Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-03-20
1991-01-15
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514326, 514378, 514380, 544367, 546209, 548243, 548248, A61K 31495, A61K 3142, C07D26118, C07D41312
Patent
active
049854283
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds with nootropic activity and, more particularly, it relates to derivatives of N-(5-isox-azolecarbonyl)-4-aminobutyric acid, the processes for their preparation, their therapeutic use and the pharmaceutical compositions containing them as active ingredient.
Piracetam, 2-pyrrolidinoneacetamide (Merck Index, X edition, page 1080, no. 7363) is a compound described in Belgian Pat. No. 667906 (Union Chimique Belge) as central stimulant.
For its action at cerebral level on glucose metabolism as well as, especially, in increasing acetylcholine release, Piracetam is considered the parent compound of nootropic drugs and it is used in therapy in the treatment of cerebral efficiency disorders, particularly in elderly patients.
Piracetam, even if it is used in therapy, shows a relative effectiveness.
In order to improve the therapeutic activity of the parent compound several different compounds have been prepared.
Among these we can mention, for example, the derivatives of 1-benzoyl-2-pyrrolidinone described in European Pat. No. 5143 (Hoffmann-La Roche) and, particularly, the derivative known as Aniracetam, 1-(4-methoxy-benzoyl)-2-pyrrolidinone (USAN and the USP Dictionary of Drug Names 1987, page 30).
It is worth noting, however, that, as far as we know, the compounds with nootropic activity developed up to now do not contain an isoxazole ring and furthermore most of them have a remarkable structural analogy with the parent compound Piracetam.
Besides, as can be seen also in Aniracetam, the pyrrolidinone ring remains present, as peculiar characteristic.
We have surprisingly found and they are the object of the present invention, compounds of formula ##STR1## wherein
n represents a number selected from 1 and 2;
R represents a hydrogen atom, a halogen atom, hydroxy, a C.sub.1 -C.sub.6 alkyl or alkoxy;
R.sub.1 represents hydroxy, an optionally unsaturated C.sub.1 -C.sub.18 alkoxy or an ##STR2## group;
R.sub.2 and R.sub.3, the same or different, represent a hydrogen atom, a linear or branched C.sub.1 -C.sub.6 alkyl, a group of formula (CH.sub.2).sub.m R.sub.4 wherein
m represents an integer selected from 1, 2 ,and 3;
R.sub.4 represents a carboxy group, an alkoxycarbonyl group having from 1 to 6 carbon atoms in the alkoxy moiety or a group of formula ##STR3##
R.sub.5 and R.sub.6, the same or different, represent a hydrogen atom or a linear or branched C.sub.1 -C.sub.6 alkyl; ##STR4## wherein R.sub.4 has the above reported meanings and R.sub.7 represents a linear or branched C.sub.1 -C.sub.4 alkyl optionally substituted by phenyl, hydroxy or by a mercapto group; and the other represents a hydrogen atom;
or, in addition, R.sub.2 and R.sub.3, together with the nitrogen atom to which they are bonded, form a 5, 6 or 7 membered heterocycle which may further contain 1 or 2 heteroatoms selected among nitrogen, oxygen and sulphur.
Specific examples are 1-pyrrolidinyl, 1-piperazinyl, 4-methyl-1-piperazinyl, 1-piperidyl and 1-pyrrolidinyl-2-one.
A further object of the present invention are the salts of the compounds of formula I, which have an acidic function, with pharmaceutically acceptable organic or inorganic bases and the salts of the compounds of formula I, wherein R.sub.1 contains a basic function, with organic or inorganic acids suitable for pharmaceutical use.
Examples of organic or inorganic bases useful as salifying agents are sodium or potassium hydroxides, ammonium hydroxide, lysine, arginine, cysteine and 2-amino-2-hydroxymethyl-1,3-propanediol. Examples of organic or inorganic acids useful as salifying agents are hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid and glutamic acid.
The compounds of formula I, object of the present invention, have nootropic activity.
Examples of compounds comprised in formula I are the following: ##STR5## wherein R has the above reported meanings but preferably it represents a chlorine or bromine atom, hydroxy, methoxy or ethoxy, methyl or ethyl.
The preparation of the compounds of formula I is another object of the
REFERENCES:
patent: 3459738 (1969-08-01), Morren et al.
patent: 4833140 (1989-05-01), Weber et al.
Branconnier et al., Psychopharmacology Bulletin, 19, p. 726.
Moos et al., Medicinal Research Reviews, 8, pp. 353-391 (1988).
Hano et al., Chemical Abstracts, vol. 72, No. 132705 (1970).
Zeeh et al., Chemical Abstracts, vol. 95, No. 62168 (1981).
Carenzi Angelo
Chiarino Dario
Della Bella Davide
Napoletano Mauro
Sala Alberto
Beinhardt E.
Shah Mukund J.
Zambon Group S.p.A.
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