Derivatives of 1,3-dioxol/4,5-h//2,3/benzodiazepine, which are inhibitors of ampa/kainite-induced receptor, the method of production thereof, pharmaceutical composition based on them, the method of treatment

 

The invention relates to a derivative of 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 substances that are used for the selective inhibition of AMPA/kainite-induced receptor.

where a and b are hydrogen atoms, R1is a group of the formula -(CH2)n-CO-(CH2)m-R, where R is a halogen atom, peredelnoj the group or the group-NR3R4where R3, R4n and m have the values defined in the claims, and R2is nitro or amino group. 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 12 C.p. f-crystals, 4 PL.

Table T%

Claims

1. Derived 1,3-dioxol/4,5-h//2,3/benzodiazepine of the formula Iwhere a is a hydrogen atom; b is a hydrogen atom; R1is a group of the formula -(CH2)n-CO-(CH2)mup>4signify, independently from each other, a hydrogen atom, a C3-6cycloalkyl group1-4alkoxygroup, amino group, phenyl group which may be substituted by one or two1-4alkyl group (groups)1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing 1 to 3 nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by phenyl group which may be substituted by 1 to 3 substituents, which are1-4alkoxygroup, or R3and R4form 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 to 3 substituents, which are1-4alkoxygroup; n = 0, 1, or 2; m = 0, 1, or 2, or a form with In the valence bond between the carbon atoms in positions 8 and 9 and in this case, R1is a group of formula-CO-(CH2)p-R6where R6is a halogen atom, Fe is t, independently from each other, a hydrogen atom, guanidino group3-6cycloalkyl group or1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing one or more nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, and the phenyl group may be substituted by 1 to 3 identical or different substituents, which are1-4alkoxygroup, or R7and R8form together with the adjacent nitrogen atom oxopyrrolidin group, phthalimidopropyl, the latter may be substituted, or a saturated five - or six-membered heterocyclic group containing one or more nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by 1 to 3 identical or different substituents selected from the group consisting of hydroxy-group, phenyl group, fenoxaprop, phenyl(C1-4alkyl group or phenoxy(C1-4alkyl) group, and the phenyl or fenoxaprop may be substituted by 1 to 3 identical or different substituents, which are the atom galvana hydroxy groups; p = 0, 1, or 2; R2is the nitro-group, amino group, and its pharmaceutically acceptable salts accession acids.

2. Derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine under item 1, where a is a hydrogen atom, is a hydrogen atom, R1is a group of the formula -(CH2)n-CO-(CH2)m-R, where R is a chlorine atom, peredelnoj group or a group of the formula-NR3R4where R3and R4signify, independently from each other, a hydrogen atom, cyclopropyl group1-4alkoxygroup, amino group, phenyl group which may be substituted by one or two methyl groups or1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing 1 to 3 nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by phenyl group which may be substituted by 1 to 3 methoxypropane, or R3and R4form 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 samewe the nitro-group or amino group, and its pharmaceutically acceptable salts accession acids.

3. Derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine under item 2, where R3and R4signify, independently from each other, a hydrogen atom, cyclopropyl group, methoxy group, amino group, dimethylaminophenyl group or a C1-2alkyl group, the latter being substituted phenyl, morpholinyl or piperazinilnom group, and piperazinilnom group substituted metoksifenilny group, or R3and R4form together with the adjacent nitrogen atom and possibly with another nitrogen atom or oxygen atom imidazolidinyl, morpholinyl or piperazinilnom group, and piperazinilnom group substituted metoksifenilny group, n = 0 or 1, m = 0 or 1, R2is the nitro-group or amino group, And is a hydrogen atom, is a hydrogen atom, and pharmaceutically acceptable salts accession acids.

4. Derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine under item 3, where R3is a hydrogen atom, R4is cyclopropenes, a methoxy group or amino group, n = 0, m = 0, R2is an amino group, a is a hydrogen atom, is a hydrogen atom, and pharmaceutically acceptable salts prisoedineniyu the relationship between the carbon atoms in positions 8 and 9, R1is a group of formula-CO-(CH2)p-R6where R6is a halogen atom, fenoxaprop,1-4alkoxygroup or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group or1-4alkyl group, the latter can be substituted by phenyl group or morpholinyl group, and the phenyl group may be substituted by one or two1-2alkoxygroup, or R7and R8form together with the adjacent nitrogen atom oxopyrrolidin group, phthalimidopropyl or saturated five - or six-membered heterocyclic group containing one or two nitrogen atom or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by one or two identical or different substituents selected from the group consisting of hydroxy-group, phenyl group, fenoxaprop, phenyl(C1-4alkyl) group or phenoxy(C1-4alkyl) group, and the phenyl or fenoxaprop may be substituted by a halogen atom or With1-4alkoxygroup, p = 0, 1, or 2, R2is the nitro-group or amino group, and its fabina by p. 5, And forms In the valence bond between the carbon atoms in positions 8 and 9, R2is the nitro-group or amino group, R1is a group of formula-CO-(CH2)p-R6where R6is a chlorine atom, fenoxaprop or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group or a C1-3alkyl group which may be substituted by phenyl, dimethoxyphenyl or morpholinyl group, or R7and R8form with the adjacent nitrogen atom oxopyrrolidin group, phthalimidopropyl or saturated five - or six-membered heterocyclic group containing one or two nitrogen atom or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by one or two identical or different substituents selected from the group consisting of hydroxy-group, metoksifenilny, forfamilies, benzyl or (methoxy-phenoxy)-(hydroxypropyl) group, p = 0, 1, or 2, and pharmaceutically acceptable salts accession acids.

