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US 5,843,952 AGranted
Tricyclic benzazepine vasopressin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay Donald Albright, Fuk-Wah Sum
Life of this patent
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Abstract
Tricyclic compounds of the general Formula I: ##STR1## as defined herein which exhibit antagonist activity at V.sub.1 and/or V.sub.2 receptors and exhibit in vivo vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and processes for preparing such compounds.
Claims28
A compound selected from Formula I:
- ##STR201## Formula I wherein;
- Y is a bond;
- A--B is ##STR202## wherein m is one:
- R.sub.1 is H, halogen (chlorine, fluorine, bromine, iodine), OH, --S-lower alkyl(C.sub.1 -C.sub.3), --SH, --SO lower alkyl(C.sub.1 -C.sub.3), --SO.sub.2 lower alkyl(C.sub.1 -C.sub.3), --CO lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3), --NO.sub.2, --NH.sub.2, --NHCO lower alkyl(C.sub.1 -C.sub.3), --N-lower alkyl( C.sub.1 -C.sub.3)!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH lower alkyl(C.sub.1 -C.sub.3), or --SO.sub.2 N lower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- R.sub.2 is H, Cl, Br, I, F, --OH, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR203## wherein Ar is a moiety selected from the group ##STR204## and X is selected from O, S, --NCH.sub.3, or --N--COCH.sub.3 ;
- R.sub.4 is seleoted 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), and the moieties of the formulae:
- ##STR205## R.sub.5 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, or --O--C.sub.2 H.sub.5 ;
- R.sub.6 is selected from:
- (a) moieties of the formula:
- ##STR206## wherein cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- R.sub.2 is as hereinbefore defined;
- n is 0-2;
- R.sub.7 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --OCH.sub.3, --OC.sub.2 H.sub.5, or --CF.sub.3 ;
- R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
- ##STR207## --(CH.sub.2).sub.2 --O-lower alkyl(C.sub.1 -C.sub.3) or --CH.sub.2 CH.sub.2 OH;
- q is one or two;
- R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- Ar' is selected from the group:
- ##STR208## wherein R.sub.4, R.sub.5 are as hereinbefore defined;
- R.sub.8 and R.sub.9 are independently hydrogen, lower alkyl(C.sub.1 -C.sub.3), O-lower alkyl(C.sub.1 -C.sub.3), S-lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH-lower alkyl(C.sub.1 -C.sub.3);
- R.sub.10 is selected from halogen, hydrogen, or lower alkyl(C.sub.1 -C.sub.3);
- W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3), --NCO-lower alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl(C.sub.1 -C.sub.3);
- and
- (b) a moiety of the formula:
- ##STR209## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR210## 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, tetrahydiofuran, tetrahydrothiophene, or --CH.sub.2 --K wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR211## 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:
- ##STR212## 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) or OH;
- R.sub.b is as hereinbefore defined;
- q is 1 or 2;
- wherein Ar' is selected from the group:
- ##STR213## R.sub.7 is hydrogen, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --OCH.sub.3, --OC.sub.2 H.sub.5, or --CF.sub.3 ;
- R.sub.8 and R.sub.9 are independently hydrogen, lower alkyl(C.sub.1 -C.sub.3), O-lower alkyl(C.sub.1 -C.sub.3), S-lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH-lower alkyl(C.sub.1 -C.sub.3);
- R.sub.10 is selected from the group of halogen, hydrogen, or lower alkyl(C.sub.1 -C.sub.3);
- W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3), --NCO-lower alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl(C.sub.1 -C.sub.3);
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
38 more elements
A compound selected from Formula I:
- ##STR218## Formula I wherein:
- Y is abond;
- A--B is ##STR219## R.sub.1 is H, halogen (chlorine, fluorine, bromine, iodine), OH, --S-lower alkyl (C.sub.1 -C.sub.3), --SH, --SO lower alkyl(C.sub.1 -C.sub.3), --SO.sub.2 lower alkyl(C.sub.1 -C.sub.3), --CO lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3), --NO.sub.2, --NH.sub.2, --NHCO lower alkyl(C.sub.1 -C.sub.3), --N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH lower alkyl(C.sub.1 -C.sub.3), or --SO.sub.2 N lower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- R.sub.2 is H, Cl, Br, I, F, --OH, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR220## wherein Ar is the moiety:
