Gsk-3 inhibitors

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

 

The invention relates to enzyme inhibitors, more specifically of urea derivatives as inhibitors of kinase-3β glikogensintetazy, GSK-3, methods of making such compounds, pharmaceutical compositions containing them and their use for the treatment and/or prevention of diseases, the development of which involved GSK-3, such as Alzheimer's disease or non-insulin-dependent diabetes mellitus.

The level of technology

The search for new therapeutics in recent years significantly contributed to a better understanding of the structure of enzymes and other biomolecules associated with the studied disease. One of the important classes of enzymes, subjected to extensive research, are protein kinases. Many diseases are related to improper cellular reactions that run associated with protein kinases events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or diseases related to hormones. Accordingly, significant efforts have been made in medicinal chemistry to search for inhibitors of protein kinases, effective as therapeutic agents.

Kinase-3 glikogensintetazy (GSK-3) is a serine/threonine protein is the nae, consisting of isoforms α and β, each of which are encoded by separate genes (Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kinnel, Curr. Opinion Genetics Dev., 10, 508 to 514 (2000)). The threonine/serine kinase kinase-3 glikogensintetazy (GSK-3) has a Central role in various related receptor signaling pathways (Double, B.W. Woodgett, J.R. J. Cell Sci. 2003, 116: 1175-1186). Improper regulation of these pathways is considered a major event in the development of some common disorders such as diabetes type II (O. Kaidanovich, Eldar-Finkelman H., Expert Opin. Ther. Targets, 2002, 6: 555-561), Alzheimer's disease (C.A. Grimes, R.S. Jope, Prog. Neurobiol. 2001, 65: 391-426), Central nervous system disorders, such as manic-depressive psychosis and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich K.P., J. Luo, maintainance and care instructions E.A., M.S. Tsao, Jin O., Woodgett J. Nature 2000, 406: 86-90). These diseases may be caused or may cause incorrect operation of certain signaling pathways of the cell in which GSK-3 plays a role.

Found that GSK-3 phosphorylates and modulates the activity of several regulatory proteins. These proteins include glikogensintetazy, which is limiting the speed of an enzyme necessary for glycogen synthesis, is associated with the microtubule protein Tau, the genetic factor transcription of β-catenin, the translation initiation factor elF2B, as well as ATP-citrate lyase, axin, factor heat shock is -1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. This variety of protein targets involves GSK-3 in many aspects of cellular metabolism, growth, differentiation and development.

Currently, the inhibition of GSK-3 may represent a viable strategy for the development of new medical substances for the treatment of incurable diseases (A. Martinez, A. Castro, Dorronostro I., Alonso M., Med. Res. Rev., 2002, 22; 373-384) using simulation insulin, dephosphorylate Tau and processing of amyloid or modulation of transcription, respectively.

In the current prior art some compounds containing the group of urea, already described as having the properties of inhibitors of GSK-3. This is, for example, the following publications: WO03/004472, WO03/004475, WO03/089419. Each of these publications is to a very large number of compounds characterized by the formula Markush, representing a large and complex structure, which makes them more difficult to obtain and increases the possibility that the reactivity of the compounds. In particular, these compounds belong to the structural sub-groups, such as substituted titlovi compounds and heterocyclic amines. These compounds can contain, along with other groups, the functional group of the urea. These compounds in General are described as having inhibiting GSK-3 effects and, thus, potential activity in the treatment and prevention of a series of diseases svyazannyhs GSK-3, such as dementia, diabetes and mood disorders. However, in none of the above-mentioned publications does not include information related to the inhibition of GSK-3 by any specific connection; thus, for containing the functional group of the urea compounds also do not show the results, really supporting any activity of these derivatives of urea.

On the other hand, publication WO03/004478 and the article "Structural Insights and Biological Effects of GSK-3 specific ingibitor AR-A014418", J. Biol. Chem., 278(46), 2003, consider one particular a derivative of urea, 4-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; the structure of this derivative is of course much smaller and simpler than the above-mentioned derivatives of urea. It is derived is described as having a GSK-3-inhibiting properties and, thus, as having potential activity for the treatment and/or prevention of numerous conditions associated with kinase-3 glikogensintetazy. However, it is unclear determined whether inhibition of GSK-3 action of the urea or neurotization as heterocyclic compounds have been described as expressing GSK-3 inhibiting properties (see, for example, the above WO03/089419).

Some other urea derivatives described in connection with the treatment of neurological disorders, but with completely different mechanisms of action, for example WO00/0616, which shows the derivative of urea is described as potentiator work of glutamate receptor.

