Peptide having neurotropic activity
SUBSTANCE: present invention relates to bioorganic chemistry and medicine and can be used to prepare medicinal agents with neurotropic activity. The technical result is achieved due to creation of a peptide with neurotropic activity and having general formula: Ac-X-Met-Pro-Arg-Gly-NH2, where X-Met - L-Met or DL-Met.
EFFECT: obtaining a novel compound - analogues of the C-terminal end of vasopressin which are capable of selectively bonding with different subtypes of vasopressin receptors and, as a result, have different types of neurotropic activity, have low toxicity and are suitable for simple intranasal administration.
The invention relates to the field of Bioorganic chemistry and medicine and can be used to create drugs with neurotropic activity.
It is known that neurohypophyseal hormone vasopressin has behavioral activity, as a stimulator of memory and learning [1, 2]. However, it has a wide spectrum of biological activity and in medicine is used primarily as a hormonal agent that regulates blood pressure, diuresis.
Known testisterone peptides that are fragments of the C-terminal sequence of vasopressin stimulating learning laboratory animals at doses 100-1000 times higher doses of vasopressin in similar tests, but deprived of its hormonal effects [3, 4].
Known peptides are C-terminal fragments of vasopressin containing cysteine, more synthetically available [5, 6]. The most active stimulant memory and learning from them is tetrapeptide Cys-Pro-Arg-Gly-NH2effective dose which is comparable with the doses of vasopressin.
Along with natural peptides sequences obtained structural analogues With the end of vasopressin. Replacement of cysteine or cysteine at residue serine led to the Hexapeptide pGlu-Asn-Ser-Pro-Arg-Gly-NH2active in tests on learning laboratory animals at doses 00 times higher doses of vasopressin . However, synthesis of these compounds is complex and multi-stage, because increasing the number of amino acid residues, increasing the number of stages of the synthesis.
In the last two decades were found several different types of vasopressin receptors and it is shown that the different activities implemented by the binding molecules of the ligand with different types of receptors [8, 9]. Obviously, a more narrow spectrum of activity C-terminal analogues in comparison with the natural hormone is associated with their higher selectivity with respect to the receptors of vasopressin.
The present invention is the creation of medicines with neurotropic activity.
The technical result that can be obtained by carrying out the claimed invention is to provide new compounds analogues of the C-terminal region of the vasopressin able to selectively connect with different subtypes of receptors of vasopressin and consequently with different types of neurotropic activity of the antidepressant effect, stimulating effect on the processes of memory, locomotor activity), low-toxic, suitable for introduction available intranasal method that can be used to create a nootropic drugs.
This result is achieved by creating with it Otradnoe activity of the peptide of General formula: Ac-X-Met-Pro-Arg-Gly-NH 2where X Is Met-L-Met and DL-Met.
To achieve this goal held modification of the C-terminal tetrapeptide vasopressin - replacement of Cys on the optical isomers of N-acetylation - Ac-D-Met, Ac-L-Met and Ac-DL-Met. Replacement of Cys at stereoisomers Ac-Met allows you to save important elements such patterns, as the presence of a nucleophilic sulfur atom, and the acylation of the α-amino group of methionine increases the enzymatic stability of the peptide. Theoretical conformational analysis showed significant differences stable conformations obtained Stereolab, which leads to high selectivity in binding with different subtypes of receptors of vasopressin.
Synthesis of tetrapeptide Ac-X-Met-Pro-Arg-Gly-NH2where X Is Met-L-Met and DL-Met is performed using reactions in peptide condensation dicyclohexylcarbodiimide (DCGK) or diisopropylcarbodiimide (DIPC) with the addition of oxibendazole (MBT). Dipeptide Boc-Pro-Arg produced by the method operations esters, then condense it with Amida glycine derived tripeptides with BOC-protected amino groups will unlock processing model HC1 in ethyl acetate, the reaction Pro-Arg-Gly-NH2and Na-acetylated of Stereolab methionine in the presence of DEPC and MBT receive stereoisomer peptides of General formula Ac-X-Met-Pro-Arg-Gly-NH2.
