Substituted imidazo{2,1-b}thiazoles and application thereof for making drug preparations

FIELD: medicine.

SUBSTANCE: there are described substituted imidazo[2,1-b]thiazoles of general formula the R1, R1, R3 R4, M1, M2 radical values are presented in the patent claim cl. 1, as well as methods for making them, drug preparations containing these compounds and application of these compounds for making the drug preparations.

EFFECT: higher efficacy.

23 cl, 3 tbl, 25 ex

 

The text descriptions are given in facsimile form.

1. Replaced imidazo[2,1-b]thiazole General formula I

in which R1and R2independently of one another denote H, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl or-C(=O)-OR13,
and R13denotes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl or neopentyl,
R3and R4independently of one another denote H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (2,4,4)-trimethylpent-2-yl or-C(=O)-R21,
and R21denotes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl or phenyl, each of which is not substituted or substituted by substituents, independently from each other selected from the group comprising F, Cl, Br, I and-O-CH3,
M1denotes a residue selected from the group including the cabbage soup residues 1-6, 21, 22, 36 and 37
,,,,
,,,,
,,
M2denotes a residue selected from the group comprising residues 1-2, 17-22, 24-26, 31 and 32
,,,,,
,,,,,
,,,
moreover, each of which is not substituted or is substituted by 1 or 2 substituents, independently from each other selected from the group comprising F, Cl, Br, I, HE, -CN and CH3,
not necessarily in the form of one of their pure stereoisomers, especially enantiomers or diastereomers, their racemates or in form of a mixture of stereoisomers, particularly the enantiomers and/or diastereomers, in any of their ratio in the mixture or in the form of corresponding salts or in the form of a corresponding solvate.

2. Compounds of General formula Ia according to claim 1

in which R1,R 2, R3and R4have specified in claim 1 values, and
R35and R36independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, and-HE,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

3. Compounds of General formula Ib according to claim 1

in which R1, R2, R3and R4have specified in claim 1 values, and
R37and R38independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, and-HE,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

4. Compounds of General formula Ic according to claim 1

in which R1, R2, R3and R4have specified in claim 1 values, and
R39and R40independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, and-HE,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

5. Compounds of General formula Id according to claim 1

in which R1, R2, R3and R4have specified in claim 1 values, and
R41and R42independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, what is IT,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

6. Compounds of General formula Ie according to claim 1

in which R1, R2, R3and R4have specified in claim 1 values, and
R43and R44independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, and-HE,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

7. Compounds of General formula If 1

in which R1, R2, R3and R4have specified in claim 1 values, and
R45and R46independently of one another denote a residue selected from the group
comprising H, F, Cl, Br, -CN, methyl, and-HE,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

8. Compounds according to claim 1, characterized in that
R1denotes hydrogen, -F, -Cl, -Br, -C(=O)-OR13, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl,
R2denotes hydrogen, -F, -Cl, -Br, -C(=O)-OR13, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl,
R3denotes hydrogen, methyl, ethyl and isopropyl,
R4denotes hydrogen, -C(=O)-R21, methyl, ethyl, n-propyl, isopropyl, n-butyl, ISO is util, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl and (2,4,4)-trimethylpent-2-yl, or
R13denotes hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl and neopentyl,
R21denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl or phenyl which is not substituted or is substituted by 1, 2, 3, 4 or 5 substituents, independently of one another selected from the group comprising F, Cl, Br, I and-O-CH3,
M1denotes a residue selected from the group comprising residues 1, 3, 5, 22, 36 and 37
,,,
,,,
each of which is not substituted and may be in any orientation through denoted by a wavy line position connected with bicyclam and carbon atom triple bond, and
M2denotes a residue selected from the group comprising phenyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-thiophenyl (2-thienyl), 3-thiophenyl (3-thienyl), 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-thiazolyl and 4-thiazolyl,
each of which is not substituted or is substituted by 1 or 2 substituents, independently from each other selected from the group comprising F, Cl, Br, -CN, -HE, methyl,
optional the nutrient in the form of corresponding salts or optionally in the form of a corresponding solvate.

