example 8399,697,6
Example 84100,0 91,7
Example 8699,575,9
Example 8799,357,2
Example 88100,283,9
Example 91of 99.145,8
Example 93100,078,2
Example 94100,165,1
Example 10099,562,4
Example 102of 99.166,7
Example 10598,856,0
Example 10699,553,7
Zolpidem99,473,6

Table 2
The affinity for α2-subunit of the GABA Andreceptor
Connection% inhibition of 10-5M% inhibition of 10-7M
Example 194,349,0
Example 298,666,1
Example 3for 91.360,8
Example 497,653,2
Example 597,745,0
Example 697,549,4
Example 961,75,9
Example 1072,019,1
Example 1147,01,7
Example 1271,92,2
Example 1376,715,5
Example 14 76,910,8
Example 1783,036,8
Example 2082,020,8
Example 2286,661,2
Example 2380,00,0
Example 2477,413,6

Connection% inhibition of 10-5M% inhibition of 10-7M
Example 2684,527,4
Example 3592,557,9
Example 4091,560,7
Example 4185,3of 17.0
Example 4279,416,3
Example 43 80,320,1
Example 6578,516,3
Example 6679,47,8
Example 6783,78,8
Example 7080,323,6
Example 7188,550,6
Example 7285,651,7
Example 7377,020,6
Example 7568,89,3
Example 77of 83.423,6
Example 8084,337,0
Example 83br93.157,7
Example 8463,93,1

Connection% inhibition of 10-5M% inhibition of 10-7M
Example 8680,923,0
Example 10073,02,3
Example 10277,913,7
Zolpidem74,1to 19.9

b) Determining the intended sedative neuroleptic activity in vivo

Activity of compounds in vivo was assessed using predictive analysis sedative neuroleptic 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).

The experiment used a group of male mice of CD1 5-8 animals weighing 22-26, the compounds were injected at a concentration of 98 mol/kg by intraperitoneal injection. Compounds were dissolved in 0.25% of agarose, for one group was made by the addition of Twin concentration of 10 ml/kg Control animals were injected only media. Using the Smart System (Panlab, S.L., Spain) recorded the distribution of the drug in centimeters for each mouse at five-minute intervals for 30 minutes after the introduction of the eskers. Expected percentage of inhibition of the propagation time in mice treated compared to control animals (first 5 minutes were discarded). Some compounds were also investigated in smaller doses - of 0.98 μm/kg to identify opportunities for the development of neurotic disorders. The results are presented in Tables 3 and 4.

Table 3
The definition of sedative neuroleptic activity in mice when 98,0 mol/kg
Connection% inhibition of motor activity
Example 194,66
Example 2low of 96,71
Example 390,94
Example 494,65
Example 593,65
Example 696,86
Example 993,85
Example 1093,47
Example 1179,82
Example 1283,44
Example 1392,08
Example 1495,56
Example 1793,08
Example 2091,51

td align="center"> Example 67
Connection% inhibition of motor activity
Example 22of 87, 97
Example 2391,74
Example 2486,54
Example 2691,55
Example 3580,60
Example 4091,79
Example 4191,18
Example 4291,01
Example 4395,72
Example 6595,46
Example 6695,95
90,81
Example 7086,98
Example 7195,96
Example 7293,35
Example 7394,07
Example 7592,56
Example 7789,35

Connection% inhibition of motor activity
Example 7891,14
Example 8094,41
Example 8190,83
Example 8294,22
Example 8388,93
Example 8490,78
Example 8692,62
Example 8790,70
Example 8888,51
Por the measures 91 93,05
Example 9393,20
Example 9493,49
Example 10093,71
Example 10285,50
Example 10594,02
Example 10694,05
Zolpidem91,70

Table 4
The definition of sedative neuroleptic activity in mice when 0,98 mol/kg
Connection% inhibition of motor activity
Example 127,56
Example 238,39
Example 314,61
Example 438,38
Example 541,15
Example 6better than anticipated at 51.90
Example 919,94
Example 1029,54
Example 1115,29
Example 1215,05
Example 1315,11
Example 144,77
Example 17to 9.91
Example 2222,21
Example 2312,37
Example 24the 3.65

Connection% inhibition of motor activity
Example 2619,19
Example 356,76
Example 4115,73
Zolpidem18,30

(C) Determining the proposed anaesthetic activity in vivo

Activity of compounds in vivo was assessed using predictive analysis of the anaesthetic aktivnosti experiments with mice oppression installation reflex (Kralic et al., Neuropharmacology, 43 (4), 685-6892002; Accumulate et al., Neuropharmacology, 45, 57-71, 2003).

The experiment used a group of male mice of CD1 5-8 animals weighing 22-26, the compounds were injected at a concentration of 98 mol/kg by intraperitoneal injection. Compounds were dissolved in 0.25% of agarose, for one group was made by the addition of Twin concentration of 10 ml/kg was Calculated the percentage of mice treated with the compound, which occurred oppression installation of reflex.