In the developed schemes of synthesis of the protection of guanidinium moiety of arginine performs the I protonation, that allows you to get a connection with a minimum number of stages of the synthesis by eliminating stages of obtaining NG-protected derivatives and removal of protective groups.
The method of synthesis of a peptide of General formula Ac-X-Met-Pro-Arg-Gly-NH2where X Is Met-L-Met and DL-Met is described in the examples. The molecular mass of the synthesized peptides identified using mass spectrometry. Mass spectra FAB recorded on a mass spectrometer LCQ FLEET ("Thermo"). The homogeneity of the compounds was checked by TLC on plates "Sorbfil" (Russia)using the following solvent mixtures as eluents: nbutanol-acetic acid-water, 4:1:1 (A); chloroform-methanol - 25% ammonia 60:45:15 (B); chloroform-methanol-25% ammonia-acetic acid 60:45:15:3 (In); ethyl acetate-pyridine-acetic acid-water 10:10:3:6 (D). Substances were detected on the chromatograms using chlorbenside samples. Specific rotation of the studied compounds were measured on spectropolarimeter J-20 "Jasco (Japan).
To a solution of 2.15 g (10 mmol) of tert-butyloxycarbonyl-Proline and 1.26 g (11 mmol) of N-oxysuccinimide in 12 ml of fresh dioxane was added when 7°C, 2.16 g (10.5 mmol) DCGK intensive mixing of the reaction mass. Stirring is carried out for 1 hour while cooling, 3 hours at room temperature. The resulting wasp is OK DCGM filtered off, washed on the filter with 2-3 ml of dioxane. Dioxane solution of the BOC-Pro-OSu was added to a solution of 1.22 g (7 mmol) of arginine in 7 ml of water. The reaction mixture is stirred at 20°C for 4 h, after the reaction is cooled to 5°C., filtered the precipitate Boc-Pro-Arg, washed it on the filter with water, cooled to 3-5°C (2×2 ml)and then with ethyl acetate (3×3 ml), dried in a vacuum desiccator to constant weight. The output of Boc-Pro-Arg 1.85 g (71%).
TPL 154-155°C [α]D20-49°(C 1, methanol), Rf0,38 (A)0,71 (B).
A mixture of 1.11 g (3.0 mmol) of Boc-Pro-Arg and 0.33 g (3.0 mmol) of the hydrochloride of glycidamide in 7 ml of DMF (reagents pre-grind in a mortar to a fine powder) is stirred for 1 h at 20°C, cooled to 0-5°C. and added 0.45 g (3.3 mmol) MBT, then of 0.68 g (3.3 mmol) DCGK. The reaction mixture was stirred 1 h at (0-5°C) and 16 h at 20°C. the Precipitate DCGM separated by filtration, washed with 2 ml of DMF. To the United dimethylformamide solution add 25 ml of ether, after compaction of the sediment layer decanted solvent, the residue is twice periostat from methanol-ether. In the presence of impurities of the source glycinamide (TLC control) is dissolved in 3-4 ml of a mixture of ethyl acetate and methanol 1:1 and to the solution was added in small portions ethyl acetate (3-5 ml) before the formation of the OS is dka. Operation repeat, if translated into the residue of the Tripeptide contains an admixture of glycinamide. Homogeneous according to TLC residue is dried in vacuum over P2O5.
The output of Boc-Pro-Arg-Gly-NH2·HCl 1.28 g (92%). TPL 85-87°C, [α]d20- 51° (C 1, methanol), Rf0,39 (B)0,51 (G).
