N-(2-thiazolyl)amide derivatives as gsk-3 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a use of N-(2-thiazolyl)amide derivatives of formula

,

where R1 and R2 are independently selected from H, -NO2, halogen, C1-C6 alkyl with a straight chain, where at least one of R1 and R2 is different from H; m equals 0, 1, 2 or 3; X is selected from a group consisting of: indole of formula (A) bound in position 2, indole of formula (B) bound in position 3 and indazole of formula (C) bound in position 3:

, , ,

where R3 is selected from H and C1-C6 alkyl with a straight chain; R4, R5, R6 and R7 are independently selected from H and C1-C6 alkoxy group; R8 is selected from H and C1-C6 alkyl, or any of its pharmaceutically acceptable salts to obtain a medicinal agent for treating or preventing diseases or conditions mediated by GSK-3, especially neurodegenerative diseases such as Alzheimer's disease or insulin-independent sugar diabetes. The invention also relates to a compound of formula (I), a pharmaceutical composition based on said compound and synthesis method thereof.

EFFECT: high efficiency of using said derivatives.

30 cl, 3 tbl, 7 ex

 

The present invention relates to the use of N-(2-thiazolyl)amide derivatives for the treatment and/or prophylaxis of diseases, in which is involved glikogensintetazy-kinase-3 (GSK-3), in particular, neurodegenerative diseases such as Alzheimer's disease or non-insulin-dependent diabetes mellitus. In addition, provide new inhibitors of GSK-3, a method of obtaining such compounds and pharmaceutical compositions containing them.

In recent years the search for new therapeutic agents is considerably facilitated a better understanding of the structure of enzymes and other biomolecules associated with this disease. Protein kinases represent one of the important classes of enzymes that are the subject of extensive research. Many diseases associated with abnormal cellular responses triggered by events, mediated by protein kinases. Such diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormonal disease. Accordingly, in medicinal chemistry, a major effort in the search for inhibitors of protein kinases, which are effective therapeutic agents.

Glikogensintetazy-kinase-3 (GSK-3 is a serine/threonine a protein kinase, consisting of α - and β-isoforms, each of which encodes a single gene (Coghlan et al.,Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev.,10, 508 to 514 (2000)). The threonine/serine kinase (glikogensintetazy-kinase-3, GSK-3) plays a key role in various related receptor signaling pathways (Doble BW, Woodgett, J.R.J Cell Sci.2003, 116:1175-1186). Dysregulation of these pathways is considered to be a critical event in the development of several common disorders in humans, such as diabetes type II (Kaidanovich O, Eldar-Finkelman H,Expert Opin. Ther. Targets, 2002, 6:555-561 ), Alzheimer's disease (Grimes CA, Jope RS,Prog. Neurobiol. 2001, 65:391-426), Central nervous system disorders, such as manic-depressive disorder and neurodegenerative diseases and chronic inflammatory diseases (Hoeflich KP, Luo J, maintainance and care instructions EA, Tsao MS, Jin O, Woodgett J,Nature2000, 406:86-90). These diseases may be caused or result from abnormal activity of certain cell signaling pathways, in which GSK-3 plays a role.

It was found that GSK-3 phosphorylates and modulates the activity of a number of regulatory proteins. Such proteins include glikogensintetazy, which is limiting the speed of an enzyme necessary for glycogen synthesis, associated with microtubules, tau protein, β-catenin transcription factor genes, e1F2B factor translation initiation, as well as ATP-citrate lyase, axin, factor th the first shock 1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. Such a variety of target proteins suggests the involvement of GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

Currently, the inhibition of GSK-3 can be a real strategy in the development of new drugs for the treatment of such diseases (Martinez A, Castro A, Dorronsoro I, Alonso M,Med. Res. Rev.,2002, 22:373-384) via insulin mimicry, dephosphorylation of tau protein processing and amyloid or modulation of transcription, respectively.

Neurotoxic effect of soluble or insoluble β-amyloid peptides (β) is characteristic of cerebral pathology in patients with Alzheimer's disease (ad). Studies conducted both in vitro and in vivo, indicate that β-peptides induce a decrease in the efficiency of the Wnt signaling pathway and this mechanism appears to be mediated destabilization of endogenous levels of β-catenin (Activation of Wnt signaling rescues neurodegeneration and behavioural impairments induced by beta-amyloid fibrilsde Ferrari et al,MoI. Psychiatry. 2003;8(2): 195-208). At the cellular models BA and animal experimental models, activation of the Wnt signaling pathway by lithium or Wnt ligands reduces the neurotoxic effect β by restoring normal levels of β-catenin and expression of certain vital genes of Wnt targets such as bcl-2. Resstr istwa in components of the Wnt pathway could run some phenomenon which can lead to onset and development of ad (Signal transduction during amyloid-beta-peptide neurotoxicity: role in Alzheimer's disease,Fuentealba et al.,Brain Res. Rev. 2004;47(1-3):275-89).

The presence of neurofibrillary tangles in neurons of the cerebral cortex is another anomalous phenomenon that occurs in the brain of patients with BA, and sverhmotivirovanny protein tau, apparently, is the main component of these deposits in neurons (Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau, Wood JG,et al.,Proc. Natl. Acad. Sci. USA.1986; 83(11):4040-3). Tau is a group of six protein isoforms that are associated with microtubules, which modulate the function of cellular structures in axonal compartments of neurons. Various kinase associated with microtubules, can fosforilirovanii tau; however, the greatest contribution to the formation of neurofibrillary tangles make the effects produced by GSK3β and cdk5 (Phosphorylation of human tau protein by microtubule-associated kinases: GSK3β and cdkδ are key participants, Flaherty et al.,J. Neurosci. Res.2000; 62:463-472). Indeed, the activity of GSK-3, apparently initiates the Association fibers, forming neurofibrillary tangles (Glycogen synthase kinase 3 alteration in Alzheimer's disease is related to neurofibrillary tangle formationBaum et al.,MoI. Chem. Neuropathol.1996;29 (2-3):253-61). Thus, phosphorylation of protein tau is another key role of GSK-3, affecting the pathology in ad.

The facts relating the I to the physiological phenomena at BA, confirm that GSK-3 may be an important target in the treatment of this disease, not only through its modulation of the Wnt pathway, but also because of its influence on the formation of neurofibrillary tangles β.

Another pathological condition, in the mechanism which is involved in Wnt signaling pathway, is Parkinson's disease. Physiological signs of this disease are reducing the number of neurons that produce dopamine, although the reasons for this phenomenon are not fully known. Wnt proteins play an important role in the process of differentiation of these cells. Normalization of the levels of β-catenin inhibitors of GSK-3 leads to increased differentiation of dopaminergic neurons (GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons, Castelo-Branco et al.,J Cell Sci.2004; 117(Pt 24):5731-7).

GSK-3 also plays an important role in modulating the cellular actions of insulin through phosphorylation glikogensintetazy, the enzyme that catalyzes the condensation of monomers of glucose with the formation of glycogen. Phosphorylation glikogensintetazy undertaken by GSK-3 and other kinases, leading to its inactivation, and this phenomenon weakens the effect of insulin in the cells. Indeed, several selective inhibitors of GSK-3 have shown themselves to mimic the actions of insulin on models in vitro and in vivo (Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kiase-3 , Plotkin et al.,Pharmacol Exp Ther. 2003; 305(3):974-80). According to these experimental results, the inhibition of GSK-3 may have a therapeutic effect in the treatment of insulin resistance and type 2 diabetes.

In accordance with the above inhibitors of GSK-3 are potential drugs for the treatment of Alzheimer's disease, Parkinson's disease, diabetes and some other diseases.

