Method of conservative treatment and prevention of nuclear type of age cataract

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular, to ophthalmology, and can be used for treatment and prevention of nuclear type of age cataract. For this purpose antagonist of serotonin receptors is applied in efficient concentration.

EFFECT: invention allows to carry out treatment and prevention of said disease, due to efficient impact on bioamine status and phenotype of lens cells.

1 tbl, 3 ex

 

The invention relates to medicine, in particular to ophthalmology, and in particular to methods of conservative treatment of age-related cataracts, and relates to a new use of known chemical compounds, namely ondansetron hydrochloride dihydrate (1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one hydrochloride dihydrate) (Patent UK 2153821), for the treatment of the nuclear form of age-related cataracts.

It is known that ondansetron hydrochloride dehydrate (1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-one hydrochloride dihydrate) (Patent UK 2153821)showing the properties of an antagonist of 5-HT3-serotonin receptors, has antiemetic activity (European Patent 0226266) and is used as a regulator of motor activity of the upper parts of the gastrointestinal tract with nausea and vomiting of different origin.

This study found that ondansetron hydrochloride dehydrate has compared with the widely known anticitrulline eye drops ("OFTAN-Catachrom", "Quinax") the superior effectiveness capacity to improve the optical properties of a cataractous lens.

Modern medicine offers information about the plasticity of the phenotype of cells of the crystalline lens in the formation of different types of his age pomot the deposits (Korsakov, NV, Sergeeva V.E., Petrov S. B. Immuno-histochemical analysis of the cells of the crystalline lens in the formation of different types of age-related cataracts in humans // Morphology. - SPb.: Aesculapius, 2007. - T. No. 5. P.47 - 51; Korsakova N.V., Sergeeva V.E., levy S.B. Immnohistochemical analysis of lens cells on formation of different types of age-related cataract in humans // Neuroscience and behavioral discrimination. - New York: Springer New York, 2008. - Vol.38. - N 9. - P.887-890). These data are compatible with many researchers have repeatedly spoken of the existence of the transformation process phenotype of the cells under the influence of certain external or internal factors (Saika s, Miyamoto T., Tanaka S. et al. "Response of lens epithelial cells to injury: role of lumican in epithelial mesenchymal transition" // Invest. Ophthalmol. Vis. Sci. - 2003. - V.44. - N 5. - P.2094-2102; Kansas state University A, Omulecka A. et al. "A study of human lens epithelial cells by light and electron microscopy and by immunohistochemistry in different types of cataracts" // Klin Oczna. - 2002. - V.104. - N 5-6. - P.369-373). Transformation phenotype of the cells is recognized as a fundamental process governing morphogenesis in multicellular organism, and in the formation of several diseases it is associated with the development of fibrosis and uncontrolled cell growth (Thiery J.P. "Epithelial-mesenchymal transitions in development and pathologies" // Curr Opin Cell Biol. - 2003. - V.15. - N-6. - P.740-746).

It is known that the phenotypic characteristics of the cells is largely determined by the quantitative and qualitative presence of neurotransmitter biogenic amines. A comparative analysis revealed fundamental differences bioamines the profile of the lens in the formation of different types of age-related cataracts in humans (Korsakov, NV, Sergeeva VE Features boninovo profile of the lens in the formation of different types of age-related cataracts in humans // Ophthalmosurgery. - Moscow, 2007. No. 3. - P.44-47). The formation of the nuclear form of age-related cataracts distinguishes significant, more than 3 times, the increase mainly serotonin levels. Thus, revealed important differences bioamines security processes in the formation of age-related cortical and nuclear cataract, initiating various changes in phenotype of the cells of the crystalline lens, which entail changes in its optical properties. These facts suggest that the impact on the lens of such causal factors as age, can be implemented through a completely different pathogenetic mechanisms leading to the formation of a particular type of age-related cataracts.

Objective: develop affordable, high-performance, pathogenetically reasonable method of conservative treatment and prevention of age-related nuclear cataract.

