Gsk-3 inhibitors

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

 

The SCOPE of the INVENTION

The present invention relates to inhibitors of enzymes and, in particular, heterocyclic inhibitors glikogensintetazy-kinase 3β, GSK-3, to methods of producing such compounds, including pharmaceutical compositions and to their use for the treatment and/or prevention of disease involving GSK-3, such as Alzheimer's disease or non-insulin-dependent diabetes mellitus.

PREREQUISITES TO the CREATION of INVENTIONS

The search for new therapeutic agents has helped considerably in recent years a better understanding of the structure of enzymes and other biomolecules associated with the target disease. One important class of enzymes that has been the object of extensive research, are protein kinases. Many diseases are associated with abnormal cellular responses caused mediated by protein kinase events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, or hormone-related diseases. Respectively, were made real efforts in the field of pharmaceutical chemistry, to find inhibitors of protein kinases, which are effective as a therapeutic agent.

Glikogensintetazy-kinase (GSK-3) is a serine/threonine a protein kinase, including isoforms α and β, each of which are encoded by different genes (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 type glikogensintetazy kinase 3 (GSK-3) plays a Central role in various related receptor signaling pathways (Doble BW, Woodgett, JRJ. Cell Sci. 2003, 116:1175-1186). Dysregulation of these pathways is considered a critical event in the development of some common disorders in humans, such as diabetes type II (Kaidanovich Oh, Eldar-Finkelman H, Expert Opin. Ther. Targets, 2002, 6:555-561), Alzheimer's disease (Grimes CA, Jope RS, Prog. Neurobiol. 2001,65:391-426), CNS disorders such as manic-depressive disorder, and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich KP, Luo J, maintainance and care instructions EA, Tsao MS, Jin Oh, Woodgett J, Nature 2000,406:86-90). These diseases can be caused by abnormal functioning of the signaling pathways in some cells, in which GSK-3 plays a role, or lead to it.

It was found that GSK-3 phosphorylates and modulates the activity of many regulatory proteins. These proteins include glikogensintetazy, which is the limiting enzyme necessary for glycogen synthesis, associated with the microtubule protein Tau, factor gene transcription of β-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, factor heat shock-1, c-Jun, c-Myc, c-Myb CREB and CEPBα. These diverse protein targets involve GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

Currently, the inhibition of GSK-3 may represent a viable strategy for the development of new medicines for the treatment of hitherto incurable diseases (Martinez A, Castro A, Dorronsoro I, Alonso M, Med. Res. Rev., 2002, 22:373-384) through the mimicry of insulin, the dephosphorylation of tau and processing of amyloid protein, or modulation of transcription, respectively.

Among the wide variety already detected chemical structures, inhibiting GSK-3 (Dorronsoro, I; Castro, A; Martinez, A Exp Opin Ther Patents 2002, 12:1527-1536; Alonso, M. and Martinez, A. Current Medicinal Chemistry, 2004, 11, 753-761), 2,4-disubstituted, thiadiazolidine (TDZD) represent the first ATP-noncompetitive inhibitors of GSK-3 (Martinez A, Alonso M, Castro A, Perez C, Moreno F, J Med Chem, 2002, 45:1292-1299; WO 01 85685 and US 2003/0195238). These compounds are of great interest because they are selective and do not demonstrate inhibition of other kinases, such as PKA, PKC, CK-2 and CDK1/cyclin B. However, thiadiazolidine tend to react with nucleophiles, and this property can reduce their potential as a drug.

There is still the need to find a good inhibitors of GSK-3, which were both effective and selective, and would have good properties in terms of use in ka is este medicines, that is a good pharmaceutical properties associated with administration, distribution, metabolism and excretion.

Description of the INVENTION

Taking advantage of some of the results of molecular modeling and theories, the authors have designed and synthesized a second generation of 2,4-disubstituted thiadiazolidine (TDZD), which are very stable against diastereomer biological molecules, such as glutathione and BSA (bovine serum albumin). Unexpectedly, these compounds are also very favorable drug profile, in particular oral bioavailability and the ability to penetrate the blood-brain barrier.

In one aspect the invention relates to compounds of General formula I:

in which:

R1denotes an organic group containing at least 8 atoms selected from C or O, which are not directly linked to N-C(O)- and includes at least an aromatic ring;

Ra, Rb, R2, R3, R4, R5, R6independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, -COR7-C(O)OR 7, -C(O)NR7R8-C=NR7, -CN, -OR7, -OC(O)R7, -S(O)t-R7, -NR7R8, -NR7C(O)R8, -NR2, -N=CR7R8or halogen,

t=0, 1, 2 or 3,

R7and R8each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted, aryloxy, halogen;

and Raand Rbtogether can form a group =O, and each of the pairs RaR2, R2R3, R3R4, R4R5, R5R6, R6Rbor R7R8may form a cyclic Deputy;

or their pharmaceutically acceptable salt, prodrug or MES.

The authors found that compounds with benzylphenol structure in position 4 and spatial hindered group comprising an aromatic ring or aromatic ring in position 2 thiadiazolidine optimally interact with the enzyme GSK-3, at the same time having good properties as pharmaceuticals.

The preferred compounds are such compounds in which R1has arene is political group, containing at least 10 aromatic carbon atoms. These compounds show good activity, stability and reduced binding to plasma proteins, such as glutathione and albumin.

Also preferred are compounds in which R1has an aromatic group is directly related to N thiadiazolidine.

In private variants of implementation of the preferred compounds in which R1is naphthyl, more preferably, when R1is α-naphthyl.

Another preferred class of compounds is of such compounds in which the substituent in position 4 TDZD is unsubstituted benzyl group.