Thus, there is still the need to find a good inhibitor of GSK-3, which is both effective and selective and having a good "lekarstvennaya properties, i.e. good pharmaceutical properties associated with the introduction, distribution, metabolism and excretion. An additional advantage is the presence of compounds with simple, stable structures, easy to manufacture by conventional methods known to the expert.

Description of the invention

Discovered that a group of small stable derivatives of urea demonstrates the inhibiting effects on the enzyme GSK-3.

The use of the compounds of formula (I)

or its pharmaceutically acceptable salt, prodrug or MES, where

RBselected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, where aryl is selected from the group consisting of phenyl, naphthyl, financila and antracol, substituted or unsubstituted aralkyl where aralkyl is benzyl, heterocycle selected from the group consisting of azepine, benzimidazole, benzothiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole, Tetra is hydrofuran, benzodioxole, thiophene, benzofuran, indazole, heatline, pyridazine, pyrimidine, pyrazine, pyridine, isoxazol, pyrrole, Piran, -OR5and-S(O)t-R5where RBincludes 8 to 15 atoms selected from C, O, N and S, provided that RBis not a heterocycle, substituted heterocycle,

R3, R4, R'2, R'3, R'4, R'5and R'6independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, -C(=O)R7, -C(=O)OR8, -C(=O)NR9R10,- (C=NR11, -CN, -OR12, -OC(=O)R13, -S(O)t-R14, -NR15R16, -NR17C(=O)R18, -NO2, -N=CR19R20or halogen, where R3and R4together may form the group =and where any pair of R3R'2, R3R'6, R4R'2, R4R'6, R'2R'3, R'3R'4, R'4R'5, R'5R'6, R15R16, R17R18or R19R20may together form a cyclic Deputy; t is 0, 1, 2, 3,

R5selected from hydrogen, alkyl, aryl and heterocycle;

R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 , R17, R18, R19and R20independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted, aryloxy, halogen, for preparing a medicinal product for treating and/or preventing mediated GSK-3 disease or condition, where the disease or condition selected from the group consisting of 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 postentsefaliticheskom parkinsonism, Boxing encephalitis, Gramsci complex parkinsonism-dementia, the disease Peak, corticobasal degeneration, frontotemporal dementia, a disease of Hungtington associated with AIDS dementia, amyotrophy lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of recovery of disturbed function of the Nations after a stroke, cerebral hemorrhage, such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, disease Taurus Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

Preferred compounds are compounds in which RBrepresents an aromatic group.

In a specific embodiment RBcontains at least 10 aromatic carbon atoms.

In an additional aspect, the invention relates to a compound of the formula

In another aspect, the invention relates to pharmaceutical compositions comprising a compound of formula (I)described above, or its pharmaceutically acceptable salt, prodrug or MES and a pharmaceutically acceptable carrier, adjuvant or diluent.

Preferably, the disease or condition mediated by GSK-3, selected from Alzheimer's disease, diabetes type II, depression, and brain damage.

In accordance with another aspect, the compounds of formula (I)described above can be used as reagents for biological research, pre is respectfully as a reagent for the inhibition of GSK-3.

Brief description of drawings

Figure 1 presents1H-NMR and13C-NMR spectra of 1-benzyl-3-naphthalene-1-rocephine.

Figure 2 presents1H-NMR and13C-NMR spectra of 1-benzo[1,3]dioxol-5-yl-3-benzyladenine.

Figure 3 presents a graph showing the activity of GSK-3, measured in the presence of 1-benzyl-3-naphthalene-1-rocephine in various concentrations. The results are shown in comparison with the control.

Figure 4 presents a graph showing the activity of GSK-3, measured in the presence of 1-benzo[1,3]dioxol-5-yl-3-benzyladenine in various concentrations. The results are shown in comparison with the control.

Detailed description of the invention

Derivatives of urea having the formula (I) in accordance with the invention, are chemical substances, which unexpectedly showed good inhibitory activity against the enzyme GSK-3, in combination with good stability and low toxicity.

As described above, the first aspect of the presents invention relates to the use of compounds of formula (I) or their pharmaceutically acceptable salts, prodrugs or MES for the preparation of drugs for the treatment of diseases or conditions mediated by GSK-3. Preferably, RBrepresents an aromatic group, and even more predpochtitel is about, to RBcontain not less than 10 aromatic carbon atoms.

In the preferred embodiment, the compound of formula (I) is an aromatic group that is directly linked to the N atom of the urea group.

In accordance with another specific embodiment, RBis substituted or unsubstituted naftilos group, preferably unsubstituted alpha-naftilos group.

Preferably RBchoose from

In a specific embodiment, R3and R4are H.