Tau is a family of proteins, the main role of which in the cell is to increase the stability of microtubules. Microtubules are a major component of the cytoskeleton, important cellular organelles, especially for neurons. The main role of the cytoskeleton in neurons is providing structural support for the formation of axonal and somatodendritic compartments that are part of a neuronal network, necessary for the proper functioning of the Central nervous system. The cytoskeleton is a critical element for the survival of neurons, and many neuronal and neurodegenerative diseases are characterized by abnormalities. Therefore, tau and other proteins related to the structure of the cytoskeleton may be a promising target in the treatment of many neuronal and neurodegenerative diseases.

Isoforms of tau protein are the result of alternative mRNA splicing of a single gene, which gives six distinguished the different peptide chains with a molecular mass of from 50 to 79 kDa. Proteins tau intensively expressed in the Central and peripheral nervous system; they are especially numerous in axona neurons, where they participate in the organization and integrity of synaptic connections in the Central nervous system.

Some studies (Brandt & Lee, J Biol. Chem. 1993, 268, 3414-3419 and Trinczek et al., Mol. Biol. Cell. 1995, 6, 1887-1902) demonstrated that tau-protein is able to stimulate the nucleation, growth and microtubule Assembly. These functions tau-protein regulated by the processes of phosphorylation/dephosphorylation, which are carried out on many sites its peptide chain. Many kinases are able to fosforilirovanii these sites in vitro, although to do so in vivo can only fewer. In normal physiological conditions there is a balance between phosphorylated and dephosphorylated tau protein which regulates its binding to microtubules and other proteins. However, some pathological phenomena can disrupt this balance, eliminating the interaction between tau-protein and microtubules and severing the assembled elements of the cytoskeleton. Phosphorylation of other sites of tau protein induces increased interaction type tau-tau and subsequent formation of oligomers of tau protein, which, in the end, aggregated into neurofibrillary tangles (NFT). All these changes provoke the destruction of the transport system of microtubules along axons is the synapses, causing a disturbance of neuronal function and possibly cell death.

Thus, the disorder of the regulation of tau-protein is considered to be a symptom of many neurological diseases, commonly known as chaupati, which are characterized by abnormal accumulation of Tau filaments in the brain. Some important toptime are, among others, Alzheimer's disease, syndrome Gerstmann-Straussler-Sheinker, the disease Peak, amyotrophic lateral sclerosis (als), a disease of Creutzfeldt-Jakob disease, down's syndrome or cerebral amyloid angiopathy caused pionowymi proteins.

Many modern researchers focused on the relationship between dysregulation of tau-protein and the accumulation of amyloid plaques, the other main pathological feature of Alzheimer's disease. Some authors (Price et al.,Annu. Rev. Genet, 1998, 32, 461-493 and Selkoe,Trends Cell Biol. 1998, 8, 447-453) suggest that amyloid pathology pathology precedes tau-proteins, although a mechanism is not yet found an explanation. I believe that the deposition of fibrillar beta-amyloid induces phosphorylation of tau-protein, which then causes the degeneration of neurons.

In light of the current level this field and taking into account that the enzyme GSK-3 and tau protein that is directly involved in the pathological mechanisms of a number of important diseases and is of ustroystv people especially neuronal and neurodegenerative disorders, there is a need for the discovery of effective inhibitors of the specified enzyme and phosphorylation of tau protein to obtain effective drugs for the treatment of such diseases and disorders.

The present invention provides a family of compounds, namely N-(2-thiazolyl)amide derivatives defined by the formula (I), as described in detail below, showing inhibitory effect on GSK-3. Therefore, they can be useful for treating diseases and pathological conditions, in which GSK-3 plays a role, especially neuronal and neurodegenerative diseases and conditions. Many of these compounds additionally demonstrate inhibitory effect on the phosphorylation of tau protein that also plays an important role in many neurodegenerative diseases, and therefore, the compounds of formula (I) can even perform a dual role in the treatment and prevention of neuronal and neurodegenerative diseases.

Accordingly, in a first aspect the present invention provides the use of compounds of formula (I):

where

R1and R2independently selected from H, -NO2, halogen, -NH2, -CF3C1-C6the linear alkyl chain, and-CN;

m is 0, 1, 2, 3, 4,5 or 6,

X is selected from the group consisting of:

indole of formula (A), linked in position 2:

indole of the formula (B), linked at position 3:

and

indazole formula (C), linked at position 3:

where

R3selected from H and C1-C6the linear alkyl chain;

R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;

R8selected from H and C1-C6of alkyl,

or any pharmaceutically acceptable salt, solvate, and prodrugs for obtaining a medicinal product for treatment or prevention of a disease or pathological condition mediated by GSK-3.

The compounds of formula (I) can be used in biological research, in which to modulate the activity of GSK-3. Therefore, in another aspect, this invention relates to the use of compounds of formula (I)as defined above, or any of its salts or MES as a reagent for modulation of GSK-3 in the biological Sciences, preferably as a reagent for inhibiting the activity of GSK-3.

Another aspect of this invention relates to a method of treatment of the disease, the mechanism of which involved GSK-3, including the introduction of a patient who, in need of such treatment, a therapeutically effective amount of at least one compound of General formula (I) or its pharmaceutical compositions.

An additional aspect of the invention is a new compound of the formula (I):

where

R1and R2independently selected from H, -NO2, halogen, -NH2, -CF3and-CN;

provided that at least one of R1and R2different from H;

m is 0, 1, 2, 3, 4, 5 or 6,

X is selected from the group consisting of:

indole of formula (A), linked in position 2:

indole of the formula (B), linked at position 3:

and

indazole formula (C), linked at position 3:

where

R3selected from H and C1-C6the linear alkyl chain;

R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;

R8selected from H and C1-C6of alkyl,

or any pharmaceutically acceptable salt, solvate and prodrug.

According to further aspect the present invention relates to a new compound of the formula (I) for use as a medicine.

A further aspect of the present invention is farmac viteska composition, containing at least one new compound of the formula (I) or any pharmaceutically acceptable salt, prodrug or MES and a pharmaceutically acceptable carrier, adjuvant or excipient.

And finally, another aspect of the invention relates to a method of obtaining new compounds of formula (I).

In the above definition of the compounds of formula (I), the following terms have the meanings specified below:

"C1-C6alkyl" means linear or branched hydrocarbon chain radical consisting of carbon atoms and hydrogen, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl etc.

"C1-C6the linear alkyl chain" means a linear hydrocarbon chain radical consisting of carbon atoms and hydrogen, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl etc.

"C1-C6alkoxygroup" means a radical of the formula-ORandwhere Randis "C1-C6alkyl" radical, as defined above, such as methoxy group, ethoxyl the PAP, propoxylate etc.

"Halogen" means chlorine, bromine, fluorine or iodine as Deputy.

In the first aspect of the present invention provides the use of compounds of formula (I):

where

R1and R2independently selected from H, -NO2, halogen, -NH2, -CF3C1-C6the linear alkyl chain, and-CN;

m is 0, 1, 2, 3, 4, 5 or 6,

X is selected from the group consisting of:

indole of formula (A), linked in position 2:

indole of the formula (B), linked at position 3:

and

indazole formula (C), linked at position 3:

where

R3selected from H and C1-C6the linear alkyl chain;

R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;

R8selected from H and C1-C6of alkyl,

or any pharmaceutically acceptable salt, solvate, and prodrugs for obtaining a medicinal product for treatment or prevention of a disease or condition mediated by GSK-3.

The preferred compounds used in the present invention are those where X is an indole of the formula (A) or (b)as defined above, bound in positions 2 or 3. After the respective preferred compounds are such where X is indazoles formula (C), as described above, connected in position 3.

Others used the preferred compounds are those where at least one of R1and R2different from N.

Others used a more preferred compounds are those where one of R1and R2is N.

Preferably one of R1or R2is NO2or halogen. Thus, the preferred compounds are those where one of R1and R2is NO2and the other is N. Even more preferred compounds are those where R1is NO2and R2is N.

In a further preferred embodiment, R3selected from H and methyl.

Further preferred compounds are those where R4-R7independently selected from C1-C6alkoxygroup and H. Preferably all R4-R7are N.

Compounds where R8selected from H and methyl, are also preferred.