The essence of the proposed method: the antagonists of serotonin receptors for the treatment and prevention of nuclear form of age-related cataracts.

Positive effect: increase treatment effectiveness, availability and cost reduction of public funding for treatment and prevention meropriyatiya.posle cataract, including by reducing the number of people in need of surgical treatment.

The most common means of conservative treatment of cataract in the world and in our country are: eye drops "Quinax, including the means of sodium isopentane polysulfone and water (Dudin H. Pharmacotherapy for age-related cataract // Medical abstract journal. - M., 1989. No. 6. - P.10. - Abstract No. 530); and eye drops "OFTAN-Catachrom, including cytochrome C, adenosine, nicotinamide, benzalkonium chloride, sodium succinate, the uranyl, sorbitol buffer and antiseptic substances, water for injection (Mashkovsky PPM "karstenia funds. - M.: Medicine, 1988. - Vol.2. - P.67).

However, the known eye drops for cataracts have shortcomings: cause side effects in the form of allergic reactions in some patients (Mashkovsky PPM Medicines. - M.: Medicine, 1986. - Vol.2. - S); do not allow to achieve a steady clinical improvement of visual acuity of patients with cataract (Dudin H. Pharmacotherapy for age-related cataract // Medical abstract journal. - M., 1989. No. 6. - P.10. - Abstract No. 530). In addition, eye drops "OFTAN-Catachrom contain one of the main components of cytochrome C, not penetrating through the cornea, which casts doubt on its effectiveness for the treatment of lens opacities (Formazyuk V.E. et al. "Anticataract druge transport across the cornea into thelens: the possible routes and molecular mechanisms" // In 3rd International Cataract Epidemiology Symposium. Satelite Meeting, March 15-16. - Singapore, 1990. - P.45).

Thus, from the available sources of patent and scientific literature methods of conservative treatment of age-related cataracts, based on the use of antagonists of serotonin receptors, today is not known.

The proposed method is based on the identified differences neurotrophic control of the formation of different types of age-related cataracts (Korsakov N., Sergeev VE Features boninovo status of the lens in the formation of different types of age-related cataracts in humans // Ophthalmosurgery. - M., 2007. No. 3. - P.44-47), indicating that natural manifestations of age-related involution of the sympathetic and parasympathetic divisions of the autonomic nervous system and dictates the need for a differentiated approach to the prevention and therapy of age-related cataracts, depending on its type.

The objective of the invention to develop an affordable, highly effective method of conservative treatment and prevention of age-related nuclear cataract, which allows pathogenetically reasonable impact on bioamines status and phenotype of cells of the lens.

A method of conservative treatment and prevention of nuclear form of age-related cataracts, based on the correction boninovo status of the cells of the lens by using the project antagonists of serotonin receptors in the composition of the dosage forms for the topical treatment of eye diseases.

The proposed method allows you to begin developing a new group of highly effective, affordable eye drops for the treatment and prevention of age-related nuclear cataract, taking into account pathogenetically substantiated the need for a differentiated approach to the treatment of different types of age-related cataracts that will significantly improve the quality, efficiency and reduce costs of public funding for treatment and preventive measures of age-related cataracts, including by reducing the number of people in need of surgical treatment.

The invention is illustrated in the following examples.

Example 1.

The study of the influence of antagonists of serotonin receptors on cataractogenic and optical properties of the lens held by the material of laboratory rats. Lenses with saved capsule, remote intracapsular, cultured for 8 days in vitro. Antagonist of serotonin receptors (ondansetron hydrochloride dehydrate) at a final concentration of 0.2 mg/ml add in the cultural medium. Clouding of the lens in vitro cause by changing the concentration of calcium ions in the environment of the cultivation or adding hydrogen peroxide. Conduct the following series of experiments:

No. 1 - a nutrient medium 199;

No. 2 nutrient medium 199 + H2O2;

No. 3 - a nutrient medium 19 + N 2About2+ antagonist of serotonin receptors;

No. 4 - a nutrient medium 199 + CaCl2;

No. 5 - a nutrient medium 199 + CaCl2+ antagonist of serotonin receptors.