In another aspect the invention relates to pharmaceutical compositions that include the compound according to formula (I) or its pharmaceutically acceptable salt, prodrug or MES, and pharmaceutically acceptable basis, adjuvant or carrier. In a preferred embodiment, the composition is for oral administration.

The present invention also relates to the use of the above defined compounds in obtaining medicines, preferably for the mediated GSK-3 disease or condition.

Alternatively, the invention also relates to a method of treatment mediated by GSK-3 disease or condition, including centuries the Denia to the patient an effective amount of the compounds of formula I, as defined above, or its pharmaceutically acceptable salt, prodrug or MES.

In another aspect the invention relates to the use of the above defined compounds as reagents for biological tests, preferably as reagents for inhibition of GSK-3.

In another aspect, the invention relates to a method for obtaining compounds of formula I by reaction of the corresponding benzylisothiocyanate with the isocyanate of formula R1-N=C=O.

DETAILED description of the INVENTION

Typical compounds of the invention selectively inhibit GSK-3β, not through the inhibition of other protein kinases, such as PKA, PKC, CK-2 and CdK2, which could depreciate their value. Additionally they are not associated significantly with model proteins, such as glutathione and bovine serum albumin, which is a good indicator as to their stability in plasma. They also show good absorption and the ability to pass through the blood-brain barrier, as demonstrated in the examples.

In the above definition of the compounds of formula (I), the following terms have the following values.

"Alkyl" refers to straight or branched hydrocarbon chain consisting of carbon atoms and hydrogen, containing no unsaturated bonds containing one to eight carbon atoms, and which is connec is on to the rest of the molecule by a simple link, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl, n-pentyl etc. Alkyl radicals may be substituted by one or more substituents, such as halogen, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio.

"Alkoxy" refers to a radical of the formula-ORa, where Ra denotes an alkyl, as defined above, such as methoxy, ethoxy, propoxy, etc.

"Alkoxycarbonyl" refers to a radical of the formula-C(O)ORa, where Ra denotes an alkyl, as defined above, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl etc.

"Alkylthio" refers to a radical of the formula-SRa, where Ra denotes an alkyl, as defined above, for example methylthio, ethylthio, propylthio etc.

"Amino" refers to a radical of the formula-NH2, -NHRa or-NRaRb, where Ra and Rb are as defined above values.

"Aryl" refers to phenyl, naphthyl, Danilo, ventrilo or intracellu, preferably, naphthyl or phenyl. Aryl can be substituted by one or more substituents such as hydroxy, mercapto, halogen, alkyl, phenyl, alkoxy, halogenated, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined in the present description.

"Aralkyl" refers to an aryl group linked to an alkyl group. Preferred examples include benzyl and phenethyl.

"Acyl" refers to the radical is ormula-C(O)-Rc, and-C(O)-Rd, where Rc represents alkyl such as defined above and Rd represents aryl, as defined above, for example acetyl, propionyl, benzoyl, etc.

"Arylalkyl" refers to alkyl, substituted-Ra-C(O)-Rd, where Ra represents alkyl. Preferred examples include benzoylmethyl.

"Carboxy" refers to a radical of the formula-C(O)HE.

"Cycloalkyl" refers to a stable 3 to 10-membered monocyclic or bicyclic the radical, which is saturated or partially saturated and which is composed solely of carbon atoms and hydrogen. Unless otherwise indicated, the term "cycloalkyl includes cycloalkyl radicals which may be substituted by one or more substituents such as alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

"Condensed aryl" refers to aryl, especially phenyl or heteroaryl condensed with another ring.

"Halogen" refers to bromine, chlorine, iodine or fluorine.

"Halogenated" refers to alkyl as defined above which is substituted by one or more Halogens, as defined above, for example trifluoromethyl, trichloromethyl, 2,2,2-triptorelin, 1-vermeil-2-torail etc.

"Heterocycle" refers to heterocyclyl. A heterocycle refers to a stable 3 to 15-membered ring which consists of carbon atoms and from one to five heteroatoms, wybran the x group, consisting of nitrogen, oxygen and sulfur, preferably, 4 to 8-membered ring with one or more heteroatoms, more preferably, 5 - or 6-membered ring with one or more heteroatoms. In the framework of the invention, the heterocycle may be monocyclic, bicyclic or tricyclic ring system, which may include a condensed ring system; and atoms of nitrogen, carbon or sulfur in heterocyclyl can be oxidized; the nitrogen atom may be quaternity; and heterocyclyl may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepine, benzimidazole, benzothiazole, furan, isothiazol, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran.

Here references to substituted groups in the compounds according to the invention belong to the specified group which may be substituted in one or more available positions by one or more suitable groups, for example halogen, such as fluorine, chlorine, bromine and iodine; cyano; hydroxyl; nitro; azido; alkanoyl, such as C1-6-alkanoyl, such as acyl and the like; carboxamido; alkyl, including groups having from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; and alkenyl quinil, including g PPI, having one or more unsaturated linkages and from 2 to about 12 carbon atoms or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bridges and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aryloxy, such as phenoxy; alkylthio, including groups having one or more thioester linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl, including groups having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl, including groups having one or more sulfanilic linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more carbon atoms, especially phenyl or naphthyl, and aralkyl, such as benzyl. Unless otherwise specified, if necessary substituted group may have a substituent in each possible to displace the position of the group, and each substitution is independent of the other.

Unless otherwise indicated, the compounds according to the invention also VK is ucaut connection which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having a structure according to the invention except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13C - or14C-enriched carbon or15N-enriched nitrogen, are within the scope of the invention.