9. Compounds according to claim 1, characterized in that
R1denotes hydrogen, -F, -Cl, -Br, -C(=O)-OR13, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl,
R2denotes hydrogen, -F, -Cl, -Br, -C(=O)-OR13, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and n-pentyl,
R3denotes hydrogen,
R4denotes hydrogen, -C(=O)-R21, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl and (2,4,4)-trimethylpent-2-Il,
R13denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl and 3-pentyl,
R21denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl or not substituted phenyl,
M1denotes a residue selected from the group comprising residues 1, 3, 5, 22 and 36
,,,,
,
each of which is not substituted and may be in any orientation through denoted by a wavy line position connected with bicyclam and carbon atom triple bond, and
M2denotes a residue selected from the group comprising phenyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-thiophenyl (2-thienyl), 3-thiophenyl (3-thienyl), 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-TIA is alil and 4-thiazolyl, each of which is not substituted or is substituted by 1 or 2 substituents, independently from each other selected from the group comprising F, Cl, Br, -CN, -HE, methyl,
not necessarily in the form of corresponding salts or optionally in the form of a corresponding solvate.

10. Compounds according to claim 1, selected from the group including
[1] 6-(5-(phenylethynyl)thiophene-2-yl)-N-(2,4,4-trimethylpentane-2-yl)imidazo[2,1-b]thiazole-5-amine,
[2] N-tert-butyl-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[3] N-tert-butyl-3-methyl-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[4] N-tert-butyl-2-methyl-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[5] N-tert-butyl-2,3-dimethyl-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[6] N-tert-butyl-2-chloro-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[7] N-tert-butyl-6-(5-(pyridine-4-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[8] the methyl ester of 5-(tert-butylamino)-6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-2-carboxylic acid,
[9] N-tert-butyl-6-(5-(pyridine-2-ylethynyl)thiazol-2-yl)imidazo[2,1-b]thiazole-5-amine,
[10] 6-(5-pyridin-2-ylethynyl)thiophene-2-yl)-N-(2,4,4-trimethylpentane-2-yl)imidazo[2,1-b]thiazole-5-amine,
[11] N-tert-butyl-2-methyl-6-(4-(pyridine-2-ylethynyl)phenyl)imidazo[2,1-b]thiazole-5-amine,
[12] N-tert-butyl-6-(5-(pyridine-2-ylethynyl)furan-2-yl)imidazo[2,1-b]thiazole-5-amine,
[13] N-tert-butyl-3-methyl-6-(5-phenylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[14] 6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[15] N-tert-butyl-6-(5-(pyrimidine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[16] N-tert-butyl-6-(5-((3-herperidin-2-yl)ethinyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[17] N-tert-butyl-6-(5-((2-herperidin-4-yl)ethinyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[18] N-tert-butyl-6-(5-(thiophene-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[19] N-tert-butyl-6-(5-(thiazol-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[20] 3-((5-(5-(tert-butylamino)imidazo[2,1-b]thiazol-6-yl)thiophene-2-yl)ethinyl)phenol,
[21] 3-((5-(5-(tert-butylamino)imidazo[2,1-b]thiazol-6-yl)thiophene-2-yl)ethinyl)benzonitrile,
[22] N-ethyl-6-(6-(phenylethynyl)pyridine-3-yl)imidazo[2,1-b]thiazole-5-amine,
[23] N-tert-butyl-6-(5-((3-methylpyridin-2-yl)ethinyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine,
[24] N-(6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-yl)ndimethylacetamide and
[25] N-(6-(5-(pyridine-2-ylethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-yl)benzamid,
not necessarily in the form of corresponding salts, primarily hydrochloride, or in the form of a corresponding solvate.

11. Compounds according to claim 1, characterized in that they after 60-minute incubation with 450 μg of protein homogenate of brain pigs at a temperature in the range from 20 to 25°C capable at a concentration of less than 2500 nm, preferably less than 1000 nm, particularly preferably less than 700 nm, most preferably m is it 100 nm, first of all, less than 70 nm, to displace 50% of [3H]-2-methyl-6-(3-methoxyphenyl)ethenylpyridine present at a concentration of 5 nm.