- ##STR221## R.sub.5 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, or --O--C.sub.2 H.sub.5 ;
- R.sub.6 is selected from moieties of the formulae:
- ##STR222## wherein:
- cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- n is 0-2;
- R.sub.7 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --OCH.sub.3, --OC.sub.2 H.sub.5, or --CF.sub.3 ;
- R.sub.a is hydrogen, CH.sub.3, or C.sub.2 H.sub.5 ;
- R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- Ar' is selected from the group of:
- ##STR223## wherein R.sub.5 is as hereinbefore defined;
- R.sub.8 and R.sub.9 are independently hydrogen, lower alkyl(C.sub.1 -C.sub.3), O-lower alkyl(C.sub.1 -C.sub.3), S-lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH-lower alkyl(C.sub.1 -C.sub.3);
- W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3), --NCO-lower alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl(C.sub.1 -C.sub.3);
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
17 more elements
A compound of the formula:
- ##STR224## wherein;
- Y is a bond;
- A--B is ##STR225## wherein m is one;
- R.sub.1 is H, halogen (Cl, F, Br, I), OH, --S-lower alkyl(C.sub.1 -C.sub.3), --SH, --SO lower alkyl(C.sub.1 -C.sub.3), --SO.sub.2 lower alkyl(C.sub.1 -C.sub.3), --CO lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3), --NO.sub.2, --NH.sub.2, --NHCO lower alkyl(C.sub.1 -C.sub.3), --N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH lower alkyl(C.sub.1 -C.sub.3), or --SO.sub.2 N lower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- R.sub.2 is selected fr om H, Cl, Br, I, F, --OH , lower alkyl(C.sub.1 -C.sub.3), or --O lower alkyl(C.sub.1 -C.sub.3);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR226## wherein Ar is a moiety selected from the group ##STR227## R.sub.5 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, or --O--C.sub.2 H.sub.5 ;
- R.sub.6 is selected from:
- ##STR228## wherein cycloalky is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- n is 0-2;
- and wherein Ar' is selected from the moieties:
- ##STR229## wherein R.sub.a and R.sub.b are independently selected from H, --CH.sub.3, or --C.sub.2 H.sub.5 ;
- R.sub.7 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, --O--C.sub.2 H.sub.5 or --CF.sub.3 ;
- R.sub.8 and R.sub.9 are independently selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3), O-lower alkyl(C.sub.1 -.sub.3), S-lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH-lower alkyl(C.sub.1 -C.sub.3);
- W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3), --NCO-lower alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl(C.sub.1 -C.sub.3);
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
14 more elements
A compound of the formula:
- ##STR230## wherein:
- A--B is ##STR231## R.sub.1 is H, halogen (Cl, F, Br, I), OH, --S-lower alkyl(C.sub.1 -C.sub.3), --SH, --SO lower alkyl(C.sub.1 -C.sub.3), --SO.sub.2 lower alkyl(C.sub.1 -C.sub.3), --CO lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, lower alkyl(C.sub.1 -C.sub.3), --O lower alkyl(C.sub.1 -C.sub.3), --NO.sub.2, --NH.sub.2, --NHCO lower alkyl(C.sub.1 -C.sub.3), --N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH lower alkyl(C.sub.1 -C.sub.3), or --SO.sub.2 N lower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- R.sub.2 is selected from H, Cl, Br, I, F, --OH, lower alkyl(C.sub.1 -C.sub.3), or --O lower alkyl(C.sub.1 -C.sub.3);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR232## wherein Ar is the moiety:
- ##STR233## R.sub.5 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, or --O--C.sub.2 H.sub.5 ;
- R.sub.6 is --NHCOAr';
- Ar' is selected from the moieties:
- ##STR234## R.sub.7 is H, --CH.sub.3, --C.sub.2 H.sub.5, Cl, Br, F, --O--CH.sub.3, --O--C.sub.2 H.sub.5 or --CF.sub.3 ;
- R.sub.8 and R.sub.9 are independently selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3), O-lower alkyl(C.sub.1 -C.sub.3), S-lower alkyl(C.sub.1 -C.sub.3), --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH-lower alkyl(C.sub.1 -C.sub.3);
- and
- W' is selected from O, S, NH, N-lower alkyl(C.sub.1 -C.sub.3), --NCO-lower alkyl(C.sub.1 -C.sub.3), or NSO.sub.2 -lower alkyl(C.sub.1 -C.sub.3);
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
11 more elements
Dependencies are inferred from the claim text.