Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-04
1999-09-28
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544383, 546158, 514312, C07D40106, C07D49504, A61K 3147
Patent
active
059589248
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT//FR96/01401 filed Sep. 12, 1996.
The present invention relates to 2(1H)-quinolone derivatives, to their preparation and to their use in therapy.
The compounds of the invention correspond to the formula (I) ##STR2## -1-piperazinyl group or a 4-(4-fluorobenzoyl)-1-piperidyl group, hydrogen atom, or a halogen atom, or an amino group, or a hydroxyl group, or a nitro group, or a cyano group, or a (C.sub.1 -C.sub.6)alkyl group, or a (C.sub.1 -C.sub.6)alkoxy group, or a trifluoromethyl group, or a trifluoromethoxy group, or a --COOH group, or a group --COOR.sub.4, or a --CONH.sub.2 group, or a group --CONHR.sub.4, or a group --CONR.sub.4 R.sub.5, or a group --SR.sub.4, or a group --SO.sub.2 R.sub.4, or a group --NHCOR.sub.4, or a group --NHSO.sub.2 R.sub.4, or a group --N(R.sub.4).sub.2, where R.sub.4 and R.sub.5 are each a (C.sub.1 -C.sub.4)alkyl group, R.sub.3 represents either a hydrogen atom, or a (C.sub.1 -C.sub.4)alkyl group, or a group --(CH.sub.2).sub.p OH, or a group --(CH.sub.2).sub.p NH.sub.2, or a group --(CH.sub.2).sub.n COOH, or a group --(CH.sub.2) COOR.sub.4, or a group --(CH.sub.2).sub.n CONH.sub.2, or a group --(CH.sub.2).sub.n CONHOH, or a group --(CH.sub.2).sub.p SH, or a group --(CH.sub.2).sub.n SO.sub.3 H, or a group --(CH.sub.2).sub.n SO.sub.2 NH.sub.2, or a group --(CH.sub.2).sub.n SO.sub.2 NHR.sub.4, or a group --(CH.sub.2).sub.n SO.sub.2 NR.sub.4 R.sub.5, or a group --(CH.sub.2).sub.n CONHR.sub.4, or a group --(CH.sub.2).sub.n CONR.sub.4 R.sub.5, or a group --(CH.sub.2).sub.p NHSO.sub.2 R.sub.4, or a group --(CH.sub.2).sub.p NHCOR.sub.4, or a group --(CH.sub.2).sub.p OCOR.sub.4, where R.sub.4 and R.sub.5 are each a (C.sub.1 -C.sub.4)alkyl group, n is equal to 1, 2, 3 or 4, p is equal to 2, 3 or 4 and m is equal to 2, 3 or 4 as well as their addition salts with pharmaceutically acceptable acids or bases.
According to the invention, the compounds of formula (I) may be synthesized according to Scheme 1.
4-(Acetyloxy)-2H,3H-pyran-2,6-dione is reacted with a compound of formula (II) (in which R.sub.1 and R.sub.2 are as defined above and R.sub.3 is a hydrogen atom or a (C.sub.1 -C.sub.4)alkyl group) at room temperature in a polar solvent such as acetic acid. After drying, the compound of formula (III) thereby obtained is cyclized in the presence of an inorganic or organic acid, preferably anhydrous, such as concentrated sulphuric acid, polyphosphoric acid or trifluoromethanesulphonic acid, at a temperature of between 10 and 150.degree. C., and a substituted or unsubstituted 2-oxo-1,2-dihydro-4-quinolineacetic acid of formula (IV) is obtained, which is esterified with an alcohol of formula R.sub.6 OH (where R.sub.6 is a (C.sub.1 -C.sub.4)alkyl group) by any esterification method, ##STR3## preferably by the action of thionyl chloride. The ester of formula (V) thereby obtained is then reduced with a hydride in an aprotic solvent such as, for example, lithium aluminium hydride in dioxane or sodium borohydride in excess in tetrahydrofuran under reflux, or lithium borohydride in tetrahydrofuran at room temperature, to obtain an alcohol of formula (VI) (in which m is equal to 2); the compounds of formula (VI) in which m is equal to 3 or 4 are obtained from those in which m is equal to 2 by homologation techniques known to a person skilled in the art. The compounds of formula (VI) (in which m is equal to 2, 3 or 4) are then activated to compounds of formula (VII) (in which X represents a leaving group such as a chlorine or bromine atom), for example by reaction with thionyl chloride in chloroform under reflux or dibromotriphenylphosphorane at room temperature in dichloromethane, or to compounds of formula (VII) (in which X represents a leaving group such as methanesulphonyloxy, trifluoromethanesulphonyloxy or para-toluenesulphonyloxy groups), for example by reaction with a sulphonic anhydride or a sulphonic acid chloride in the presence of a base such as pyridine or triethylamine. Finally, the compounds of formula (VII) are reacted with 4-(4-fluorobenzoyl)piperidine wi
REFERENCES:
patent: 5077288 (1991-12-01), Lavielle et al.
Journal of Medicinal Chemistry, vol. 35, No. 26, Dec. 25, 1992 pp. 4903-4910.
Journal of Medicinal Chemistry, vol. 32, No. 6, Jun. 1989, pp. 1147-1156.
Aletru Michel
Dellac Genevieve
Hoornaert Christian
McCort Gary
Raymond Richard L.
Razgunas Ann
Synthelabo
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