Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-10
2002-11-19
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S562000
Reexamination Certificate
active
06482819
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to new tricyclic 2,3-benzodiazepine derivatives substituted by halogen atom and to pharmaceutical compositions containing the same.
Among the 2,3-benzodiazepines with dimethoxy or methylenedioxy substitution at the benzene ring several became known for their biological activity and therapeutic use. The Hungarian patent specifications Nos. 155,572, 179,018, 191,702 and 195,788 disclose 7,8-dimethoxy derivatives. These compounds exhibit primarily anxiolytic and/or antidepressant as well as positive inotropic effect. Compounds having methylenedioxy substitution at the same position of the benzene ring are disclosed in the Hungarian patent specifications Nos. 191,698, 191,702, 206,719, in the U.S. Pat. No. 5,459,137 and the published international patent application No. WO 96/04283.
Unlike the former compounds the 2,3-benzodiazepine derivatives substituted with a methylenedioxy group have mainly anticonvulsive, muscle relaxant and neuroprotective effect. In the literature it is widely known that the noncompetitive inhibition of the AMPA receptor constitutes the basis of the action of these compounds [S. D. Donevan et al.: Neuron 10, 51-59 (1993), J. Pharmacol. Exp. Ther. 271, 25-29 (1994), I. Tarnawa et al.: Bioorg. Med. Chem. Lett., 3, 99-104 (1993)].
It is known that in the central nervous system of mammals L-glutamic acid is the most important excitatory neurotransmitter. At pathological conditions the extracellular glutamic acid concentration is pathologically increased causing acute or chronic damage in the neurons of the central nervous system.
The effect of excitatory amino acids (such as glutamic acid) is exerted by the activation of the inotropic (ion channel) and G-protein bound metabotropic receptors. The types of ionotropic glutamate receptors were designated according to the agonists which are suitable for their selective excitation. Accordingly three types of receptors are differentiated: NMDA, AMPA and kainate (formerly quisqualate) receptors which are subdivided into further subgroups [Ann. Rev. Neurosci. 17, 31, (1994)].
It was confirmed that in several acute and chronic diseases where the central nervous system is involved, e. g. epilepsy, diseases with adjuvant muscle spasms and various neurodegenerative diseases, AMPA-type glutamate receptors are playing a major role, and anticonvulsive, muscle relaxant and neuroprotective effect may be achieved by inhibiting the AMPA receptors [Cerebrovasc. Brain Metab. Rev. 6, 225 (1994); Neurology 44, Suppl. 8, S14 (1994); J. Pharmacol. Exp. Ther. 260, 742 (1992)].
The inhibition of AMPA receptor activation may be attained with both competitive and noncompetitive antagonists. The use of noncompetitive antagonists may be generally more advantageous than that of competitive antagonists as they give a higher level of protection at extremely high endogenous concentrations of excitatory amino acids [Epilepsy Res., 15, 179 (1993)].
SUMMARY OF THE INVENTION
Based on the above it was an observation of major importance that the types of 2,3-benzodiazepines, substituted with a methylenedioxy group, described in the introduction, possess anticonvulsive, muscle relaxant and neuroprotective properties due to their noncompetitive AMPA antagonist effect and consequently can be used in therapy as anticonvulsive, antiepileptic agents in acute and chronic neurodegenerative diseases as well as potentially in all diseases where the inhibition of excitatory amino acids is desirable at receptor levels.
Research involving the synthesis and pharmacological investigation of novel 2,3-benzodiazepines designed for therapeutic use revealed that the novel 2,3-benzodiazepine derivatives according to the invention, substituted with halogen on the benzene ring and having a heterocyclic ring fused to the 7-membered ring, possess significant AMPA antagonistic effect and thus can be used for the treatment of the diseases of the central nervous system mentioned above. Furthermore it was found that the novel compounds according to the invention have more advantageous properties than the known compounds.