In another specific embodiment, R'2, R'3, R'4, R'5and R'6independently selected from hydrogen, substituted or unsubstituted alkyl, -C(=O)R7, -C(=O)R8, -OR12, -NR15R16or halogen, where R7, R8, R12, R15and R16correspond to the above definition.

Preferably R'2, R'3, R'4, R'5and R'6are H.

Two preferred compounds are:

In the context of the present invention, the expression "GSK-3-mediated disease or condition" means any disease or other pathological or disease state, which is known that it is mediated by GSK-3. This disease or SOS is the right can be represented as, but not limited to, 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 postentsefaliticheskom parkinsonism, Boxing encephalitis, Gramsci complex parkinsonism-dementia, the disease Peak, corticobasal degeneration, frontotemporal dementia, a disease of Hungtington associated with AIDS dementia, amyotrophy lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of recovery of disturbed functions after a stroke, cerebral bleeding, such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, a disease Taurus Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

Preferably, the GSK-3 mediated disease or condition selected among diseases ALC is Amara, diabetes type II, depression, and brain damage.

In accordance with further aspects of the invention, it relates to the compound of the formula

and to its use as a medicine.

Another aspect of the present invention is a pharmaceutical composition comprising a compound as defined above, or its pharmaceutically acceptable salt, prodrug or MES and a pharmaceutically acceptable carrier, adjuvant or diluent; preferably said composition is intended for oral administration. Preferably the disease or condition that can be treated with the indicated pharmaceutical composition can be, but are not limited to, 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 postentsefaliticheskom parkinsonism, Boxing encephalitis, Gramsci complex parkinsonism-dementia, the disease Peak, corticobasal degeneration, frontotemporal dementia, a disease of Hungtington, AIDS-dementia, amyotrophy lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, EPI is Asia, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of recovery after stroke, cerebral bleeding, such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, a disease Taurus Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

Another aspect of the invention relates to a method of treating or preventing a GSK-3-mediated diseases or conditions using an inhibitor of GSK-3, the method includes assigning a patient in need of such treatment, a therapeutically effective amount of the compounds of formula (I)as described above, or pharmaceutical compositions based on it.

In another aspect the invention relates to the inhibition of the activity of GSK-3 in a biological sample, the compounds of formula (I), the method comprising contacting a biological sample with an inhibitor of GSK-3 formula (I). The term "biological sample", as used in this description, includes, without limitation, cell cultures or extracts; preparations of the enzyme, th the derivative to analyze in vitro; material biopsies obtained from a mammal or extracts; blood, saliva, urine, feces, semen, tears, or other body fluids or extracts. Thus, in one aspect the invention is directed to compounds of formula I as agents for biological analyses, namely as reagents for inhibition of GSK-3.

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

"Alkyl" refers to a radical with a straight or branched hydrocarbon chain consisting of carbon and hydrogen atoms, containing no saturated, having from one to eight carbon atoms, which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl etc. Alkyl radicals may be optionally 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 with the formula-ORawhere Rais an alkyl radical as described above, for example methoxy, ethoxy, propoxy, etc.

"Alkoxycarbonyl" refers to a radical with the formula-C(O)ORawhere Rais an alkyl radical as described above, for example methoxycarbonyl, etoxycarbonyl, ProPak carbonyl etc.

"Alkylthio" refers to a radical with the formula-SRawhere Rais an alkyl radical as described above, for example methylthio, ethylthio, propylthio etc.

"Amino" refers to a radical with the formula-NH2-The othera, -NRaRbwhere Raand Rbindependently are alkyl radicals described above.

"Aryl" refers to phenyl, naftalina, angenlina, phenanthridinone or anthracyclinone radicals, preferably by phenyl or naftalina radicals. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halogen, alkyl, phenyl, alkoxy, halogenated, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as described in the present description.

"Acyl" refers to a radical with the formula-C(O)-Rcand-C(O)-Rdwhere Rcis an alkyl radical as described above, and Rdis aryl radical, described above, for example acetyl, propionyl, benzoyl and the like.

"Areilly" refers to an alkyl group substituted by - Ra-C(O)-Rdwhere Rais an alkyl radical as described above, and Rdis aryl radical as described above. Preferred examples include benzoylmethyl.

"Carboxy" refers to a radical with the formula-C(O)OH.