7. Derived 8-methyl-7H-1,3-dioxol-(4,5-h)(2,3) benzodiazepine under item 6, where R2is an amino group, R11is a group of the formula -(CH2)n-CO-(CH2)m-R, where R is a halogen atom or peredelnoj group, n = 0, 1, or 2, m = 0, 1, or 2, R2is the nitrogroup, a and b are hydrogen atoms, and pharmaceutically acceptable salts accession acids, characterized by the fact that 7,8-dihydro-8-methyl-5-(4-nitrophenyl)-N-1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula III
interacts with the reagent of formula VI

where Y is tsepliaeva group;
R5is a halogen atom or peredelnoj group,
and, if necessary, the obtained compound of formula I, where R2is the nitro-group, R1And In such, as indicated in formula I, is converted into a compound of formula I, where R2is an amino group, by restoring; and, if necessary, the obtained base of the formula I is converted into pharmaceutically acceptable salt accession acid or separated from salt accession acid.

9. Pharmaceutical composition having inhibitory activity against of AMPA/kainite-induced receptor containing as an active ingredient derived 1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula I is a group of the formula -(CH2)n-CO-(CH2)m-R, where R is a halogen atom, peredelnoj group or a group of the formula-NR3R4where R3and R4signify, independently from each other, a hydrogen atom, a C3-6cycloalkyl group1-4alkoxygroup, amino group, phenyl group which may be substituted by one or two1-4alkyl group (groups)1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing 1 to 3 nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by phenyl group which may be substituted by 1 to 3 substituent (Vice), (s) is(are) a1-4alkoxygroup, or R3and R4form 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 to 3 substituent (Vice), (s) is(are) a1-4and, the R1is a group of formula-CO-(CH2)p-R6where R6is a halogen atom, fenoxaprop,1-4alkoxygroup or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group3-6cycloalkyl group or1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom as a heteroatom, and the phenyl group may be substituted by 1 to 3 same or different substituent (Vice), (s) is(are) a1-4alkoxygroup, or R7and R8form together with the adjacent nitrogen atom oxopyrrolidin group, phthalimidopropyl, the latter may be substituted, or a saturated five - or six-membered heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by 1 to 3 identical or different substituents selected from the group consisting and Kilroy) group, moreover phenyl or fenoxaprop may be substituted by 1 to 3 same or different substituent (Vice), (s) represent a halogen atom or With1-4alkoxygroup, and phenoxy(C1-4alkyl), the alkyl group may be substituted by one or two hydroxy groups, R = 0, 1, or 2,
R2is the nitro-group, amino group,
or its pharmaceutically acceptable salt accession acid in a mixture with one or more traditional media.

10. The pharmaceutical composition according to p. 9, containing as an active ingredient derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where a is a hydrogen atom, is a hydrogen atom, R1is a group of the formula -(CH2)n-CO-(CH2)m-R, where R is a chlorine atom, peredelnoj group or a group of the formula-NR3R4where R3and R4signify, independently from each other, a hydrogen atom, cyclopropyl group1-4alkoxygroup, amino group, phenyl group which may be substituted by one or two methyl groups, or With1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered, heterocyclic this heterocyclic group may be a substituted phenyl group, which may be substituted by from 1 to 3 methoxypropane, or R3and R4form 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 from 1 to 3 methoxypropane, n = 0, 1, or 2, m = 0, 1, or 2, R2is the nitro-group or amino group, or its pharmaceutically acceptable salt accession acid.

11. The pharmaceutical composition according to p. 10, containing as an active ingredient derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where R3and R4signify, independently from each other, a hydrogen atom, cyclopropyl group, methoxy group, amino group, dimethylaminophenyl group or a C1-2alkyl group, the latter being substituted phenyl, morpholinyl or piperazinilnom group, and this piperazinilnom group substituted metoksifenilny group, or R3and R4form together with the adjacent nitrogen atom and possibly with another nitrogen atom or oxygen atom imidazolidinyl, morpholinyl or piperazinilnom group, and this piperazinilnom group substituted labels is aroda, In an atom of hydrogen, or its pharmaceutically acceptable salt accession acid.