The term "pharmaceutically acceptable salt, derivative, solvate, prodrug" refers to any pharmaceutically acceptable salt, complex ether, MES or any other compound which, upon administration to the recipient is able to form a connection as described here. However, it should be borne in mind that non-pharmaceutical acceptable salts also fall within the scope of the invention as they may be useful in obtaining pharmaceutically acceptable salts. Obtaining salts, prodrugs and derivatives can be made by methods known in the art.

For example, pharmaceutically acceptable salts of the compounds according to the invention are synthesized from the parent compound which contains a basic or acidic group, conventional chemical methods. Generally, such salts are, for example, receive, entering in the reaction of the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent is, or mixtures thereof. In General, the preferred non-aqueous environment, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of salts of Association with an acid include salts joining with an inorganic acid, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and salts of joining with an organic acid, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methylsulfonate and p-toluensulfonate. Examples of salts of joining with the base include inorganic salts such as, for example, salts of sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and an organic salt of an alkali metal, such as, for example, Ethylenediamine, ethanolamine, N,N-dialkylimidazolium, triethanolamine, glucamine and salts of basic amino acids.

Especially preferred derivatives or prodrugs are those that increase the bioavailability of the compounds according to the invention with the introduction of such compounds to a patient (for example, by oral input connection is quickly absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (for example, the brain or lymphatic system) compared to the original varieties.

Any compound that is a prodrug of compounds of formula (I), nah is implemented in the framework of the invention. The term "prodrug" is used in its broadest sense and encompasses derivatives, which in vivo are converted into compounds according to the invention. Such derivatives can easily be determined by the specialist and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds according to the invention: esters, esters of amino acids, phosphate esters, sulfonates of metal salts, carbamates and amides. Examples of known methods of obtaining the prodrugs of this active compound known to the expert and can be found, for example, Krogsgaard-Larsen et al. "In Textbook of Drugdesign and Discovery" Taylor & Francis (april 2002).

Compounds according to the invention may be in crystalline form as free compounds or as a solvate (e.g. hydrate), and both forms are within the scope of the present invention. Methods solutionone are known from the prior art.

Suitable solvate are pharmaceutically acceptable solvate. In the private embodiment, the MES is a hydrate.

The compounds of formula (I)or its salt, or a solvate are preferably in pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable form is, among other things, the form with pharmaceutically acceptable level of purity, drop the I conventional pharmaceutical additives, such as diluents and carriers, and do not include any material that is toxic in normal doses. The purity levels for substances of the medicinal product, preferably above 50%, more preferably above 70%, most preferably above 90%. In the preferred embodiment, it is more than 95% in relation to the compounds of formula (I) or its salt, solvate or prodrugs.

Compounds according to the invention represented by the above formula (I)may include enantiomers depending on the presence of chiral centers, or isomers, depending on the availability of multiple links (e.g., Z, E). Individual isomers, enantiomers or diastereoisomers and mixtures thereof are within the scope of the present invention.

The authors found that the compounds of formula I are selective inhibitors of GSK-3 (they do not show inhibition of other kinases), and additionally they are good pharmacological properties which make them suitable for obtaining medicines. Indeed, through appropriate selection of the size and chemical characteristics of the substituents on the ring TDZD, the authors obtained the compounds that are very stable against molecules of the plasma, such as glutathione and BSA, and show good oral bioavailability and the ability to pass through heme is encephalocele barrier.

R1includes an aromatic group, it improves the properties of stability. In one embodiment, R1has at least 10 aromatic carbon atoms. Alternatively, a good connection is obtained with groups of donors of electrons on the aromatic ring, such as alkoxyl or methylendioxy.

Although R1may be associated with TDZD through any groups, provided that he does not denote-C(O)- (due to decomposition and low stability in plasma), preferably, if the aromatic radical is directly linked to the N atom TDZD.

Examples of substituents that can be used as R1are as follows:

Very good results stability and bioavailability in vivo have been on the particular spatial difficult aromatic radical, such as naphthyl. In particular, alpha-naphthyl gave good results. When R1indicates alpha-naphthyl, it is preferably unsubstituted alpha-naphthyl.

Relative to the substituent in position 4 TDZD, preferably, Ra and Rb denote N.

In another embodiment, preferably, when R2, R3, R4, R5, R6independently selected from hydrogen, substituted or unsubstituted alkyl, COR7, -C(O)OR7, -OR7, -NR7R8or halogen.

Most preferably, the substituent in position 4 represents unsubstituted benzyl. Examples of compounds according to the invention are the following compounds:

and their salts, prodrugs and solvate.

The compounds of formula (I)defined above can be obtained in accordance with reasonable procedures of synthesis. Some examples of these procedures are described in WO 01/85685 and US 2003/0195238 and found in them the links. The contents of these documents are fully incorporated into this description by reference.

Therefore, in another aspect, the invention relates to a method for obtaining compounds of formula (I) or its salt or MES, as stated in any of paragraphs 1-11 of the claims, which includes the introduction in the reaction of benzyl-substituted isothiocyanate formula

to link the m formula R 1-N=C=O.

For example, the following procedure can be used to obtain 4-N-benzyl-substituted thiadiazolidine:

General experimental procedure according to Scheme 1 is described, for example, Slomczynska, U.; Barany, G., "Efficient Synthesis of 1,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl-amines) and observation on formation of 1,2,4-Thiadiazolidine-3,5-dione by related Chemistry",J. Heterocyclic Chem., 1984, 21, 241-246.

For example, sulfurylchloride added dropwise under stirring in nitrogen atmosphere, preferably at a low temperature, preferably at about 5°C, to a solution of benzylisothiocyanate and isocyanate indicated in each case, in a suitable solvent, such as hexane, simple ether or THF. Upon completion of the addition, the mixture is left for the reaction, for example, with stirring for 20 hours at room temperature. After this time, the resulting product produce by conventional means, such as filtration with suction or evaporation of the solvent, and then do the cleaning (for example, by recrystallization or by chromatography on a column of silica gel using a suitable eluent).