Shed-arginyl-glycinamide the dihydrochloride (V) (Pro-Arg-Gly-NH2·2HCl)
A suspension of 0.93 g (2.0 mmol) of Boc-Pro-Arg-Gly-NH2·HCl in 10 ml of 4.8 n HCl solution in ethyl acetate is stirred for 120 min, monitoring completeness of removal of the BOC-group TLC systems (A) or (G), then evaporated in vacuo of the solvent, to the residue was added 5 ml of dry ethyl acetate is added and the evaporation repeated. The residue is dissolved in 3 ml of methanol, transferred to precipitate by adding 12 ml of ether. The residue Pro-Arg-Gly-NH2·2HCl-EA is separated by filtration, washed it with ethyl acetate, ether, dried in vacuum over KOH. Get 0,94 g (96%) Pro-Arg-Gly-NH2·2HCl in the form of MES with one molecule of ethyl acetate.
[α]d20- 38° (C 1, methanol), Rf0,31 (B)0,34 (G).
N-Acetyl-L-methionyl-shed-arginyl-glycinamide (VI) (Ac-L-Met - Pro-Arg-GIy-NH2)
To a cooled to 3°C. to a solution of 0.49 g (1.0 mmol) Pro-Arg-Gly-NH2·2HCl-EA in 3 ml of DMF is added is 0.135 ml (1.2 mmol) of N-methyl-research, after 10 min of 0.23 g (1.2 mmol) of N-acetyl-D-methionine, 0.16 g (1.2 mmol) MBT, to 0.23 g (1.1 mmol) DCGK. The reaction mixture was stirred at 3-5°C in t the value of 1 h and 3 h at 20°C, then separate the precipitate by filtration DCGM, washed it 0.5 ml of DMF. To the United dimethylformamide solution add 15 ml of ether, after compaction of sludge decanted the supernatant, the residue is dried in vacuum over P2About5, periostat from chloroform-ether from methanol-ethyl acetate. The precipitate was separated by filtration, dried in vacuum over P2O5. Get 0,42 g (83%) of N-Ac-L-Met - Pro-Arg-Gly-NH2.
In the presence of impurities of the source compounds according to TLC, a portion of the peptide is dissolved in a minimum amount of methanol and applied on a column of silica gel L 40/100, swollen in eluent chloroform-methanol-water 10:10:1. Spend elution with use of the above solvent mixture and collect the fractions containing pure product (TLC control). The combined fractions are evaporated, the residue periostat from methanol-acetone. After drying over P2O5get clean tetrapeptide in the form of white crystalline powder. Yield N-Ac-L-Met - Pro-Arg-Gly-NH20,215 g (43%).
TPL 109-110°C, [α]d20-57° (C 1, methanol),), Rf0,64 (B)0,42 (G).
N-Acetyl-DL-methionyl-shed-arginyl-glycinamide (VI) (Ac-DL-Met - Pro-Arg-Gly-NH2).
N-Acetyl-DL-methionyl-shed-arginyl-glycinamide receive according to the method described in example 4 for the L-isomer of 0,49 g (1.0 mmol) Pro-Arg-Gly-NH2·2HCl-EA and 0.23 g (1.2 mmol) of N-D-methionine. The output Ac-DL-Met-Pro-Arg-Gly-NH20,275 g (55%).
TPL 109-110°C, [α]d20-40° (C 1, methanol),), Rf0,64 (B)0,42 (G).
Experiments to study the effect·of peptides on the behavioral reactions were performed on male outbred rats weighing 180±30 g of the Investigated peptides were administered intranasally in aqueous solution in a volume of 1 μl/10 g body weight for 5 min before testing in the study of orienting-exploratory behavior, levels of anxiety and depression level and every day after training session in the formulation of the conditional reaction active avoidance. Animals of the control group was administered distilled water in an equivalent amount. The drugs were administered in the following doses of 0.01 mg/kg, of 0.1, 1.0 and 10.0 mg/kg
Orienting-exploratory behavior of animals investigated in the tests open field ("bestreshma" and "stress" version) and "mink camera, the level of anxiety in the test, the elevated plus maze and light-dark chamber", the degree of depression - in test "forced swim".
The production conditions one-way active avoidance reaction was carried out for four consecutive days.