Preferably m is selected from 0, 1, 2 or 3, and m equal to 0 indicates that the amide group is directly linked to X via a carbonyl group.

According to a preferred variant implementation, the compound of formula (I)used in the present invention, selected from the following link is:

or any pharmaceutically acceptable salt, solvate, and prodrugs.

In the framework of the present invention, the disease or condition mediated by GSK-3, means any disease or condition, which involved GSK-3, preferably any disease or condition requiring inhibition of GSK-3. Such diseases or conditions include, but are not limited to, any disease or condition selected from diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, Boxing parkinsonism, Gramsci complex parkinsonism-dementia, a disease of the Peak, the syndrome of Gerstmann-Straussler-Sheinker disease Creutzfeldt-Jakob disease, cerebral amyloid angiopathy caused pionowymi proteins, corticobasal degeneration, frontotemporal dementia, Huntington's disease, dementia associated with AIDS, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases, such as OS is a kind of stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, manic-depressive disorder, promotion of functional recovery after stroke, cerebral bleeding (for example, due to cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome X, ischemia, brain injury, especially traumatic brain injury, cancer, leukopenia, down's syndrome, dementia with calves Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

In a preferred embodiment, the disease or condition selected from the progressive supranuclear paralysis, disease of the Peak corticobasal degeneration, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorder, manic-depressive disorders, promotion of functional recovery after stroke, cerebral bleeding (for example, due to cerebral AMILO the Noah angiopathy), obesity, syndrome X, ischemia, brain injury, especially traumatic brain injury, down syndrome, dementia with calves Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia. Preferred disease or condition selected from Alzheimer's disease, diabetes, Parkinson's disease, epilepsy and mood disorders. Even more preferred the disease or condition selected from Alzheimer's disease, Parkinson's disease, epilepsy and mood disorders.

Unless otherwise specified, it is assumed that the compounds of formula (I)used in this invention also include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the fact that hydrogen is replaced by deuterium or tritium, or the carbon replaced with a carbon enriched13C or14C, or use the nitrogen enriched15N; all such compounds are included in the scope of this invention.

The term "pharmaceutically acceptable salt, solvate or prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES or any other compound, which after administration to the recipient is capable of providing (directly or OPOS edavanna) connection, described above. However, it should be recognized that the salts that are not pharmaceutically acceptable, also included in the scope of this invention because they can be used to obtain pharmaceutically acceptable salts. Salts, prodrugs and derivatives can be obtained by methods known in this field.

For example, pharmaceutically acceptable salts of compounds of formula (I) are synthesized from the parent compound that contains a basic or acidic group, traditional chemical methods. Typically, such salts are produced by interaction of free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or in mixtures thereof. Usually such preferred non-aqueous environment, as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the acid additive salts include acid additive salts of mineral acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and acid additive salts of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate. Examples of primary additive salts include inorganic salts such as, for example, salts of sodium, potassium, calcium, Ammon is I, magnesium, aluminum and lithium, and organic salts such as, for example, salts of Ethylenediamine, ethanolamine, N,N-dialkylacrylamide, triethanolamine, glucamine and basic amino acids.

Particularly preferred derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, giving oral input connection is more quickly absorbed into the blood)or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the original types.

The compounds of formula (I)used in this invention may be in crystalline form of the free compounds or in the form of a solvate (e.g. hydrate), and it is assumed that both forms are included in the scope of the present invention. Methods of solvation well-known in this field. Acceptable solvate are pharmaceutically acceptable solvate. In a specific embodiment, the MES is a hydrate.

The compounds of formula (I) or their salts or solvate mainly presented in pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable form consider, among other things, one which is pharmaceutically acceptable level of purity, excluding normal the major pharmaceutical additives, such as diluents and carriers, and including material that is not considered toxic at normal dosage. The degree of purity of a drug substance is preferably above 50%, more preferably above 70%, most preferably above 90%. In the preferred embodiment, it is above 95% for the compounds of formula (I) or its salt, solvate or prodrugs.

The compounds used in this invention and represented by the above formula (I)may include enantiomers depending on the presence of chiral centers, or isomers, depending on the presence of multiple bonds (e.g., Z, E). Individual isomers, enantiomers and diastereoisomers and their mixtures are included in the scope of the present invention.

The compounds of formula (I) can be used in biological research, where we need to modulate the activity of GSK-3. Therefore, in another aspect, the invention relates to the use of compounds of formula (I)defined above, as a reagent for modulation of GSK-3 in the biological Sciences, preferably, as a reagent for inhibiting the activity of GSK-3.

A further aspect of the invention relates to a method for treating or preventing the disease, disorder or condition, which involved GSK-3, where the method includes Vedenyapin, in need of such treatment, a therapeutically effective amount of at least one compound of General formula (I) or any of its salts or MES or pharmaceutical compositions.

Another aspect of the invention relates to a new compound of the formula (I):

where

R1and R2independently selected from H, -NO2, halogen, -NH2, -CF3and-CN;

provided that at least one of R1and R2different from N;

m is an integer from 0 to 6,

X is selected from the group consisting of:

indole of formula (A), linked in position 2:

indole of formula (V), linked at position 3:

and

indazole formula (C), linked at position 3:

where

R3selected from H and C1-C6the linear alkyl chain;

R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;

R8selected from H and C1-C6of alkyl,

or any pharmaceutically acceptable salts, solvate and prodrugs.

The preferred compounds used in the present invention are those where X is an indole of the formula (A) or (b)as defined above, bound in position is s 2 or 3. The following preferred compounds are those where X is indazoles formula (C), as described above, connected in position 3.

Other preferred compounds are those where one of R1and R2is N.

Preferably one of R1or R2is-NO2or halogen. Thus, the preferred compounds are those where one of R1and R2is-NO2and the other is N. Even more preferred compounds are those where R1is-NO2and R2is N.

In the following preferred embodiment, R3selected from H and methyl.

Further preferred compounds are those where R4-R7independently selected from C1-C6alkoxygroup and H. Preferably all R4-R7are N.

Compounds where R8selected from H and methyl, are also preferred.

Preferably m is selected from 0, 1, 2 or 3, and m equal to 0 indicates that the amide group is directly linked to X via a carbonyl group.

According to a preferred variant implementation, the compound of formula (I) selected from the following compounds:

or any pharmaceutically acceptable salt, solvate, and prodrugs.

Unless otherwise noted, it is also assumed that the new compounds of formula (I) include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the fact that hydrogen is replaced by deuterium or tritium, or the carbon replaced with a carbon enriched13C or14C, or use the nitrogen enriched15N; all such compounds are included in the scope of this invention.

The term "pharmaceutically acceptable salt, solvate or prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES or any other compound, which after administration to the recipient is capable of providing (directly or indirectly) the compound described above. However, it should be noted that salts that are not pharmaceutically acceptable, also included in the scope of this invention because they can be used to obtain pharmaceutically acceptable salts. Salts, prodrugs and derivatives can be obtained by methods known in this field.

For example, pharmaceutically acceptable salts of the new compounds of the formula (I) are synthesized from the parent compound that contains a basic or acidic group, traditional x the economic ways. Typically, such salts are produced by interaction of free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or in mixtures thereof. Usually such preferred non-aqueous environment, as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the acid additive salts include acid additive salts of mineral acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and acid additive salts of organic acids, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluensulfonate. Examples of primary additive salts include inorganic salts such as, for example, salts of sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and organic salts such as, for example, salts of Ethylenediamine, ethanolamine, N,N-dialkylacrylamide, triethanolamine, glucamine and basic amino acids.

Particularly preferred derivatives are those that increase the bioavailability of the compounds of the present invention, when such new compounds administered to a patient (for example, giving oral input connection is more quickly absorbed into the blood)or which enhance delivery of the source connected to the Oia to a biological compartment (e.g., in the brain or lymphatic system) relative to the original types.