For a specified period of time in lenses cultured in a nutrient medium without the addition of harmful agents, fully retained their transparency and morphology.

In series No. 1 cataract is not supervised during the whole cultivation period.

In series 2 and 4 (the action of damaging agents) for 3-4 days cultivation observe the formation of pronounced cataract nuclear and cortical type, respectively.

In series 3 and 5 (the combined effect of the damaging agent and antagonist of serotonin receptors) see the almost complete transparency of the lens and the decrease of optical density in comparison with lots No. 2 and 4 (in 4 and 3.7 times, respectively).

These estimates of the degree of cataract in different series, obtained through visual observation during biomicroscopy, coincide with the results of photometric studies of the crystalline lens after in vitro cultivation. The results indicate that adding on Wednesday cultivation antagonist of serotonin receptors (ondansetron hydrochloride dehydrate) helps support aniu transparency of the lens is almost on the level of intact (series No. 1), as compared with series No. 2, 4 (the action of damaging agents) significantly improves the optical properties of a cataractous lenses, reducing the optical density 4 and 3.7 times, respectively.

Example 2.

Investigation of the influence of eye drops "Oftan-Katahrom on cataractogenic and optical properties of the lens held by the material of laboratory rats. Lenses with saved capsule, remote intracapsular, cultured for 8 days in vitro. Eye drops "Oftan-Katahrom containing the active substance cytochrome C, adenosine and nicotinamide in the final concentration is 0.135, 0.4 and 4 mg/ml, respectively, add in the cultural medium. Clouding of the lens in vitro cause by changing the concentration of calcium ions in the environment of the cultivation or adding hydrogen peroxide. Conduct the following series of experiments:

No. 1 - a nutrient medium 199;

No. 2 nutrient medium 199 + H2About2;

No. 3 - a nutrient medium 199 + H2About2+ eye drops "Oftan-Katahrom;

No. 4 - a nutrient medium 199 + CaCl2;

No. 5 - a nutrient medium 199 + CaCl2+ eye drops "Oftan-Katahrom.

For a specified period of time in lenses cultured in a nutrient medium without the addition of harmful agents, fully retained their transparency and morphology. In series No. 1 cataract't nab utaut during the whole cultivation period.

In series 2 and 4 (the action of damaging agents) for 3-4 days cultivation observe the formation of pronounced cataract nuclear and cortical type, respectively.

In series 3 and 5 (the combined effect of the damaging agent and eye drops "Oftan-Katahrom) observed the formation of moderately expressed cataract and some improvement of the optical properties of 1.7 and 3.7 times compared to the series 2 and 4, respectively.

These estimates of the degree of cataract in different series, obtained through visual observation during biomicroscopy, coincide with the results of photometric studies of the crystalline lens after in vitro cultivation. The results demonstrate that the addition of the environment of the cultivation of eye drops "Oftan-Katahrom promotes reduction of the optical density of a cataractous lens in 1.7 and 3.7 times compared to lenses cultured in medium with the addition of only cataractogenic agents (series No. 2, 4).

Example 3.

Investigation of the influence of eye drops "Twinax" cataractogenic and optical properties of the lens held by the material of laboratory rats. Lenses with saved capsule, remote intracapsular, cultured for 8 days in vitro. Eye drops "Twinax"containing the active ve is estvo sodium isopentane polysulfonic at a final concentration of 0.03 mg/ml, accordingly, add in the cultural medium. Clouding of the lens in vitro cause by changing the concentration of calcium ions in the environment of the cultivation or adding hydrogen peroxide. Conduct the following series of experiments:

No. 1 - a nutrient medium 199;

No. 2 nutrient medium 199 + H2O2;

No. 3 - a nutrient medium 199 + H2About2+ eye drops "Twinax";

No. 4 - a nutrient medium 199 + CaCl2;

No. 5 - a nutrient medium 199 + CaCl2+ eye drops "Twinax".