Interestingly, the compounds according to Examples 2, 3 and 82 caused 90%, 100% and 30% of the animals oppression installation of reflex, respectively. In contrast, zolpidem, connection predecessor, has a lower anesthetic action that leads to the necessity to introduce a double dose compared with the compounds described in this invention, in order to have 80% of the animals occurred oppression installation of reflex.

d) Comparative analysis

To show that the compounds proposed in the present invention, superior known particularly described in the application PCT to WO 89/01333, calculated IC value50for connections 22, 26, 88, 95, 96, 97 and 98 and compared with structurally similar compounds described in the application PCT, i.e. compounds 317 and 318. All these compounds are in the third position imidazo[1,2-b]pyridazinone ring acetone is. Other compounds described in WO 89/01333, have no structural similarity to the compounds proposed in the present invention.

The values of the IC50were determined using the equation of Cheng-Prusoff (Cheng Y.C. and W.H. Prusoff; Biochem. Pharmacol. 22, 3099-3108, 1973)

Ki=IC501+[RL*]Kd

where

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

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

Kd is the affinity constant (cerebellum of 1.34 nm/spinal cord 1,19 nm).

Table 5 presents the values of the IC50obtained for the compounds proposed in the present invention, as well as the IC50for connections 317 and 318 of application PCT KWO 89/01333:

Table 5
Comparing values IC50
Compounds of the invention
Number exampleIC50(nM)
22 17,2
8813
9517,1
9714,6
9812,2
Compounds of WO 89/01333
31755
318474

As can be seen from the obtained results, the IC50for connections proposed in the present invention, is lower than the value of the IC50for compounds of WO 89/01333, which means that to achieve the same therapeutic effect required a lower dose of the compounds of the present invention.

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

Example: a General method for obtaining amides (IV)

To a solution of acid (III) (1 EQ.) in dichloromethane was added a solution of water-soluble carbodiimide (1.5 EQ.) in dichloromethane. The mixture is incubated for 30 minutes at room temperature with constant stirring. After this solution was added 0.5 EQ. 4-dimethylamino-pyridine and 1.5 EQ. the appropriate amine and the mixture is incubated for 30 minutes prepostional stirring. The crude compound was washed twice 1N HCl, the organic layer was dried using Na2SO4was filtered and transferred into vacuum (IV).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,80-to 7.15 (m, 4H, Ar), 3,30 (t, 4H, CH2N), 2,87 (t, 2H, CH2CO)to 2.74 (t, 2H, H2CON), 1,58 with 0.93 (m, 14H, CH2CH2CH3). MS (ES) m/z=308 (MH+)

HPLC =100%

Yield =80%

Example: a Common way of obtaining bromamide (V, X=CO)

To a solution of the compound (IV) (1 EQ.) in acetic acid was added dropwise a solution of bromine (2.2 EQ.) in acetic acid. The mixture is incubated at room temperature for 24 hours under constant stirring. The solvent was collected in vacuo and the residue was extracted using a mixture of dichloromethane/1N NaOH and using a mixture of dichloromethane/water.

The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, thus received bracketology (V).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,97-of 7.23 (m, 4H, Ar), 5,20 (t, 2H, CHBr), 3,24 (t, 4H, CH2N), 2,87 (t, 2H, CH2CON), a 1.75-0,76 (m, 14H, CH2CH2CH3).

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

HPLC =95%

Yield =34%

Example: a Common way of obtaining imidazopyridines (I, X=CO)

To a solution of the value (V) (1 EQ.) in acetonitrile solution was added the compound (VI) (1.2 EQ.) in acetonitrile. The mixture is incubated for 2 hours with heating and constant stirring. The solvent was collected in vacuo and the residue was extracted using a mixture of dichloromethane/HCl 1 N and using a mixture of DMC/water. The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, thus received imidazopyridine (1).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,30-7,03 (m, 6N, Ar), of 3.48 (s, 2H, CH2), 2,32 (s, 3H, CH3), 3,21-to 0.96 (m, 18H, CH2CH2CH2CH3).

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

HPLC =89%

Output =60%

Connection 1-98 were obtained by this method.

Example D: a General method of obtaining complex ketoesters (VII)

To a solution of compound (III) (1 EQ.) in methanol (ROH, R=CH3) was added dropwise a solution of concentrated sulfuric acid (0.5 EQ.) in methanol. The mixture is incubated for 30 minutes with heating and constant stirring. The solvent was collected in vacuo and the residue was extracted using a mixture of dichloromethane/1N NaOH and using a mixture of dichloromethane/water. The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, thus received complex keeep is R (VIII).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,89-to 6.88 (m, 4H, Ar), of 3.75 (s, 3H, OCH3), of 3.77 (s, 3H, OCH3), to 2.65 (t, 2H, CH2CO in), 2.25 (t, 2H, CH2COO).

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

HPLC =95%

Yield =93%

Example E: a Common way of obtaining bracketeer (VIII)

To a solution of compound (VII) in acetic acid dropwise a solution of bromine (2.2 EQ.) in acetic acid. The mixture is incubated at room temperature with constant stirring for 24 hours. The solvent was collected in vacuo and the residue was extracted using a mixture of dichloromethane/NaOH 1 N and using a mixture of dichloromethane/water. The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, was thus given a complex bracketeer (VIII).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,98-PC 6.82 (m, 4H, Ar), 5,38 (t, 1H, CHBr), 3,98 (s, 3H, och3), of 3.54 (s, 3H, OCH3), a 2.75 (t, 2H, CH2COO).