DETAILED DESCRIPTION OF THE INVENTION
Based on the above the invention relates to novel 2,3-benzo-diazepines of general formula (I), their potential stereoisomers and acid addition salts,
wherein
R
1
and R
2
represent independently hydrogen, halogen, a C
1-4
alkyl, C
1-4
alkoxy, nitro, trifluoromethyl group or a group of general formula NR
8
R
9
, wherein
R
8
and R
9
represent independently hydrogen, a C
1-4
alkyl group or a group of general formula —COR
10
, wherein
R
10
represents hydrogen, an optionally substituted C
1-4
alkyl group, C
6-10
aryl group, C
1-4
alkoxy group, C
3-5
cyclo-alkyl group, C
2-6
alkenyl group, C
3-5
cycloalkoxy group or a group of general formula —NR
11
R
12
, wherein
R
11
and R
12
represent independently hydrogen, a C
1-4
alkyl group, C
3-5
cycloalkyl group or C
6-10
aryl group,
X represents hydrogen or chlorine atom,
Y represents chlorine or bromine atom,
A represents a group of general formula (a), (b), (c) or (d),
wherein
R
3
, R
4
, R
5
, R
6
and R
7
represent independently hydrogen, a C
1-4
alkyl group, C
3-5
cycloalkyl group, C
2-4
alkenyl group, C
2-4
alkinyl group or C
6-10
aryl group which can optionally be substituted by one or more halogen, nitro, alkoxy or amino groups; furthermore heteroaryl group; groups of general formula —COOR
13
or —CO—NR
14
R
15
, wherein
R
13
represents hydrogen or C
1-4
alkyl group,
R
14
and R
15
represent independently hydrogen or a C
1-4
alkyl group or form together with the nitrogen atom a 5 to 7-membered saturated heterocycle which can contain further oxygen, sulfur or nitrogen atoms.
In the groups of general formula (I) the alkyl and alkenyl groups can be both straight and branched groups. The cycloalkyl group can be a cyclopropyl, cyclobutyl or cyclopentyl group. The aryl group can be a phenyl or naphthyl group. The heteroaryl group can be an aromatic heterocyclic group, e.g. thienyl, furyl, pyridyl, etc.
When compounds of general formula (I) have a chiral centrum, the term “isomer” represents both enantiomers, furthermore, due to stereoisomers developing because of particular substitutions, E and Z isomers, diastereomers, tautomers as well as mixtures thereof, e. g. racemates.
The salts of the compounds of general formula (I) are physiologically acceptable salts formed with inorganic and organic acids. Suitable inorganic acids are e.g. hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. Suitable organic acids are formic acid, acetic acid, maleic and fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid or methanesulfonic acid.
A preferred group of the compounds of general formula (I) of the invention are those of general formula (Ia) wherein X and Y, or at least Y represent a chlorine atom, R
1
represents an amino group in position 4 and R
2
stands for hydrogen, furthermore one of R
3
or R
4
stands for a methyl group.
Compounds of general formula (I) of the invention are prepared by
a) reacting a compound of general formula (II) or (III),
wherein R
1
, R
2
, X and Y have the same meaning as above and Z represents a C
1-3
alkylthio group, with
&agr;) an aminoacetal or aminoketal of general formula (IV),
wherein R
3
and R
4
have the same meaning as above, R
16
and R
17
represent independently C
1-4
alkyl group or together a C
2-4
alkylene group,
the intermediate formed in the reaction is submitted to acidic ring closure resulting in a compound of general formula (I), wherein R
1
, R
2
, X and Y have the same meaning as above and (A) represents a group of general formula (a), wherein R
3
and R
4
have the same meaning as above, or
&bgr;) an acid hydrazide of general formula (V)
wherein R
5
has the same meaning as above, or the compounds of general formula (II) or (III) are first reacted with hydrazine hydrate and the resulting intermediates are treated with an acid anhydride, yielding compounds of general
Ábrahám Gizella
Andrási Ferenc
Berzsenyi Pál
Csuzdi Emese
Hámori Tamás
Ford John M.
Gyogyszerkutato Intezet Kft.
Keil & Weinkauf
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