12. The method of obtaining substituted imidazo[2,1-b]thiazolo General formula I according to one of claims 1 to 11, characterized in that at least one compound of General formula II

in which R1and R2are specified in claims 1 to 11 values are subjected in the reaction medium, optionally in the presence of at least one organic or inorganic acid or at least one salt of a transition metal, interaction with at least one isocyanides General formula III
,
in which R3is specified in claims 1 to 11 values, and at least one aldehyde of General formula IV

in which M1and M2are specified in claims 1 to 11 values, and obtained 15 by the connection of General formula V

in which R1, R2, R3M1and M2have the above values, if necessary, purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, 20 or at least one compound of General formula II

in which R1and R2have specified the s in claims 1 to 11 values, put in a reaction medium, optionally in the presence of at least one organic or inorganic acid or at least one salt of a transition metal, interaction with at least one isocyanides General formula III
,
in which R3is specified in claims 1 to 11 values, and at least one aldehyde of General formula VI

in which M1is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, bromine or triftorbyenzola, and thus obtained compound of General formula VII

in which R1, R2, R3M1and X have the above values, if necessary, purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, and interaction with at least one acetylene General formula XI

in which the substituents R independently of one another represent linear or branched alkyl residue or an unsubstituted phenyl residue, in a reaction medium, optionally in the presence of at least one acceptable catalyst and optionally in the presence the basis of at least one inorganic and/or organic bases, transferred to the appropriately substituted compound of General formula XII

in which R1, R2, R3and M1have the above values, and the substituents R independently of one another represent linear or branched alkyl residue or an unsubstituted phenyl residue, and, if necessary, this compound is purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, then at least one compound of General formula XII in a reaction medium, optionally in the presence of at least one inorganic and/or organic base and optionally in the presence of at least one inorganic salt, and optionally in the presence of at least one ammonium salt, was transferred to a suitably substituted compound of General formula XIII

in which R1, R2, R3and M1have the above values, and, if necessary, this compound is purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, and then at least one compound of General formula XIII and/or at least one compound of General formula XII interaction with the about at least one compound of General formula M 2-X, where M2is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, bromine or triftorbyenzola, in a reaction medium, optionally in the presence of at least one acceptable catalyst and optionally in the presence of at least one inorganic and/or organic base, and optionally in the presence of at least one inorganic salt and optionally in the presence of at least one ammonium salt, was transferred to a suitably substituted compound of General formula V

in which R1, R2, R3M1and M2have the above values, and, if necessary, this compound is purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or produce, or compound of General formula VII by interaction with at least one acetylene General formula VIII

in which M2is specified in claims 1 to 11 values in a reaction medium, optionally in the presence of at least one acceptable catalyst and optionally in the presence of at least one inorganic and/or organicheskikh the base, transferred to the appropriately substituted compound of General formula V

in which R1, R2, R3M1and M2have the above values, and, if necessary, this compound is purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, and then, if necessary, the compound of General formula V by interaction with at least one compound of General formula R4-X, where R4is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, in a reaction medium in the presence of at least one organic or inorganic bases, preferably in the presence of at least one metal hydride, or by interaction with at least one compound of General formula R21-C(=O)-OH, where R21is specified in claims 1 to 11 values in a reaction medium, optionally in the presence of at least one organic or inorganic bases and/or in the presence of at least one agent combination or interaction with at least one compound of General formula R21-C(=O)-X, where R21is specified in claims 1 to 11 values, and X denotes a leaving group,preferably halogen or ether sulfonic acid, most preferably chlorine, bromine or triftorbyenzola, in a reaction medium, optionally in the presence of at least one organic or inorganic bases, or by interaction with at least one compound of General formula R21-C(=O)-N, where R21is specified in claims 1 to 11 values in a reaction medium, optionally in the presence of at least one reducing agent is transferred to the compound of General formula I, optionally in the form of a corresponding salt

in which R1, R2, R3, R4M1and M2are specified in claims 1 to 11 values, and then, if necessary, this compound is purified and/or isolated.

13. The method of obtaining substituted imidazo[2,1-b]thiazolo General formula I according to one of claims 1 to 11, characterized in that at least one compound of General formula V

in which R1, R2, R3M1and M2are specified in claims 1 to 11 values, is subjected to chemical conversion, if necessary, in a reaction medium in the presence of at least one organic or inorganic acid, and the thus obtained compound of General formula IX

