Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-06-17
1993-03-30
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544354, C07D24144, A61K 31495
Patent
active
051984415
DESCRIPTION:
BRIEF SUMMARY
The object of the present invention is new derivatives of 1,2-dihydro 2-oxo quinoxalines, their preparation and their use in therapy.
The compounds of the invention have general formula I: ##STR3## in which R is a hydrogen or halogen atom radical, -C.sub.4 alkyl group -C.sub.4 alkyl group or a phenyl group cycloalkyl radical, an alkylnyl, nitrile, hydroxyl, carboxamido, pyridyl, phenyl group, or phenyl group substituted by a halogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group or a nitro group ##STR4## in which R.sub.6, R.sub.7 may, independently of each other, be a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group, a phenyl group or an alkoxycarbonyl group group or a phenyl group
Furthermore, the invention covers the salts of compounds of general formula I with pharmaceutically acceptable acids in the case of compounds having sufficient basicity.
The compounds of general formula I (R.sub.2 =H) of the invention can be prepared in accordance with the following reaction mechanism: ##STR5##
The initial keto acids of formula II can be obtained by known methods, for instance the method described by Korte et al., Chem. Ber. 92, 877-83 (1959).
The reaction of the keto acid of formula II with an orthophenylene diamine is preferably carried out in an alcoholic solvent such as ethanol, or an acid solvent such as acetic acid. The reaction can be carried out at room temperature or at a temperature ranging up to the boiling point of the solvent.
The 1,2-dihydro 2-oxo quinoxalines of general formula III thus obtained are then treated by a reagent R.sub.3 -A-X and which R.sub.3 in A are defined as above and X represents a nucleofuge atom such as iodine, chlorine, bromine or a mesylate or tosylate group, in the presence of a base such as sodium hydroxide. The reaction is carried out within an aprotic solvent such as DMF.
The quinoxalines of formula IV which are thus obtained correspond to the compounds of formula I in which R.sub.2 represents a hydrogen atom.
In order to prepare a compound of formula I in which R.sub.2 represents a group of the formula --C(O)R.sub.4 (R.sub.4 being defined as above), the compound of formula IV is reacted with an excess of anhydride of formula (R.sub.4 CO).sub.2 O, preferably in the hot. A compound of formula I can also be prepared in which R.sub.2 represents a group of the formula --C(O)R.sub.4 by reacting a compound of general formula III with an excess of anhydride of formula (R.sub.4 CO).sub.2 O and then alkylating this product by a reagent of the formula R.sub.3 -A-X in a manner similar to that described above.
In order to prepare a compound of formula I in which R.sub.2 represents a group of formula --C(O)NHR.sub.5 (R.sub.5 being defined as above), a compound of formula IV is reacted with an isocyanate of formula R.sub.5 NCO in an aprotic solvent such as toluene at a temperature ranging up to the boiling point of the solvent, or else a compound of formula IV is reacted with phosgene in an aprotic solvent, for instance toluene, and then with an amine of formula R.sub.5 NH.sub.2.
In order to prepare a compound of formula I in which R.sub.3 represents a radical --OC(O)R.sub.8 (R.sub.8 being defined as above), a compound of formula I in which R.sub.3 represents a hydroxyl group can be reacted with an excess of anhydride of formula (R.sub.8 CO).sub.2 O, preferably in the hot.
In order to prepare a compound of formula I in which R.sub.3 represents a radical --OC(O)NHR.sub.9 (R.sub.9 being defined as above), a compound of formula I in which R.sub.3 represents a hydroxyl group can be reacted with an isocyanate of formula R.sub.9 NCO in an aprotic solvent such as toluene or xylene at the reflux temperature of the solvent.
The following examples illustrate the invention without, however, limiting its scope.
The analyses and the RMN and IR spectra confirm the structure of the compounds obtained in accordance with the invention.
EXAMPLE 1
1-prenyl 3-(3-hydroxy propyl) 1,2-dihydro 2-oxo quinoxaline [I; R=R.sub.1
=R.sub.2 =H, n=2, A=CH.sub.2, R.sub.3 =CH.dbd.C(CH.sub.3).s
REFERENCES:
patent: 4140789 (1979-02-01), Jaeggi et al.
patent: 4181724 (1980-01-01), Hall et al.
patent: 5034537 (1991-07-01), Frazee
"Advanced Organic Chemistry" (2nd ed.) by Jerry March, pp. 361-362 (1977).
Bigg Dennis
Couret Francoise
Faure Christian
Pitet Guy
Tarayre Jean-Pierre
Bernhardt E.
Hueschen Gordon W.
Pierre Fabre Medicament
Rizzo Nicholas S.
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