The new compounds of formula (I) can be in crystalline form of the free compounds or in the form of a solvate (e.g. hydrate), and it is assumed that both forms are included in the scope of the present invention. Methods of solvation well-known in this field. Acceptable solvate are pharmaceutically acceptable solvate. In a specific embodiment, the MES is a hydrate.

The new compounds of formula (I) or their salts or solvate mainly presented in pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable form consider, among other things, one which is pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and carriers, and including material that is not considered toxic at normal dosing levels. The degree of purity of a drug substance is preferably above 50%, more preferably above 70%, most preferably above 90%. In the preferred embodiment, it is above 95% for the compounds of formula (I) or its salt, solvate or prodrugs.

Novel compounds represented by the above formula (I)may include enantiomers depending on the presence of Hira is lnyh centers, or isomers, depending on the presence of multiple bonds (e.g., Z, E). Individual isomers, enantiomers and diastereoisomers and their mixtures are included in the scope of the present invention.

In addition, the present invention provides pharmaceutical compositions containing at least one new compound of the formula (I) of the present invention or its pharmaceutically acceptable salt, prodrug or stereometry with a pharmaceutically acceptable carrier, adjuvant or excipient for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules and the like) or liquid (solutions, suspensions or emulsions) a composition for oral, local or parenteral use.

In a preferred embodiment, the pharmaceutical composition is presented in oral form. Suitable dosage forms for oral administration may be tablets and capsules and may contain conventional excipients known in this area, such as a binder such as syrup, gum acacia, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; for tabletting lubricants, for example magnesium stearate; disintegrant, for example starch, polyvinyle alidon, nitroglycerol or microcrystalline cellulose; or pharmaceutically acceptable moisturizers, such as sodium lauryl sulfate.

Solid oral composition can be obtained with traditional methods of blending, filling or tableting. To distribute the active agent throughout the volume in compositions with large quantities of fillers can be used to re-blending operation. Such operations are traditional in this area. For example, tablets can be obtained wet or dry granulation, and, optionally, can be coated by methods well known in normal pharmaceutical practice, in particular, for applying enteric-soluble coating.

Pharmaceutical compositions can also be adapted for parenteral administration, for example, in the form of sterile solutions, suspensions or liofilizovannyh products in appropriate unit dosage forms. You can use the appropriate excipients, such as fillers, buffer or surfactants.

The above dosage forms will be prepared using standard methods, such as described, or listed in the pharmacopoeias of Spain and the United States and similar reference publications.

The introduction of the new compounds of the formula (I) or compositions of the present invention is one performed in any suitable way, such as intravenous infusion, oral drugs and intraperitoneal and intravenous administration. Oral administration is preferred due to convenience for the patient and chronic nature of many diseases for which treatment is used such drugs.

Typically, the effective amount of the new compounds of this invention will depend on the relative efficiency of the selected connection, the severity of the disorder, treatment for which it is used, and the patient's body weight. However, the active compound is usually injected once or a few times a day, for example 1, 2, 3 or 4 times a day, in a specific daily doses in the range from 0.1 to 1000 mg/kg / day.

New compounds and compositions of this invention can be used with other drugs in the combined treatment. Other medicines may form a part of the same composition, or be provided as a separate composition for administration at the same or at another time.

In another aspect, the present invention relates to a new compound of the formula (I) for use as a medicine.

The new compounds of formula (I) can be obtained according to the reaction scheme, which includes a combination of indazolinone or indolenine acids of formulas (II) and (III) respectively:

where

R3selected from H and C1-C6the linear alkyl chain;

R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;

R8selected from H and C1-C6of alkyl, and

m is 0, 1, 2, 3, 4, 5 or 6;

with a thiazole of the formula (IV):

where R1and R2independently selected from H, -NO2, halogen, -NH2and-CN, provided that at least one of R1and R2differs from H.

All compounds of formula (II), (III) and (IV) are commercially available.

A General method for a group of compounds, where X is indazoles

In another specific embodiment of the invention the compound of formula (I), where X is indazoles receive the following General method. To a solution of the corresponding indazol acid of formula (II) in anhydrous tetrahydrofuran (THF) is added as an activating reagent 1.5 equivalent of CDI in anhydrous THF. The resulting mixture was stirred at room temperature for 4-5 hours. Then to the reaction mixture was added 1 equivalent of the corresponding thiazole of the formula (IV) in THF and the resulting mixture was stirred at room temperature for 8-10 hours. After completion of the reaction the solvent is evaporated, the crude substance was dissolved in CH Cl2and washed with water. Cleaning is performed by usual purification methods known to the expert in this field.

A General method for a group of compounds, where X is an indole:

The following specific embodiment of the invention the compound of formula (I), where X is an indole receive the following General method. To a solution of indole acid of formula (III) in anhydrous THF added as an activating reagent 1.5 equivalent of CDI in anhydrous THF. The resulting mixture was stirred at room temperature for 4-5 hours. Then to the reaction mixture was added 1 equivalent of the corresponding thiazole of the formula (IV) in THF and the resulting mixture was stirred at room temperature for 8-10 hours. After completion of the reaction the solvent is evaporated, the crude substance was dissolved in CH2Cl2and washed with water. Cleaning is performed by usual purification methods known to the expert in this field.

The following examples are given as further illustrations of the present invention; in no case should not be understood as limiting the invention.

Examples

Preparative approx the market

Below is given a detailed description of the preparation of some compounds of formula (I) according to the present invention.

Example 1

Receive (5-nitrothiazol-2-yl)amide 1H-indazol-3-carboxylic acid (compound 11)

To a solution of 3-indazol acid (3 mmol, 486 mg) in anhydrous THF and 1 ml of anhydrous dimethylformamide (DMF), was added to increase the solubility of indazole, was added 1.5 equivalent of CDI (4.5 mmol, 729 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 4.5 hours. Then to the reaction mixture were added 2-amino-5-nitrothiazole (3 mmol, 435 mg) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated, the crude substance was dissolved in CH2Cl2and washed with water (3×10 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed, the resulting residue was washed with a mixture of CH2Cl2/MeOH to give the desired compound as a yellow solid (550 mg, 63%, 290 M+).

1H-NMR (DMSO): 7,37 (t, 1H); 7,51 (t, 1H); 7,72 (d, 1H); 8,21 (d, 1H); 8,67 (s, 1H).

13C-NMR (DMSO): 107,9; 111,2; 120,8; 122,0; 123,4; 127,1; 135,5; 141,2; 141,8; 142,7; 161,7; 161,8.

Example 2

Getting 2-(indol-3-yl)-N-(5-nitrothiazol-2-yl)ndimethylacetamide (compound 4)

To a solution of 3-endolysosomal acid (2.10 g, 12 mmol) in anhydrous THF was added 1.5 equivalent of CDI (18 mmol, 2,916 g) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-nitrothiazole (12 mmol, 1,740 g) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated, the obtained brown crude substance was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed, the resulting residue was washed with a mixture of CH2Cl2/MeOH to give the desired compound as a yellow solid (2,260 g, 62%, 303 M+).

1H-NMR (DMSO): 3,96 (s, 2H); 6,97-7.5 (m, 5H); and 8.6 (s, 1H); 10,9 (NH); 13,26 (NH).

13C-NMR (DMSO): 32,1; 106,4; 111,4; 118,4; 118,6; 121,1; 124,4; 126,9; 136,0; 141,7; 142,6; 161,9; 171,5.

Example 3

Obtaining N-(5-chlorothiazole-2-yl)-2-(indol-2-yl)ndimethylacetamide (compound 6)

To a solution of 3-endolysosomal acid (525,5 mg, 3 mmol) in anhydrous THF was added 1.5 equivalent of CDI (4.5 mmol, 729 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-chlorothiazole (3 mmol, 513.5 mg) with 1 equivalent NEt3(0,41 ml) in THF and the resulting mixture is stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated, the crude red oil was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed, the residue was purified column chromatography on silica gel (CH2Cl2/MeOH; 30/1) to give the desired compound as a white solid (500 mg, yield: 57%, 293 M+, 290 M).