Other alternative procedures will be obvious to the expert, for example the use of any other glorieuses means instead of sulfurylchloride, changes in the order of addition of reagents and the reaction conditions (dissolve the ate, temperature and so on).

The reaction products, if required, can be purified by conventional means such as crystallization, chromatography and grinding.

One preferred pharmaceutically acceptable form is a crystalline form, including a form in the form of pharmaceutical compositions. In the case of salts and solvate, additional ion and solvent components must also be non-toxic. Compounds according to the invention can be present in various polymorphic forms, and the invention encompasses all such forms.

Another aspect of the present invention relates to a method of treatment or prevention mediated GSK-3 disease with an inhibitor of GSK-3, as described above, comprising the administration to a patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutical compositions.

The terms "mediated GSK-3 disease” or "mediated GSK-3 state" in the context of the invention means any disease or other deleterious condition or status, in which GSK-3 plays a known role. Such diseases or conditions include, without limitation, diabetes, conditions associated with diabetes, chronic neurodegenerative conditions, including dementia, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sklerosiruuschem panencephalitis parkinsonism, postencephalitic parkinsonism, Boxing encephalitis complex of the island of GUAM, the disease Peak, corticobasal degeneration, frontotemporal dementia, Huntington's disease, AIDS dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, support for functional recovery after stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain brain, especially traumatic brain injury, cancer, leukopenia, down's syndrome, a disease of calves Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia, and immunodeficiency.

In the private embodiment of the invention the compounds of formula (I) or their pharmaceutical compositions, for example, in oral form used for the treatment of Alzheimer's Disease.

In another embodiment of the invention the compounds of formula (I) or their pharmaceutical compositions, for example, in oral form ispolzuyutsa treatment of diabetes.

In another embodiment of the invention the compounds of formula (I) or their pharmaceutical compositions, for example, in oral form is used to treat depression.

In another embodiment of the invention the compounds of formula (I) or their pharmaceutical compositions, for example, in oral form is used to treat brain damage.

The present invention also relates to pharmaceutical compositions comprising the compound according to the invention, its pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers with a pharmaceutically acceptable base, adjuvant or carrier, for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment, the pharmaceutical compositions are in oral form. Suitable dosage forms for oral administration may be tablets and capsules and may contain conventional excipients known in this field, such as binding agents, for example syrup, gum Arabic, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, F. the SFAT calcium, sorbitol or glycine; for tabletting lubricants, for example magnesium stearate; a disintegrator such as starch, polyvinylpyrrolidone, starch glycolate sodium or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

Solid oral compositions may be obtained by conventional methods of blending, filling or tableting. Re-blending operation can be used to distribute the active agent throughout the composition with the use of large quantities of fillers. Such operations are conventional in the art. Tablets can be obtained by wet or dry granulation, and, if necessary, they can be coated according to methods well known in normal pharmaceutical practice, in particular with intersolubility the floor.

Pharmaceutical compositions can also be adapted for parenteral administration, for example, in the form of sterile solutions, suspensions or lyophilized products in suitable form single dose. Can be used with suitable excipients, such as fillers, buffers, or surface-active substances.

These structures receive, using standard methods, such as are described or referred to in the Spanish and American farm is copiah and similar sources.

Introduction compounds or compositions according to the invention can be carried out in any suitable way, such as intravenous infusion, oral drugs and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and chronic nature of many of the diseases that are subject to treatment according to the invention.

Normally, the effective input the number of compounds according to the invention depends on the relative efficiency of selected compounds the seriousness of the offence and the patient's body weight. However, the active compound is usually administered one or more times a day, for example 1, 2, 3 or 4 times a day, with a typical full daily doses in the range from 0.1 to 1000 mg/kg/day.

The compounds and compositions according to the invention can be used with other drugs to provide a combination therapy. Other drugs may be part of the same composition, or be in the form of a separate composition for administration at the same time or at another time.

In another aspect the invention relates to the inhibition of the activity of GSK-3 in a biological sample, using compounds of formula (I), and this method includes the introduction into contact the biological sample with an inhibitor of GSK-3 formula (I). The term "biological sample", in the framework of the invention,includes, without limitation, cell cultures or extracts; preparations of the enzyme suitable for the analysis ofin vitro; the biopsy material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts. Thus, in one aspect the invention relates to the use of compounds of formula I as agents for biological samples, in particular as agents for the inhibition of GSK-3.

The following examples are intended to further illustrate the invention. They should not be interpreted as limiting the scope of the invention defined by the claims.

EXAMPLES

The synthesis of compounds

General experimental procedure

Sulfurylchloride was added dropwise under stirring in nitrogen atmosphere at 5°C to a solution of benzylisothiocyanate and isocyanate indicated in each case, in hexane, simple ether or THF. Upon completion of the addition, the mixture was stirred for 20 hours at room temperature. After this time, the obtained product was isolated by filtration with suction or by evaporating the solvent and then carried out the purification by recrystallization or by chromatography on a column of silica gel using a suitable eluent. A more detailed description can be found in Slomczynska, U.; Barany, G., "Effiient Synthesis of 1,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl-amines) and observation on formation of 1,2,4-Thiadiazolidine-3,5-dione by related Chemistry", J. Heterocyclic Chem., 1984, 21, 241-246.

Example 1

2-Phenethyl-4-benzyl-(1,2,4)-thiadiazolidin-3,5-dione(1)

Reagents: Benzyl isothiocyanate (6.5 mmol, 0,85 ml), geneticization (6.5 mmol, 0,89 ml) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: the evaporation of the solvent. Purification: chromatography on a column of silica gel (AcOEt/ hexane, 1:4).

