Derivatives of 8-substituted-9h-1,3-dioxol/4,5-h//2, 3/benzodiazepine, which are inhibitors of ampa/kainite-induced receptor, the method of production thereof, pharmaceutical composition and method of treatment

 

The invention relates to new derivatives of 8-substituted-N-1,3-dioxol/4,5-h//2,3/benzodiazepine of formula I, process for the preparation of these compounds and to pharmaceutical compositions containing these active ingredients. The compound (I) inhibit AMPA/kainite-induced receptorswhere X is carbonyl or methylene group, Y is hydrogen or a metal group, or together with R3form a valence bond, R1-R3have such values as defined in the claims. The invention also relates to a method for treatment of epilepsy or neurodegenerative diseases. The technical result is to provide new compounds with therapeutic activity, which allows their use in medicine. 4 C. and 9 C.p. f-crystals, 5 PL.

Description text in facsimile form (see graphic part). T T

Claims

1. Derivative of 8-substituted-N-1,3-dioxol/4,5-h//2,3/benzodiazepine of the formula Iwhere X is carbonyl or methylene group; R1is a hydrogen atom, hydroxy-group, C1-4alkoxygroup,1-4alkanoyloxy, (C1-4alkyl) sulfonyl is a hydrogen atom, C1-4alkoxygroup, C1-4alkanoyloxy or C1-6alkyl group, the latter can be substituted saturated or unsaturated five - or six-membered heterocyclic group containing 1 or 2 nitrogen atom or a nitrogen atom and an oxygen atom as a heteroatom, or N/a phenyl-(C1-4alkyl)/-N-(C1-4alkyl)amino group in which the phenyl group may be substituted by 1 to 3 substituent (Vice), (s) is(are) a C1-4alkoxygroup, or R4and R5form with the adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom, a saturated or unsaturated five - decatizing heterocyclic group, or X forms with R1the cyano, tetrazolyl group, a group of the formula-CHNOH or a group of the formula-COR6where R6is a hydroxy-group, C1-4alkoxygroup, fenoxaprop, NATEXPO or amino group, and amino group may be substituted C1-4alkyl group; R2is the nitro-group, amino group or (C1-4alkanoyl) amino group; R3is a hydrogen atom, a C1-4alkyl group or a group of the formula-COR7where R7is a hydrogen atom, a Cis Oh, phenoxypropane, peredelnoj group, phenyl group or naftilos group, with the latter two groups may be substituted by 1-3 substituents, or a group of the formula -(CH2)n-NR8R9where R8and R9signify, independently from each other, a hydrogen atom, a C1-4alkyl group which may be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing one nitrogen group, or a nitrogen and an oxygen group, with the phenyl group may be substituted by 1 to 3 substituent (Vice), (s) is(are) a1-4alkoxygroup, or R8and R9form together with the adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom, a saturated or unsaturated five - or six-membered heterocyclic group which may be substituted by phenyl group which may be substituted by 1-3 substituents selected from the group consisting of a halogen atom or With1-4alkoxygroup, n is 0, 1 or 2;
Y is a hydrogen atom or a methyl group, or Y forms with R3valence bond between the carbon atom in position 8 and the nitrogen atom in position 7,
provided group, R1is not a hydrogen atom, and 2) if Y is a hydrogen atom or methyl group, and R3is1-4alkyl group or a group of the formula-COR7then X is a methylene group,
and its pharmaceutically acceptable salts accession acid and its derivatives, Quaternary ammonium.

2. Derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine by p. 1, where X is carbonyl or methylene group, and1is a hydrogen atom, hydroxy-group, a methoxy group, acetoxypropionyl, methylsulfonylamino or a group of the formula-NR4R5where R4and R5signify, independently from each other, a hydrogen atom, a methoxy group, acetyl group or1-4alkyl group, the latter can be substituted morpholinyl or N-(dimethoxytrityl)-N-(methyl)-amino group, or R4and R5form with the adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom, a saturated or unsaturated five - deletechannel heterocyclic group, or X forms together with R1the cyano, tetrazolyl group or a group of the formula-CHNOH, R2is the nitro-group or amino group, R3is the atom of the ü between the carbon atom in position 8 and the nitrogen atom in position 7, provided that 1) if Y is a hydrogen atom or forms together with R3valence bond and X is a methylene group, R1is not a hydrogen atom, and 2) if Y is a hydrogen atom or methyl group, and R3is1-4alkyl group or a group of the formula-COR7then X is a methylene group, and its pharmaceutically acceptable salts accession acid and its derivatives, Quaternary ammonium.

3. 5-(4-AMINOPHENYL)-N-1,3-dioxol/4,5-h//2,3-benzodiazepine-8-carboxylate, 5-(4-AMINOPHENYL)-8-cyano-N-1,3-dioxol/4,5-h//2,3-benzodiazepine, 5-(4-AMINOPHENYL)-8-(5-tetrazolyl)-N-1,3-dioxol/4,5-h//2,3-benzodiazepine and their pharmaceutically acceptable salts accession acids, and their derivatives of Quaternary ammonium.

4. Derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine by p. 1, where R3is a hydrogen atom or a group of the formula-COR7where R7is a hydrogen atom, a C1-4alkyl group, a C1-4alkyl group substituted by 1-3 halogen atoms, or a group of the formula -(CH2)n-NR8R9where R8and R9signify, independently from each other, a hydrogen atom, a C1-4alkyl group which may be substituted Hairdryers, or R8and R9form together with the adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom, a saturated or unsaturated five - or six-membered heterocyclic group which may be substituted by phenyl group and the phenyl group may be substituted by a halogen atom or a methoxy group, n is 0, 1 or 2, X forms together with R1the cyano or a group of the formula-COR6where R6is a hydroxy-group or amino group, Y is a methyl group, R2is the nitro-group, amino group or (C1-4alkanoyl)amino group, and its pharmaceutically acceptable salts accession acids.

5. Derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine under item 4, where R3is a hydrogen atom or a group of the formula-COR7where R7is a hydrogen atom, a C1-4alkyl group, a C1-2alkyl group substituted by a chlorine atom, triptorelin group, trichlorethylene group or a group of the formula -(CH2)n-NR8R9where R8and R9signify, independently from each other, a hydrogen atom, a C1-2alkyl group which may be substituted by phenyl or morpholinyl group adjacent nitrogen atom and, perhaps with another nitrogen atom or oxygen atom pyridinoline, pyrrolidinyloxy, morpholinyl or piperazinilnom group, and piperazinilnom group substituted forfamilies or metoksifenilny group, n has a value of 0,1 or 2, X forms together with R1the cyano, R2is an amino group or (C1-4alkanoyl)amino group, Y is a methyl group, and its pharmaceutically acceptable salts accession acids.

6. Derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine under item 5, where R2is acetylamino or propionamidoxime, R1, R3X and Y are such as defined in paragraph 5, and its pharmaceutically acceptable salts accession acids.

7. The way to obtain 8-formyl-5-(4-nitrophenyl)-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula II

which belongs to a group of compounds of formula I and its pharmaceutically acceptable salts accession acid and its derivatives, Quaternary ammonium compounds, characterized in that 8-methyl-5-(4-nitrophenyl)-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine is subjected to interaction with an oxidizing agent, and, if necessary, the obtained compound of formula I, where R2is the nitro-group, R1,POI, by restoring and, if necessary, the obtained compound of formula I, where R2is an amino group, R1, R3X and Y are such as defined in formula I, interacts with C1-4alkenylboronic acid or its reactive allermuir derived, and, if necessary, the obtained base of the formula I is converted into pharmaceutically acceptable salt accession acid or separated from salt accession acid, and, if necessary, the obtained compound of formula I or its pharmaceutically acceptable salt accession acid in turn derived Quaternary ammonium.

8. Pharmaceutical composition having inhibitory activity against of AMPA/kainite-induced receptor containing as active ingredient a derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula I

where X, Y, R1, R2and R3such as specified in paragraph 1,
or its pharmaceutically acceptable salt accession acid, or its derivative Quaternary ammonium compounds in a mixture with one or more traditional media.

9. The pharmaceutical composition according to p. 8, containing as active ingredient a derivative of 8-substituted-o pharmaceutically acceptable salt accession acid, or its derivative Quaternary ammonium.

10. The pharmaceutical composition under item 8 or 9, containing as active ingredient one of the following compounds: 5-(4-AMINOPHENYL)-N-1,3-dioxol/4,5-h//2,3-benzodiazepine-8-carboxylate, 5-(4-AMINOPHENYL)-8-cyano-N-1,3-dioxol/4,5-h//2,3-benzodiazepine, 5-(4-AMINOPHENYL)-8-(5-tetrazolyl)-N-1,3-dioxol/4,5-h//2,3-benzodiazepine, or their pharmaceutically acceptable salt accession acid, or their derived Quaternary ammonium.

11. The pharmaceutical composition according to p. 8, containing as active ingredient a derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula I, where X, Y, R1, R2and R3such as indicated in paragraph 4, or its pharmaceutically acceptable salt accession acid.

12. The pharmaceutical composition according to p. 11, containing as active ingredient a derivative of 8-substituted-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula I, where X, Y, R1, R2and R3such as indicated in paragraph 5, or its pharmaceutically acceptable salt accession acid.

13. The method of treatment which comprises the administration to a patient suffering especially from epilepsy or neurodegenerative disease, or in a state after the impact, detox the>/img>
where X, Y, R1, R2and R3such as specified in paragraph 1,
or its pharmaceutically acceptable salt accession acid, or its derivative Quaternary ammonium.

 

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