1H-NMR (DMSO): to 3.92 (s, 2H); 6,97 (m, 1H); was 7.08 (m, 1H); to 7.25 (d, 1H); of 7.36 (m, 1H); 7.50 for (s, 1H); 7,56 (d, 1H); and 8.6 (s, 1H); 10,9 (NH); 12,56 (NH).

13C-NMR (DMSO): 31,85; 107,05; 111,38; 117,88; 118,45; 118,51; 121,06; 124,21; 126,96; 135,51; 135,99; 156,00; 170,20.

Example 4

Getting 2-(5-methoxyindol-3-yl)-N-(5-nitrothiazol-2-yl)ndimethylacetamide (compound 7)

To a solution of (5-methoxyindol-3-yl)acetic acid (410 mg, 2 mmol) in anhydrous THF was added 1.5 equivalent of CDI (3 mmol, 486 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-nitrothiazole (2 mmol, 290 mg) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated, the remaining brown crude substance was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed, the scientists, the residue was washed with a mixture of CH 2Cl2/MeOH to give the desired compound as a yellow solid (384,5 mg, yield: 50%, 333 M+).

1H-NMR (DMSO): to 3.73 (s, 3H); of 3.95 (s, 2H); 6.75 in (DD, 1H); to 7.09 (s, 1H); 7,25 (m, 2H); 8,71 (s, 1H); 10,90 (1H, NH).

13C-NMR (DMSO): 32,17; 55,33; 100,40; 106,18; 111,15; 112,09; 125,01; 127,31; 131,13; 141,62; 142,71; 153,15; 162,01; 171,60.

Example 5

Getting 2-(1-methylindol-3-yl)-N-(5-nitrothiazol-2-yl)ndimethylacetamide (compound 8)

To a solution of (1-methylindol-3-yl)acetic acid (567,6 mg, 3 mmol) in anhydrous THF was added 1.5 equivalent of CDI (4.5 mmol, 729 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-nitrothiazole (3 mmol, 435 mg) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated, the obtained brown crude residue was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed, the residue was purified column chromatography on silica gel (CH2Cl2/MeOH; 40/1) to give the desired compound as a yellow solid (755,5 mg, yield 80%; 317M+).

1H-NMR (DMSO): 3,76 (s, 3H); 3.96 points (s, 2H);? 7.04 baby mortality (t, 1H); 7,13 (t, 1H); 7,28 (s, 1H); 7,41 (d, 1H); EUR 7.57 (d, 1H); to 8.62 (s, 1H).

13C-NMR (DMSO): 31,80; 32,25; 105,64; 109,61; 118,59; 118,67; 121,20; 127,21; 28,56; 136,39; 141,69; 142,59; 161,78; 171,31.

Example 6

Obtaining 2-(2-methylindol-3-yl)-N-(5-nitrothiazol-2-yl)ndimethylacetamide (compound 9)

To a solution of (2-methylindol-3-yl)acetic acid (567,6 mg, 3 mmol) in anhydrous THF was added 1.5 equivalent of CDI (4.5 mmol, 729 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-nitrothiazole (3 mmol, 435 mg) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated and the resulting brown crude residue was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed and the residue was purified column chromatography on silica gel (CH2Cl2/MeOH; 40/1) to give the desired compound as a yellow solid (726 mg, yield: 77%, 317 M+).

1H-NMR (DMSO): 2,30 (s, 3H); 3.96 points (s, 2H); of 6.71 (t, 1H); 6,86 (t, 1H); 7,21 (d, 1H); 7,41 (d, 1H); at 8.60 (s, 1H); 10,90 (1H, NH); 13,21 (1H, NH).

13C-NMR (DMSO): 11,35; 30,83; 102,66; 110,35; 117,49; 118,36; 120,13; 128,09; 133,68; 134,96; 141,67; 142,58; 161,79; 171,58.

Example 7

Receive (5-nitrothiazol-2-yl)amide 5-methoxyindol-2-carboxylic acid (compound 10)

To a solution of 5-methoxyindole-2-carboxylic acid (382 mg, 2 mmol) in betwedn the m THF was added 1.5 equivalent of CDI (3 mmol, 486 mg) in anhydrous THF. The resulting mixture was stirred at room temperature for 5 hours Then the reaction mixture was added 2-amino-5-nitrothiazole (2 mmol, 290 mg) in THF and the resulting mixture was stirred at room temperature for 10 hours After completion of the reaction the solvent evaporated and the crude brown residue was dissolved in CH2Cl2and washed with water (3×30 ml). The organic layer was dried Na2SO4. Then in a vacuum solvent was removed and the resulting residue was purified column chromatography on silica gel (CH2Cl2/MeOH; 40/1) to give the desired compound as a yellow solid (48 mg, yield: 5%, 317 M).

1H-NMR (DMSO): 3,79 (s, 3H); to 6.95 (DD, 1H); to 7.15 (s, 1H); 7,37 (d, 1H); to 7.67 (s, 1H); 8,71 (s, 1H); 11,90 (1H, NH); 13,41 (1H, NH).

13C-NMR (DMSO): 55,19; 102,08; 107,11; 113,45; 117,11; 127,07; 128,14; 133,27; 141,75; 142,74; 154,07; 159,98; 162,41.

Biological examples

The compounds obtained in examples 1-7, together with other 6 compounds of formula (I) were subjected to two different tests at different concentrations to determine their biological activity.

Inhibition of GSK-3β

This research is based on the Protocol described by the manufacturer Upstate under cat. No. 14-306, with minor modifications.

Recombinant human glikogensintetazy-kinase 3β analyzed in a solution of 11 m is MOPS (pH 7,4), 0.2 mm EDTA, 1.25 mm EGTA, 26,25 mm Mgl2and 0.25 mm orthovanadate sodium in the presence of 62.5 μm peptide-2 phosphoglyceromutase (GS-2) (TOCRIS, cat. No. 1352), with 0.5 µci of γ-33P-ATP and unlabeled ATP (Sigma, A-9187) at a final concentration of 12.5 μm. After 30 min incubation at 30°C. aliquots were applied to phosphocellulose P81 paper. Filters were washed four times for 10 min in 1%phosphoric acid, and counted with a scintillation cocktail scintillation counter (PerkinElmer, 1450 Microbeta). The activity of GSK-3 was tested at concentrations of 25 and 50 µm in the presence of compounds synthesized in accordance with examples 1-7 and in the presence of 6 other compounds of formula (I). The results are shown in table 1 (see below) as percent activity of GSK-3.

Inhibition of phosphorylation of tau-protein

Cells human neuroblastoma SHSY5Y were sown in the medium Minimum Essential Medium/Nutrient Mixture F-12. After one day, cells were treated with test samples for 18 h at 37°C. After treatment, cultures were washed in phosphate buffered saline and literally for 30 min at 4°C in extraction buffer (10 mm Tris-HCl, pH of 7.4, 100 mm NaCl, 1 mm EDTA, 2 mm Na3VO4, 1% Triton X-100, 10% glycerol, 0,1% SDS, 0.5% deoxycholate sodium, 1 mm PMSF and a mixture of protease inhibitors (Roche, Cat 1 697 498)).

Quantification of phosphorylated human tau-protein was in al the quota lysate of cells with antibodies against tau protein [pS396], specific phosphorylation using sandwich option ELISA (Biosource, cat. No. KHB7031). Phosphorylation of tau protein was evaluated by measuring the absorption at 450 nm on a microtiter plate reader (Cultek, Anthos 2010).

The effect of the compounds synthesized in accordance with examples 1-7, and 6 other compounds of formula (I) was determined at different final concentrations, namely 50, 100 and 200 μm. Not all compounds of formula (I) experienced with all these concentrations. The results are presented in table 1 (see below) marked "negative" and "b" respectively, which means "negative" and "positive". "Negative" means that for a given concentration of the compound (I) inhibition of phosphorylation of tau-protein was not registered; "position" means that the specified concentration registered the inhibition of phosphorylation of tau-protein.