Yield: 1.5 g (74%), yellow oil.

1H-NMR (CDCl3): or 2.9 (t, 2H, CH2CH2Ph, J=7.2 Hz); of 3.9 (t, 2H, CH2CH2Ph, J=7.2 Hz); and 4.8 (s, 2H, CH2Ph); of 7.2 to 7.4 (m, 10H, arene)

13C-NMR (CDCl3): 34,9 (CH2CH2Ph)and 4.9 (CH2CH2Ph); 46,2 (CH2Ph); 126,9; 128,5; 128,6; 136,6 (C arene CH2Ph); 128,1; 128,6; 128,6; 135,0 (C arene CH2CH2Ph); 152,6 (3-C=O); 165,6 (5-C=O)

Anal. (C17H16N2About2S), C, H, N, S.

Example 2

4-Benzyl-2-naphthalene-1-yl-[1,2,4]-thiadiazolidine-3,5-dione (2)

Reagents: Benzyl isothiocyanate (13 mmol, 1,72 ml), 1-naphthyl isocyanate (13 mmol, 1.9 ml) and SO2Cl2(13 mmol, was 1.04 ml) in hexane (50 ml). Selection: filtering the reaction mixture. Purification: recrystallization from EtOH.

Yield: 3.8 g (87%), white needles. MP=150°C.

1H-NMR (CDCl3): of 4.9 (s, 2H, CH2Ph); and 7.3 to 7.9 (m, N, arene)

13C-NMR (CDCl3): 46,5 (CH2Ph); 128,3; 128,6; 129,0; 135,0 (C arene, Ph); 122,0; 125,3; 126,8; 127,2; 127,5; 128,5; 130,8; 134,4 (C arene, naphthyl); 152,2 (3-C=O); 165,9 (5-C=O)

Anal. (C19H14N2About2S), C, H, N, S.

When is EP 3 (comparative)

2-(1-substituted)-4-benzyl-[1,2,4]-thiadiazolidine-3,5-dione (3)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), 1-substituted isocyanate (6.5 mmol, 1,15 g) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: the evaporation of the solvent. Purification: chromatography on a column of silica gel (AcOEt/hexane, 1:4).

Output: 0,89 g (40%), yellow crystals. TPL=128,8°C.

1H-NMR (CDCl3): 1,7 (m, 6H, substituted); 2,2 (m, 3H, substituted); 2,3 (m, 6H, substituted); and 4.8 (s, 2H, CH2Ph); of 7.2 to 7.4 (m, 5H, arene)

13C-NMR (CDCl3): 29,9; 30,0; 35,9; 41,0; 60,0 (C substituted); 45,3 (CH2Ph); 127,8; 128,5; 128,6; 135,4 (C arene)

Anal. (C19H22N2About2S), C, H, N, S.

Example 4

4-Benzyl-2-(4-methylbenzyl)-[1,2,4]-thiadiazolidine-3,5-dione (4)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), 4-methylbenzyl-isocyanate (6.5 mmol, of 0.90 ml) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: filtering the reaction mixture. Purification: recrystallization from MeOH.

Yield: 0.95 g (48%), solid white. TPL=69,1°C.

1H-NMR (CDCl3): of 2.4 (s, 3H, CH3); the 4.7 (s, 2H, CH2-Ph); and 4.8 (2H, s, CH2-Ph); to 7.2 (s, 4H, arene); 7,2-7,5 (m, 5H, arene).

13C-NMR (CDCl3): 21,3 (CH3); 45,9 (CH2Ph); 48,5 (CH2Ph); 128,1; 128,6; 128,7; 135,0 (C arene); 128,4; 129,5; 131,1; 138,6 (C arene); 152,8 (3-C=O); 165,7 (5-C=O)

Anal. (C17H16N2About2S), C, H, N, S.

Example 5

4-benzyl--((3,4-methylenedioxy)phenyl)-[1,2,4]-thiadiazolidine-3,5-dione (5)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), 3,4-(methylendioxy)phenylisocyanate (6.5 mmol, of 1.06 ml) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: filtering the reaction mixture. Purification: recrystallization from MeOH.

Yield: 1.4 g (66%), solid white. MP=126,5°C.

1H-NMR (CDCl3): of 4.9 (s, 2H, CH2Ph); 6,0 (s, 2H, O-CH2-O); 6,7-7,0 (m, 3H, arene); and 7.3-7.5 (m, 5H, arene)

13C-NMR (CDCl3): 46,2 (CH2Ph); 128,2; 128,6; 129,0; 134,9 (C arene); 101,8 (O-CH2-About); 106,4; 108,3; 118,2; 129,0; 148,1; 146,8 (C arene); 151,2 (3-C=O); 164,9 (5-C=O)

Anal. (C16H12N2About4S), C, H, N, S.

Example 6

4-Benzyl-2-diphenylmethyl-1,2,4-thiadiazolidine-3,5-dione (6)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), diphenyldiisocyanate (6.5 mmol, 1.23 ml) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: filtering the reaction mixture. Purification: recrystallization from MeOH.

Output: 1,79 g (80%), solid white MP=111,5°C.

1H-NMR (CDCl3): is 4.85 (s, 2H, CH2Ph); at 6.8 (s, 1H, Ph-CH-Ph); of 7.2 to 7.4 (m, 15 H, arene)

C-NMR (CDCl3): 45,9 (CH2Ph); 61,6 (Ph-CH-Ph); 128,0; 128,6; 128,7; 135,0 (C arene); 128,1; 128,5; 128,5; 137,5 (2xPh); 152,6 (3-C=O); is 165.8 (5-C=O)

Anal. (C22H18N2About2S), C, H, N, S.

