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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-thiazolyl)amide derivatives of formula wherein R1 and R2 are independently selected from H, -NO2, fluorine, chlorine and iodine, provided at least one of R1 and R2 is different from H; m is equal to 1 or 2, or to its pharmaceutically acceptable salts.

EFFECT: invention refers to a method for preparing said compounds, based pharmaceutical composition and applying them for preparing a drug for treating or preventing GSK-3 mediated diseases or conditions, especially neurodegenerative diseases, such as Alzheimer's disease or insulin-independent diabetes.

24 cl, 3 tbl, 1 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 insulin-independent 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, where 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 heat the Oka 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 the expression of certain vital genes of Wnt targets such as bcl-2. The Sam the STS 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 cdk5 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.

Facts, atacamas 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 foregoing, 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 different is cnyh peptide chain 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 RA the disorders in humans, 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, where 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 ,

X is selected from the group consisting of:

pyridine associated with any of the provisions 2-6; and

phenyl,

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 compounds of formula (I) can be used in biological research, where it is necessary 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, comprising the administration to a patient 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 present 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 Rawa is 0, 1, 2, 3, 4, 5 or 6,

or any pharmaceutically acceptable salt, solvate and prodrug.

According to a 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 a pharmaceutical 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-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, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl 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 R 2independently 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:

pyridine associated with any of the provisions 2-6; and

phenyl,

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 pyridine.

Other preferred compounds used are those in which m is 1, 2, 3, 4, 5 or 6. More preferred compounds are those in which m is 1 or 2.

Other preferred compounds used are those in which the halogen is fluorine, chlorine or iodine.

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 NO2. Thus, more preferred are such compounds where one of R1and R2is NO2and the other is H. Tighter preferred compounds are such where R1means NO2and R2is H.

Other preferred compounds are those where one of R1and R2is Cl and the other is H. Even more preferred are such compounds where R1is Cl, and R2is H.

In accordance with the preferred embodiment, the compound of formula (I)used in the present invention are selected from the following compounds:

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, the disease Peak, Sindh is the MD of Gerstmann-Straussler-Sheinker, the disease of 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, 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 narottam the political 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 amyloid 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 enriched1 N; 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 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, hydropram is d, 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 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. The spiral is Mr. 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 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 d the I modulation of GSK-3 in biological research, 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 the administration to a patient 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 this 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 H;

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

or any pharmaceutically acceptable salts, solvate and prodrugs.

The preferred compounds are those in which m is 1, 2, 3, 4, 5 or 6. More preferred compounds are those in which m is 1 or 2.

Other preferred compounds used are those in which the halogen is fluorine, chlorine or iodine.

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

Preferably, one of R1or R2is NO2. In affect, the, more preferred are such compounds where one of R1and R2is NO2and the other is H. Even more preferred compounds are those where R1means NO2and R2is H.

Other preferred compounds are those where one of R1and R2is Cl and the other is H. Even more preferred are such compounds where R1is Cl, and R2is H.

In accordance with the preferred embodiment, 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, ester is, the 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 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 is 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 parent compound to a biological compartment (e.g., 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 midrange is melting, among others, 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 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.

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, suspen the AI or emulsion) 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, polyvinylpyrrolidone, 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 kishen is soluble coatings.

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 can be 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 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 compound of the formula (I) can be obtained in accordance with the strategic framework, which includes the direct combination of pyridyl-acid of the formula (II):

where

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

with a thiazole of the formula (III):

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

The compounds of formula (II) and (III) are commercially available.

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

In a specific embodiment of this invention the compound of formula (I) are obtained in accordance with the following General methodology. To a solution of the corresponding pyridyl-acid of the formula (II) in anhydrous tetrahydrofuran (hereinafter abbreviated as THF) is added to 1.5 N,N'-carbonyldiimidazole (hereinafter abbreviated DCI) as the activating agent in anhydrous THF. The resulting mixture was stirred at room temperature for about 4-5 hours Then the reaction mixture was added 1 equivalent of the corresponding thiazole of the formula (III) in THF and stirring is continued at room temperature for approximately 8-10 hours. Upon completion of the reaction, the solvent evaporated, the crude residue dissolved in CH2Cl2and washed with water. Cleaning is carried out in accordance with the General purification methods known to experts in this field.

