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US 5,516,774 AGranted
Tricyclic diazepine vasopressin antagonists and oxytocin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay D. Albright, Marvin F. Reich, Fuk-Wah Sum, Efren G. 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.
Claims54
A compound selected from Formula I:
- ##STR236## wherein;
- A-B is ##STR237## the moiety ##STR238## represents a fused phenyl or fuse 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:
- ##STR239## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D, 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, COCl, COCF.sub.3, ##STR240## --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 --CON.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 ##STR241## wherein Ar is a moiety selected from the group ##STR242## 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:
- ##STR243## 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:
- ##STR244## wherein cycloalky 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, ##STR245## --(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:
- ##STR246## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR247## wherein J is Ra, 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, -0-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:
- ##STR248## 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:
- ##STR249## 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 ##STR250## ##STR251## q is 1 or 2;
- R.sub.a and R.sub.b are as hereinbefore defined;
- wherein Ar' is selected from the group:
- ##STR252## 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 -C.sub.3);
- and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
30 more elements
A compound selected from the formulae:
- ##STR268## wherein R.sup.3 is the moiety:
- ##STR269## and Ar is the moiety ##STR270## R.sup.6 is selected from:
- (a) moieties of the formula:
- ##STR271## 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, ##STR272## --(CH.sub.2).sub.q --O-lower alkyl (C.sub.1 -C.sub.3), or --CH.sub.2 CH.sub.2 OH;
- q is 1 or 2;
- R.sub.b is independently selected from H, --CH.sub.3, and --C.sub.2 H.sub.5 ;
- or
- (b) a moiety of the formula:
- ##STR273## 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:
- ##STR274## 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 independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5 ;
- or
- (c) a moiety selected from those of the formulae:
- ##STR275## 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, ##STR276## q is 1 or 2;
- and R.sub.a and R.sub.b are as hereinbefore defined;
- wherein Ar' is selected from the group:
- ##STR277## wherein X is selected from O, S, NH, NCH.sub.3, or NCOCH.sub.3 ;
- R.sub.5 is H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy or halogen;
- R.sup.7 is selected from H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, halogen or CF.sub.3 ;
- R.sup.8 and R.sup.9 are independently selected from H, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, --S-lower alkyl (C.sub.1 -C.sub.3), halogen, --NH-lower alkyl (C.sub.1 -C.sub.3), --OCF.sub.3, --OH, --CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, --CF.sub.3, or ##STR278## R.sup.11 is selected from H, Halogen, (C.sub.1 -C.sub.3) lower alkyl, --OH, COCl, COCF.sub.3, CHO, (C.sub.1 -C.sub.3) lower alkoxy, ##STR279## q is 1 or 2;
- 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:
- ##STR280## R.sub.1 and R.sub.2 are independently selected from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.12 and R.sup.13 are independently selected from H, halogen, amino, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy, or (C.sub.1 -C.sub.3) lower alkylamino;
- W' is selected from O, S, --NH, --NH-lower alkyl (C.sub.1 -C.sub.3), --NHCO-lower alkyl (C.sub.1 -C.sub.3), --NSO.sub.2 -lower alkyl (C.sub.1 -C.sub.3);
- or a pharmaceutically acceptable salt, ester or pro-drug form thereof.
25 more elements
Dependencies are inferred from the claim text.