"Cycloalkyl" refers to a stable 3 to 10-membered mono is ilicheskom or the bicyclic radical, saturated or partially saturated, which consists only of carbon atoms and hydrogen. Unless stated otherwise specifically in the specification, the term "cycloalkyl also implies cycloalkyl radicals, optionally substituted by one or more radicals, such as alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

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

"Heterocycle" refers to heterocyclic radicals. A heterocycle refers to a stable 3 to 15-membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, preferably 4-8-membered ring with one or more heteroatoms, more preferably a 5 - or 6-membered ring with one or more heteroatoms. For the purposes of the invention, the heterocycle may be monocyclic, bicyclic or tricyclic ring system, which may include fused ring system; the atoms of nitrogen, carbon and sulfur in the heterocyclic radical may be optionally oxidized; the nitrogen atom may be optionally quaternion; and the heterocyclic radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepine, benzimidazole, benzothiazole, furan,isothiazol, the imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofuran, indazole, hinzelin, pyridazine, pyrimidine, pyrazin, pyridine, isoxazol, pyrrole, pyrazole, Piran.

Mention of the substituted groups in the compounds of the presented invention relates to a group which can 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 C1-6alcoolica group such as acyl and the like; carboxamido; alkyl groups including groups having from 1 to 12 carbon atoms or from 1 to 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and altenergy, including groups having one or more unsaturated linkages and from 2 to 12 carbon atoms or from 2 to 6 carbon atoms; alkoxygroup having one or more oxygen linkages and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; aryloxy, such as phenoxy; allylthiourea, including groups with one or more thioester linkages and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; alkylsulfonyl, including groups having one or more sulfinyl linkages and from 1 to 12 carbon and the Ohm, or 1 to 6 carbon atoms; alkylsulfonyl, including groups having one or more sulfanilic linkages and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; aminoalkyl, such as groups having one or more N atom and from 1 to 12 carbon atoms or from 1 to 6 carbon atoms; an unsubstituted cycloalkyl where cycloalkyl such as it is described above; unsubstituted aryl, where cycloalkyl such as it is described above, namely phenyl or naphthyl; and aralkyl, such as benzyl. Unless otherwise specified, optional substituted group may have a Deputy at each substitutable position independently of the other.

Unless otherwise stated, the compounds of the invention are considered to include compounds that differ only in the presence of one or more enriched isotopes of atoms. For example, compounds having presented the structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13C - or14C - enriched carbon or15N-enriched nitrogen is in the scope of this 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 (directly or indirectly) described here is the link. However, the South to take into account, what pharmaceutically unacceptable salts also fall within the scope of the invention as they may be applicable in obtaining pharmaceutically acceptable salts. Obtaining salts, prodrugs and derivatives can be carried out by methods known in the art.

For example, pharmaceutically acceptable salts of the compounds described in the present description, are synthesized from starting compounds which contain a basic or acidic group, conventional chemical methods. Typically, such salts are, for example, obtained by reaction of the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or mixtures thereof. Usually preferred non-aqueous environment, such as a simple ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of the salt of the added acid include salts of inorganic acids, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfates, nitrates, phosphates, and organic acid salts, such as acetates, maleate, fumarate, citrates, oxalates, succinate, tartratami, malaty, mandelate, methanesulfonate and para-toluensulfonate. Examples of salts of the added alkali include inorganic salts such as, for example, salts of sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and salt body of the economic alkalis, such as, for example, salts of Ethylenediamine, ethanolamine, N,N-dialkylacrylamide, triethanolamine, glucamine and basic amino acids.

A special advantage of the use of derivatives or prodrugs of increasing the bioavailability of the compounds of the invention, when these compounds are introduced to the patient (for example, allowing administered orally connection more quickly absorbed into the blood)or which enhance targeted delivery of the parent compound in the body (for example, the brain or lymphatic system) relative to the initial state.

Any connection, which prodrugs of the compounds of formula (I), is within the scope of the invention. The term "prodrug" is used in its broadest sense and separates derivatives, which in vivo are converted into compounds according to the invention. Such derivatives can be easily obtained by specialists in the field of machinery and shall include, depending on the functional groups present in the molecule, and without limitation, the following derivative represented compounds: esters, esters of amino acids, phosphate esters, metal salts and sulfate esters, carbamates and amides. Examples of well-known ways to obtain prodrugs of this active compound known to experts in the field of machinery and can be found, for example, in "Textbook of Drugdesign and Disovery", Taylor & Francis (April 2002).

Compounds according to the invention may be in crystalline form, both in free form and in the form of MES (e.g., hydrates), and assumes that both forms are within the scope of the presented invention. Methods of solvation well-known in the field of technology. Suitable solvate are pharmaceutically acceptable solvate. In a particular method of implementing the MES is a hydrate.

The compounds of formula (I) or their salts or solvate are preferably in pharmaceutically acceptable or a chemically pure form. Under a pharmaceutically acceptable form meant, among other things, with a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as solvents and carriers, and not including material considered toxic at normal dosage. The levels of purity of the drug substance, preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment, the purity of the compounds of formula (I) or its salt, solvate and prodrugs above 95%.

