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US 5,854,237 AGranted
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay Donald Albright, Marvin Fred Reich, Fuk-Wah Sum, Efren Guillermo Delos Santos
Life of this patent
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Abstract
Tricyclic diazepines of the formula: ##STR1## wherein A, B, D, E, F, Y and Z are defined in the specification which compounds have vasopressin and oxytocin antagonist activity.
Claims39
A compound selected from Formula I:
- ##STR290## wherein;
- A-B is ##STR291## wherein m is one or two;
- the moiety ##STR292## represents a fused phenyl or fused substituted phenyl optionally substituted by one or two substituents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen, amino, (C.sub.1 -C.sub.3) lower alkoxy, or (C.sub.1 -C.sub.3) lower alkylamino;
- the moiety:
- ##STR293## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C.sub.1 -C.sub.3) lower alkyl, hydroxy, COCCl.sub.3, COCF.sub.3, ##STR294## --CHO, amino, (C.sub.1 -C.sub.3) lower alkoxy, (C.sub.1 -C.sub.3) lower alkylamino , CONH (C.sub.1 -C.sub.3) lower alkyl, or --CONlower alkyl (C.sub.1 -C.sub.3)!.sub.2,
- R.sub.b is independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5 ;
- q is 1 or 2;
- R.sub.3 is the moiety ##STR295## wherein Ar is a moiety selected from the group ##STR296## and X is selected from O, S, NH, --NCH.sub.3, or --N--COCH.sub.3 ;
- R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), --CO-lower alkyl (C.sub.1 -C.sub.3), SO.sub.2 lower alkyl (C.sub.1 -C.sub.3), or the moieties of the formulae:
- ##STR297## R.sub.1 and R.sub.2 are, independently, H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, or halogen;
- R.sub.5 is H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy or halogen;
- R.sub.6 is selected from:
- (a) moieties of the formula:
- ##STR298## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- n is 0-2;
- R.sub.a is independently selected from H, --CH.sub.3, --C.sub.2 H.sub.5, ##STR299## --(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 -C.sub.3), or --CH.sub.2 CH.sub.2 OH;
- R.sub.b is as hereinbefore defined;
- q is 1 or 2;
- (b) a moiety of the formula:
- ##STR300## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR301## wherein J is R.sub.a, lower alkyl (C.sub.1 -C.sub.8) branched or unbranched, lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, --O-lower alkyl (C.sub.1 -.sub.8) branched or unbranched, --O-lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH.sub.2 --K wherein K is halogen, (C.sub.1 -C.sub.3) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR302## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C.sub.1 -C.sub.3)lower alkyl, hydroxy, --CO-lower alkyl (C.sub.1 -C.sub.3), CHO, (C.sub.1 -C.sub.3)lower alkoxy, or --CO2-lower alkyl (C.sub.1 -C.sub.3);
- and
- R.sub.a and R.sub.b are as hereinbefore defined;
- (d) a moiety selected from those of the formulae:
- ##STR303## wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3)lower alkyl, --O-lower alkyl (C.sub.1 -C.sub.3), OH ##STR304## q is 1 or 2;
- R.sub.a and R.sub.b are as hereinbefore defined;
- wherein Ar' is selected from the group:
- ##STR305## wherein W' is selected from 0, S, NH, N-lower alkyl (C.sub.1 -C.sub.3), --NHCO-lower alkyl (C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- R.sup.7 is selected from H, lower alkyl (C.sub.1 -C.sub.3), halogen, --O-lower alkyl (C.sub.1 -C.sub.3), or CF.sub.3 ;
- R.sup.8 and R.sup.9 are independently selected from hydrogen, lower alkyl (C.sub.1 -C.sub.3), S-lower alkyl (C.sub.1 -C.sub.3), halogen, --NH--lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --CN, --OH, --S--CF.sub.3, --NO.sub.2, NH.sub.2, or --O-lower alkyl (C.sub.1 -C.sub.3);
- R.sup.10 is H, halogen, or lower alkyl-(C.sub.1 -C.sub.3);
- and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
31 more elements
A compound selected from Formula I:
- ##STR320## wherein;
- A-B is ##STR321## wherein m is one;
- the moiety ##STR322## represents a fused phenyl or fused substituted phenyl optionally substituted by one or two substituents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen, amino, (C.sub.1 -.sub.3) lower alkoxy, or (C.sub.1 -C.sub.3) lower alkylamino;
- the moiety:
- ##STR323## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C.sub.1 -C.sub.3) lower alkyl, hydroxy, COCCl.sub.3, COCF.sub.3, ##STR324## --CHO, amino, (C.sub.1 -C.sub.3) lower alkoxy, (C.sub.1 -C.sub.3) lower alkylamino , CONH (C.sub.1 -C.sub.3) lower alkyl, or --CONlower alkyl (C.sub.1 -.sub.3)!.sub.2,
- R.sub.b is independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5 ;
- q is 1 or 2;
- R.sub.3 is the moiety ##STR325## wherein Ar is a moiety selected from the group ##STR326## and x is selected from O, S, NH, --NCH.sub.3, or --N--COCH.sub.3 ;
- R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), --CO-lower alkyl (C.sub.1 -.sub.3), SO.sub.2 lower alkyl (C.sub.1 -C.sub.3), or the moieties of the formulae:
- ##STR327## R.sub.1 and R.sub.2 are, independently, H, (C.sub.1 -.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, or halogen;
- R.sub.5 is H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy or halogen;
- R.sub.6 is selected from:
- (a) moieties of the formula:
- ##STR328## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalky, cyclohexenyl or cyclopentenyl;
- n is 0-2;