Ac-L-Met-Pro-Arg-Gly-NI-b, with intranasal injection in doses of 1.0 to 10.0 μg/kg had no effect on the orienting-exploratory behavior and anxiety level of animals. But is this tetrapeptide had a strong antidepressant effect. In the test "forced swim" its introduction has affected virtually all the analyzed indicators registered a significant increase as the duration of the first period of active swimming, and total time of active swimming, increase the total time and average length of passive navigation; the total time of immobilization and the number of periods of decline.
Thus, the replacement amino acid residue in tetrapeptide fragment molecules of vasopressin on L-Met has led to the loss of influence of the peptide on the orienting-exploratory behavior and anxiety level of animals. However, the high level of the antidepressant effect of Ac-L-Met-Pro-Arg-Gly-NH2shows, apparently, that the peptide is a selective agonist V1bR receptors of vasopressin.
Tetrapeptide with racemic methionine residue Ac-DL-Met-Pro-Arg-Gly-NH2showed a range of behavioral activity, similar to the D-isomer (patent for invention №1623166 SU, 15,02 .1994 "Neuropeptides with behavioral activity"), he encouraged the learning of animals in the test of the conditional reaction active avoidance, increased motor activity and reduced emotional reactivity. In these tests, the effective doses were 5 to 10 times less compared to the D-isomer and 2 orders of magnitude lower than that of the vases is pressin.
In addition, he, like the L-isomer had a marked antidepressant effect, which was evident at doses of 1-10 mg/kg Thus, Ac-DL-Met-Pro-Arg-Gly-NH2found properties inherent and D - and L-isomers of tetrapeptide General formula Ac-X-Met-Pro-Arg-Gly-NH2where X-Met - D-Met, L-Met and DL-Met.
Sources of information
1. Patsevich O.S, Chipens GI, S.V. Mikhailov Neurohypophyseal hormones. - Riga: Zinatne. in 1986, 282 S.
2. Walter R., Van Ree J.M., de Wied D. Modification of conditioned benavior of rats by neurohypophysial hormones and analogues // Proc. Nat. Acad. Sci USA. - 1978. V.75, N 5. - P.2493-2496.
3. J.P.H. Burbach, Leboille J.L.M. Proteolytic conversion of arginine vasopressin and oxytocin by brain synaptic membranes. Characterization of peptides formed and mechanisms of proteolysis // J. Biol. Chem. - 1983. - V.258, N 3. - P.1487-1489.
4. Valter M.P., De Wied D., Van Ree J.M. Vasopressin fragment, AVP(4-9), improves long-term and short-term memory in the hole board search task // Neuropeptides. - 1997. - V.31, N 5. - P.489-494.
5. Golubovich VP, Martinovich VP, Usenko AB and other //. Chemical pharmaceutial, 1888. No. 6. - S.675-679.
6. Martinovich VP, Slobodchikov L.K., Golubovich VP, Akhrem A.A., Titov S.A., resurrection OG Synthesis and study of biological activity of C-terminal fragments of vasopressin AVP5-9and pGlu--WUA5-9// Chemical-pharmaceutcal - 1989. No. 9. - S-1057.
7. Sato, T., Tanaka K., Teramoto T et. Al. Effect of pretraining administration of NC-1900, a vasopressin fragment analog, on memory performance in non - or CO2-amnesic mice Pharmacol. Biochem. Behav. - 2004. V.78. - P.309-317.
8. Lolait S.J., O Carrol A.M. Brownstein M.J. Molekular biology of vasopressin receptors. Ann. N.Y. Acad. Sci. - 1995 - V.771. P.23-292.
9. J.p.H. Burbach, Schoots o, Hernando F. Biochemistry of vasopressin fragments. Prog /Brain res. 1998. - Vol.119. - P.127-136/.
Peptide with neurotropic activity, of General formula: Ac-X-Met-Pro-Arg-Gly-NH2,
where X Is Met-L-Met and DL-Met.