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

HPLC =95%

Yield =35%

Example F: a General method of obtaining imidazopyridines (II)

To a solution of the compound (VIII) (1 EQ.) in acetonitrile solution was added the compound (VI) (1.2 EQ.) in acetonitrile. The mixture is incubated for 2 hours with heating and constant stirring. The solvent was collected in vacuo the residue was extracted using a mixture of dichloromethane/HCl 1N and using a mixture of dichloromethane/water. The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, thus received imidazopyridine (II).

For example,

1H NMR (400 MHz, DMSO-d6): δ 7,69-6,79 (m, 6N, Ar in), 3.75 (s, 3H, OCH3), to 3.67 (s, 3H, OCH3), to 3.35 (s, 2H, CH2), 2,17 (s, 3H, CH3).

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

HPLC =90%

Output =60%

Example G: a General method of obtaining imidazopyridines (I, X=CO, R3or R4substituted amino groups)

To a solution of compound (II) (1 EQ.) in methanol solution was added (substituted) hydrazine (5 EQ.) in methanol. The mixture is incubated for 24 hours while heating and stirring. The solvent was collected in vacuo and the residue was extracted using a mixture of dichloromethane/HCl 1N and using a mixture of dichloromethane/water. The organic layer was dried over Na2SO4and filtered, the solvent is selected in vacuo, thus received imidazopyridine (I).

For example,

1H NMR (400 MHz, DMSO-d6): δ 8,00 (bs, 1 H, NH), 7,50-6,93 (m, 6H, Ar), of 3.78 (s, 3H, OCH3), of 3.96 (s, 3H, OCH3), or 3.28 (s, 2H, CH2), 2,12 (bs, 2H, NH2).

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

HPLC =93%

Yield =65%

Connection 99-107 also have been obtained by the above method.

An example of the composition is 1: 5 mg tablets

The active ingredient5.0 mg
Colloidal silicon dioxide0.6 mg
Crosscarmellose sodium12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Polysorbate 801.0 mg
Lactose75,0 mg
The hypromellose3.0 mg
Polyethylene glycol 40000.5 mg
Titanium dioxide E1711.5 mg
Microcrystalline cellulose to125,0 mg

Example composition 2: capsules 10 mg

The active ingredient10.0 mg
Colloidal silicon dioxide0.6 mg
Crosspovidone12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Sodium lauryl sulfate1.5 mg
Lactose77.0 mg
Gelatin28.5 mg
Titanium dioxide E1711.5 mg
Indigotin e0.02 mg
Microcrystalline cellulose to155,0 mg

An example of a song 3: oral drops

The active ingredient0.5 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium0.1 g
Polysorbate 801.0 g
Flavouring lemon0.2 g
Ethanol 25,0 Il
Purified water to100 Il

Example compositions 4: tablets 2.5 mg

The active ingredient2.5 mg
Colloidal silicon dioxide0.6 mg
Crosscarmellose sodium12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Polysorbate 801.0 mg
Lactose75,0 mg
Hydroxypropyl methylcellulose3.0 mg
Polyethylene glycol 40000.5 mg
Titanium dioxide E1711.5 mg
Microcrystalline cellulose to125,0 mg

Example compositions 5: capsules 5 mg

The active ingredient5.0 mg
The colloid is first silicon dioxide 0.6 mg
Crosspovidone12,0 mg
Talc4.0 mg
Magnesium stearate1.5 mg
Sodium lauryl sulfate1.5 mg
Lactose77.0 mg
Gelatin28.5 mg
Titanium dioxide E1711.5 mg
Indigotin e0.02 mg
Microcrystalline cellulose to155,0 mg

Example compositions 6: oral drops

The active ingredient0.25 g
Propylene glycol10.0 g
Glycerin5.0 g
Saccharin sodium0.1 g
Polysorbate 801.0 g
Flavouring lemon0.2 g
Ethanol25,0 Il
Purified water to100 Il

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

where R1selected from the group including linear or branched alkyl(C1-C6), -O-alkyl(C1-C6), 1-pyrrolidinyl, halogen;
R2represents a phenyl group or a phenyl group substituted in the para-position by a group Z;
R3and R4independently selected from the group comprising hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), quinil(C2-C6), cycloalkyl(C3-C6), an amino group, -NH-alkyl(C1-C6), -N-dialkyl(C1-C6), pyrrolidinyl, morpholinyl, piperidinyl, pyridine-2-ylmethyl, -CH2-CH2-O-C(O)-CH3, -CH2-C3-cycloalkyl, phenyl, optionally substituted by alkyl(C1-C6or-O-alkyl(C1-C6), and heteroaryl selected from the group of heteroaryl, including thiazolyl, pyridinyl, isoxazolyl substituted by one or two alkilani(C1-C6), chinosol and 1,3,4-thiadiazolyl, or both R3and R4may form together with the nitrogen atom to which they are attached, 5-6-membered heterocycle, select the tion from the group heterocyclyl, including pyrrolidinyl, morpholinyl, piperidinyl, optionally substituted by two groups of alkyl(C1-C6), provided that R3and R4cannot simultaneously denote a hydrogen atom, pyridine-2-ylmethyl, -CH2-CH2-O-C(O)-CH3, -CH2-C3-cycloalkyl;
X means WITH;
Z is selected from the group including linear or branched alkyl(C1-C6), -O-alkyl(C1-C6and halogen,
in this case, if one of R3and R4represents pyridine-2-ylmethyl, the other of R3and R4represents hydrogen, R1represents a C1alkyl, R2represents a phenyl group substituted in the para-position by a group Z, Z represents a C1alkyl,
if one of R3and R4represents-CH2-CH2-O-C(O)-CH3then the other of R3and R4is a linear C3alkyl, R1represents a C1alkyl, R2represents a phenyl group substituted in the para-position by a group Z, Z represents a C1alkyl,
if one of R3and R4represents-CH2-C3-cycloalkyl, the other of R3and R4is a linear C3alkyl, R1represents a C1alkyl, R2represents phenyl, y is the SCP, substituted in the para-position by a group Z, Z represents a C1alkyl,
or their pharmaceutically acceptable salts.