Table 1
Connection # Formula% the activity of GSK-3Inhibition of phosphorylation of tau-protein in cells
25 mcm50 mcm50 mcm 100 mm200 mcm
Connection 137,35rate 18.89The negativeThe negativeThe negative
Connection 259,6438,96---
Connection 373,7953,35---
Connection 4
(example 2)
6,298,51The negativePositionPosition
Connection 519,0512,45PositionPosition Position
Connection 6
(example 3)
29,3814,61---
Connection 7
(example 4)
43,9432,2The negativePosition-
Compound 8
(example 5)
17,89,27PositionPosition-
Connection 9
(example 6)
of 7.962,61PositionPosition-
Connection 10
(example 7)
18,910,99PositionPosition -
Connection 11
(example 1)
34,7918,24The negativeThe negative-
Connection 1249,1137,11---
Connection 13is 70.9442,68---

Together with studies of the phosphorylation of tau protein were conducted quantitative studies of cell death, due to the possible toxicity of the compounds 1, 4, 5, 7, 8, 9, 10 and 11 described above. The study was carried out by measuring the allocation of LDH (Roche, cat. No. 1644793). For the quantitative determination of survival rate of cells aliquots of cell lysate were incubated with an equal volume of the reaction mixture at room temperature for 20-30 minutes Measuring light absorption was performed on a microtiter plate reader with a filter 490-492 nm (Cultek, Anthos 2010).

For the unity 4 and 5 cell survival was measured during processing within 24 hours (see table 2) and for compounds 1, 7, 8, 9, 10 and 11 measurements were carried out after treatment for 18 h (see table 3) in cells SH-SY5Y. Usually the connection acknowledge toxic, if after processing the data connection survives less than 80% of the cells.

Table 2
Connection # % surviving cells
10 mcm25 mcm50 mcm100 mm
Connection 491,7±1,990±3,7--
Connection 5of 87.8±3,8of 86.1±8,4--

Table 3
Connection # % surviving cells
50 mcm100 mm
Connection 1 103,2±17101,0±17
Connection 7and 99.8±8,6of 92.9±11,1
Compound 8103±7,7to 85.5±6,5
Connection 9to 91.6±5,9the 90.8±5,5
Connection 1084,7±2,7of 90.6±7,2
Connection 11to 95.3±3,3for 93.9±5,6

According to the obtained results, the compounds of formula (I) can be considered as non-toxic.

1. The use of the compounds of formula (I)

where R1and R2independently selected from H, -NR2, halogen and C1-C6the linear alkyl chain, where at least one of R1and R2different from N;
m is 0, 1, 2 or 3;
X is selected from the group consisting of:
indole of formula (A), linked in position 2:

indole of formula (V), linked at position 3:

and
indazole formula (C), linked at position 3:

where R3selected from N and C1-C6the linear alkyl chain;
R4, R5 , R6and R7independently selected from N and C1-C6alkoxygroup;
R8selected from N and C1-C6of alkyl,
or any farmatsevticheskii acceptable salts, for obtaining a medicinal product for treatment or prevention of a disease or condition mediated by GSK-3.

2. The use according to claim 1, where X is an indole of the formula (A) or (b)as defined in claim 1, connected in positions 2 or 3, respectively.

3. The use according to claim 1, where X is indazoles formula (C), as defined in claim 1, connected in position 3.

4. The use according to any one of claims 1 to 3, where one of R1and R2is N.

5. The use according to any one of claims 1 to 3, where one of R1and R2is-NO2.

6. The use according to claims 1-3, where R1is-NO2and R2is N.

7. The use according to claim 1, where R4-R7are N.

8. The use according to claim 1, where R3selected from H and methyl.

9. The use according to claim 1, where R8selected from H and methyl.

10. The use according to claim 1, where X is an indole of formula (V),
R1is-NR3,
R2is H,
m is 0,1,2 or 3,
R4-R7independently selected from C1-C6alkoxygroup and H,
R3selected from H and methyl, and
R8selected from H and methyl.

11. The use according to claim 1, where the compound of formula (I) selected from the following compounds:






or any pharmaceutically acceptable salts.

12. The use according to claim 1, where the drug is intended for treatment or prevention of a disease or condition requiring inhibition of GSK-3.

13. The application indicated in paragraph 12, where the disease or condition selected from diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, Boxing parkinsonism, Gramsci complex parkinsonism-dementia, a disease of the Peak, the syndrome of Gerstmann-Straussler-Sheinker disease Creutzfeldt-Jakob disease, cerebral amyloid angiopathy caused pionowymi proteins, corticobasal degeneration, frontotemporal dementia, Huntington's disease, dementia associated with AIDS, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, resstr istwa mood, such as depression, schizophrenia and bipolar disorder, manic-depressive disorder, promotion of functional recovery after stroke, cerebral bleeding (for example, due to cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome X, ischemia, brain injury, especially traumatic brain injury, leukopenia, down's syndrome, dementia with calves Levi, inflammation, chronic inflammatory diseases and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

14. Use item 13, where the disease or condition selected from Alzheimer's disease, diabetes, Parkinson's disease, epilepsy and mood disorders.

15. The application 14, where the disease or condition selected from Alzheimer's disease, Parkinson's disease, epilepsy and mood disorders.

16. The use of the compounds of formula (I)as defined in any one of claims 1 to 11, or any of its salts or MES as a reagent for modulation of GSK-3 in vitro biological studies, preferably as a reagent for inhibiting the activity of GSK-3.

17. The compound of formula (I):

where R1and R2independently selected from H, -NR and halogen, provided that at least one of R1and R2different from N;
m is 0, 1, 2 or 3;
X is selected from the group consisting of:
indole of formula (A), linked in position 2:

indole of formula (V), linked at position 3:

and
indazole formula (C), linked at position 3:

where R3selected from N and C1-C6the linear alkyl chain;
R4, R5, R6and R7independently selected from N and C1-C6alkoxygroup;
R8selected from N and C1-C6of alkyl,
R8selected from N and C1-C6the alkyl, or any of its pharmaceutically acceptable salts.

18. The connection 17, where X is an indole of the formula (A) or (b)as defined in 17 connected at positions 2 or 3, respectively.

19. The connection 17, where X is indazoles formula (C), as defined in 17 connected in position 3.

20. The compound according to any one of PP-19, where one of R1and R2is N.

21. The compound according to any one of PP-19, where one of R1and R2is-NO2.

22. The compound according to any one of PP-19, where R1is-NO2,
and R2is N.

23. The connection 17, where R4-R7are N.

24. The connection 17, where R3selected from H and methyl.

8selected from H and methyl.

26. The connection 17, where X is an indole of formula (V),
R1is - NO2,
R2is H,
m is 0,1,2 or 3,
R4-R7independently selected from C1-C6alkoxygroup and H,
R3selected from H and methyl, and
R8selected from H and methyl.

27. The connection 17, selected from the following compounds:





or any pharmaceutically acceptable salts.

28. The compound according to any one of p-27 for use as a drug for treatment or prevention of a disease or condition mediated by GSK-3.

29. Pharmaceutical composition for treatment or prevention of a disease or condition mediated by GSK-3, containing at least one compound of formula (I)as defined in any of PP-21, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, adjuvant or excipient.