SUBSTANCE: invention relates to peptides of general formula , and to their cosmetically or dermopharmaceutically acceptable salts, where: X is chosen from the group formed by cysteinyl, seryl, threonyl and aminobutyryl; R1 is chosen from the group formed by H or a saturated linear C2-C24 acyl group; R2 is chosen from the group formed by an amino group optionally substituted with C1-C24 alkyl, or a hydroxy group. Besides the invention covers a method for making said peptides, their cosmetic or dermopharmaceutical compositions intended for reducing or eliminating baggy lower eyelids.
EFFECT: higher effectiveness.
12 cl, 7 ex
FIELD: chemistry; biochemistry.
SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth-stimulating factor of the human granulocyte colon-stimulating factor and can be used in medicine. An oligopeptide of general formula I A-X1-X2-X3-X4-B (I) is obtained through in silico construction, where A is Boc - tert-butyloxycarbonyl or Ac -acetyl; X1 is E, or D, or L, or P, or S; X2 is N, or Q, or A, or G; X3 is G, or N, or V, or (β-A) - β-alanine; X4 is K or is absent and B is OMe - methyl.
EFFECT: invention enables obtaining an oligopeptide with growth-stimulating activity of the granulocyte colon-stimulating factor and which is capable of stimulating stem cell differentiation in vitro in the direction of epithelial progenitors and expand the range of effective therapeutic agents for treating diseases accompanied by myelosuppression and infectious complications.
4 dwg, 2 ex
FIELD: chemistry; biochemistry.
SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards fibroblast proliferation and can be used in medicine. An oligopeptide of formula A-X1-X2-X3-X4-X5-B is obtained through in silico construction, where A is F; X1 is E, or Q, or S; X2 is N, or Q, or A, or G; X3 is K, or R, or T; X4 is K, or E, or is absent, X5 is K, or L, or is absent and B is OMe - methyl.
EFFECT: invention enables obtaining an oligopeptide with transformation growth factor (TGF-β) and oncostatin M (OSM) towards fibroblast proliferation, and expansion of the range of effective therapeutic agents with wound-healing effect, which take part in closing wounds during inflammation and cicatrisation.
4 dwg, 2 ex
FIELD: chemistry; biochemistry.
SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards collagen synthesis stimulation and can be used in medicine. An oligopeptide of general formula A-X1-X2-X3-X4-X5-B (I) is obtained through in silico construction, where A is Ac - acetyl; X1 is G or A or is absent; X2 is P or I, or L, or V, or A; X3 is G; X4 is P or I, or L, or V, or A; X5 is G or A, or is absent and B is OMe - methyl.
EFFECT: invention enables obtaining an oligopeptide with acidic (aFGF) and transformation (TGF-β) growth factor activity towards stimulation of collagen biosynthesis, and expansion of the range of effective therapeutic agents with wound-healing effect, which speed up regeneration of damaged tissue and cicatrisation.
4 dwg, 2 ex
SUBSTANCE: invention relates to α',β'-epoxides of peptides of formulae (III) and (IV) which inhibit chymotrypsin-like activity of 20S proteasome.
EFFECT: increased effectiveness of the compounds.
19 cl, 29 ex
SUBSTANCE: invention relates to low-molecular derivatives of peptides which are used for preparing a pharmaceutical agent which inhibits laminin/nidogen reaction.
EFFECT: increased effectiveness of compounds.
2 cl, 12 dwg, 2 tbl, 30 ex
SUBSTANCE: present invention refers to compounds of Formula II and to methods of immune response suppression, e.g. by inhibition of indirect MHC type II of T-cells activation. Compounds under invention can be applied to treatment or prevention of derangements, such as rheumatoid arthritis and/or multiple sclerosis.
EFFECT: production of compounds which can be used for immune response suppression.
25 cl, 19 dwg, 4 tbl, 22 ex
FIELD: pharmaceutical chemistry, chemistry of peptides, hormones.