2. Compounds according to claim 1, in which R1selected from the group comprising methyl, chlorine, methoxy group, ethoxypropan or 1-pyrrolidinyl, a R2represents a phenyl group or a phenyl group substituted in the para-position the stands, halogen, methoxy group.

3. Compounds according to claim 1, in which X represents CO, R3selected from the group comprising hydrogen, linear alkyl(C1-C6), phenyl, optionally substituted by alkyl(C1-C6or-O-alkyl(C1-C6), heteroaryl selected from the group of heteroaryl, including thiazolyl, pyridinyl, isoxazolyl substituted by one or two alkilani(C1-C6), chinosol and 1,3,4-thiadiazolyl, an amino group, -NH-alkyl(C1-C6), -N-dialkyl(C1-C6), 1-pyrrolidinyl, 4-morpholinyl and 1-piperidinyl; a R4selected from the group comprising hydrogen, linear alkyl(C1-C6), phenyl, optionally substituted by alkyl(C1-C6or-O-alkyl(C1-C6), heteroaryl selected from the group of heteroaryl, including thiazolyl, pyridinyl, isoxazolyl substituted by one or two alkilani(C1-C6), chinosol and 1,3,4-thiadiazolyl, or both R3and R4may form together salomom nitrogen, to which they are attached, 5-6 membered heterocycle selected from the group heterocyclyl, including pyrrolidinyl, morpholinyl, piperidinyl optionally substituted by two groups of alkyl(C1-C6), provided that R3and R4cannot simultaneously denote a hydrogen atom.

4. Compounds according to claim 1, which is selected from the group including:
2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-ndimethylacetamide;
2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholine-4-yl-Etalon;
2-(6-chloro-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;
N,N-diethyl-2-(6-pyrrolidin-1-yl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dibutil-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyrido the Jn-3-yl]-N,N-dibutil-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
2-[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;
2-[2-(4-chlorophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;
2-[2-(4-chlorophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;
2-[2-(4-chlorophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[2-(4-chlorophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-chlorophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropylacetamide;
N,N-dibutil-2-[2-(4-chlorophenyl)-6-ethoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
N,N-diethyl-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholine-4-yl-Etalon;
2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-diethyl-ndimethylacetamide;
2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholine-4-yl-Etalon;
2-(6-ethoxy-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
N,N-diethyl-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide; N,N-dibutil-2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholine-4-yl-Etalon;
2-(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
N,N-diethyl-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)N,N-diethyl-ndimethylacetamide;
2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;
2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-orfelin-4-yl-Etalon;
2-(6-ethoxy-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
N,N-diethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-pyrrolidin-1-yl-Etalon;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-morpholine-4-yl-Etalon;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-1-piperidine-1-yl-Etalon;
N,N-diethyl-2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
N,N-diethyl-2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-N,N-diethyl-ndimethylacetamide;
2-[6-ethoxy-2-(4-forfinal)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
2-[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
2-[2-(4-forfinal)-6-methoxy-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
N,N-diethyl-2-[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[2-(4-netoxygen the l)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
2-[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
N,N-diethyl-2-[6-methoxy-2-(4-methoxyphenyl)-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[6-methoxy-2-(4-methoxyphenyl)-imidazo[1,2-b]pyridazin-3-yl]-N,N-dipropyl-ndimethylacetamide;
N,N-dibutil-2-[6-methoxy-2-(4-methoxyphenyl)-imidazo[1,2-b]pyridazin-3-yl]-ndimethylacetamide;
2-[6-methoxy-2-(4-methoxyphenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-piperidine-1-yl-Etalon;
2-[6-methoxy-2-(4-methoxyphenyl)-imidazo[1,2-b]pyridazin-3-yl]-1-morpholine-4-yl-Etalon;
2-{[2-(6-methyl-2-p-tolyl-imidazo[1,2-b]-pyridazin-3-yl]-N-propylacetamide}acetate;
1-(3,5-dimethyl-piperidine-1-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-Etalon;
N-cyclopropylmethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-propyl-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-thiazol-2-yl-ndimethylacetamide;
N,N-aminobutiramida 2-(6-methyl-2-p-tolyl-imidazo[l,2-b]pyridazin-3-yl)-ndimethylacetamide;
N-cyclohexyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-phenyl-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-p-tolyl-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-pyridin-2-yl-methyl-ndimethylacetamide;
N-(3,5-dimethyl-isoxazol-4-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
N-cyclopentyl-2-(6-methyl-2-p-tolyl-it is dazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
N,N-diallyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
N-cyclopropyl-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-quinoline-2-yl-ndimethylacetamide;
N-(5-methyl-isoxazol-3-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
N-(4-methoxyphenyl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
N-(3-methyl-isoxazol-5-yl)-2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-[1,3,4]thiadiazole-2-yl-ndimethylacetamide;
[2-(4-forfinal)-6-pyrrolidin-1-yl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;
[2-(4-bromophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;
[2-(4-methoxyphenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;
[2-(4-chlorophenyl)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;
[2-(4-forfinal)-6-methyl-imidazo[1,2-b]pyridazin-3-yl]-acetic acid hydrazide;
(6-methyl-2-phenyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid hydrazide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-morpholine-4-yl-ndimethylacetamide;
2-(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-N-piperidine-1-yl-ndimethylacetamide; and
(6-methyl-2-p-tolyl-imidazo[1,2-b]pyridazin-3-yl)-acetic acid N',N'-dimethylhydrazide.