The following examples are given to further illustrate the present invention, however, they should not be construed as limiting the invention.

EXAMPLES

Preparative examples

In the future, provides a detailed description of obtaining the compounds of Formula (I) in accordance with the present invention.

Example 1

Obtaining N-(5-Nitrothiazol-2-yl)-2-pyridin-3-ylacetamide (compound 1)

To a solution of hydrochloride of 3-peridiocally acid (2,076 g, 12 mmol) in anhydrous THF was added 1.5 equivalent of CDI (18 mmol, 2,916 g) and 1 equivalent NEt3(of 1.66 ml). The resulting mixture was stirred at room temperature for 4 hours. Then to the reaction mixture were added 2-amino-5-nitrothiazole (12 mmol, 1,740 g) in THF and stirring PR which was continued for 10 hours Upon completion of the reaction the solvent was evaporated and the resulting brown residue was dissolved between CH2Cl2and water. The mixture gave a yellow precipitate, which was filtered and washed with water, which gave the desired compound as a yellow solid (2,300 g, yield: 73%, 265 M+).

1H-NMR (DMSO): 3,95 (s, 2H); 7,38 (DD, 1H); 7,74 (d, 1H); and 8.50 (d, 1H); charged 8.52 (s, 1H); 8,63 (s, 1H).

13C-NMR (DMSO): 38,52; 123,4; 129,7; 137,1; 141,7; 142,6; 148,1; 150,3; 161,8; 170,7

Biological examples

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

GSK-3β inhibition

This analysis is based on the Protocol described in detail in Upstate Cat. 14-306, with minor modifications.

Recombinant human glikogensintetazy-kinase 3β analyzed in solution 11 mm MOPS (pH of 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 (PerkinEmer, Microbeta 1450). 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 tau phosphorylation

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 the aliquot of the cell lysate 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 example 1, and 6 other compounds of formula (I) was determined at different final concentrations, namely 50, 100 and 200 μm. Not all with the unity of formula (I) experienced with all these concentrations. The results are presented in table 1 (see below) marked "negative" and "position", 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.

td align="center"> position
Table 1
Connection # Formula% the activity of GSK-3Inhibition of phosphorylation of tau-protein in cells
25 mcm50 mcm50 mcm100 mm200 mcm
Connection 1
(example 1)
to 5.212,78positionposition-
Connection 2 8,3are 5.36positionposition-
Connection 39,494,1the negativeposition-
Connection 45,613,8the negativeposition-
Connection 576,7243,78---
Connection 622,2950,90---
Connection 713,738,05position-

Together with studies of the phosphorylation of tau protein were conducted quantitative studies of cell death, due to the possible toxicity of compounds 1 and 3 described above, 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 compounds 1 and 3, the cell survival was measured during processing within 24 hours (see table 2), and for compound 2 was measured 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 1- -94,1±1,886,5±4,7
Connection 3--87±6,085,4±2,7

Table 3
Connection # % surviving cells
50 mcm100 mm
Connection 295,7±4,293,7±7,1

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 X is selected from pyridine, associated with any of the provisions 2-6;
when X is pyridine,
R1and R2independently selected from H, -NO2, fluorine, chlorine, iodine;
m is equal to 0, 1, 2, 3, 4, 5 or 6, and
or any pharmaceutically acceptable salts for obtaining a medicinal product for treatment or prevention of diseases or conditions mediated by GSK-3.

2. The use according to claim 1, where m is equal to 0, 1, 2, 3, 4, 5 or 6.

3. The use according to claim 2, where m is equal to 1 or 2.

4. The use according to any one of paragraphs.-3, where at least one of R1and R2different from N.

5. The use according to claim 1, where one of R1and R2is N.

6. The use according to claim 1, where one of R1and R2is NO2.

7. The use according to claim 5, where R1is NO2and R2is N.

8. The use according to claim 5, where R1is C1, and R2is N.

9. The use according to claim 1, where R1is NO2and R2is H, m is 0, 1 or 2, and X is pyridine.

10. The use according to claim 1, where the compound is selected from the following compounds:

or any pharmaceutically acceptable salts.