SUBSTANCE: invention relates to a method for preparing analogs of adrenocorticotropic hormone (ACTH) (4-10) possessing neurotropic activity. Method for preparing analogs of adrenocorticotropic hormone (ACTH), a sequence (4-10), of the general formula (I): A-Glu-His-Phe-Pro-Gly-Pro-OH (I) wherein A means hydrogen atom (H), Met, Met(O), Lys, Ser, Trp, Ala, Gly, Thr is carried out by liquid-phase method by step-by-step splicing peptide chain beginning from C-terminal protected tetrapeptide of the formula: H-Phe-Pro-Gly-Pro-OH (II) wherein X means a protective group and using corresponding fully protected amino acids in activated form followed by removal of protective groups at each step and purification of the end product by liquid chromatography. Method provides simplifying the process and to enhance the yield of the end product.
EFFECT: improved preparing method.
5 cl, 1 tbl, 5 ex
FIELD: biotechnology, medicine, oncology.
SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.
EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.
20 cl, 48 tbl
FIELD: medicine, chemistry of peptides, amino acids.
SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).
EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.
4 cl, 16 tbl, 9 ex
SUBSTANCE: there is claimed application of dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor), vildagliptin or its salt for production of medication for prevention, retardation of progress or treatment of peripheral diseases such as peripheral neuropatia, neurodegenerative disorders, cognitive disorders, as well as for improvement of memory and ability to learn, and pharmaceutical composition for the same purpose. It is demonstrated: vildagliptin increases stage of wakefulness and response to external stimuli, increases REM sleep phase.
EFFECT: combination of vildagliptin with donepezil considerably improves disturbed ability to learn.
23 cl, 5 ex
SUBSTANCE: present invention relates to a compound having the structural formula I , or its pharmaceutically acceptable salt, ester or amide, where A has the structure , where each bond in A, represented by a dotted and a solid line, represents a carbon-carbon single bond; each of a, b and c is a carbon atom; each of e, f, g and h is a carbon atom; X is nitrogen; X' is C; L is absent; each n equals 1; Y is nitrogen; W is nitrogen; R1 is hydrogen; each of R2, R3 and R4 is a hydrogen atom; each of R6, R8 and R9 is a hydrogen atom; R5 is selected from a group consisting of halogen, C1-6alkyl, optionally substituted with a hydroxy group, and C1-6alkoxy; R7 is selected from a group consisting of halogen, C1-6alkyl and perhalogenalkyl; Z is selected from a group consisting of NR11, oxygen and CH2; R11 is hydrogen; and each bond in formula I, represented by a dotted and a solid line, is a carbon-carbon double bond. The invention also relates to a method for synthesis of a formula V compound, a pharmaceutical composition based on a formula I compound, methods of treating psychoneurological disorders, a pharmaceutical composition containing a formula I compound and a psychoneurological agent.
EFFECT: obtaining novel compounds useful for modulating muscarine receptor activity.
37 cl, 1 tbl, 141 ex
SUBSTANCE: invention refers to psychoneurology, particularly to an agent for treating multiple sclerosis. A composition (solid or liquid dosage form) contains triiodide 1,3-diethylbenzimidazolium as an agent, low-molecular surgical polyvinylpyrrolidone, presented as a solubiliser, and an agent stabiliser, and in addition in the liquid dosage form - ethanol as a solvent.
EFFECT: composition under the invention exhibits high therapeutic effectiveness in treating multiple sclerosis, and is characterised by relieving undesirable by-effects.
2 cl, 4 ex
SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri 5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.
EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.
25 cl, 2 tbl, 12 ex
SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).
EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.
