Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-19
2003-05-13
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S557000
Reexamination Certificate
active
06562810
ABSTRACT:
The invention refers to novel 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives, a pharmaceutical composition containing the same, and a process for the preparation of the active ingredient.
More specifically, the invention refers to novel 8-substituted-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine derivatives of the formula I
wherein
X represents a carbonyl group or a methylene group, and
R
1
stands for a hydrogen atom, a hydroxy group, a C
1-4
alkoxy group, a C
1-4
alkanoyloxy group, a (C
1-4
alkyl)sulfonyloxy group or a group of the formula —NR
4
R
5
, wherein
R
4
and R
5
mean, independently, a hydrogen atom, a C
1-4
alkoxy group, a C
1-4
alkanoyl group or a C
1-6
alkyl group which latter is optionally substituted by a saturated or unsaturated heterocyclic group having 5 or 6 members and comprising one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom as the heteroatom, or by an N-/phenyl-(C
1-4
alkyl)/-N-(C
1-4
alkyl)amino group, wherein the phenyl group is optionally substituted by 1 to 3 substituent(s), wherein the substituent consists of a C
1-4
alkoxy group, or
R
4
and R
5
form with the adjacent nitrogen atom and optionally with a further nitrogen atom or an oxygen atom a saturated or unsaturated heterocyclic group having 5 to 10 members, or
X forms together with R
1
a cyano group, a tetrazolyl group, a group of the formula —CHNOH, or a group of the formula —COR
6
, wherein
R
6
means a hydroxy group, a C
1-4
alkoxy group, a phenoxy group, a naphthyloxy group, or an amino group which latter is optionally substituted by a C
1-4
alkyl group,
R
2
stands for a nitro group, an amino group or a (C
1-4
alkanoyl)amino group,
R
3
represents a hydrogen atom, a C
1-4
alkyl group, or a group of the formula —COR
7
, wherein
R
7
represents a hydrogen atom, a C
1-6
alkyl group, a C
1-6
alkyl group substituted by 1 to 3 halo atom(s), a C
1-4
alkoxy group, a phenoxy group, a pyridyl group, a phenyl group or a naphthyl group which two latter groups are optionally substituted by 1 to 3 substituent(s), or a group of the formula —(CH
2
)
n
—NR
8
R
9
, wherein
R
8
and R
9
represent, independently, a hydrogen atom, a C
1-4
alkyl group optionally substituted by a phenyl group or a saturated heterocyclic group having 5 or 6 members and containing a nitrogen group or a nitrogen and an oxygen group, and said phenyl group is optionally substituted by 1 to 3 substituent(s), wherein the substituent consists of a C
1-4
alkoxy group, or
R
8
and R
9
form, together with the adjacent nitrogen atom and optionally a further nitrogen or oxygen atom, a saturated or unsaturated hetero-cyclic group having 5 or 6 members and being optionally substituted by a phenyl group that is optionally substituted by 1 to 3 substituents, wherein the substituent consists of a halo atom or a C
1-4
alkoxy group,
n has a value of 0, 1 or 2,
Y is a hydrogen atom, or a methyl group, or
Y forms together with R
3
a valence bond between the carbon atom in position 8 and the nitrogen atom in position 7,
with the proviso that
1) if Y stands for a hydrogen atom or forms together with R
3
a valence bond and X represents a methylene group, then R
1
is other than a hydrogen atom, and
2) if Y stands for a hydrogen atom or a methyl group and R
3
represents a C
1-4
alkyl group or a group of the formula —COR
7
, then X is other than a methylene group,
and pharmaceutically suitable acid addition salts or quaternary ammonium derivatives thereof.
Several 2,3-benzodiazepine derivatives having biological activity are known.
Tofisopam i.e. 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine having anxiolytic effect is known from HU-P No. 155 572 and GB-P No. 1 202 579, respectively. The known compound does not comprise the ring system 1,3-dioxolo-/4,5-h//2,3/benzodiazepine.