11. The use according to claim 1, where the drug is used to treat and prevent illness or condition requiring inhibition of GSK-3.

12. The application of claim 11, 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, also decided the Lenna 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, 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.

13. The application indicated in paragraph 12, where the disease or condition selected from Alzheimer's disease, diabetes, Parkinson's disease, epilepsy and mood disorders.

14. The use of the compounds of formula (I)as defined according to any one of claims 1 to 10, or any salts as reagents for modulating GSK-3 in biological analyses, preferably as a reagent for inhibiting GSK-3 activity.

15. Link the formula (I):

where R1and R2independently selected from H, -NO2, fluorine, chlorine and iodine, provided that at least one of R1and R2different from N;
m is 1 or 2,
or any of its pharmaceutically acceptable salts.

16. The connection indicated in paragraph 15, where one of R1and R2is N.

17. The connection indicated in paragraph 15, where one of R1and R2is NO2.

18. The compound according to any one of p-17, where R1is NO2and R2is N.

19. The compound according to any one of p-16, where R1is C1, and R2is N.

20. The connection indicated in paragraph 15, where R1is NO2and R2is H, m is 1 or 2.

21. The connection 15, selected from the following compounds:

or any pharmaceutically acceptable salts.

22. The connection 15 for use as a drug for treatment or prevention of a disease or condition mediated by GSK-3.

23. Pharmaceutical composition for treatment or prevention of a disease or condition mediated by GSK-3, containing a therapeutically effective amount of at least one of the compounds of formula (I)as defined according to any one of p-21, or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier, adjuvant and and filling.

24. The method of obtaining the compounds of formula (I)as defined according to any one of p-21, including the combination of a pyridyl-acid of the formula (II):

where m is 1 or 2;
with a thiazole of the formula (III):

where R1and R2independently selected from H, -NO2, fluorine, chlorine and iodine, provided that at least one of R1and R2differs from N.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 5-amino-3-(2-aminopropyl)-[1,2,4]thiadiazole derivatives of general formula wherein R1, R2, R3 can be identical or different independently means hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, heteroaralkyl (wherein 5- or 6-member N-, O- or S-heteroaromatic cycle), cycloalkyl, 2,2,6,6-tetramethyl-piperidin-4-yl, and also R1+R2 can mean heterocycle specified in optionally substituted pyrrolidine, piperidine, azepane, piperazine, morpholine wherein optional substitutes can be hydroxyl, cyanogroup, halogens, alkyls, lower alkoxy groups, lower alkothio groups, trihalogen methyl, sulphamide, optionally substituted amino groups (amino, dimethyl amino, diethyl amino) provided R1=H, R2 is different from hydrogen or methyl.

EFFECT: there are produced new compounds which can find application in medicine as the substances possessing neuromodulatory activity.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, where Ar denotes a phenyl group substituted with piperazine or benzo[d]thiazole, with a phenyl part bonded to B, where the piperazine or benzo[d]thiazole can be unsubstituted or substituted with substitutes selected from alkyl or acetyl; B denotes -O-; R1 denotes hydrogen; R2 denotes S(O)2R4 or C(O)(CH2)n-C(O)OR5; R3 denotes halogen; R4 denotes an aryl which can be unsubstituted or substituted with substitutes selected from a group comprising halogen, alkyl, fluoroalkyl, alkoxy and trifluoromethoxy; R5 denotes hydrogen; n is a whole number from 1 to 3. The invention also relates to a method of producing said compounds and a pharmaceutical composition for treating metabolic disorders associated with insulin resistance or hyperglycaemia, based on said compounds.

EFFECT: novel compounds are obtained, which can be used in medicine to treat type 2 diabetes, obesity, glucose intolerance, dyslipidaemia, hyperinsulinaemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension or non-alcoholic fatty liver disease.

