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US 5,348,962 AGranted
Hydroxyquinolone derivatives compounds which have pharmaceutical utility
AssigneeMerck Sharpe & Dohme Ltd.
InventorsJanusz J. Kulagowski, Ian M. Mawer, Paul D. Leeson, Michael Rowley
Life of this patent
Estimating the term…
Abstract
This present invention relates to a class of 4-hydroxy-2-(1H)-quinolones which are substituted in the 3-position by an optionally substituted aryl substituent. These compounds are selective non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors.
Claims16
A method for the treatment and/or prevention of conditions which require the administration of a selective non-competitive antagonist of NMDA receptors which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I:
- ##STR14## pharmaceutically acceptable salt or prodrug thereof wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- or R.sup.1 and R.sup.2 together represent the residue of a carbocyclic ring;
- R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, 13 NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- and
- R.sup.a and R.sup.b are independently represent hydrogen or hydrocarbon.
2 more elements
A pharmaceutical composition comprising an effective amount of a compound of formula IA:
- ##STR15## salt or prodrug thereof wherein:
- R.sup.11 and R.sup.12 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- or R.sup.11 and R.sup.12 together represent the residue of a carbocyclic ring;
- R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, 13 NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- and
- R.sup.a and R.sup.b independently represent hydrogen or hydrocarbon;
- provided that, when R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.16 each represents hydrogen, then R.sup.15 does not represent an unsubstituted straight or branched alkoxy group containing 2 to 10 carbon atoms or a straight or branched alkoxy group containing 1 to 6 carbon atoms having at least one substituent selected from hydroxy, carboxy and carbamoyl;
- in association with one or more pharmaceutically acceptable carriers and/or excipients.
5 more elements
A compound of formula IB:
- ##STR16## salt or prodrug thereof wherein:
- R.sup.21 and R.sup.22 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- or R.sup.21 and R.sup.22 together represent the residue of a carbocyclic ring;
- R.sup.23, R.sup.24, R.sup.25 and R.sup.26 are independently selected from the group consisting of hydrogen, hydrocarbon, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a and --CONR.sup.a R.sup.b ;
- and
- R.sup.a and R.sup.b independently represent hydrogen or hydrocarbon;
- provided that, when R.sup.21 and R.sup.22 each represents hydrogen, then:
- (i) R.sup.24 does not represent hydrogen, methyl, chloro, hydroxy, methoxy or acetoxy when R.sup.23, R.sup.25 and R.sup.26 each represents hydrogen;
- and
- (ii) R.sup.25 does not represent methyl, chloro, trifluoromethyl, hydroxy, benzoyloxy or an unsubstituted straight or branched alkoxy group containing 1 to 10 carbon atoms or a straight or branched alkoxy group containing 1 to 6 carbon atoms having at least one substituent selected from hydroxy, carboxy and carbamoyl when R.sup.23, R.sup.24 and R.sup.26 each represents hydrogen;
- and
- (iii) R.sup.26 does not represent methyl, phenyl, chloro or methoxy when R.sup.23, R.sup.24 and R.sup.25 each represents hydrogen;
- and
- (iv) R.sup.25 does not represent chloro when R.sup.23 and R.sup.24 each represents hydrogen and R.sup.26 is methoxy, or when R.sup.23 and R.sup.26 each represents hydrogen and R.sup.24 is chloro;
- and
- (v) R.sup.26 does not represent chloro when R.sup.23 and R.sup.25 each represent hydrogen and R.sup.24 is chloro, or when R.sup.24 and R.sup.25 each represents hydrogen and R.sup.23 is chloro;
- provided also that, when one of R.sup.21 and R.sup.22 represents hydroxy or lower alkoxy and the other represents hydrogen, hydroxy or lower alkoxy, and R.sup.23, R.sup.24 and R.sup.26 each represents hydrogen, then R.sup.25 does not represent hydroxy or lower alkoxy;
- provided also that, when R.sup.21 is 2'-methyl and R.sup.22 is hydrogen, then:
- (i) R.sup.24 does not represent hydrogen, chloro or methoxy when R.sup.23, R.sup.25 and R.sup.26 each represents hydrogen;
- and
- (ii) R.sup.25 does not represent chloro or methoxy when R.sup.23, R.sup.24 and R.sup.26 each represents hydrogen;
- and
- (iii) R.sup.26 does not represent chloro when R.sup.23, R.sup.24 and R.sup.25 each represent hydrogen;
- provided also that, when R.sup.21 and R.sup.23 each represents hydrogen, one of the substituents R.sup.24, R.sup.25 and R.sup.26 is chloro and the remainder represent hydrogen, then R.sup.22 does not represent 4'-methyl;
- provided also that, when R.sup.21 is 2'-methoxy and R.sup.22, R.sup.23, R.sup.25 and R.sup.26 each represents hydrogen then R.sup.24 does not represent hydrogen, fluoro, chloro or bromo;
- further provided that, when R.sup.21, R.sup.23, R.sup.24, R.sup.25 and R.sup.26 each represents hydrogen, then R.sup.22 does not represent 2'-fluoro, 2'-nitro, 2'-amino, 4'-chloro, 4'-hydroxy or 4'-methoxy.