From HU-P No. 186 760, 7,8-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having effect on the central nervous system are known, among others. The known compounds are prepared by reducing the corresponding 8-methyl-9H-1,3-dioxolo-/4,5-h//2,3/benzodiazepine derivative.
Various substituted 8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives are known from HU-P No. 191 698 and the corresponding GB-P No. 2 162 184. The known compounds have antiaggressive and anxiolytic activities.
A novel process for the preparation of partly new 8-methyl-9H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine derivatives having antiaggressive activity is known from HU-P No. 191 702. According to the novel process, the suitably substituted 2-acetonyl-4,5-methylenedioxybenzophenone is reacted with an excess of hydrazine hydrate.
Further 7,8-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having antidepressant and antiparkinsonian activities are known from HU-P No. 206 719.
A physical form of (R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo/4,5-h//2,3/benzodiazepine useful as an AMPA antagonist is described in EP No. 699 678.
7-Acyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives having anticonvulsive and muscle-relaxant activity are known from EP No. 492 485.
Enantiomers of 7,8-dihydro-8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine are described in WO 95/01357. The known enantiomers are useful as intermediates in the synthesis of therapeutically active compounds.
In EP No. 699 677 a stereoselective process for producing known dihydro-2,3-benzodiazepine derivatives is described.
5-(4-Substituted phenyl)-8-methyl-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives are described in FR 2 566 774. The compounds have antiagressive activity.
In J. Am. Chem. Soc., 117, 12358-9 (1995) an enantioselective synthesis for the preparation of 7-acetyl-5-(4-aminophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo/4,5-h/-/2,3/benzodiazepine is described.
7-Acyl-5-(4-aminophenyl)-8-alkyl-7H-1,3-dioxolo/4,5-h//2,3/benzodiazepines are described in DE-P No. 44 28 835. The known compounds inhibit the AMPA receptors.
An enantioselective synthesis for the preparation of 7-acyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo/4,5-h//2,3/-benzodiazepine derivatives is known from J. Chem. Sac. Perkin Trans I, 1995, 1423-1427.
Some of the 2,3-benzodiazepine derivatives elicit their effect through the non-competitive inhibition of the AMPA/kainate receptors /Donevan, S. D. et al., J. Pharmacol. Exp. Ther., 271, 25-29 (1994)/.
From the literature it is known that AMPA/kainate receptors play an important role in the acute and chronic diseases of the central nervous system. Through the inhibition of these receptors, muscle relaxant, neuro-protective and spasm inhibiting effects can be achieved /Vizi, E. S. et al., CNS Drug Reviews, 2, 91-126 (1996); Lees, G. L., CNS Drugs, 5, 51-74 (1996)/.
The aim of the invention is to prepare novel 2,3-benzodiazepine derivatives that are more effective than the known 2,3-benzodiazepine derivatives.
It was found that the above aim is achieved by the novel 8-substituted-9H-1,3-dioxolo/4,5-h//2,3/benzodiazepine derivatives which have—due to their non-competitive AMPA/kainate effect—considerable muscle relaxant, neuroprotective and anticonvulsive activities.
Thus, the novel compounds can be employed for the treatment of any diseases (such as epilepsy, diseases resulting in muscle spasm, various neurodegenerative diseases, stroke) in which the inhibition of the AMPA/kainate receptors is favourable.
In the description and Claims, in the definition of the substituents, under a C
1-4
alkoxy group primarily a methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy group, preferably a methoxy group is meant.
A C
1-4
alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C
1-4
alkyl group is a methyl or an ethyl group.
A C
1-6
alkyl group can be, in addition to alkyl groups listed above, for example a n-pentyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group etc.
A C
1-4
alkanoyl group is, primarily, a formyl, ac
Balázs László
Barkóczy József
Cselenyák Judit
Domán Imre
Egyed András
Birch & Stewart Kolasch & Birch, LLP
Coleman Brenda
Egis Gyogyszergyar RT.
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