in which R1, R2M1and M2are specified in claims 1 to 11 values, if not the bhotekoshi purified and/or isolated and, if necessary, translated into the corresponding salt, which is optionally purified and/or emit, and then this connection/this salt interaction in the reaction medium in the presence of at least one inorganic or organic base, preferably in the presence of at least one metal hydride, at least one compound of General formula R3-X, where R3is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, or interaction in a reaction medium, optionally in the presence of at least one organic or inorganic bases and/or optionally in the presence of at least one agent combinations, with at least one compound of General formula R21-C(=O)-OH, where R21is specified in claims 1 to 11 values, or interaction in a reaction medium, optionally in the presence of at least one organic or inorganic bases, with at least one compound of General formula R21-C(=O)-X, where R21is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, bromine or triftorbyenzola, or interaction in a reaction medium, optionally in the presence of the tvii at least one reducing agent, with at least one compound of General formula R21-C(=O)-H, where R21is specified in claims 1 to 11 values, translated into the corresponding compound of General formula X, optionally in the form of a corresponding salt

in which R1, R2, R3M1and M2are specified in claims 1 to 11 values, and if necessary, the connection is cleaned and/or distinguish, then, if necessary, the compound of General formula X by interaction with at least one compound of General formula R4-X, where R4is specified in claims 1 to 11 values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, in a reaction medium in the presence of at least one organic or inorganic bases, preferably in the presence of at least one metal hydride, or by interaction with at least one compound of General formula R21-C(=O)-OH, where R21is specified in claims 1 to 11 values in a reaction medium, optionally in the presence of at least one organic or inorganic bases and/or in the presence of at least one agent combination or interaction with at least one compound of General formula R21-C(=O)-X, where R21is specified in claims 1 to 11 the values, and X denotes a leaving group, preferably halogen or ether sulfonic acid, most preferably chlorine, bromine or triftorbyenzola, in a reaction medium, optionally in the presence of at least one organic or inorganic bases, or by interaction with at least one compound of General formula R21-C(=O)-H, where R21is specified in claims 1 to 11 values in a reaction medium, optionally in the presence of at least one reducing agent is transferred to the compound of General formula I, optionally in the form of a corresponding salt

in which R1, R2, R3, R4M1and M2are specified in claims 1 to 11 values, and then, if necessary, this compound is purified and/or isolated.

14. Medicinal product intended for the regulation of mGluR5-receptor containing at least one compound according to one of claims 1 to 11, and optionally one or more physiologically compatible excipients.

15. Drug for 14 intended for inhibiting mGluR5-receptor.

16. Drug for 14 or 15, intended for the prevention and/or treatment of disorders and/or diseases which are at least partially mediated by mGluR5 receptors.

17. Drug medium is in 14 designed for the treatment and/or prophylaxis of pain, preferably pain chosen from the group comprising acute pain, chronic pain, neuropathic pain and visceral pain, migraine, depression, neurodegenerative diseases, preferably selected from the group comprising multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive disorders, preferably of the state, manifested in the deficit cognitive abilities, most preferably of attention deficit disorder, mental disorders, preferably selected from the group including fear and panic attacks, epilepsy, schizophrenia, cerebral ischemia, muscle spasms, seizures, alcohol dependence, drug dependence, drug dependence, mainly nicotine and/or cocaine addiction, alcohol abuse, abuse of drugs, drug abuse, mainly nicotine and/or cocaine withdrawal symptoms when alcohol, drugs and/or drugs (primarily nicotine and/or cocaine) dependence, the development of tolerance to medication, mainly to natural or synthetic opioids.

18. The use of at least one compound according to one of claims 1 to 11 for the preparation of cartonnage means, intended for the regulation of mGluR5-receptor, preferably for inhibiting mGluR5-receptor.

19. The use of at least one compound according to one of claims 1 to 11 for the preparation of a medicinal product intended for the prevention and/or treatment of disorders and/or diseases which are at least partially mediated by mGluR5 receptors.

20. The use of at least one compound according to one of claims 1 to 11 for the preparation of medicines intended for the treatment and/or prophylaxis of pain, preferably pain chosen from the group comprising acute pain, chronic pain, neuropathic pain and visceral pain, migraine, depression, neurodegenerative diseases, preferably selected from the group comprising multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, cognitive disorders, preferably of the state, manifested in the deficit cognitive abilities, most preferably of attention deficit disorder, mental disorders, preferably selected from the group including fear syndrome and panic attacks, epilepsy, schizophrenia, cerebral ischemia, muscle spasms, seizures, alcohol dependence, drug dependence, drug dependence, mainly nicotine and/or kokinov the th dependencies the abuse of alcohol, abuse of drugs, drug abuse, mainly nicotine and/or cocaine withdrawal symptoms when alcohol, drugs and/or drugs (primarily nicotine and/or cocaine) dependence, the development of tolerance to medication, mainly to natural or synthetic opioids.