24 cl, 9 dwg, 4 tbl, 19 ex
SUBSTANCE: present invention relates to novel 2-alkylamino-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used to treat and prevent development of various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly Alzheimer's disease, Parkinson's disease, Huntington disease, schizophrenia, other neurodegenerative diseases and cognitive disorders. In general formula 1 , R1 is a hydrogen atom, C1-C3alkyl, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl, adamantyl, optionally substituted phenyl, 5-6-member heterocyclyl containing a nitrogen or oxygen heteroatom, possibly condensed with a benzene ring; R2 is a hydrogen atom, halogen atom, C1-C3alkyl, pyridyloxy; R3 is a hydrogen atom; C1-C3alkyl; optionally substituted amino group selected from amino, mono- or di(C1-C3alkyl)amino, di(C1-C3alkyl)aminoC2-C3alkylamino, N-[di(C1-C3alkyl)aminoC2-C3alkyl]-N-(C1-C3alkyl)-amino; C1-C3alkyloxy, C1-C3alkyloxyC1-C3alkyl, hydroxyC1-C3alkyl; 6-member azaheterocyclyl, possibly containing an extra nitrogen or oxygen atom, a -N(C1-C3alkyl) group; R4 is C1-C3alkyl; R5 is a hydrogen atom, one or two halogen atoms or C1-C3alkyl.
EFFECT: design of a method of obtaining compounds, a pharmaceutical composition and a medicinal agent for treating and preventing various diseases of the central nervous system.
25 cl, 12 dwg, 3 tbl, 20 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine and aims at treating the conditions associated with amnesia and impaired cognition. A medically indigent patient is prescribed with the effective amount of a composition containing a mixed extract prepared of Scutellaria plants with high concentration of free V-ring flavonoids, including Baicalin, and an extract of Acacia plants with high concentration of flavanes, including catechine and epicatechin.
EFFECT: methods ensure restoration and preservation of cognition and memory.
44 cl, 15 ex, 2 tbl, 17 dwg
SUBSTANCE: invention refers to novel compounds of the general formula (I) , where R1, R2 are independently H or C1-C6-alkyl; R3, R4 are independently H or C1-C6-alkyl; R5 is halogen, CN; n, m or o are 0, 1 or 2; and to pharmaceutically acceptable salts thereof.
EFFECT: compounds with monoaminooxidase B inhibition properties applicable in obtainment of pharmaceutical drugs with relevant effect.
14 cl, 3 dwg, 31 ex
SUBSTANCE: present invention relates to serotonin 5-HT6 receptor antagonists - new substituted 3-sulphonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-e]pyrimidines of formula and substituted 3-sulphonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-c1]pyrimidines of general formula 2, a medicinal base and pharmaceutical compositions containing the medicinal base in form of the said compounds, as well as to a method of treating and preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals. In formulae and Ar is phenyl which is optionally substituted with halogen atoms, or a 6-member heteroaryl which contains a nitrogen atom in the ring; R1 is a hydrogen atom, C1-C3alkyl, hydroxy C1-C3alkyloxy group, C1-C3alkylsulphanyl group; R2 is a hydrogen atom or C1-C3alkyl, R3 is a hydrogen atom optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.
EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.
16 cl, 3 tbl, 1 dwg, 10 ex
SUBSTANCE: invention relates to field of medicine and pharmaceutical industry and represents pharmaceutical combination for treatment of cerebral circulatory insufficiency and psychodependent form of erectile dysfunction, including choline alfoscetate in amount 50-600 mg per one intake and hopantenic acid or its pharmaceutically acceptable salt in amount 20-800 mg per one intake.
EFFECT: invention ensures reduction of frequency, duration and intensity of headache, dizziness, fatigability, irritability, improvement of memory for current events and sleep, as well as increase of erectile dysfunction (ED), reduction and fixation of stable positive motivation for quality erection and full orgasm in case of psychodependent form of ED; simultaneously, due to manifestation of synergic effect, which results from the use of claimed combination, it became possible to reduce day dose of hopantenic acid or its salt from 1,5 mg to 0,5 mg.
12 cl, 4 ex, 24 tbl, 4 dwg
SUBSTANCE: invention relates to novel peptide compounds and their use in diagnostic optical visualisation techniques. More specifically, the present invention pertains to use of such peptide compounds as targeted vectors which are related to receptors associated with angiogenesis. The compounds are labelled using at least one cyanine reporter dye.
EFFECT: obtaining compounds which can be used as contrast agents in optical visualisation when diagnosing diseases related to angiogenesis.
9 cl, 5 ex