Compounds of the present invention, is characterized by the above formula (I)may include enantiomers depending on the presence of chiral centers or isomers, depending on the presence of the edge is different connections (for example, Z, E). Individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the presented invention.

The compounds of formula (I)defined above can be obtained available synthetic methods, for example by reacting the following compounds:

in a suitable solvent such as N,N-dimethylformamide, dimethylsulfoxide, dioxane, dichloromethane or tetrahydrofuran, at a temperature in the range from +20 to +150°C.

One of the preferred pharmaceutically acceptable form is a crystalline form, including a form of pharmaceutical compositions. In the case of salts and solvate additional ion and solvate fragments must be non-toxic. Compounds of the invention can exist in different polymorphic forms, it is understood that the invention includes all such forms.

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

In a preferred method of implementation of the composition are in oral form. Suitable dosage forms for oral administration may be tablets and capsules and may contain conventional additives, known what's in the prior art, such as binders such as syrup, gum Arabic, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletiruemye lubricants, for example magnesium stearate; disintegrant, for example starch, polyvinylpyrrolidone, sodium salt starch glycolate, or microcrystalline cellulose; or pharmaceutically acceptable means to wetting, such as sodium lauryl sulfate.

Solid compositions for oral administration can be obtained by conventional methods of blending, filling or tableting. Repeat the blending operation can be used to distribute the active agent in the compositions, uses large quantities of fillers. Such operations are common in the prior art. Tablets can be, for example, prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular intersolubility coated tablets.

Pharmaceutical compositions may also be adapted for parenteral administration such as sterile solutions, suspensions or lyophilized products in the appropriate dosage form. Can be used suitable additional substances, such is how obamarelease means, buferiruemoi means or surface-active substances.

The above formulations are prepared using standard methods, such as are described or referred to in Spanish or American Pharmacopoeias and similar reference texts.

Introduction compounds or compositions of the presented invention can be implemented using any applicable means, such as intravenous infusion, oral medications and intraperitoneal and intravenous administration. Oral administration is preferable because of convenience for the patient and chronic nature of many of the diseases curable.

Normally, the effective input the number of compounds according to the invention depends on the comparative efficacy of the selected compound, the severity of treatable disorders and weight of the patient. However, the active components are usually put one or more times a day, for example 1, 2, 3 or 4 times a day, the usual daily dose in the range from 0.1 to 1000 mg/kg/day.

Compounds and compositions of the invention can be used together with other medicines for carrying out the combined treatment. Other medicines can also be part of a single composition, or can be represented as a single composition for simultaneous or non-simultaneous injection.

In the following representatives of the feudal invention is further illustrated by examples. They in no case should not be interpreted as a limitation described in the claims volume.

Examples

Obtaining compounds of formula II

The compounds of formula II according to the present invention is produced by the interaction of the appropriate isocyanate with a suitable amine to obtain the corresponding urea, as described above.

EXAMPLE 1

Obtain 1-benzyl-3-naphthalene-1-rocephine

of 0.44 ml (4 mmol) of benzylamine subjected to interaction of 0.58 ml (4 mmol) of 2-isocyanatomethyl in dichloromethane at room temperature over night:

The obtained white precipitate is filtered off and washed with diethyl ether. Obtain 1.18 g of a white powder with a molecular weight of 276. Appropriate1H-NMR and13C-NMR spectra shown in figure 1. They suggest that the white compound is 1-benzyl-3-naphthalene-1-ilocanos.

EXAMPLE 2

Getting 1-benzo[1,3]dioxol-5-yl-3-benzyladenine

of 0.44 ml (4 mmol) of benzylamine subjected to interaction with 654,5 mg (4 mmol) of 5-isocyanatobenzene[1,3]dioxol in dichloromethane at room temperature over night:

The obtained white precipitate is filtered off and washed with diethyl ether. Receive 1 g of a white powder with a molecular weight of 276. With the marijuana 1H-NMR and13C-NMR spectra shown in figure 2. They show that white compound is 1-benzyl-3-naphthalene-1-ilocanos.

Biological methods

Inhibition of GSK-3

The activity of GSK-3 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 mixture.

Recombinant human kinase-3β, glikogensintetazy were studied in 8 mm MOPS, pH 7.3, with the addition of 0.2 mm EDTA, 10 mm MgCl2and 0.25 mm orthovanadate sodium in the presence of 62.5 μm phosphoglyceromutase peptide-2 (GS-2), 0.5 microcurie γ33P-ATP and unlabeled ATP to a final concentration of 12.5 μm. The final volume of the sample was 20 μl. After incubation for 30 minutes at 30°C in aliquots of 15 μl were deposited drops on phosphocellulose P81 paper. The filters were washed four times for at least 10 minutes each, after which 1.5 ml scintillation cocktail in scintilation the counter was measured radioactivity.