For a specified period of time in lenses cultured in a nutrient medium without the addition of harmful agents, fully retained their transparency and morphology. In series No. 1 cataract is not supervised during the whole cultivation period.

In series 2 and 4 (the action of damaging agents) for 3-4 days cultivation observe the formation of pronounced cataract nuclear and cortical type, respectively.

In series 3 and 5 (the combined effect of the damaging agent and eye drops "Twinax") see the formation of the moderately expressed cataract and some improvement of the optical properties of the lens compared to the series 2 and 4, respectively, 1.9 and 2.7 times.

These estimates of the degree of cataract in different series, obtained using the visual the observation that when biomicroscopy, fully coincide with the results of photometric studies of the crystalline lens after in vitro cultivation. The results indicate that adding in the environment of the cultivation of eye drops "Twinax" promotes reduction of the optical density of a cataractous lens in 1.9 and 2.7 times in comparison with lenses cultured in a medium containing only cataractogenic agents (series No. 2, 4).

Thus, the proposed method of conservative treatment and prevention of nuclear form of age-related cataract has a more pronounced anticatarrhal action.

The proposed method is as follows:

In the method of obtaining drugs for the treatment of cataracts as one of the main components of the active substance having the properties of antagonists of serotonin receptors.

The invention has novelty, meets the requirements of inventive step and may find wide application in ophthalmology.

The table below shows the advantages of using the proposed method in comparison with the known.

Table
BenchmarksEye drops "Oftan-Katahrom Eye drops "Twinax"The inventive method
Costs cash++++ (high)+++++ (maximum)+ (low)
Complexity, complexity, R & d expenses+++++ (maximum)+++++ (maximum)++ (moderate)
The cost of working time+++++ (maximum)++++ (high)++ (moderate)
Predictable therapeutic effect for treatment of the nuclear form of age-related cataracts+ (low efficiency)++ (moderate effect)+++++ (maximum preservation of lens transparency)
The expediency of application for the treatment and prevention of nuclear form of age-related cataracts-
(impractical)
++ (moderate feasibility)+++++ (maximum expediency)

Method for the treatment and prevention of the nuclear age is ataractic, wherein the topically applied antagonist of serotonin receptors in an effective concentration.



 

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, where: U, V and W independently represent CR5 where R5 stands for H, C1-C6alkyl; Q stands for NR5, NNR5, NO, CR5, where R5 stands for H, C1-C6alkyl; L1 stands for -NR5C(O)-, -NR5C(O)NR5-, -C(O)NR5-, -NR5- and C5heteroaryl, containing 2 N atoms and 1 O atom, where R5 stands for H, C1-C6alkyl; L2 represents bond, -O-, -NR5C(O)-, -NR5C(O)NR5-, -C(O)NR5- ,-NR5-, where R5 stands for H, C1-C6alkyl; n = 0 or 1; m = 0, 1, 2, 3 or 4; R1 stands for C6-C10aryl and C5heteroaryl, containing 1 N atom, condensed with benzene; where any aryl, heteroaryl, contained in R1, can be optionally substituted with 1-3 radicals, which represent halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, C6-C10aryl-C0-C4alkyl, C5-C6heteroaryl-C0-C4alkyl, containing 1 or 2 N, C5-C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N and/or O atoms; where methylene fragment of any alkyl group can be optionally substituted with O; where any aryl, heteroaryl or heterocycloalkyl substituent, contained in R1, can be optionally substituted with 1-3 radicals, which independently represent C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup and hydroxy-substituted C1-C6alkyl; R2 represents halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, C6-C10aryl-C0-C4alkyl, C5heteroaryl-C0-C4alkyl, containing 1 or 2 N, C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N atoms and/or O; where any aryl, heteroaryl or heterocycloalkyl, contained in R2, is optionally substituted with 1-3 radicals, which independently represent halogen, NH2, NO2, CN, C1-C6alkyl, C1-C6alkoxygroup, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxygroup; R3 represents H, C1-C6alkyl; R4 represents H, -XR6, -XNR5XR6, -XOXR6 and -XNR5XNR5R6; where each X independently represents bond and C1-C4alkylene; where any alkylene, contained in X can be optionally substituted with OH; R5 represents H, C1-C6alkyl; R6 represents C6-C10aryl and C5heteroaryl, containing 1 or 2 N and/or O, optionally condensed with benzene; where any aryl, heteroaryl, contained in R6, can be optionally substituted with 1-3 radicals, which independently represent C1-C6alkyl, OH, CN, -NR5S(O)0-2R5, -S(O)0-2NR5R5, - NR5S(O)0-2NR5R5, -C(O)NR5XNR5R5, -XNR5XNR5R5, -C(O)R7, -C(O)NR5XOR5, -C(O)NR5R5, -C(O)NR5R7, -C(O)NR5XR7 and -XC(O)OR5; where each X independently represent bond and C1-C4alkylene; where any alkylene, contained in X, is optionally substituted with OH; where each; R5 represents H, C1-C6alkyl; R7 represents C5-C6heterocycloalkyl-C0-C4alkyl, containing 1 or 2 N and/or O, where any heterocycloalkyl, contained in R7, is optionally substituted with radical, which represents diethylaminoethyl, dimethylaminogroup, aminogroup, C1-C6alkyl, pyrimidinyl, pyrazinyl, halogen-substituted C1-C6alkyl and -C(O)OR5; and its pharmaceutically acceptable salts, hydrates, solvates.