5. A method of obtaining a compound according to claim 1, where R3and R4independently selected from the group on the emitting hydrogen, linear or branched alkyl(C1-C6), alkenyl(C2-C6), quinil(C2-C6), cycloalkyl(C3-C6), pyridine-2-yl-methyl, -CH2-CH2-O-C(O)-CH3, -CH2-C3-cycloalkyl, phenyl, optionally substituted by alkyl(C1-C6or-O-alkyl(C1-C6), and heteroaryl selected from the group of heteroaryl, including thiazolyl, pyridinyl, isoxazolyl substituted by one or two alkilani(C1-C6), chinosol and 1,3,4-thiadiazolyl, or both R3and R4may form together with the nitrogen atom to which they are attached, 5-6-membered heterocycle selected from the group heterocyclyl, including pyrrolidinyl, morpholinyl, piperidinyl, optionally substituted by two groups of alkyl(C1-C6), provided that R3and R4cannot simultaneously denote a hydrogen atom, pyridine-2-ylmethyl, -CH2-CH2-O-C(O)-CH3and CH2-C3-cycloalkyl, in which the interaction of the intermediate compound (V)

with substituted 3-aminopyridazine (VI)

where R1selected from the group including linear or branched alkyl(C1-C6), -O-alkyl(C1-C6), 1-pyrrolidinyl, halogen;
R2represents a phenyl group is or phenyl group, substituted in the para-position by a group Z,
Z is selected from the group including linear or branched alkyl(C1-C6), -O-alkyl(C1-C6and halogen, and
X means WITH,
in this case, if one of R3and R4represents pyridine-2-ylmethyl, the other of R3and R4represents hydrogen, R1represents a C1alkyl, R2represents a phenyl group substituted in the para-position by a group Z, Z represents a C1alkyl,
if one of R3and R4represents-CH2-CH2-O-C(O)-CH3then the other of R3and R4is a linear C1alkyl, R1represents a C3alkyl, R2represents a phenyl group substituted in the para-position by a group Z, Z represents a C1alkyl, if one of R3and R4represents-CH2-C3-cycloalkyl, the other of R3and R4is a linear C3alkyl, R1represents a C1alkyl, R2represents a phenyl group substituted in the para-position by a group Z, Z represents a C1alkyl.

6. A method of obtaining a compound according to claim 1, where X represents CO, R3and R4independently selected from the group comprising hydrogen, the amino group, -NH-alkyl(C1-sub> 6), -N-dialkyl(C1-C6), provided that R3and R4cannot simultaneously denote a hydrogen atom, in which the interaction of the intermediate compound (II)

where R represents a linear or branched alkyl(C1-C6), a R1and R2defined above, with a compound HNR3R4.

7. The method according to claim 6, in which R represents methyl.

8. Connect imidazo[1,2-b]pyridazine covered by the General structural formula (II)

where R is methyl, R is selected from the group comprising methyl, methoxy group, ethoxypropan, 1-pyrrolidyl or chlorine, a R2represents phenyl or phenyl, optionally substituted in the para-position the stands, halogen or methoxy group,
and their pharmaceutically acceptable salts.

9. The use of compounds according to claim 1 for obtaining a medicinal product intended for treating or preventing diseases associated with inhibition of GABAAndreceptors in in need of such treatment of a human or other mammal.

10. The use according to claim 9, in which the GABAAndthe receptor is an α2-GABAAndthe receptor.

11. The use according to claim 9, in which the GABAAndthe receptor is an α2-GABAAndthe receptor.

12. Use the s compounds according to claim 1 for obtaining a medicinal product, intended for treating or preventing anxiety in a human or other mammal.

13. The use of compounds according to claim 1 for obtaining a medicinal product intended for treating or preventing epilepsy in humans or other mammals.

14. The use of compounds according to claim 1 for obtaining a medicinal product intended for treating or preventing sleep disorders in a human or other mammal.

15. The use of compounds according to claim 1 for obtaining a medicinal product intended for treating or preventing insomnia in humans or other mammals.