The values of the activity of GSK-3 in the presence of compounds in accordance with the present invention were measured at various concentrations, the results shown in comparison with the control, shown in figure 3 and 4.

The values of the IC50for the compounds were calculated in the analysis of curves and is generowania method of nonlinear regression using GraphPad Prism. The values of the IC50(concentration, which is shown by 50% enzyme inhibition) are collected in the table.

ConnectionIC50
1-Benzyl-3-naphthalene-1-rocephine17,1
1-Benzo[1,3]dioxol-5-yl-3-benzyladenine38,4

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

or its pharmaceutically acceptable salt,
where Rb is a group selected from:

R3, R4, R'2, R'3, R'4, R'5andR'6represent hydrogen, for preparing a medicinal product for treating and/or preventing mediated GSK-3 disease or condition, where the disease or condition selected from the group consisting of diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear paralysis postentsefaliticheskom parkinsonism, Gramsci complex parkinsonism-dementia, the disease Peak, corticobasal degeneration, frontotemporal dementia, a disease Gene is tingtone, AIDS-dementia, amyotrophy lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar affective disorder, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, disease Taurus Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency.

2. The use according to claim 1 in which the compound of formula (I) is a

3. The use according to claim 1 in which the compound of formula (I) is a

4. The use according to claim 1, in which the disease is a disease of Alzheimer's.

5. The use according to claim 1, in which the disease is a progressive supranuclear paralysis.

6. The use of claim 1, wherein the disease is diabetes type II.

7. The use according to claim 1, in which the disease is a depression.

8. The use according to claim 1, in which the disease is a brain damage.

9. The compound of the formula

10. The compound of the formula

designed for use as a drug with GSK-3 inhibitory activity.

11. Pharmaceutical composition having GSK-3 inhibitory activity and comprising an effective amount of the compounds of formula (I)as defined in any one of claims 1 to 3, or pharmaceutically acceptable salt, pharmaceutically acceptable carrier, adjuvant or diluent.

12. The pharmaceutical composition according to claim 11 for oral administration.

13. The use of the compounds of formula (I)as described in any one of claims 1 to 3, as a reagent for biological assays of inhibition of GSK-3 in vitro.

14. A method of treating or preventing a GSK-3-mediated disease or condition is by using an inhibitor of GSK-3, where the disease or condition selected from the group consisting of diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear paralysis postentsefaliticheskom parkinsonism, Gramsci complex parkinsonism-dementia, the disease Peak, corticobasal degeneration, frontotemporal dementia, a disease of Hungtington, AIDS-dementia, amyotrophy lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders, so is e as depression, schizophrenia and bipolar affective disorder, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischemia, brain injury, traumatic brain injury, cancer, leukopenia, down's syndrome, disease Taurus Levi, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases, such as hyperplasia and immunodeficiency, which includes an introduction to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula (I)according to claims 1 to 3, or a pharmaceutical composition of claim 11 or 12.



 

Same patents:

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

The invention relates to new compounds to metabolites ecteinascidin, namely ETM-305, ETM-204 and ETM-775, having the following structural formula:

These compounds are strong antitumor agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing arterial hypertension containing an angiotensin converting enzyme (ACE) inhibitor and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: ACE inhibitor - 2-4; N-acetyl-5-methoxytriptamine (melatonin) - 2-8; excipients - up to 100 mg with the ACE inhibitor being presented by the compounds specified in a group of enalapril, captopril, perindopril, lisinopril, fozinopril, quinapril, spirapril. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a softgel capsule, a solid gel capsule, by a soft dosage form - a rectal suppositorium.

EFFECT: providing a therapeutically significant effect (stable night-time blood pressure profile) and a lower risk of side effects due to using the doses low for the ACE inhibitors specified above have been shown.

3 cl, 3 tbl

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, namely to - physiotherapy, balneology. A method involves basic drug-induced therapy, transcranial electrical stimulation and balneotherapy. The transcranial electrical stimulation is performed within the period from 11.00 to 15.00. The exposure is enabled by a frontooccipital technique with using pulse bipolar current with gradually increased current intensity from 0.8 to 1.2 mA to make evident painless vibration observed under electrode. Duration of a procedure is 30-40 minutes. The procedures are daily; the therapeutic course is 10-12 procedures. Within the period from 14.00 to 18.00, balneotherapy is prescribed with iodine-bromine baths at the concentration of sodium chloride 10 g/l, potassium bromide 25 g/l, potassium iodide 25 g/l. The procedures are daily; the therapeutic course is 9-10 procedures.