Example 7

4-Benzyl-2-(4-methoxybenzyl)-[1,2,4]-thiadiazolidine-3,5-dione (7)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), p-methoxybenzylidene (6.5 mmol, 0,92 ml) and SO2Cl2(6.5 mmol, of 0.52 ml) in diethyl ether (25 ml). Selection: the evaporation of the solvent. Purification: chromatography on a column of silica gel (AcOEt/hexane, 1:4).

Yield: 1.30 grams (61%), solid yellow; MP=86,4°C.

1H-NMR (CDCl3): of 3.8 (s, 3H, CH3); the 4.7 (s, 2H, CH2-Ph-OMe); and 4.8 (s, CH2-Ph); of 7.2 to 7.4 (m, 5H, arene); to 6.8 (d, 2H, J=8.6 Hz); of 7.2 (d, 2H, J=8.6 Hz) (arene)

13C-NMR (CDCl3): 45,9 (CH2-Ph); 48,2 (CH2-Ph-OMe); 55,2 (O-CH3); 128,0; 129,8; 128,4; 135,0 (C arene-Ph); 126,2; 128,5; 114,2; 159,7 (C arene Ph-OMe); 152,7 (3-C=O); 165,6 (5-C=O)

Anal. (C17H13N2About3S), C, H, N, S.

Example 8

4-Benzyl-2-(2-tert.-butyl-6-methyl-phenyl)-(1,2,4)-thiadiazolidin-3,5-dione (8)

Reagents: Benzylisothiocyanate (3.5 mmol, 0.45 ml), 2-tert.-butyl-6-methyl isocyanate (3.5 mmol, 662,5 mg), and SO2Cl2(3.5 mmol, 0.25 ml) in diethyl ether (15 ml). Selection: the evaporation of the solvent. Purification: chromatography on a column of silica gel (AcOEt/hexane, 1:10). Yield: 0.17 g (14%), solid brown color. TPL=89,8°C.

1H-NMR (CDCl3): 1,4 (s, 9H, C(CH3)3); 2,1 (s, 3H, CH3)and 4.9 (2D, 2H, CH2-Ph, J=6.3 Hz); and 7.1-7.5 (m, 8H, arene)

13C-NMR (CDCl3): 17,8 (CH3); 31,9 (C(CH3)); 35,9 (C(CH3)); 46,2 (CH2-Ph); 126,1; 128,6; 128,5; 135,1 (C arene-Bn); 131,5; 150,4; 139,4; 128,1; 129,5; 129,9 (C arene-Ph); 152,4 (3-C=O); 165,7 (5-C=O)

Anal. (C20H22N2About2S), C, H, N, S.

Note the R 9

4-Benzyl-2-(2-benzoylphenyl)-[1,2,4]thiadiazolidin-3,5-dione (9)

Reagents: Benzylisothiocyanate (6.5 mmol, 0,85 ml), 2-benzylphenol-isocyanate (6.5 mmol, of 0.82 ml) and SO2Cl2(6.5 mmol, 0.5 ml) in diethyl ether (25 ml). Selection: filtering the reaction mixture. Purification: recrystallization from EtOH. Yield: 1.50 g (62%), solid white. TPL=154,9°C.

1H-NMR (CDCl3): of 3.9 (s, 2H, Ph-CH2-Ph); a 4.86 (s, 2H, CH2Ph); and 6.9-7.5 (m, 14 H, arene)

13C-NMR (CDCl3): 38,1 (Ph-CH2-Ph); 46,1 (CH2-Ph); 135,1; 128,5; 128,6; 129,2 (C-Bn); 138,9; 129,9; 131,6; 128,4; 127,9; 133,1 (Ph-CH2-Ph); 140,9; 128,7; 128,6; 126,4 (Ph-CH2-Ph); 151,2 (3-C=O); 166,0 (5-C=O)

Anal. (C22H18N2About2S), C, H, N, S.

Example 10

4-Benzyl-2-(4-phenoxyphenyl)-[1,2,4]-thiadiazolidine-3,5-dione (10)

Reagents: Benzylisothiocyanate (13 mmol, 1.6 ml), 4-phenoxyphenyl-isocyanate (13 mmol, 2.3 ml) and SO2Cl2(13 mmol, 1 ml) in diethyl ether (50 ml). Selection: filtering the reaction mixture. Purification: recrystallization from EtOH.

Output: 4.12 g (84%), solid white. MP=88,8°C.

1H-NMR (CDCl3): to 4.92 (s, 2H, CH2Ph); of 7.0 and 7.6 (m, 14 H, arene)

13C-NMR (CDCl3): 46,1 (CH2Ph); 134,9; 128,7; 129,1; 128,3 (CH2-Ph); 130,1; 125,7; 119,2; 156,3 (Ph-O-Ph); 156,3; 119,1; 129,8; 123,8 (Ph-O-Ph); 151,1 (3-C=O); 165,0 (5-C=O)

Anal. (C21H16N203S), C, H, N, S.

Biological methods

Example 11

Inhibi the Finance GSK-3β

The activity of GSK-3β was determined by incubation of a mixture of recombinant human enzyme GSK-3, the source of phosphate and substrate of GSK-3 in the presence and in the absence of the test compound and measuring the activity of GSK-3 of this mixture.

