Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-15
2003-08-05
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211070, C514S211090, C514S221000, C540S491000, C540S502000, C540S552000, C540S568000
Reexamination Certificate
active
06602865
ABSTRACT:
The invention relates to novel pyridazino[4,5-b][1,5]oxazepinone, -thiazepinone and -diazepinone derivatives as well as to pharmaceutical compositions containing these compounds.
The compounds according to the invention have valuable biological properties, namely, they show significant memory-enhancing effect, which is associated with considerable neuroprotective character.
DESCRIPTION OF THE PRIOR ART
According to a nowadays accepted view, glutamate the most important neurotransmitter of stimulating character, plays a decisive role in the memory processes. In pathological conditions resulting in dementia, the underfunction of the glutamatergic system can be demonstrated [Danysz W. et al., Drug News & Persp., 8, 263 (1995)]. The role of ionotropic glutamate receptors of the NMDA type played in memory functions has been experimentally proved; following their special, voltage-dependent activation the calcium permeability is enhanced, whereby certain memory processes can be readily explained on the neuronal level. Accordingly, compounds having glutamate agonist effect may stimulate the cognitive functions [Granger, R. et al., Synapse, 15, 326 (1993); Nicholson, C. D. et al., Psychopharmacology, 101, 147 (1994)). The effect of aniracetame and related compounds, which are long used in the therapy as memory-enhancers, is also based on the potentiation of the glutamate neurotransmission [Ito, l. et al., J. Physiol., 424, 533 (1990)].
Overactivity of the glutamatergic system, however, can result in excitotoxicity-induced neuronal cell loss, which is observed in several neurodegenerative disorders. In such diseases glutamate agonists can counter-balance the memory deficit resulted from the neuronal damage, while neuroprotective effect can be expected from glutamate antagonists.
Now it has been found that the novel compounds according to the invention are very effective in in vivo memory models, wherein they simultaneously show NMDA-activating and AMPA-inhibiting effects. Such novel type drugs of combined effect may result in definite advantages over the known memory-enhancing agents. Namely, reduced risk of side-effects (e.g. epileptogenic or neurone-damaging effect) inherently associated with the target effects (i.e. enhancing glutamatergic neurotransmission) during long-term use can be expected. Further, the AMPA antagonist character of the compounds can result in moderation of excitotoxicity-related neurodegeneration. Thus, besides palliative treatment the compounds of the invention may also slow down the progress of the diseases.
Some derivates of formula (I) of the present invention, in which R stands for hydrogen atom, R
1
is methyl group, X is oxygen or sulphur atom, W is methylene group and Y stands for a group of formula NR
3
, wherein R
3
is hydrogen atom or benzyl group, are mentioned in the literature as intermediates in the synthesis of novel pyridazino [4,5-b][1,5]oxazepines [P. Matyus et al.: Bioorganic and Medicinal Chemistry Letters, Vol. 7, No. 22, pp. 2857-2862 (1997)], but the synthesis, the physical data and the biological activity of these compounds has not been described so far.
DESCRIPTION OF THE INVENTION
The invention relates to novel pyridazino[4,5-b][1,5]oxazepinone, -thiazepinone and -diazepinone derivatives of general formula (I)
wherein
R stands for hydrogen atom or a group of formula NHR
4
, wherein R
4
stands for hydrogen, C
1-4
alkyl or C
2-5
acyl group,
R
1
stands for C
1-4
alkyl or C
2-4
alkenyl group, which may be substituted by a phenyl group, or phenyl group,
W stands for methylene or carbonyl group,
X and Y stand independently for oxygen or sulphur atom, SO, SO
2
or NR
3
group, wherein R
3
is hydrogen atom, C
1-4
alkyl group or a group of formula (II),
wherein R
2
stands for hydrogen or halogen atom, C
1-4
alkoxy or nitro group or a group of formula NHR
4
, wherein R
4
has the above meaning, and Z stands for methylene or carbonyl group, further n has a value of 0, 1 or 2,
with the proviso that when any of X or Y stands for oxygen or sulphur atom, SO or SO
2
group or a group of formula NR
3
,
wherein R
3
stands for hydrogenatom or a C
1-4
alkyl group, then the other may stand only for an NR
3
group, wherein R
3
stands for a group of formula (II)—wherein R
2
, Z and n have the above meaning
and their tautomers and the acid-addition salts of all these compounds. Furthermore, the invention relates to pharmaceutical compositions containing the compounds of general formula (I) as active agents.