28 cl, 3 dwg, 4 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing amide-containing 1,3,5-dithiazinanes of general formula , where R=H (Ia), CH3 (Ib). The method is realised by reacting hydrogen sulphide-saturated aldehyde (formal or acetic) with a mixture of isonicotinic acid hydrazide - BuONa (1:3, pH>11.5). The process is carried out at ratio hydrazide: aldehyde: H2S equal to 1:3:2, at temperature 40°C while stirring constantly for 4 hours, followed by neutralisation with a calculated quantity of dilute HCl and purification via column chromatography on SiO2. The substances obtained using the disclosed method can be used as radiation protection, antitumour and diuretic agents, as well as selective sorbents and extractants of noble and precious metals.

EFFECT: obtaining amide-containing 1,3,5-dithiazinanes of general formula (I).

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3,4-thiadiazolines (I), thiadiazinones (II) and thiadiazepines (III), obtained based on thiohydrazides of oxamic acids, which can be used to inhibit pathogenic bacteria, and can particularly affect type III secretion system in pathogens, having general formula:

, , ,

where R denotes H; R1 denotes H, pyridinyl; phenyl, substituted with alkyl C1-C5, Hal, CF3; a group , where X denotes S, substituted with alkyl C1-C5, COOR4; R2, R3 denotes alkyl C1-C5, pyridinyl, phenyl, substituted Hal, OH, OR4, a R4 denotes unsubstituted alkyl C1-C4.

EFFECT: obtaining compounds which can be used to inhibit pathogenic bacteria.

2 cl, 2 dwg, 6 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and ,

where the ring X represents benzole or pyridine; R1 represents substituted alkyl; R2 represents optionally substituted aryl or optionally substituted 4-7-member monocyclic heterocyclic group or optionally substituted condensed group of heterocyclic group with the benzole ring where the substitutes of optionally substituted aryl, optionally substituted 4-7-member monocyclic heterocyclic group and optionally substituted condensed group of heterocyclic group with the benzole ring are selected from a group consisting of; (1) alkyl optionally substituted by a group selected from halogen and alkoxycarbonyl, (2) alkoxy optionally substituted by halogen, (3) halogen, (4) 4-7-member monocyclic heterocyclic group or (5) amino, optionally mono- or disubstituted alkyl, and (6) hydroxyl, R3 represents hydrogen or alkyl: R4 represents hydrogen, halogen or alkyl; R5 represents hydrogen or alkyl; R6 and R7 are identical or different, and each represents hydrogen or halogen; or pharmaceutically acceptable salt. Also, the invention refers to a IKur blocker containing the compounds described above as an active ingredient, and also to a preventive and therapeutic agent for cardiac arrhythmia and atrial fibrillation.

EFFECT: there are produced and described new compounds applicable as a IKur blocker effective for preventing or treating cardiac arrhythmia, such as atrial fibrillation.

12 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

Gsk-3 inhibitors // 2449998

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula , wherein RB is specified in: while R3, R4, R'2, R'3, R'4, R'5, and R'6 represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to cardiology and laser therapy, and may be used in treating the patients with ischemic heart disease (IHD) or patients with IHD combined with diabetes. A method involves standard therapeutic treatment of the disease. Before the beginning of treatment, blood glucose and total blood cholesterol are evaluated. If blood glucose in the patients with IHD is less than 4.75 mmol/l and total blood cholesterol in the patients with IHD combined with diabetes is less than 5.5 mmol/l, laser therapy is additionally prescribed.

EFFECT: method provides proved prescription of an additional type of treatment in the form of laser therapy due to prediction of its efficacy on the basis of simple objective criteria without using expensive examination in the patients.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a method for preparing a dosage form of a hypolipidemic, hypoglycemic agent of thioctic (α-lipoic) acid. A mixture of thioctic acid, microcrystalline cellulose and lactose is wetted with hydroxypropyl methyl cellulose in the mixture of water and ethanol; the wetted mass is mixed, dried, granulated; the granulate is added with magnesium alumomethasilicate, primojel, magnesium and/or calcium stearate, sodium stearylfumarate, aerosil and/or talc; the tablets are pressed and coated with the film Opadry II. As a result, there are produced the coated tablets containing thioctic acid 300 mg and 600 mg as the active substance.