Recombinant human glikogensintetazy-kinase 3β were analyzed using 8 mm MOPS pH of 7.3, 0.2 mm EDTA, MgCl210 mm and orthovanadate sodium 0.25 mm in the presence of 62.5 μm peptide-2 phospho-glycogen synthase (GS 2), 0,5 MX γ33P-ATP and its ATP at a final concentration of 12.5 μm. The final volume of the sample was 20 μl. After incubation for 30 minutes at 30°C, 15 ál aliquot was applied to the filters of the D81 phosphocellulose paper. Filters were washed four times for at least 10 minutes each and were calculated with 1.5 ml of scintillation cocktail in a scintillation counter.

Expected value IC50connections, analyzing inhibition curves by nonlinear regression using GraphPad Prism.

The values of the IC50(the concentration at which see 50% enzyme inhibition) are shown in table 1.

Table 1
the values of the IC50
Compo is. R1IC50GSK-3 (µm)The HDMI.R1IC50GSK-3 (µm)
1362
22,47<50
3>5083
41,898
54,2 103

Example 12

Binding to GSH-and BSA

Obtaining samples

Connection (working solution (1 mm) were incubated for 30 minutes at room temperature with glutathione (Sigma) and bovine serum albumin (Fraction V) (Sigma) in equimolecular concentrations (1 mm). After this time the solution was filtered and analyzed by HPLC-UV/MS.

Chromatographic methods

HPLC was performed with a symmetric C18 column (2.1mm×150 mm, 3.5 µm), using Water Aliance 2695 led matrix 2996 and mass spectrometer ZQ2000 used for analytical separation and UV and mass spectrometric detection. The gradient used for elution was as follows:

Time (min)%A%B
01000
200100
211000
251000

/ Min net is ü flow: 0.25 ml/min; temperature: 30°C; detection: 250 nm; volume of injection: 10 µl.

The results are presented in Table 2

Table 2
Track% unrelated connections
Glutathionealbumin
134,7an 80.2
295,098,0
3 (comparative)15,054,0
432,367,2
572,065,5
652,084,0
731,068,3
8to 59.462,3
971,791,4
10100,0 the 98.9

The table clearly shows that all compounds except for compound 3, which does not contain aromatic rings, at least one of the two analyzed properties have more than 50% unrelated compounds. There are also some compounds showing the result of more than 70% of the unbound compounds in the two tests. The presence of the aromatic radical in position 2 (R1) TDZD significantly improves the properties of these compounds. This effect is greater if there is at least 10 aromatic carbon atoms in the Deputy or electron-donor substituents, as in compounds 5 and 10. It can also be observed that when the aromatic moiety is directly linked to N TDZD, the results are better. The best results were obtained with phenoxyphenyl and alpha-naphthyl.

These data significantly better than those obtained with compounds TDZD from the prior art. Indeed, as described earlier 2,4-dibenzyl-1,2,4-thiadiazolidine-3,5-dione with a smaller substituent in position 2 of thiadiazolidine gives a value of 17.1 in the test with glutathione and 57,0 in the test with albumin, is much lower than, for example, compound 4 according to the invention, which has an additional methyl group, and in the same range as the connection according to comparative example 3, which has no aromatic rings. And the compound in which R1=benzo is Il, decomposes in the course of the test, thus showing much worse results than the compounds of formula I.

Example 13

Penetration into the brain after oral and intravenous

The study was carried out in CIDA S.A.L., Sta Perpetua de Mogola (Barcelona), Spain.

The purpose of this research was to study the pharmacokinetic behavior of compound 2 (R1=alpha-naphthyl) and its possible accumulation in brain tissues after oral and intravenous administration.

In this study, the researchers used mice C57/BL6 (15-30 g)obtained from Charles River laboratories, Spain. All mice had free access to dry preformed standard diet to mice. Water was availablead libitum. Animals stopped feeding for 4 hours before treatment, but retained access to waterad libitum. They were given 2 hours after injection.

Compound 2 was 10.0% PEG400, 10,0% Cremophor in double-distilled water. Compounds were administered once by oral administration in the amount of 20 g/kg (10 ml/kg) and a single intravenous injection of 2 mg/kg (10 ml/kg). An additional experiment was carried out with the introduction of 200 mg/kg by mouth only to determine the proportionality of absorption.

Four animals (2 males and 2 females) were used in each time of extraction. The blood was Gaprindashvili and the settlement of the E. centrifugation (3000 rpm, 10 minutes, 5°C) two aliquots of plasma were kept at -20°C and -30°C until analysis (HPLC/MS-MS).

The results of the experiment are shown in table 3.

Table 3
Dose200 mg/kg20 mg/kg
Max9061,34 ng/ml904,95 ng/ml
BioavailabilityNot defined31,87%

Compound 2 is rapidly absorbed from the gastrointestinal tract after oral administration. The half-life after oral administration of 20 mg/kg is 6 hours. Compound 2 shows bioavailability 31,87%. The levels of Compound 2 were detected in the brain after oral and after intravenous injection. This shows that the above-described compounds of formula I have good bioavailability properties and are suitable for use as a drug for the treatment of mediated GSK-3 diseases or conditions.

1. The compound of General formula (I)

in which
R1denotes an organic group containing at least 8 atoms selected from s or O, and include the second aromatic ring phenyl, naphthyl or methylendioxyphenyl, which are not directly linked to N-C(O) -- or oxygen;
Ra, Rb, R2, R3, R4, R5and R6represent hydrogen;
or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, in which R1has at least 10 aromatic carbon atoms.

3. The compound according to claim 1, in which the aromatic group is directly linked to N of thiadiazolidine.

4. The compound according to claim 3 in which R1denotes a substituted or unsubstituted naphthyl.

5. The compound according to claim 4, in which R1denotes a substituted or unsubstituted alpha-naphthyl.

6. The compound according to claim 5, in which R1denotes unsubstituted alpha-naphthyl.

7. The compound according to claim 1, in which R1denotes a group selected from

8. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

9. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

10. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

11. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

12. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

13. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

14. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

15. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

16. The compound according to claim 1, which has the formula

or its pharmaceutically acceptable salt or MES.