In the general formula (I) the alkyl, acyl and alkenyl groups may have straight or branched chain, and the term “halogen atom” relates to chlorine or bromine atom.
The salts of the compounds of general formula (I) are pharmaceutically acceptable salts formed with inorganic and organic acids. Inorganic acids suitable for this purpose are e.g. hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid. From the organic acids to be used for this purpose formic acid, acetic acid, maleic and fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid and methanesulphonic acid are mentioned.
A preferred group of the compounds according to the invention of general formula (I) comprises compounds wherein R is hydrogen atom, R
1
stands for methyl or cinnamyl group, X is oxygen or sulphur atom or a group of formula NCH
3
, W is methylene group and Y stands for a group of formula NR
3
, wherein R
3
is a benzyl or a substituted benzyl group. Especially preferred are those compounds wherein X stands for sulphur atom.
The compounds of general formula (I) according to the invention can be prepared e.g. by the intramolecular cyclization of a compound of general formula (IIIa)
wherein A is a hydroxyl group or a halogen atom—and, if desired, by the subsequent transformation of the substituents.
a) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR
3
—wherein R
3
is a group of general formula (II), wherein R
2
, Z and n have the above meanings—and the other stands for oxygen atom, a compound of general formula (IIIa) or (IIIb)—wherein A stands for hydroxyl group, and R, R
1
, R
2
, W, Z and n have the above meaning—is reacted with a base, e.g. sodium ethylate.
b) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR
3
—wherein R
3
is a group of general formula (II), wherein R
2
, Z and n have the above meaning—and the other stands for sulphur atom, a compound of general formula (IIIa) or (IIIb), wherein A stands for halogen atom, and R, R
1
, R
2
, W, Z and n have the above meaning, is reacted with an inorganic sulphide, e.g. sodium sulphide.
c) For preparing compounds of general formula (I), wherein one of X and Y stands for a group of formula NR
3
—wherein R
3
stands for a group of general formula (II), wherein R
2
, Z and a have the above meaning—and the other stands for a group of formula NR
3
, wherein R
3
is hydrogen atom or a C
1-4
alkyl group—a compound of general formula (IIIa) or (IIIb), wherein A is halogen atom, and R, R
1
, R
2
, W, and n have the above meaning, is reacted with ammonia or an aliphatic amine.
d) For preparing compounds of general formula (I)—wherein one of X and Y stands for a group of formula NR
3
, wherein R
3
is a group of general formula (II)—wherein R
2
, Z and n have the above meaning—and the other is an SO or SO
2
group, a compound of general formula (I)—wherein one of X and Y is a group of formula NR
3
, wherein R
3
stands for a group of formula (II), wherein R
2
, Z and n have the above meaning—and the other is a sulphur atom, is reacted with an oxidating agent (e.g. alkali metaperiodate or hydrogen peroxide).
e) For preparing compounds of general formula (I)—wherein one of X or Y is a group of formula NR
3
, wherein R
3
has a meaning different from benzyl group—a compound of general formula (I), wherein R, R
1
and W has the above meaning, further one of X and Y stands for a
Andrasi Ferenc
Angyal nee Pataky Agnes
Berzsenyi Pal
Boros Sandor
Harsing Laszlo
Coleman Brenda
IVAX Drug Research Institute, Ltd.
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