21. The application of claim 20 for the preparation of medicines intended for the treatment and/or prophylaxis of pain, preferably pain chosen from the group comprising acute pain, chronic pain, neuropathic pain and visceral pain, mental disorders, preferably selected from the group including fear and panic attacks, alcohol dependence, drug dependence, cognitive disorders, preferably of the state, manifested in the deficit cognitive abilities, most preferably of attention deficit disorder, drug dependence, mainly nicotine and/or cocaine addiction, alcohol abuse, abuse of drugs, drug abuse, mainly nicotine and/or cocaine withdrawal symptoms when alcohol, drugs and/or drugs (primarily nicotine and/or cocaine) dependence, the development of t is lerotholi to medication and/or drugs, mainly to natural or synthetic opioids.

22. The application of claim 20 or 21 for the preparation of medicines intended for the treatment and/or prophylaxis of pain, preferably pain chosen from the group comprising acute pain, chronic pain, neuropathic pain and visceral pain.

23. The application of claim 20 or 21 for the preparation of medicines intended for the treatment and/or prevention of mental disorders, preferably selected from the group including fear and panic attacks.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula

wherein: m, n, R0, R1, R2, R3 and R4 have the values presented in clause 1 of the patent claim provided the compound of formula (I) cannot represent N-methyl-1-(phenylsulphonyl)-1H-indole-4-methanamine.

EFFECT: compounds show 5-NT6 receptor antagonist activity that that allows them being used in the pharmaceutical composition.

19 cl, 3 tbl, 192 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel agents for controlling plant fungal diseases, specifically 3,7-dithia-1,5-diazabicyclo[3,3,0]octane as an agent against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger, synthesis of which takes place in a single step using readily available reactants in contrast to multi-step synthesis of existing agents used for controlling fungal diseases of plants and materials.

EFFECT: obtaining novel agents for controlling plant fungal diseases.

1 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to (R)-N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide substantially free from (S)-N-(3-amino-propyl)-N[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methypropyl]-4-methyl-benzamide, or its pharmaceutically acceptable salt which shows the properties of Eg5 inhibitor.

EFFECT: invention also refers to a pharmaceutical composition containing said compound and its pharmaceutically acceptable salt.

4 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

,

where R1 represents CH3; R2 represents halogeno or CN; R3 represents H or CH3; R4 represents H or CH3; n represents 0, 1 or 2; and to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition and to application of the compounds of formula (I) in preparing a drug exhibiting antagonist activity in relation to CX3CR1 receptor.

EFFECT: provided the compounds of formula (I) as CX3CR1 receptor antagonists.

20 cl, 1 tbl, 3 dwg, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) where the bond b represents a double bond; X represents -S-; each Z1 and Z3 independently represents a direct bond, -N(R5) - or - (CH2)q; Z2 represent -C(O)- or -C(S)-; m represents an integer equal to 1; n represents an integer equal to 1; each of q independently represents an integer varying within 1 to 4; R0 represents hydrogen, halogen, hydroxy, unsubstituted C1-C3alkyl or unsubstituted C1-C3alkoxy; R1 is independently selected from a group consisting of halogen, optionally substituted C1-C3alkyl, -R6OR7, -R6N(R7)2, -R6C(O)R7, -R6C(O)OR7, -R6C(O)N(R7)R9N(R7)2, -R6OC(O)R8, -R6C(O)N(R7)2 or -R6OR9N(R7)2; R2 represents hydrogen; R4 is selected from a group consisting of morpholine, isoxazolyl, thiazolyl, oxazolyl, benzisoxazolyl, benzothiazolyl, dioxynyl, dioxolyl, and optionally substituted phenyl. Also, the invention refers to pharmaceutically acceptable salts of the compounds of formula (I) and to a pharmaceutical composition exhibiting antiproliferative activity and containing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) exhibiting antiproliferative activity.

