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US 5,747,487 AGranted
Tricyclic benzazepine vasopressin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay Donald Albright, Marvin Fred Reich
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 viva vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and processes for preparing such compounds.
Claims77
A compound selected from Formula I:
- ##STR167## wherein;
- Y is a bond;
- A-B is ##STR168## 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 ##STR169## wherein Ar is a moiety selected from the group ##STR170## and X is selected from O, S, --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:
- ##STR171## 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:
- ##STR172## 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, --CH.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:
- ##STR173## --(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:
- ##STR174## 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);
- or
- (b) a moiety of the formula:
- ##STR175## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR176## 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, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR177## 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:
- ##STR178## 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:
- ##STR179## 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);
- the moiety ##STR180## represents a fused thiazole ring or fused substituted thiazole ring optionally substituted by one or two substituents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen, formyl, (C.sub.1 -C.sub.3) lower alkoxy or a moiety of the formula:
- ##STR181## q is one or two;
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
39 more elements
A compound of the formula:
- ##STR186## wherein;
- Y is a bond;
- A-B is ##STR187## 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 ##STR188## wherein Ar is a moiety selected from the group ##STR189## 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:
- ##STR190## wherein cycloalkyl 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:
- ##STR191## 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 -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);
- the moiety ##STR192## represents a fused thiazole ring or fused substituted thiazole ring optionally substituted by one or two substituents selected from (C.sub.1 -C.sub.3) lower alkyl, halogen, formyl, (C.sub.1 -C.sub.3) lower alkoxy or a moiety of the formula:
- ##STR193## q is one or two;
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
15 more elements
Dependencies are inferred from the claim text.