17. The method of obtaining the compounds of formula (a) or its salt or MES according to any one of claims 1 to 16, which includes the introduction into the reaction benzylamino isothiocyanate formula II

with the compound of the formula R1-N=C=O in the presence of glorieuses agent.

18. The method according to 17, which includes reaction

where R1has the meaning given in claim 1, preferably defined in claim 6.

19. Pharmaceutical composition for inhibiting GSK-3, which includes an effective amount of a compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt or MES and pharmaceutically acceptable basis, adjuvant or carrier.

20. The pharmaceutical composition according to claim 19 for oral administration.

21. The use of compounds according to any one of claims 1 to 16 in getting medicines for treating diseases and conditions mediated by GSK-3.

22. Use item 21, in which the disease or condition is a diabetes, conditions associated with diabetes, chronic neurodegenerative conditions, including dementia, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis parkinsonism, postencephalitic parkinsonism, Boxing encephalitis complex of the island of GUAM, the disease Peak, corticobasal degeneration, frontotemporal dementia, Huntington's disease, AIDS-Damen the Oia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, support for functional recovery after stroke, brain hemorrhage, for example, due to solitary cerebral amyloid angiopathy, hair loss, obesity, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, a disease of calves Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases such as hyperplasia, and immunodeficiency.

23. The application of article 22, in which the disease is a disease of Alzheimer's.

24. The application of article 22, in which the disease is a type II diabetes.

25. The application of article 22, in which the disease is a depression.

26. The application of article 22, in which the disease is a brain damage.

27. The application of article 22, in which the disease is a progressive supranuclear palsy.

28. The use of compounds of formula (I)defined in any one of claims 1 to 16, as the e reagents for biological assays for inhibition of GSK-3.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns improved method of obtaining 3,5-diamino-1,2,4-thiadizol applied in synthesis of medicines, macroheterocyclic compounds, bioactive substances etc. Invention claims method of obtaining 3,5-diamino-1,2,4-thiadizol by reaction of 2-imino-4-thiobiuret with equimolecular quantity of hydrogen peroxide of 26-35% concentration in boiling alcohol for 20-30 minutes.

EFFECT: increased output to by 86% of target product with melting temperature of 172-174°C and reduced general process duration from 60 to 2 hours.

1 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel derivatives of 1,2,4-thiadiazole-2-il formula (I), , where R1, R2 and R4 present the radicals containing cyclic fragments, R3 designates hydrogen, alkyl, alkenyl or alkinyl that can be used as the agonists and antagonists of melanokortin receptors. Also, in this invention, the pharmaceutical composition, which shows the activity of modulator of melanokortin receptors, and the method of its preparation, are described. The purpose of this invention is to obtain the pharmaceutical compositions, which contain the therapeutically effective amount of compounds, as well as the pharmaceutically acceptable carrier, which are administered to the subject that suffers the melanokortin-mediated diseases, from the group with metabolic disturbances, abnormalities related to CNS and dermatologic abnormalities.

EFFECT: compounds can be used in treatment of CNS and dermatologic diseases.

21 cl, 13 ex, 13 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1,2,4-thiadiazole of the formula (II): wherein R1, R2 and R4 represent radicals comprising cyclic fragments that can be used as agonists or antagonists of melanocortin receptors. Invention provides preparing pharmaceutical compositions comprising the claimed compounds taken in the therapeutically effective dose that can be used in treatment of diseases mediated by melanocortin receptors, for example, such as metabolic disorders, disorders associated with the central nervous system, and dermatological disorders.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

20 cl, 13 tbl, 5 sch, 13 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to using compounds represented by the general formula (II): wherein Ra and Rb are chosen independently from hydrogen atom, alkyl, cycloalkyl, aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)n-aryl (optionally substituted with a group chosen from alkyl, halogen atom and alkoxy-group), -(Z)nC(O)OR3; Z is chosen independently from -C(R3)(R4)-; R3 and R4 are chosen independently from hydrogen atom, alkyl and 6-membered cycle with nitrogen atom as a heteroatom; n has values 0, 1 or 2; X and Y are chosen independently from =O, =S and =N(R3). These compounds are active component in preparing a pharmaceutical composition designated in treatment of diseases wherein glycogen synthase-kinase 3-beta (GSK-3) is involved. Also, invention relates to compounds represented by the general formula (II) wherein Ra is chosen from -CH2Ph, -CH2CO2Et, 4-OMePh, 4-MePh and 4-BrPh; Rb is chosen from Me and -CH2CO2Et; X and Y represent =O. Also, invention relates to a pharmaceutical composition possessing GSK-3-inhibitory activity and containing compound of the general formula (II) as an active component. Invention provides using heterocyclic inhibitors of glycogen synthase-kinase-3β.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

17 cl, 5 tbl, 5 ex

The invention relates to cavemosum derivative of formula (1) with a broad spectrum of antibacterial activity against different species of pathogenic bacteria, including MRSA

< / BR>
where X Is N or CY and Y denotes H or halogen; R1is amino or a protected amino group; R2is hydrogen or optionally substituted (ness.)alkyl; R3denotes hydrogen or lower alkyl; R4indicates Bogoroditse optionally substituted (NISS

The invention relates to aryl - and getelemen carboalkoxylation acids of formula 1

< / BR>
where R1selected from the group of arrow or getarrow, R2selected from the group of Akilov

The invention relates to new heterocyclic substituted phenoxyacetamide, methods for their preparation and use as a means protivodiareynogo

FIELD: medicine.

SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.

EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.

9 cl, 3 ex

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