EFFECT: prepared drug preparation provides effective daily dosage - 600 mg/day for 1 - 2 intakes; the preparation is storage stable.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, where Ar denotes a phenyl group substituted with piperazine or benzo[d]thiazole, with a phenyl part bonded to B, where the piperazine or benzo[d]thiazole can be unsubstituted or substituted with substitutes selected from alkyl or acetyl; B denotes -O-; R1 denotes hydrogen; R2 denotes S(O)2R4 or C(O)(CH2)n-C(O)OR5; R3 denotes halogen; R4 denotes an aryl which can be unsubstituted or substituted with substitutes selected from a group comprising halogen, alkyl, fluoroalkyl, alkoxy and trifluoromethoxy; R5 denotes hydrogen; n is a whole number from 1 to 3. The invention also relates to a method of producing said compounds and a pharmaceutical composition for treating metabolic disorders associated with insulin resistance or hyperglycaemia, based on said compounds.

EFFECT: novel compounds are obtained, which can be used in medicine to treat type 2 diabetes, obesity, glucose intolerance, dyslipidaemia, hyperinsulinaemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension or non-alcoholic fatty liver disease.

28 cl, 3 dwg, 4 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns an effect for suppressing the transplanted island damage following island transplantation by IL-6 receptor antibodies.

EFFECT: decreased transplanted island damage, increased island survival rate and corrected hyperglycemia in recipients.

17 cl, 3 ex, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and more specifically to an antidiabetic composition. What is offered is a pharmaceutical composition containing Glimepiride, poloxamer, sodium croscarmellose and other excipients - povidone, lactose monohydrate, microcrystalline cellulose, stearic acid salt and a colourant.

EFFECT: pharmaceutical composition is characterised by high therapeutic activity, satisfactory technical characteristics and shelf life of more than 2 years.

11 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely endocrinology, cardiology and can be used for treating dislipidemia. That is ensured by introducing a pharmaceutical composition containing a thiazolidinedione analogue of formula

EFFECT: introducing the compound of formula 1 having decreased binding and activation of PPAR-gamma nuclear transcription factor, enables effective treatment of dislipidemia with no adverse side effects typical for PPAR-gamma agonists.

2 dwg, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology and represents using a composition containing sebacic acid and/or its derivatives selected from salts and esters for making a product for oral and enteral introduction which is applicable for: (i) treating or preventing peripheral insulin resistance, impaired glucose tolerance, diabetes, hyperglycemia and related disorders, such as nephropathy, retinopathy, cardiac and cardiovascular diseases (ii) increased glucose clearance and/or insulin responsitivity; (iii) hepatic glucose formation inhibition or (iv) reduced endogenous glucose production.

EFFECT: invention provides regulation and control of the glucose and insulin levels in healthy individuals and diabetic patients.

22 cl, 3 tbl, 5 dwg

FIELD: food industry.

SUBSTANCE: present invention relates to prevention of subsequent diseases by way of a specific nutritive composition prescription to children at an age of up to 3 years. One proposes the composition application; for production of the nutritive composition for: prevention and/or therapy of visceral adiposopathy and/or prevention and/or therapy of visceral fat mass accumulation up to an excessive quantity where the nutritive composition is prescribed for administration to a child at an age of 0 - 36 months. The composition contains a lipid, a protein components and a digestible carbohydrates component. The lipid component accounts for 35 - 55% of the total calorie content and contains less than 14.5 wt % of linoleic acid of the total fatty acids weight, the weight ratio of linoleic acid (LA) to alfa-linolenic acid (ALA) is 2 - 6. The protein component accounts for 5 - 15% of the total calorie content, the digestive carbohydrates component for 30-60% of the total calorie content. Additionally the composition may contain galactooligosaccharides, long chain polyunsaturated fatty acids (LC-PUFA) and 10-50 wt % of medium-chain fatty acids (MCFA).

EFFECT: invention allows to prevent development of disorders related to visceral adiposopathy with humans at an age over 36 months.

18 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

Gsk-3 inhibitors // 2449998

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula , wherein RB is specified in: while R3, R4, R'2, R'3, R'4, R'5, and R'6 represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

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