Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-10-12
1997-08-19
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544282, 5462721, C07D40314, C07D40114, A61K 31505
Patent
active
056589166
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/ES95/00015 filed Feb. 2, 1995.
DESCRIPTION
The invention relates to a compound, 3-{2-[4-(6-fluoro-benzo[d ]isoxazol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetra hydropyrido [1,2-a]pyrimidin-4-one, of ##STR2## which is useful as a drug active on the central nervous system and to the pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
EP-A-O 196 132 describes 3-piperidinyl-1,2-benzoisoxa-zoles of formula (II) as having antipsychotic properties. ##STR3##
EP-A-O 037 265 describes 3-[(1-piperidinyl)-4H-pyrido-[1,2-a]pyrimidin-4-ones of formula (III) ##STR4## where R may be H, alkyl, OH, RO or CH.sub.2 OH in positions 2, 3 or 4 of the piperidine ring, useful as cardiovascular agents and which act on the central nervous system.
The compound of formula (I) of the invention differs from the known compounds in the presence of a double bond between the 3 and 4 positions of the piperidine ring and in its pharmacological activity.
SUMMARY OF THE INVENTION
The compound 3-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-3,6-dihydro-2H-pyridin-1-yl ]-ethyl}-2-methyl-6,7,8,9-tetra-hydroprido[1,2-a]pyrimidin-4-one of formula (I) of the invention has interesting pharmacological properties, particularly in the treatment of psychotic disorders and alterations related with the capturing and/or release of dopamine and/or serotonin.
The invention also provides a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent. The composition is preferably for human use, in the form of tablets, capsules, injectables or suspension. Its use in the treatment of psychotic diseases is particularly outstanding.
The compound of formula (I) may be prepared by a process consisting of the reduction of the pyridinium salt of formula (IV) ##STR5## where W.sup.- is an organic or inorganic anion, such as a halide or a sulfonate.
The pyridinium salt of formula (IV) may be conveniently reduced with a metal borohydride, such as sodium borohydride, in an adequate protic solvent, such as water, alkanols or carboxylic acids. (R. E. Lyle and P. S. Anderson, Adv. Hetero-cycl. Chem. 6, 45-93 (1966)).
The intermediates and the starting compounds used in the process of the present invention are known products or may be easily prepared from known products.
The intermediates of formula (IV) may be easily prepared by N-alkylation of the pyridine of formula (V) with a reactant of formula (VI), where W is an appropriate leaving group such as, for example, a halide or a sulfonate. ##STR6##
The N-alkylation reaction is conducted in a solvent inert to the reaction, such as 4-methyl-2-pentanone, aceto-nitrile, N-methylpyrrolidone or N,N-dimethylformamide, optionally at a slightly raised temperature and adding potasium iodide as catalyst.
The pyridine of formula (V) may be obtained by cyclization of the oxime (VII) in an inert solvent, such as tetrahydrofurane, dioxane or N,N-dimethylformamide in the presence of an appropriate base, such as an alkaline carbonate or an alkaline hydride or alkoxide. ##STR7##
Alternatively, the pyridine of formula (V) may also be prepared by cyclization of the acetylated derivative of formula (VIII) of the oxime of formula (IX) (L. Davis et Drug Design and Discovery, 8, 225-240 (1992)). ##STR8##
The ketone of formula (X) precursor of (VII) may be prepared by Friedel-Crafts acylation of 1,3-difluorobenzene with isonicotinoyl chloride (F. J. Villani et al., J. Org. Chem. 17, 249 (1952)). ##STR9##
Likewise, the ketone of formula (XI) precursor of the oxime of formula (IX) may be prepared by Fries reaction, from 3-fluorophenol and isonicotinoyl chloride. ##STR10##
The compounds of formula (VI) have been described (H. Fujita et al., Ann. Rep. Sankyo Res. Lab. 29, 75-98 (1977)).
The preferred pharmaceutically acceptable salts are the acid addition salts. The pharmaceutically acceptable addition salts of the compounds of formula (I) are those formed from acids forming non toxic additi
REFERENCES:
patent: 5158952 (1992-10-01), Janssen et al.
patent: 5482943 (1996-01-01), Kennis et al.
R.E. Lyle et al., The Reduction of Nitrogen Heterocycles with Complex Metal Hydrides, Chem. 6, pp. 45-93 (1966).
L. Davis et al., Drug Design and Discovery8, pp. 225-240 (1992).
F.J. Villani et al., J. Org. Chem. 17, p. 249 (1952).
H. Fujita et al., Ann. Rep. Sankyo Res. Lab 29, pp. 75-78 (1977).
J.E. Leysen et al., Biochem. Pharmacol., 27: pp. 307-316 (1978).
A.L. Morrow et al., Eur. J. Pharmacol, 109: pp. 285-287 (1985).
Barjoan Pere Dalmases
Bosch Rovira Anna
Caldero Ges Jose Maria
Clotet Joan Huguet
Del Castillo Nieto Juan Carlos
Grumbling Matthew V.
Vita-Invest S.A.
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