30. The method of obtaining the compounds of formula (I)as defined in any of PP-27, including the combination of indazol the school or indolines acid of formula (II) and (III) respectively:

where R3selected from N and C1-C6the linear alkyl chain;
R4, R5, R6and R7independently selected from H, C1-C6of alkyl, C1-C6alkoxygroup and halogen;
R8selected from N and C1-C6the alkyl and m is 0, 1, 2 or 3;
with a thiazole of the formula (IV):

where R1and R2independently selected from H, -NO2and halogen, provided that at least one of R1and R2differs from N.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of general formula I and pharmaceutically acceptable salts thereof, where R1 is selected from a group comprising aryl and alkyl, optionally substituted hydroxy; R2 is selected from a group comprising hydrogen and alkyl; R3 is selected from a group comprising hydrogen and -X-A, where X is selected from a group comprising -C(O)- and -S(O)2-; and A is selected from a group comprising hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle and optionally substituted cycloalkyl, where the optionally substituted groups are substituted with 1-2 substitutes selected from a group comprising alkyl, substituted alkyl, alkoxy, substituted amine which is a -NRR group, substituted aryloxy, heteroaryl, heterocycle, halogen, hydroxy and -S(O)2-R9, where R9 is an alkyl; or R1 and R3 together with a carbon atom bonded to R1 and a nitrogen atom bonded to R3 form a heterocyclic or substituted heterocyclic group; R4 is selected from a group comprising hydrogen, linear alkyl, -alkylene-aminoacyl-, -alkylene-hydroxy-, -[alkylene]p-nitrogen-containing heterocycle, -[alkylene]p-nitrogen-containing substituted heterocycle, -[alkylene]p-nitrogen-containing heteroaryl, -[alkylene]p-nitrogen-containing substituted heteroaryl and -[alkylene]p-NR10R11, where p equals 0 or 1, the alkylene contains 1-5 carbon atoms and can have 1 or 2 substitutes selected from a group comprising amine, hydroxy and halogen, aminoacyl relates to a group -C(O)NRR, where each R is independently selected from a group comprising hydrogen and alkyl, R10 and R11 are independently selected from a group comprising hydrogen, alkyl, substituted alkyl, -S(O)2-alkyl, substituted aryl, substituted heteroaryl, cycloalkyl, or when R10 is hydrogen, R11 is hydroxy, alkoxy or substituted alkoxy; or when R1 and R3 together with carbon and nitrogen atoms respectively bonded to them do not form a heterocyclic or a substituted heterocyclic group, R3 and R4 together with a nitrogen atom to which they are bonded form a spiro-condensed heterocyclic group; R5 is selected from a group comprising L-A1, where L is selected from a group comprising C1-C5alkylene, where the alkylene is defined above; and A1 is selected from a group comprising aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle; and one of R6 or R7 is selected from a group comprising aryl and heteroaryl, each of which can optionally be substituted with -(R8)m, where m equals a whole number from 1 to 2, and the other of R6 or R7 is selected from a group comprising hydrogen, halogen and alkyl; or R6 as well as R7 denotes hydrogen; R8 is selected from a group comprising cyano, alkyl, -CF3, alkoxy, halogen, where alkyl, aryl, aryloxy, cycloalkyl, heterocycle, heteraryl and substituted alkyl, aryl, aryloxy, cycloalkyl, heterocycle and heteroaryl are described in claim 1. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula I, a method of inhibiting KSP and use of the composition to prepare a medicinal agent.

EFFECT: novel imidazole derivatives are useful as kinesin spindle protein inhibitors for treating cancer.

25 cl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula as well as separate enantiomers, diastereomers, racemic mixures and pharmaceutically acceptable salts thereof, having mitotic kinesin KSP inhibiting activity, as well as inhibitory action on tumour cells, use thereof in preparing a medicinal agent and a pharmaceutical composition based on said compounds. In said formula, R denotes Z-NR2R3, Z-OH, Ar1 and Ar2 independently denote a phenyl which, if needed, is substituted with one or more groups independently selected from: F, CI, Br, I, OH, Z denotes an alkylene having 1-6 carbon atoms which, if needed, is substituted with C1-6alkyl, and R1 assumes values given in the claim.

EFFECT: improved method.

16 cl, 3 dwg, 124 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting P2X3 receptor antagonist activity. In formula (I), X represents -O-; Y represents -NRdRe where one of radicals Rd and Re means hydrogen, and the other means hydrogen; C1-C12alkyl; C5-C7cycloalkyl; C5-C7cycloalky-C1-C12alkyl; hydroxy-C1-C12alkyl; acetyl; aminocarbonyloxy- C1-C12alkyl or heterocyclyl representing a 6-members saturated ring containing heteroatom S substituted by two oxo groups; D represents optional oxygen; R1 represents isopropyl; R2 represents hydrogen; R5 represents hydrogen or C1-C12alkyl; R4 means hydrogen; C1-C12alkyl; halogen; halogen- C1-C12alkyl; C1-C12alkoxy; hydroxy; halogen- C1-C12alkoxy; nitro; amino; hydroxy- C1-C12alkyl; C1-C12alkoxyalkyl; hydroxy- C1-C12alkoxy; C1-C12alkylsulphonyl; cyano; heteroaryl representing a 5-members aromatic ring containing one, two or three heteroatoms selected from O, S and N which can be optionally substituted by a thio group, C1-C12alkyl or C1-C12alkylsulphonyl; heterocyclyl representing a 6-members saturated ring containing two heteroatoms N, one of which is substituted C1-C12alkylsulphonyl; -(CH2)m-(Z)n-(CO)-Rf or -(CH2)m-(Z)n-SO2-(NRg)n-Rf where each m and n independently represents 0 or 1, Z means NR8, Rf means C1-C12alkyl, hydroxy, amino or hydroxy- C1-C12alkyl, and Rg means hydrogen; R3 represents methoxy; R6 represents hydrogen; and one of radicals R7 and R8 represents hydrogen, and the other represents hydrogen, acetyl or phenyl.

EFFECT: also, the invention refers to a pharmaceutical composition and to an application of the compound of formula (I) for preparing a drug.

8 cl, 3 tbl, 70 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a EP2 agonist which exhibits the EP3 agonist action, and induce a neurotising and/or protective effect and thereby is effective as a therapeutic agent for a peripheral nerve disease, such as lower and upper motor neuron disorder, nerve root disease, plexopathy, brachial plexus compression syndrome, peripheral neuropathy, neurofibromatosis and nervomuscular conduction disease.

EFFECT: EP2 agonist which exhibits the EP3 agonist action; it is a safe and effective neurotisation and/or protection agent which has an insignificant impact on the cardiovascular system.

13 cl, 36 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to hot or sweet flavourants in form of a synthetic amide compound or edible salt thereof in amount ranging from approximately 0.001 parts per million to approximately 100 parts per million. The amide compound has formula

where A is a phenyl or a 5- or 6-member heteroaryl ring selected from a group comprising pyridine, pyrazine, pyrazole, thiazole, furan, thiophene, benzofuran and benzothiophene; m equals 1, 2 or 3, each R1 is independently selected from hydroxyl, fluorine, chlorine, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy and isopropoxy, or alternatively two R1 are bonded to form a saturated C1-C3 alkylenedioxy ring on the phenyl; and R2 is a C3-C10 branched alkyl. The amide compound also has formula

in which substitutes A, B, R50, R60, R70, R80, n and m assume values given in the formula of invention. The amide compound is also a specific chemical compound.

EFFECT: obtaining hot and sweet taste modifiers and boosters for food and medicinal products.

39 cl, 7 tbl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a compound of formula I

, in which radicals and groups are described in the claims. Said compounds are 5-hydroxytryptamine-6 (5-HT6) ligands and can be used to treat central nervous system disorders associated with or influenced by the 5-HT6 receptor. The invention also relates to a pharmaceutical composition and a method of treating said disorders.

EFFECT: high efficiency of using said derivatives.

19 cl, 13 tbl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate which is a levodopa prodrug and can be used to treat Parkinson's disease, schizophrenia, cognitive disorders, restless legs syndrome, periodic limp movement disorder, tardive dyskinesia, Huntington's disease, arterial hypertension and excessive diurnal drowsiness. The invention also relates to the crystalline form of the said compound, methods of producing said compound and its crystalline form, pharmaceutical compositions and treatment methods.

EFFECT: highly effective treatment.