23 more elements
A compound represented by formula IIA:
- ##STR17## salt or prodrug thereof wherein:
- R.sup.31 and R.sup.32 are independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, aryl(C.sub.1-6 )alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy, aryloxy, aryl(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C.sub.1-6 )alkylamino, di(C.sub.1-6 )alkylamino, arylcarbonylamino, arylcarbonyl, or C.sub.2-7 alkoxycarbonyl, any of which groups may be optionally substituted;
- and hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy;
- or
- R.sup.31 and R.sup.32 together represent the residue of a carbocyclic ring;
- R.sup.33 and R.sup.35 are independently selected from the group consisting of halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and C.sub.2-7 alkoxycarbonyl;
- and
- R.sup.34 represents hydrogen or halogen.
5 more elements
A compound represented by formula IIB:
- ##STR18## salt or prodrug thereof wherein:
- R.sup.41 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, aryl(C.sub.1-6)alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy, aryloxy, aryl(C.sub.1-6 )alkoxy, C.sub.1-6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, arylcarbonylamino, arylcarbonyl, or C.sub.2-7 alkoxycarbonyl, any of which groups may be optionally substituted;
- and halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy;
- and
- R.sup.42 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, aryl(C.sub.1-6 )alkyl, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy, aryloxy, aryl(C.sub.1-6)alkoxy, C.sub.1-6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, arylcarbonylamino, arylcarbonyl, or C.sub.2-7 alkoxycarbonyl, any of which groups may be optionally substituted;
- and hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy;
- or
- R.sup.41 and R.sup.42 together represent the residue of a carbocyclic ring;
- R.sup.43 and R.sup.44 are independently selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and C.sub.2-7 alkoxycarbonyl;
- and
- R.sup.45 is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 alkylthio and C.sub.2-7 alkoxycarbonyl.
8 more elements
A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of:
- 4-hydroxy-3-phenyl-2(1H)-quinolone;
- 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone;
- 7-chloro-4-hydroxy-3-(2-methylphenyl)-2(1H)-quinolone;
- 7-chloro-4-hydroxy-3-(4-methylphenyl)-2(1H)-quinolone;
- 4-hydroxy-3-phenyl-7-trifluoromethyl-2(1H)-quinolone;
- 6,7-dichloro-4-hydroxy-3-phenyl-2(1H)-quinolone;
- pharmaceutically acceptable salt or prodrug thereof.
4 more elements
The compound which is 7-chloro-4-hydroxy-3-(3-phenoxyphenyl)-2(1H)-quinolone or salt thereof.
A pharmaceutical composition comprising an effective amount of 7-chloro-4-hydroxy-3-(3-phenoxyphenyl)-2(1H)-quinolone or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable carriers and/or excipients.
A method for the treatment and/or prevention of schizophrenia which comprises administering to a patient in need of such treatment an effective amount of 7-chloro-4-hydroxy-3-(3-phenoxyphenyl )-2(1H)-quinolone or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.