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10 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

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16 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds can be used as a medicinal agent having CXCR2 inhibiting properties. In formula I , X denotes -CR3=CR4-, -CR5=N-, -N=CR6-, -NR7- or -S-; R3, R4, R5 and R6 independently denote hydrogen, F, CI, Br, I; R7 denotes hydrogen; Y1, Y2, Y3 and Y4 independently denote -CR8- or nitrogen, provided that at least two of Y1, Y2, Y3 and Y4 denote -CR8-; where R8 denotes hydrogen, F, CI, Br, I; A denotes a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms; a bicyclic partially saturated 9-member cycloalkyl; a bicyclic partially saturated 9-10-member heterocycle in which two atoms in the ring are oxygen atoms; phenyl; naphthyl; a 5-6-member heteroaryl in which 1-3 atoms in the ring are oxygen, sulphur and nitrogen atoms; a 9-10-member bicyclic heteroaryl in which 1-3 atoms in the ring are nitrogen, oxygen and sulphur atoms; a 6-member heterocycle in which one atom in the ring is a nitrogen atom and which can be unsubstituted or substituted with alkyl having 1, 2, 3 or 4 carbon atoms, -C(O)CH3, -C(O)CH2CH3, -C(O)cyclopropyl, -C(O)CF3 and -C(O)OC(CH3)3; where phenyl, heterocyclic or heteroaryl radical is substituted with 1, 2 or 3 radicals selected from a group consisting of F, O, Br, I, OH, CN, NO2, SCF3, SF3, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; cycloalkyl having 3, 4, 5 or 6 carbon atoms; alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -S-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; -NR9R10, C(O)R44, S(O)SR47, -(CH2)k-phenyl, 5-6-member heteroaryl, in which 1-3 atoms in the ring are nitrogen and sulphur atoms; where the phenyl radical may be substituted with F, CI, Br, I; R9 is an alkyl having 1, 2, 3 or 4 carbon atoms; R10 is an alkyl having 1, 2, 3 or 4 carbon atoms; R44 is an alkyl having 1, 2, 3 or 4 carbon atoms, where 1, 2, 3 hydrogen atoms may be substituted with fluorine atoms; alkoxy having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms; R47 is an alkyl having 1, 2, 3 or 4 carbon atoms; k equals 0, 1, 2 or 3; s equals 1 or 2; B is -O-C(R11R12), -C≡C-, -CR52=CR53-, -C(R13R14)C(R15R16), -NR17-C(R18R19); R11, R12, R13, R14, R15, R16, R17, R18, R19, R52, R53 independently denote hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is C(O)OH, C(O)NHR21 or C(=NR58)NHR22; R21 and R22 independently denote hydrogen, -SO2-alkyl having 1, 2, 3 or 4 carbon atoms, -SO2-phenyl; R58 is OH; R1 and R2 independently denote an alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where the alkyl radicals are unsubstituted or substituted with 1 radical selected from a group consisting of F, Cl, Br, I, phenyl substituted with OH; or R1 and R2, taken together with a carbon atom with which they are bonded form a 3-, 4-, 5- or 6-member carbocycle. The invention also relates to use of formula I compounds in preparing a medicinal agent which has CXCR2 inhibiting properties, to a medicinal agent which containing an effective amount of the disclosed compound and having CXCR2 inhibiting properties, as well as to use of formula II compounds (formula and values of radicals are given in the formula of invention) in preparing a medicinal agent having CXCR2 inhibiting properties.