46 cl, 6 dwg, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate which is a levodopa prodrug and can be used to treat Parkinson's disease, schizophrenia, cognitive disorders, restless legs syndrome, periodic limp movement disorder, tardive dyskinesia, Huntington's disease, arterial hypertension and excessive diurnal drowsiness. The invention also relates to the crystalline form of the said compound, methods of producing said compound and its crystalline form, pharmaceutical compositions and treatment methods.

EFFECT: highly effective treatment.

46 cl, 6 dwg, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel aminoindane derivatives of formula (Ia) or pharmaceutically acceptable salts thereof, which have NMDA receptor antagonist effect, and can be used to prepare a medicinal agent for treating dementia. In formula (Ia):

,

R1 is a lower alkyl, C5-C6 cycloalkyl, phenyl which can be substituted with OH, lower alkyl, halogen atom, O-alkyl, C5-C6 heteroaryl containing a S atom as a heteroatom, or lower alkyl substituted with one or more halogen atoms, R2 and R3 are identical or different, each denoting alkyl or phenyl, R4 and R5 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, -lower alkylene-OH or -lower alkylene-O-lower alkyl, R6-R9 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, halogen atom, lower alkyl substituted with one or more halogen atoms, OH, CN, lower alkenyl or nitrogen-containing C5-C6 heterocyclic group, R10 and R11 are identical or different and each denotes a hydrogen atom or lower alkyl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: improved properties of the derivative.

6 cl, 15 tbl, 130 ex

FIELD: medicine.

SUBSTANCE: invention represents application of nerve growth factor (NGF) for obtaining eye composition for introduction on eye surface for treatment and/or prevention of pathologies affecting central nervous system, said eye composition is in form of eye drops and contains from 10 to 500 mcg/ml NGF.

EFFECT: increase of NGF level in all brain tissues, including cerebrospinal fluid, which makes it possible to demonstrate its therapeutic abilities in situ in case of neurodegenerative and ischemic diseases of brain, including, in particular, Alzheimer's disease and Parkinson's disease.

21 cl, 3 tbl

FIELD: medication.

SUBSTANCE: invention relates to tetrapeptide of formula Phe-β-Ala-Gly-Trp-NH2, possessing anxiolytic action.

EFFECT: increased biological activity.

1 dwg

FIELD: medicine.

SUBSTANCE: medication includes lithium oxybate, sodium selenite, ascorbic acid and water for injections with the following component ratio, wt %: lithium oxybate - 4.0-7.0, sodium selenite - 0.2-0.5, ascorbic acid - 3.0-12-0, water for injections - the remaining part.

EFFECT: medication possesses expressed nootropic activity and immunostimulating action, is convenient to introduce.

1 dwg, 4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: in order to reduce volume of ischemic stroke infarction, improve functional recovery, increase of eNOS expression, inhibit apoptosis and increase eNOS expression, treat symptoms of ischemic stroke or delivery of bile acid product to brain in patient after ischemic stroke or subjected to risk of ischemic stroke, composition which includes ursodeoxycholic acid, maltodextrin and water, is introduced. In said composition ursodeoxycholic acid and maltodextrin remain in solution at all values of solution pH in selected range from pH=1 to pH=10.

EFFECT: invention makes it possible to produce efficient impact on said states due to improved bioaccessibility of ursodeoxycholic acid to patient's brain.

8 cl, 2 tbl, 11 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention relates to drug form for treatment pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist, which includes from 10 to 40 mg of oxycodon and/or its pharmaceutically acceptable salt and from 5 to 20 mg of naloxon and/or its pharmaceutically acceptable salt, present in ratio 2:1 by weight.

EFFECT: providing drug form for treatment of pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist.

9 cl, 51 dwg, 38 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: in order to stop alcohol abstinence introduction of naloxon in strict sequence after fixed 45 minutes is performed, initially medication is introduced intravenously in dose 0.8 mg slowly during 1-2 minutes, and then only intramuscularly in dose 1.2 mg if weight is lower or equals 75 kg, or in dose 1.6 mg if weight is over 75 kg. In case of necessity intramuscular injections are continued after patient's awakening from drug-induced sleep to repeated sleep and complete stop of abstinence effects.

EFFECT: fast and efficient stop of main symptoms of alcohol abstinence with absence of side effects due to elaborated methods of naloxon introduction.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (11) given below and pharmaceutically acceptable salts thereof: chemical formula 1

in which: each of G1, G2, G3 and G8 independently denotes -N=, -CR1= or -C(-G9-X)=; one of G1, G2, G3 and G8 is-C(-G9-X)=; X is C1-6 alkyl (where C1-6 can be optionally substituted with a group selected from a halogen atom, hydroxy, cyano and -NR56R57), aryl, heterocycle (where the heterocycle denotes a 5-9-member saturated or unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur atoms, and can be a monocycle or condensed ring, and can be optionally substituted with a halogen atom, C1-6 alkyl; C1-6 alkoxy, R33R34NCS-, R3R4NCO-); G9 denotes a single bond, an oxygen atom, a sulphur atom, ring G6 denotes a divalent aryl group or divalent pyridyl group (where the divalent pyridyl group can be optionally substituted with a halogen atom); A is a group of formula (2) given below, or a group of formula (3) given below. Chemical formula 2

, chemical formula 3 , G4 is an oxygen atom or sulphur atom; G5 is an oxygen atom or sulphur atom; G7 is an oxygen atom, -CR42R43-, -CONR44-, -NR44CO, -NR45-, CR42R43NR45-, -S-, -NR44S(=O)2-; R1 is a hydrogen atom, a halogen atom, cyano, C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a halogen atom), carbamoyl or C2-7 alkynyl (where C2-7 alkynyl can be optionally substituted with C1-4 acyl); when G2 or G3 denotes -CR1=, then G8 is -C(-G9-X)=, and X is R3R4NCO-, R33R34NCS-; when G8 is -CR1=, then G3 denotes -C(-G9-X)=, and X is R3R4NCO, or R33R34NCS-; when G1 or G8 denotes -CR4 then G2 is -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; or when G2 is -CR1=, then G1 denotes -C(-G9-X)=, and X denotes R3R4NCO-, or R33R34NCS-; R1 can form a single bond or -CH2- with R4 or R34; R2 denotes hydroxy or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from a halogen atom, hydroxy, C1-6 alkoxy, formyl and -CO2R50); R3, R4, R9 and R10 each independently denotes a hydrogen atom, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, a halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R6 and R7 each independently denotes a hydrogen atom, C1-6 alkoxy, C3-8 cycloalkyl or C1-6 alkyl (where C1-6 alkyl can be optionally substituted with a group selected from cyano, halogen atom, hydroxy, C1-6 alkoxy, -NR13R14, and CONR28R29); R33 and R34 each independently denotes a hydrogen atom, C1-6 alkyl, the combination of R3 and R4 together with a nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom or C1-6 alkyl; the combination of R6 and R7 together with the nitrogen atom to which they are bonded can form a 5-6-member heterocyclic group containing at least one nitrogen atom (where the 5-6-member heterocyclic group which contains at least one nitrogen atom is a saturated or unsaturated heterocyclic group containing 5-6 atoms in the ring and which, in addition to one or more nitrogen atoms, can contain one or more heteroatoms selected from oxygen and sulphur atoms (where the 5-6-member heterocyclic group can be optionally condensed with a benzene ring); and which can be optionally substituted with a halogen atom, C1-6 alkyl or an oxo group; R45 is a hydrogen atom, R13 and R14 each independently denotes a hydrogen atom, C1-6 alkyl or COR32; R56 and R57 each independently denotes a hydrogen atom or C1-6 alkyl, and R5, R8, R28, R29, R32, R42, R43, R44, and R50 each independently denotes a hydrogen atom or C1-6 alkyl. The invention also relates to a pharmaceutical composition, as well as to a medicinal agent for treating cell proliferative disorder.

EFFECT: obtaining novel biologically active compounds having inhibitory effect on cell proliferation.

15 cl, 2 tbl

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