21 cl, 11 dwg, 5 tbl, 19 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), which can be used as a medicinal agent having PI3-kinase inhibiting properties. In general formula (I)

,

A denotes N, Ra denotes C1-C8alkyl, phenyl substituted with 1-2 residues selected from a group comprising halogen and C1-C6halogenalkyl, Rb denotes hydrogen, R1 denotes hydrogen or C1-C8alkyl, R2 denotes hydrogen or a substitute selected from a group comprising: C1-C8alkyl, substituted with one substitute selected from C1-C6alkoxy group, -(CO)-O-C1-C6alkyl, N(C1-C6alkyl)2; 6-member heterocycloalkyl containing a nitrogen atom as a heteroatom, substituted with 1-2 substitutes selected from an oxo group and phenyl; (5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-C1-C4alkyl, optionally substituted with 1-2 substitutes independently selected from -(CO)-O-C1-C6alkyl, C1-C6alkyl, -(CO)-O-benzyl, oxo group, benzyl substituted with C1-C6alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms; phenyl which is optionally substituted with 1 substitute selected from a 6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, optionally substituted with -(CO)-O-C1-C6alkyl, (5-6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl)-C1-C4alkyl, optionally substituted with an oxo group, -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl; phenyl-C1-C5alkyl, optionally substituted with 1-2 substitutes selected from NH2, N(C1-C6alkyl)2, C1-C6alkyl, N(C1-C6alkyl)2-C1-C6alkyl, OR7, OCF3, haloC1-C6alkyl, CN, SO2R7, NR7COR8, CONH2, NR7-(CO)O-C,-C6alkyl; -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl, 5-member heteroaryl containing 2 nitrogen atoms as heteroatoms, (5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen), optionally substituted with an oxo group, (5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms substituted with 1-3 substitutes independently selected from oxo group, C1-C6alkyl)-C1-C4alkyl, -C(O)-NH-(C3-C8cycloalkyl), -C(O)-NH-(C1-C6alkyl), -C(O)-N(C1-C6alkyl)2, COR7, NR7(CO)NR8R9; (5-6-member heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, sulphur and oxygen)-C1-C6alkyl, optionally substituted with 1-2 substitutes selected from C1-C6alkyl, C3-C8cycloalkyl, CN and OH; (9-member heteroaryl containing a nitrogen atom as a heteroatom)-C1-C4alkyl; C3-C8cycloalkyl, optionally substituted with a 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group; C3-C8cycloalkyl-C1-C4alkyl, optionally substituted with 1 substitute selected from C1-C4alkyl-(CO)OR8, NR (CO)OR8; 1,3-benzodioxole-C1-C4alkyl; 1,4-benzodioxane-C1-C4alkyl; isoindoline-C1-C4alkyl substituted with 1 CO-NH2 substitute; or R1 and R2 together form a 5- or 6-member saturated ring which optionally contains an additional heteroatom selected from oxygen and nitrogen, and optionally substituted with 1-3 substitutes independently selected from OH, C1-C6alkyl, (CO)OR8, (C1-C4alkyl)-(CO)OR8, NR7(CO)OR8, -(C1-C4alkyl)-NR7(CO)OR8, NR7COR8, -(C1-C4alkyl)-NR7COR8, -NH-C(O)CF3, -CH(OH)-phenyl, NR7(CO)NR8R9, NR7(CO)CH2NR8R8, -NR7(SO2)R8, phenyl, optionally substituted C1-C6alkoxy, OH, 9-10-member bicyclic heteroaryl containing 1-2 nitrogen atoms as heteroatoms, optionally substituted with a phenyl oxo group, substituted with a hydroxy group, -CH2-isoquinoline, substituted with an oxo group, 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group, -CH2-O-(phenyl, substituted with 3 substitutes independently selected from halogen and amino); or R1 and R2 together form a saturated 9-11-member spirocyclic system with 1-2 additional nitrogen heteroatoms, substituted with 1-2 substitutes independently selected from -C1-C6alkyl, OH, oxo group and phenyl; or R2 denotes a residue selected from a group of residues of general formulae:

, , , , , and , where X denotes C1-C7alkylene, Q denotes C1-C7alkylene, R3, R4 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 9-member bicyclic heteroaryl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl, phenyl substituted with C1-C4alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms, 5-member heterocyclyl containing 1 nitrogen atom as a heteroatom, (C3-C8cycloalkyl)-C1-C4alkyl-, or R3, R4 together form a 6-member saturated ring containing an oxygen atom as an additional heteroatom, R7, R8, R9 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen, C3-C8cycloalkyl, C1-C6haloalkyl, C3-C8cycloalkyl- C1-C4alkyl-, C1-C4alkoxy-C1-C4alkyl-.