16. The use of compounds according to claim 1 for obtaining a medicinal product intended for the induction of sedative neuroleptic effect in humans or other mammals.

17. The use of compounds according to claim 1 for obtaining a medicinal product intended for the induction of an anesthetic effect in humans or other mammals.

18. The use of compounds according to claim 1 for obtaining a medicinal product intended for modulation of time required for sleep and duration of sleep a person or other mammal.

19. The use of compounds according to claim 1 for obtaining a medicinal product intended for the induction of myorelaxation human or other mammal.

20. Pharmaceutical composition for inhibiting GABAAndreceptors, comprising a therapeutically effective amount of a compound according to claim 1 together with an acceptable amount of pharmaceutical excipients or carriers.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to octahydro-pyrrolo[3,4-b]pyrrol N-oxides or pharmaceutically acceptable salts thereof of general formula (I) wherein Z1 represents N or CH. Octahydro-pyrrolo[3,4-b]pyrrol N-oxides of formula (I) are prodrugs of histamine-3 antagonists, and effective in treating conditions and disorders that can be prevented or relieved by H3-histamine receptor ligands. The present paper discloses N-oxide derivatives of octahydro-pyrrolo[3,4-b]pyrrol, the use of these compounds, compositions thereof and methods of treating a mammal having a condition or disorder wherein the H3-histamine receptor modulation has a therapeutic effect.

EFFECT: new compounds are presented.

11 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new triazolopyrimidine derivatives of general formula (I): wherein R1 means hydrogen or alkyl; R2 means hydrogen; R3 means optionally substituted C3-8cycloalkyl, optionally substituted bridged monocyclic C6-cycloalkyl, optionally substituted phenyl, optionally substituted 6-member heterocyclyl containing one or two heteroatoms specified in O and N, etc., a pharmaceutical composition containing them, and using the compounds and composition for inhibiting the enzyme type 1 diacylglycerol-O-acyltransferase (DGAT) for treating type 2 diabetes mellitus, obesity, high plasma triglycerides, metabolic syndrome, etc.

EFFECT: there are presented new triazolopyrimidine derivatives.

11 cl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to isoxazole-pyridine derivatives of formula , where X; R1; R2, R3, R4, R5 and R6 are as described in claim 1 of the invention and a pharmaceutically acceptable salt thereof. The invention also relates to a medicinal agent for treating diseases associated with the binding site of the GABA A α5 receptor based on compounds of formula I and use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds are active towards the binding site of said receptor and are useful in treating cognitive disorders such as Alzheimer's disease.

22 cl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to tetrahydroimidazo[1,5-a]pyrazine derivatives of formula I or to their pharmaceutically acceptable salts (I), wherein: Ar represents phenyl, wherein phenyl is additionally substituted by 1-3 substitutes independently specified in halogen; R1 represents trifluoromethyl; R2 is specified in a group consisting of hydrohyl, alkyl having 1 to 4 carbon atoms, alkoxyl having having 1 to 4 carbon atoms, cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely, and -NR4R5, wherein each alkoxyl is optionally substituted by one group specified in a group consisting of phenyl and -OC(O)OR8; R3 is specified in a group consisting of a hydrogen atom and alkyl having 1 to 4 carbon atoms; each of R4 and R5 is independently specified is a group consisting of a hydrogen atom, alkyl having 1 to 4 carbon atoms, cycloalkyl representing a 3-8-member monocyclic ring group consisting of carbon completely, phenyl and pyridinyl, wherein each alkyl or phenyl is optionally substituted by one or more group specified in a group consisting of halogen, a cyano group, -SO2R7, -NR4R5 and -C(=O)OCH3; or R4 and R5 together with an atom, whereto attached form a 5-6-member heterocycle wherein the 5-6-member heterocycle optionally contains one or more N, O or S atom, and each 5-6-member heterocycle is optionally substituted by one or more groups consisting of halogen, hydroxyl, an amino group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl 1 to 4 carbon atoms, -SO2R7, -C(O)NR4R5, -C(O)R7, =O; R7 represents alkyl 1 to 4 carbon atoms; and R8 is specified in a group consisting of alkyl 1 to 4 carbon atoms, and cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely. The invention also refers to methods for preparing them, a pharmaceutical composition having dipeptidyl peptidase IV inhibitory activity and containing said derivatives.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating type 2 diabetes mellitus or hyperglycemia.

17 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel azoindolizines or pharmaceutically acceptable salts thereof having Mek-kinase inhibitory activity in formula : ZA means CRA; RA means H or halogen; each of R1, R2 and R3 means H; W means: , each R4 and R5 means H; X1 represents -OR7; each R7 means C2-C12-hydroxyalkyl, 2,3-dihydroxypropyl, C2-C3-alkenoxyC1-C6-alkoxy, (2,2-dimethyl-[1,3]dioxalan-4-yl)-methyl or piperidinyl; X4 means: R6 means halogen or -SR16; R6 means halogen; p is equal to 1; R16 means C1-C12-alkyl.

EFFECT: invention relates to a pharmaceutical compositions containing these compounds, to a method of inhibiting the abnormal cell growth and the use of the compounds for preparing a drug preparation for inhibiting the abnormal cell growth.