12. The pharmaceutical composition according to p. 11, containing as an active ingredient derived 1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where R3is a hydrogen atom, R4is cyclopropenes, a methoxy group or amino group, n = 0, m = 0, R2is an amino group, a is a hydrogen atom, is a hydrogen atom, or its pharmaceutically acceptable salt accession acid.

13. The pharmaceutical composition according to p. 9, containing as active ingredient a derivative of 8-methyl-7H-1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where And forms In the valence bond between the carbon atoms in positions 8 and 9, R1is a group of formula-CO-(CH2)p-R6where R6is a halogen atom, fenoxaprop,1-4alkoxygroup or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group or1-4alkyl group, the latter can be substituted by phenyl or morpholinyl group, and the phenyl group may be substituted by one or two1-2alkoxygroup or saturated five - or six-membered heterocyclic group, containing one or two nitrogen atom or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by one or two identical or different substituents selected from the group consisting of hydroxy-group, phenyl group, fenoxaprop, phenyl(C1-4alkyl) group or phenoxy(C1-4alkyl) group, and the phenyl or fenoxaprop may be substituted by a halogen atom or With1-4alkoxygroup, p = 0, 1, or 2, R2is the nitro-group or amino group, or its pharmaceutically acceptable salt accession acid.

14. The pharmaceutical composition according to p. 13, containing as active ingredient a derivative of 8-methyl-7H-1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where And forms In the valence bond between the carbon atoms in positions 8 and 9, R2is the nitro-group or amino group, R1is a group of formula-CO-(CH2)p-R6where R6is a chlorine atom, fenoxaprop or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group or1-3alkyl group which may be substituted by phenyl, dimatix pyrrolidinyloxy group, phthalimidopropyl or saturated five - or six-membered heterocyclic group containing one or two nitrogen atom or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by one or two identical or different substituents selected from the group consisting of hydroxy-group, metoksifenilny, forfamilies, benzyl or (methoxy-phenoxy)-(hydroxypropyl) group, p = 0, 1, or 2, or its pharmaceutically acceptable salt accession acid.

15. The pharmaceutical composition according to p. 14, containing as active ingredient a derivative of 8-methyl-7H-1,3-dioxol-(4,5-h)(2,3) benzodiazepine of formula I, where R2is an amino group, R1And In such, as indicated in paragraph 6, or its pharmaceutically acceptable salt accession acid.

16. The method of treatment which comprises the administration to a patient suffering especially from epilepsy or neurodegenerative disease, or the post-impact, non-toxic doses derived 1,3-dioxol-/4,5-h//2,3-benzodiazepine of the formula I

where a is a hydrogen atom;
Is a hydrogen atom;
R1is a group of the formula -(CH2R4where R3and R4signify, independently from each other, a hydrogen atom, a C3-6cycloalkyl group1-4alkoxygroup, amino group, phenyl group which may be substituted by one or two1-4alkyl group (groups)1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - go six-membered heterocyclic group containing 1 to 3 nitrogen atoms or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by phenyl group which may be substituted by 1 to 3 substituent (Vice), (s) is(are) a1-4alkoxygroup, or R3and R4form 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 to 3 substituent (Vice), (s) is(are) a1-4alkoxygroup, n = 0, 1, or 2, m = 0, 1, or 2,
or As forms In the valence bond between the carbon atoms in positions 8 and 9, and in this case, R1is b> alkoxygroup or a group of the formula-NR7R8where R7and R8signify, independently from each other, a hydrogen atom, guanidino group3-6cycloalkyl group or1-4alkyl group, the latter can be substituted by phenyl group or a saturated five - or six-membered heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom as a heteroatom, and the phenyl group may be substituted by 1 to 3 same or different substituent (Vice), (s) is(are) a1-4alkoxygroup, or R7and R8form together with the adjacent nitrogen atom oxopyrrolidin group, phthalimidopropyl, the latter may be substituted, or a saturated five - or six-membered heterocyclic group containing one or more atom(s) of nitrogen or a nitrogen atom and an oxygen atom as a heteroatom, which heterocyclic group may be substituted by 1 to 3 identical or different substituents selected from the group consisting of hydroxy-group, phenyl group, fenoxaprop, phenyl(C1-4alkyl) group or phenoxy(C1-4alkyl) group, and the phenyl is th(s) represent a halogen atom or With1-4alkoxygroup, and phenoxy(C1-4alkyl), the alkyl group may be substituted by one or two hydroxy groups, R = 0, 1, or 2;
R2is the nitro-group, amino group,
or its pharmaceutically acceptable salt accession acid.

 

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