EFFECT: method provides higher therapeutic effectiveness ensured by improved psychological status, central and intracardial hemodynamic parameters, values of lipid exchange and antioxidant protection, intensified hypotension effect and improved microcirculation in reducing drug-induced load on patient's body.

2 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to combined drugs, and can be used for treating arterial hypertension. The drug is prepared by direct compression. A preparation with low residual humidity is more storage stable, shows high processibility and biological availability. The combined hypotensive drug contains a combination of enalapril maleate and hydrochlorthiazide as an agent, and lactose anhydride, microcrystalline cellulose, povidone, colloidal silicon dioxide, croscarmellose sodium and stearic acid salt as excipients. The optimum proportions of the components makes, wt %: The agent 11.0-18.0; Lactose anhydride 56.0-78.0; Microcrystalline cellulose 5.0-15.0; Povidone 2.0-4.0; Colloidal silicon dioxide 0.5-1.0; Magnesium stearate 0.5-1.0; Croscarmellose sodium 3.0-5.0.

EFFECT: making the drug preparation for treating arterial hypertension.

12 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is referred to the area of medicine, namely to hematology and cardiology and can be used for optimization of spontaneous RBC aggregation in patients with arterial hypertension and disrupted glucose tolerance. To do that the dosed static and dynamic physical exercises are given including the combination of morning hygiene gymnastics, therapeutic gymnastics and single physical exercises during the day. Additionally the fozinopril is given in the dose 10 mg once a day at 6 AM. The treatment shall be performed for 6 months.

EFFECT: increased effectiveness of correction of spontaneous RBC aggregation putting it on the level close to that of healthy people due to selected components of complex treatment and developed treatment regime.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to arylamines of formula (I) and their pharmaceutically acceptable salts which are active in relation to 5HT receptors, particularly show 5-HT6 modulating activity, and can be used for treating a number of diseases, such as obesity, or the other diseases, for treating 5-HT-associated condition selected from a group containing Alzheimer's disease, Hundington's disease, obesity, obesity-related disorder, insulin-independent diabetes, Alzheimer's disease related cognitive disorders, schizophrenia related cognitive disorders, reflux gastroesophagitis, non-ulcer dyspepsia, depression, anxiety, migraine, gastritis, gastric emptying disorder, eating disorders, gastrointestinal disorders, constipations, panic attacks, memory impairment, disturbed sleep, alcohol-use disorders, anorexia, bulimia, obsessive-compulsive disorders, psychosis, Parkinson's disease, Hundington's chorea, and/or schizophrenia, drug abuse and attention deficit/hyperactivity disorder (ADHD). In the compound of formula (I) n means 1; A means C1-C3alkylene; R1 means hydrogen or C1-C10alkyl; R2 means C1-C10alkoxy, C(O)CF3 or SO2R6, where R6 can be C1-C4 alkyl R3 and R4 independently means hydrogen, substituted or unsubstituted C1-C7alkyl, where a substituted is selected from dihydrobenzodioxidine or benzodioxole, probably substituted by halogen; phenyl, probably substituted by C1-C4alkyl, C1-C4alkoxy, halogen, trifluoromethyl; aryl selected form naphthyl or tetrahydronaphthyl, optionally substituted by C1-C4alkyl, C1-C4alkoxy; heteroaryl, 5-members heteroaryl condensed with the benzoic ring with sulphur atom as a heteroatom, chromanyl probably substituted by halogen; B means a bound; and X and Y means -CH-.

EFFECT: preparing pharmaceutically acceptable salts which are active in relation to 5HT receptors.

59 cl, 9 dwg, 1 tbl, 57 ex

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: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or formula (I') where values of the substitutes are disclosed in the patent claim. The present compounds are able to inhibit Rho-kinase.

EFFECT: making the compounds effective for treating and/or preventing the Rho-kinase-associated and/or Rho-kinase-mediated diseases by phosphorylation of myosin light chain phosphatise.

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, in particular to device for transdermal bisoprolol introduction, which includes base and layer of sensitive to pressure adhesive, which contains bisoprolol, which is layered on one base surface, where maximal value of bisoprolol release in time period immediately from application on skin within 24 hours constitutes 30 mcg/cm2/hour or less; and where velocity of bisoprolol release 24 hours after application on skin constitutes 10 mcg/cm2/hour or less.

EFFECT: device for transdermal introduction reduces skin irritation, especially in case of layering, and can constantly introduce into living organism therapeutically or preventively efficient amount of bioprolol.

5 cl, 3 tbl, 3 dwg, 3 ex

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.