EFFECT: high efficiency of using the disclosed compounds in preparing a medicinal agent.

10 cl, 1 tbl, 299 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for pain management and controlled release of 3-(2-dimethylaminomethylcyclohexyl)phenol or one of its pharmaceutically acceptable salts contains said active substance and a polymer matrix of cellulose ether, which has a viscosity ranging within 3000 to 150000 mPa·s in the concentration of 2.0 wt % in a water solution at 20°C. Cellulose ether is selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. The dosage form ensures in vivo a maximum plasma level of the active substance in 2-10 h.

EFFECT: dosage form under the invention provides maintaining the plasma concentration of the active substance 3-(2-dimethylaminomethylcyclohexyl)phenol at a pharmacologically effective level for at least 12 h and shows minimum spectrum of side effects including nausea and/or vomiting.

35 cl, 1 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a sublingual tablet and a method for preparing it. The sublingual tablet contains an opioid 20 mg/tablet applicable for sublingual application, a directly compressible diluent in the form of an inert core presenting considerably spherical granules containing sucrose and starch. The inert core is covered with at least one active layer containing at least 5 wt % of the inert core of said opioid. A method for preparing the sublingual low-dose opioid tablet involves a stage of producing microgranules by spraying a solution, a suspension or a colloidal dispersion containing said opioid on a surface of the inert core, and compressing the prepared microgranules. The sublingual tablets under the invention have disintegration time making less than 15 min., and fragility making less than 1%.

EFFECT: fast opioid release promotes immediate absorption of the latter in a buccal cavity and fast pain management.

22 cl, 1 dwg, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method involves application of IL-31 antagonist for IL-31 induced signal transduction inhibition in dorsal root ganglion cells. The IL-31 antagonist inhibits IL-31 polypeptide binding containing amino acid residues 27-164 SEQ ID NO:2 with its heterodimeric receptor containing IL-31RA and OSMR-beta. The antagonist represents a humanized monoclonal antibody or a chimeric antibody.

EFFECT: use of the method effectively relieves inflammation, pain and itching.

8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]phenol maleate of formula in form of enantiomer with absolute configuration (1R, 2R), which possesses pain-killing action.

EFFECT: invention relates to methods of obtaining said maleate, including crystalline forms A and B, pharmaceutical composition and application of maleate of formula (i) for preparation of pharmaceutical composition, intended for treatment of pain states.

33 cl, 4 dwg, 4 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and deals with medical form and method for delivery of medical substances, in particular, dependence habit-forming medical substances, which are characterised by stability to solvent extraction, compression, crushing and milling.

EFFECT: ensuring initial fast release of medicinal substance with following continuous period of controlled release of medicinal substance.

42 cl, 9 ex, 34 tbl, 22 dwg

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: medicine.

SUBSTANCE: invention relates to drug form for treatment pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist, which includes from 10 to 40 mg of oxycodon and/or its pharmaceutically acceptable salt and from 5 to 20 mg of naloxon and/or its pharmaceutically acceptable salt, present in ratio 2:1 by weight.

EFFECT: providing drug form for treatment of pain in patients suffering from diarrhea using medications, simultaneously containing opioid analgesic and opioid antagonist.

9 cl, 51 dwg, 38 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is a preparation for percutaneous absorption containing a medical composition for percutaneous absorption in which an active component selected from morphine and its salts, is mixed in such amount which matches with saturation solubility or more, with an excipients keeping an active ingredient, having fluidity at temperature approximately equal to human skin surface temperature, and at least a portion of the active ingredient is found as crystals. The preparation is applied to an intact skin of a back of a white rabbit cut by electric shaver for 72 o'clock; an available dose of the active component in one dose of the preparation makes 10 mg to 400 mg of morphine at the morphine base, and the plasma concentration of the active ingredient 24 hours and 48 hours after the preparation application in the conditions specified above makes in each case at least 40 ng/ml at the morphine base.

EFFECT: preparation for percutaneous absorption is capable to support blood morphine concentration for a log time at an effective level for at least 48 hours.

35 cl, 2 dwg, 6 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

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