EFFECT: high effectiveness of application.

10 cl, 384 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to development of a medical product intended for treatment and prevention of eye diseases. A pharmaceutical antiglaucoma composition contains active substances of pilocarpine - hydrochloride and hypromellose, besides - pharmaceutical aids - disodium edetate, benzalkonium chloride, sodium chloride, boric acid and water for injections in a certain ratio.

EFFECT: invention provides prolonged contact of the medicinal substance and cornea.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: medicine.

SUBSTANCE: there are offered a pharmaceutical composition for prevention or treatment of cardiovascular disturbances, containing Amlodipine or its pharmaceutically acceptable salt and Losartan or its pharmaceutically acceptable salt wherein Amlodipine or its pharmaceutically acceptable salt and Losartan or its pharmaceutically acceptable salt are physically separated from each other, and a method for preparing thereof. The method includes the following stages: a) wet granulation and drying of mixed Amlodipine or its salts and pharmaceutically acceptable excipients to prepare a portion containing Amlodipine granules; and b) mixing of the portion containing Amlodipine granules prepared at the stage a) and pre-mixed Losartan or its salt and pharmaceutically acceptable excipients.

EFFECT: improved preventive and therapeutic effects in cardiovascular disturbances, better stability, solubility, absence of hygroscopicity in making the tablets.

12 cl, 5 dwg, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology and can be used for fluorescent diagnostics in the course of photodynamic therapy of eye diseases. Photosensitiser (PS) is introduced to patient intravenously, fluorescent diagnostics is carried out by means of device which contains a source of laser irradiation, system of its delivery with optic adaptor for transpuppilar irradiation, homogenising element, microscope, highly sensitive black-and white videocamera with filter for formation of image of examined part of eye, system of videoinformation presentation. Used filter has the following characteristics: optic density of range 400-750 nm - not less that 4; for range 780-890 nm - not more than 1. System of videoinformation presentation is represented by personal computer with software for image registration and processing. In the course of diagnostics patient's eye is irradiated by wide homogeneous laser beam with 6-12 mm diametre with wavelength corresponding to maximum of light irradiation absorption by chlorine PS. Power density is 20-40 mW/ cm2.

EFFECT: method ensures clearness of PS fluorescence visualization in the course of photodynamic therapy with simultaneous visualisation of irradiated details of eye structure in light spot with 6-12 mm diametre.

5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to ophthalmology, and can be used for surgical management of cataract. A crystalline lens is removed through two microincisions with using an aspiration and irrigation cannula by phakoaspiration. The aspiration cannula forms a cup recess in the centre of a crystalline lens substance with turning a nucleus around 90°, then 180° and 270°; then the aspiration cannula fixes the created cup plate thinned to 1 mm; said plate is raised slightly to deliver the irrigation cannula thereunder; the cannulas advance to each other to break off smaller fragments and remove them with the aspiration cannula. The method allows removing through microincisions both soft cataracts, and those associated with crystalline lens density.

EFFECT: invention allows to extend indications for surgical management, to provide higher clinical effectiveness and safety, to reduce a number of complications.

3 dwg, 1 ex

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