SUBSTANCE: group of inventions refers to medicine and biotechnology, and may be used for intensifying the vascular growth in ischemic tissues. An agent under the invention contains the plasmid construct pC4W-hVEGFopt bearing the optimised gene hVEGFopt of vascular endothelial growth factor, and in addition the plasmid construct pC4W-hHGFopt bearing the optimized gene hHGFopt hepatocyte growth factor. The method under the invention consists in the intramuscular introduction of a mixture of the plasmid constructs pC4W-hVEGFopt and pC4W-hHGFopt in 0.9% NaCl in ischemic extremity.

EFFECT: use of inventions allows providing effective angiogenesis in ischemic tissue.

4 cl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: solid dosage form contains valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives and is presented in the form of a two-layer tablet. Quantitative proportions of valsartan, amlodipine and hydrochlorothiazide are selected from the following: 160 mg/12.5 mg/5 mg, 160 mg/12.5 mg/10 mg, 160 mg/25 mg/10 mg, 160 mg/25 mg/5 mg and 320 mg/25 mg/10 mg. Preferentially, amlodipine is used in the form of amlodipine besylate. The two-layer tablet can contain valsartan and hydrochlorothiazide in the first layer, and amlodipine in the second layer, or valsartan in the first layer, and amlodipine and hydrochlorothiazide in the second layer. Also, there are described methods for making a two-layer tablet.

EFFECT: two-layer tablet under the invention with the fixed combination of valsartan, amlodipine and hydrochlorothiazide have the biological properties equivalent to those of a free combination of said medical agents.

17 cl, 11 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: solid dosage form contains valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives and is presented in the form of a two-layer tablet. Quantitative proportions of valsartan, amlodipine and hydrochlorothiazide are selected from the following: 160 mg/12.5 mg/5 mg, 160 mg/12.5 mg/10 mg, 160 mg/25 mg/10 mg, 160 mg/25 mg/5 mg and 320 mg/25 mg/10 mg. Preferentially, amlodipine is used in the form of amlodipine besylate. The two-layer tablet can contain valsartan and hydrochlorothiazide in the first layer, and amlodipine in the second layer, or valsartan in the first layer, and amlodipine and hydrochlorothiazide in the second layer. Also, there are described methods for making a two-layer tablet.

EFFECT: two-layer tablet under the invention with the fixed combination of valsartan, amlodipine and hydrochlorothiazide have the biological properties equivalent to those of a free combination of said medical agents.

17 cl, 11 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method for correction of L-NAME induced nitrogen oxide deficiency consists in the fact that with underlying simulation thereof, L-norvaline 10 mg/kg is intragastrically introduced to white Wistar male rats with the induced nitrogen oxide deficiency daily, for 7 days.

EFFECT: method allows assessing the dynamics of correction of nitrogen oxide deficiency in the given model after the introduction of L-norvaline.

2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, namely to composition for transcutaneous delivery of medication, which is realised from mixture, which contains: therapeutically efficient amount of medication, including initial medication and promedicine, as well as pharmaceutically acceptable carrier, both initial medication and promedicine being present in amount sufficient for manifestation of pharmacologic activity.

EFFECT: in preferable version of invention implementation mixture includes therapeutically efficient amount of pharmaceutically active agent, which contains ACE inhibitor, such as ramipril, promedicine being promedicine of ACE inhibitor, such as ethyl ester of ramipril and/or methyl ester of ramipril.

5 cl, 10 ex, 9 dwg

FIELD: medicine.

SUBSTANCE: modeling of ADMA-like model of gestosis in laboratory pregnant rats of Wistar line is carried out by daily introduction of inhibitor of NO-synthase L-NAME in dose 25 mg/kg from 14 to 20 day of pregnancy. Correction of endothelial dysfunction is performed by L-norvalin, which at the background of modeling is introduced intragastrically daily for 7 days in dose 10 mg/kg once per day.

EFFECT: method leads to expressed dysfunction correction under conditions of specific mechanisms of pathological process course in pregnant women.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing arterial hypertension containing an angiotensin converting enzyme (ACE) inhibitor and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: ACE inhibitor - 2-4; N-acetyl-5-methoxytriptamine (melatonin) - 2-8; excipients - up to 100 mg with the ACE inhibitor being presented by the compounds specified in a group of enalapril, captopril, perindopril, lisinopril, fozinopril, quinapril, spirapril. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a softgel capsule, a solid gel capsule, by a soft dosage form - a rectal suppositorium.

EFFECT: providing a therapeutically significant effect (stable night-time blood pressure profile) and a lower risk of side effects due to using the doses low for the ACE inhibitors specified above have been shown.

3 cl, 3 tbl

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