9 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel quinoline compounds of formula (I) and physiologically acceptable acid addition salts and N oxides thereof, wherein R denotes a polycyclic group of formula (R) wherein * indicates the quinolinyl radical binding site; A denotes (CH2)a, where a equals 0, 1, 2 or 3; B denotes (CH2)b, where b equals 0, 1, 2 or 3; X' denotes (CH2)x where x equals 0, 1, 2 or 3; Y denotes (CH2)y where y equals 0, 1, 2 or 3; provided that a+b=1, 2, 3 or 4, x+y=1, 2, 3 or 4, and a+b+x+y=3, 4, 5, 6 or 7; Q denotes N; R1 denotes hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, phenyl-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl, where phenyl rings in last two said groups are unsubstituted or carry 1, 2 or 3 substitutes selected from halogen, C1-C4-alkyl or C1-C4-halogenalkyl; R2 denotes hydrogen; R3 denotes hydrogen; p=0, 1 or 2; R4, if present, denotes C1-C4-alkyl and is bonded with X and/or Y, if p=2, two radicals R4, which are bonded with adjacent carbon atoms of X or Y, together can also denote a straight C2-C5-alkylene; q=0; n=0; m=0; X denotes S(O)2; which is located in position 3 of quinoline; Ar denotes a radical Ar1, wherein Ar1 is a phenyl, wherein the phenyl can be unsubstituted or can carry 1 substitute Rx wherein Rx denotes halogen, CN, C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogenalkoxy, C1-C6-alkylthio, C1-C6-halogenalkylthio, NRx1 Rx2, wherein Rx1 and Rx2 independently denote hydrogen, C1-C6-alkyl, or Rx1 and Rx2 together with a nitrogen atom form an N-bonded 5-, 6- or 7-member saturated heteromonocyclic ring or an N-boned 7-, 8-, 9- or 10-member saturated heterobicyclic ring, which are unsubstituted or carry 1, 2, 3 or 4 radicals selected from C1-C4-alkyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treatment using the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel quinoline derivatives are obtained, which respond to modulation of the serotonin 5-HT6 receptor.

23 cl, 2 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new tetracyclic compounds of general formula (I), wherein is a single or double bond; no bonds or a single bond; or V means N; T and X as shown in structure fragments above; U and W independently mean C or N with one of them shall be N; R3, R4, R5 and R6 - H; Rv is absent; Ru and Rw are independently absent or mean (C1-12)alkyl; Y =N-OR1 or NP'1, wherein R1 - H, (C1-12)alkyl optionally substituted by phenyl, phenyloxy, carboxy, (C1-12)alkoxy, (C1-12)alkoxycarbonyl, or (C2-12)alkenyl; R'1 is phenyl, or pharmaceutically acceptable salts thereof, or diastereomers thereof, or regioisomers thereof, or: mixtures thereof, a pharmaceutical composition containing them, and specific compounds for cysteine protease inhibition.

EFFECT: compounds may be used in medicine in treating cancer, neurodegenerative diseases, inflammatory disorders, cardiovascular diseases, etc.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new pyrimidine substituted macrocyclic compounds of genral formula (I) , wherein A= -C(=O)OR1 or -C(=O)-NH-SO2-R2; R1 = H or C1-6alkyl; R2 = phenyl, thienyl, C3-7cycloalkyl optionally substituted by C1-6alkyl; X = N or CH; E = NR5; R5 = H or C1-6alkyl; n = 4 or 5; R7=H, C1-6alkyl, C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy; R8 =C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy, morpholino or -NRaRb, wherein Ra and Rb independently mean H or C1-6alkyl; R9 = Rq = H; or their pharmaceutically acceptable addition salts, or stereoisomers, and pharmaceutical compositions containing them.

EFFECT: compounds are inhibitors of HCV NS3 serine protease and can find application in treating chronic hepatic disorders, particularly chronic hepatitis.

10 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing new 5,8,9,10-tetrahydropyrimido[4,5-d]azocine derivatives having triflate, secondary and tertiary amino groups in the 4th position of general formula specified below. In general structural formula: 2-12 2 X=OTf (Tf means triflate), X means NR1R22 related to the groups 3-12

.

The method consists in the fact that 6-isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one reacts with methyl propyolate in methanol at room temperature to produce methyl 8-isopropyl-4-oxo-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (1). Thereafter, the prepared compound reacts with triftalane hydride in dichloromethane in the presence of pyridine at t°=-10°C; it is recovered and purified with by means of column chromatography to prepare methyl 8-isopropyl-2-phenyl-4-{[(trifluoromethyl)sulphonyl]oxy}-5,8,9,10-tetrahydropyrimido[4,5-d]azocine-6-carboxylate (2); then the solution I mmole of the prepared product (2) in absolute dioxide is added with 2 mmole of K2CO3 and 1.5 mmole of appropriate amine. After being boiled for two hours and removing the solvent, respective 4-amino substituted 5,8,9,10-tetrahydropyrimido[4,5-d]azocine of formula 3-12 is prepared. The method is directed to prepare the products in the form of white or yellow powder, or in the form of drying oil.

EFFECT: after the primary screening, the compounds appeared to be acetyl- and butyrylcholin esterase inhibitors and can find application as scaffolds in searching the preparations for treating neurodegenerative diseases.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient.

EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of desmethylvenlafaxine of formula in form of a hydrochloride salt of a stereomerically pure compound which is suitable for treating, preventing or managing a disease selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause. The crystalline form contains water in amount of about 4% to about 8% of the total weight of the sample, and molar ratio of the water to the hydrochloride salt is about 1:1, and the crystalline form has X-ray powder diffraction peaks at positions of about 12.7, 14.5, 19.1, 21.4, 23.0, 25.5 and 27.3°2θ, and is characterised by the following corresponding unit cell parameters measured at 150 K: a=6.78 A; b=9.29 A; c=27.65 A; α=90°; β=90°; γ=90°. The crystalline form is characterised by weight loss during thermal gravimetric analysis of about 4% to about 8%, primarily about 5.6% of the total weight of the sample when heated from about 25°C to about 110°C and endothermic effect during differential scanning calorimetry with onset temperature of the effect of about 50°C to about 125°C, primarily about 93°C. The crystalline form is non-hygroscopic at relative humidity from about 5% to about 85% and absolute form.

EFFECT: obtaining a compound which is suitable for treating, preventing or managing a disease selected from depression, pain, anxiety, incontinence or vasomotor symptoms caused by menopause.

20 cl, 58 dwg, 7 tbl, 18 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: 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: medicine.

SUBSTANCE: invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide.

EFFECT: higher efficacy of the applied derivatives.

6 cl, 17 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl- and heteroarylsubstituted diasaspiropyridine derivatives of formula (I) to its pharmaceutically acceptable acid- or base-additive salt wherein A represents a radical of formula (II) wherein each k, l, m, n independently represents an integer equal to 0, 1, 2, 3 or 4, provided (k+1) and (m+n) are equal to 2, 3, 4 or 5; wherein one of -CH2-fragments can be substituted by atom O; and wherein one of -CH2-fragments can be substituted by an oxo group; X represents CH or N; R3 is specified in a group consisting of hydrogen, C1-5alkyl and C3-6cycloalkyl; each R4, R5 is independently specified in a group including hydrogen, halogen, oxo, C1-3alkyl and C1-3alkyloxy; p represents an integer equal to zero, 1, 2 or 3; q represents an integer equal to zero, 1, 2 or 3; each Y1, Y3, is independently specified in a group including a single bond and O; Y2 represents saturated or unsaturated C1-6hydrocarbon radical with a straight chain; B is specified in a group including phenyl optionally substituted by the number of the substitutes R6 each of which is independently specified in halogen; and wherein r represents an integer equal to zero, 1 or 2; alkyl represents a saturated hydrocarbon radical with a straight and branched chain containing said number of carbon atoms; wherein said radical can be optionally substituted by one or more carbon atoms or more radicals specified in a group including halogen, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl; and halogen represents fluorine, chlorine, bromine or iodine. Also, the invention refers to a pharmaceutical composition based on the compounds of formula I as an active ingredient for preparing a drug for preventing and/or treating mental disorders, including but not limited to anxiety, eating behavior disorder, affective disorders, such as bipolar disorders and depression, psychosis, such as schizophrenia, and sleeping disorders; obesity, diabetes; sexual disorders and neurological disorders; to a method for preparing a pharmaceutical composition, and to using the compounds of formula I for preparing the drug.

EFFECT: there are prepared and described new compounds possessing melanin-concentrating hormone (MCH), particularly MCH-1 antagonist activity.

19 cl, 4 ex, 7 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics, particularly a method for producing a preparation possessing anxiolytic activity. A method for producing the preparation possessing anxiolytic activity wherein ground hop cones are sequentially extracted in 60-70% ethanol under certain conditions; thereafter aqueous-alcoholic extracts are concentrated under vacuum; stillage residue are combined with the aqueous extract, filtered, boiled out, purified by separation, boiled out additionally, dried in a vacuum drier and ground.

EFFECT: preparation produced by the method described above is characterised by higher active substance content and exhibits high anxiolytic activity.

2 dwg, 13 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pyrazolo[1,5-a]-pyrimidine compounds according to the invention are specified in a group consisting of: N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-ethylmethanesulphonamide; {2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2,4-difluor-5-[3-(thiophene_2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide and N-{5-fluor-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide.

EFFECT: preparing pyrazolo[1,5-a]pyrimidine compounds, their pharmaceutically acceptable salts and hydrates showing an ability to inhibit GABAA receptors, and applicable for treating and preventing anxiety, epilepsy and sleeping disorders, including insomnia, as well as for inducing a sedative-hypnotic, analgesic and sleeping effects and myorelaxation.

14 cl, 6 tbl, 4 dwg, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a pharmaceutical composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility. As an active ingredient, the composition contains a solution of a hormone specified in a group consisting of melatonin, oestrogens, progesterone, testosterone and dihydrotestosterone in a pharmaceutically acceptable solvent, adsorbed or absorbed on particles of a pharmaceutically acceptable carrier. The invention also concerns methods for preparing and using the above pharmaceutical composition.

EFFECT: what is presented is the new composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility.

19 cl, 4 ex, 2 tbl, 2 dwg

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