- R.sub.a is independently selected from H, --CH.sub.3, --C.sub.2 H.sub.5, ##STR329## --(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 C.sub.3), or --CH.sub.2 CH.sub.2 OH;
- R.sub.b is as hereinbefore defined;
- q is 1 or 2;
- (b) a moiety of the formula:
- ##STR330## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR331## wherein J is R.sub.a, lower alkyl (C.sub.1 -C.sub.8) branched or unbranched, lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, --O-lower alkyl (C.sub.1 -.sub.8) branched or unbranched, --O-lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH.sub.2 --K wherein K is halogen, (C.sub.1 -C.sub.3) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR332## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C.sub.1 -C.sub.3)lower alkyl, hydroxy, --CO-lower alkyl (C.sub.1 -C.sub.3), CHO, (C.sub.1 -.sub.3)lower alkoxy, or --CO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- and
- R.sub.a and R.sub.b are as hereinbefore defined;
- (d) a moiety selected from those of the formulae:
- ##STR333## wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3)lower alkyl, --O-lower alkyl (C.sub.1 -C.sub.3), OH ##STR334## q is 1 or 2;
- R.sub.a and R.sub.b are as hereinbefore defined;
- wherein Ar' is selected from the group:
- ##STR335## wherein W' is selected from O, S, NH, N-lower alkyl (C.sub.1 -C.sub.3), --NHCO-lower alkyl (C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- R.sup.7 is selected from H, lower alkyl (C.sub.1 -C.sub.3), halogen, --O-lower alkyl (C.sub.1 -C.sub.3), or CF.sub.3 ;
- R.sup.8 and R.sup.9 are independently selected from hydrogen, lower alkyl (C.sub.1 -C.sub.3), S-lower alkyl (C.sub.1 -.sub.3), halogen, --NH-lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --CN, --OH, --S--CF.sub.3, --NO.sub.2, NH.sub.2, or --O-lower alkyl (C.sub.1 -C.sub.3);
- R.sup.10 is H, halogen, or lower alkyl-(C.sub.1 -C.sub.3);
- and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
31 more elements
A compound selected from Formula I:
- ##STR336## wherein;
- A-B is ##STR337## wherein m is two;
- the moiety ##STR338## represents a fused phenyl or fused substituted phenyl optionally substituted by one or two substituents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen, amino, (C.sub.1 -C.sub.3) lower alkoxy, or (C.sub.1 -C.sub.3) lower alkylamino;
- the moiety:
- ##STR339## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C.sub.1 -C.sub.3) lower alkyl, hydroxy, COCCl.sub.3, COCF.sub.3, ##STR340## --CHO, amino, (C.sub.1 -C.sub.3) lower alkoxy, (C.sub.1 -C.sub.3) lower alkylamino , CONH (C.sub.1 -C.sub.3) lower alkyl, or --CONlower alkyl (C.sub.1 -C.sub.3)!.sub.2,
- R.sub.b is independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5 ;
- q is 1 or 2;
- R.sub.3 is the moiety ##STR341## wherein Ar is a moiety selected from the group ##STR342## and x is selected from O, S, NH, --NCH.sub.3, or --N--COCH.sub.3 ;
- R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), --CO-lower alkyl (C.sub.1 -C.sub.3), SO.sub.2 lower alkyl (C.sub.1 -C.sub.3), or the moieties of the formulae:
- ##STR343## R.sub.1 and R.sub.2 are, independently, H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, or halogen;
- R.sub.5 is H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy or halogen;
- R.sub.6 is selected from:
- (a) moieties of the formula:
- ##STR344## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- n is 0-2;
- R.sub.a is independently selected from H, --CH.sub.3, --C.sub.2 H.sub.5, ##STR345## --(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 C.sub.3), or --CH.sub.2 CH.sub.2 OH;
- R.sub.b is as hereinbefore defined;
- q is 1 or 2;
- (b) a moiety of the formula:
- ##STR346## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR347## wherein J is R.sub.a, lower alkyl (C.sub.1 -C.sub.8) branched or unbranched, lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, --O-lower alkyl (C.sub.1 -C.sub.8) branched or unbranched, --O-lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH.sub.2 --K wherein K is halogen, (C.sub.1 -C.sub.3) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR348## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C.sub.1 -C.sub.3)lower alkyl, hydroxy, --CO-lower alkyl (C.sub.1 -C.sub.3), CHO, (C.sub.1 -C.sub.3)lower alkoxy, or --CO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- and
- R.sub.a and R.sub.b are as hereinbefore defined;
- (d) a moiety selected from those of the formulae:
- ##STR349## wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3)lower alkyl, --O-lower alkyl (C.sub.1 -C.sub.3), OH ##STR350## q is 1 or 2;
- R.sub.a and R.sub.b are as hereinbefore defined;
- wherein Ar' is selected from the group:
- ##STR351## wherein W' is selected from O, S, NH, N--lower alkyl (C.sub.1 -C.sub.3), --NHCO-lower alkyl (C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- R.sup.7 is selected from H, lower alkyl (C.sub.1 -C.sub.3), halogen, --O-lower alkyl (C.sub.1 -C.sub.3), or CF.sub.3 ;
- R.sup.8 and R.sup.9 are independently selected from hydrogen, lower alkyl (C.sub.1 -C.sub.3), S-lower alkyl (C.sub.1 -C.sub.3), halogen, --NH--lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --CN, --OH, --S--CF.sub.3, --NO.sub.2, NH.sub.2, or --O-lower alkyl (C.sub.1 -C.sub.3);
- R.sup.10 is H, halogen, or lower alkyl-(C.sub.1 -.sub.3);
- and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
31 more elements
Dependencies are inferred from the claim text.