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US 5,854,236 AGranted
Tricyclic benzazepine vasopressin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay Donald Albright, Xuemei Du
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.
Claims21
A compound selected from Formula I:
- ##STR181## wherein;
- Y is NH, NCOCH.sub.3, N-lower alkyl (C.sub.1 -C.sub.3);
- ##STR182## R.sub.1 is H, chlorine, fluorine, bromine, iodine, OH, --S--(C.sub.1 -C.sub.3) alkyl, --SH, --SO(C.sub.1 -C.sub.3) alkyl, --SO.sub.2 (C.sub.1 -C.sub.3) alkyl, --CO(C.sub.1 -C.sub.3)alkyl, --CF.sub.3, (C.sub.1 -C.sub.3) alkyl, --O (C.sub.1 -C.sub.3)alkyl, --NO.sub.2, --NH.sub.2, --NHCO(C.sub.1 -C.sub.3)alkyl, --N--(C.sub.1 -C.sub.3)alkyl!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH (C.sub.1 -C.sub.3)alkyl, or --SO.sub.2 N--(C.sub.1 -C.sub.3)alkyl!.sub.2 ;
- R.sub.2 is H, Cl, Br, I, F, --OH, (C.sub.1 -C.sub.3) alkyl, --O--(C.sub.1 -C.sub.3)alkyl);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR183## wherein Ar is a moiety selected from the group ##STR184## and X is selected from O, S, --NCH.sub.3, or --N--COCH.sub.3 ;
- R.sub.4 is selected from H, (C.sub.1 -C.sub.3) alkyl, --CO--(C.sub.1 -C.sub.3)alkyl, SO.sub.2 (C.sub.1 -C.sub.3)alkyl, and the moieties of the formulae:
- ##STR185## 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:
- ##STR186## 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:
- ##STR187## --(CH.sub.2).sub.2 --O--(C.sub.1 -C.sub.3)alkyl 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:
- ##STR188## wherein R.sub.4, R.sub.5 are as hereinbefore defined;
- R.sub.8 and R.sub.9 are independently hydrogen, (C.sub.1 -C.sub.3)alkyl, O--(C.sub.1 -C.sub.3) alkyl, S--(C.sub.1 -C.sub.3) alkyl, --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH--(C.sub.1 -C.sub.3)alkyl;
- R.sub.10 is selected from halogen, hydrogen, or (C.sub.1 -C.sub.3) alkyl;
- W' is selected from O, S, NH, N--(C.sub.1 -C.sub.3)alkyl, --NCO--(C.sub.1 -C.sub.3) alkyl, or NSO.sub.2 --(C.sub.1 -C.sub.3) alkyl;
- and
- (b) a moiety of the formula:
- ##STR189## where R.sub.2 is as hereinbefore defined;
- (c) a moiety of the formula:
- ##STR190## wherein J is R.sub.a, (C.sub.1 -C.sub.8)alkyl branched or unbranched, (C.sub.2 -C.sub.8) alkenyl branched or unbranched, --O--(C.sub.1 -C.sub.8) alkyl branched or unbranched, --O--(C.sub.2 -C.sub.8) alkenyl branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH.sub.2 --K wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR191## 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) alkyl, hydroxy, --CO--(C.sub.1 -C.sub.3)alkyl, CHO, (C.sub.1 -C.sub.3) alkoxy, or --CO.sub.2 --(C.sub.1 -C.sub.3) alkyl, and R.sub.a and R.sub.b are as hereinbefore defined;
- (d) a moiety selected from those of the formulae:
- ##STR192## wherein R.sub.c is selected from halogen, (C.sub.1 -C.sub.3) alkyl, --O--(C.sub.1 -C.sub.3) alkyl or OH;
- R.sub.b is as hereinbefore defined;
- q is 1 or 2;
- wherein Ar' is selected from the group:
- ##STR193## 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, (C.sub.1 -C.sub.3) alkyl, O--(C.sub.1 -C.sub.3) alkyl, S--(C.sub.1 -C.sub.3) alkyl, --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH--(C.sub.1 -C.sub.3) alkyl;
- R.sub.10 is selected from the group of halogen, hydrogen, or (C.sub.1 -C.sub.3) alkyl;
- W' is selected from O, S, NH, N--(C.sub.1 -C.sub.3) alkyl, --NCO--(C.sub.1 -C.sub.3) alkyl, or NSO.sub.2 --(C.sub.1 -C.sub.3) alkyl;
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
37 more elements
A compound of the formula:
- ##STR198## wherein;
- Y is NH, NCOCH.sub.3, N--(C.sub.1 -C.sub.3) alkyl;
- ##STR199## R.sub.1 is H, chlorine, fluorine, bromine, iodine, OH, --S--(C.sub.1 -C.sub.3) alkyl, --SH, --SO(C.sub.1 -C.sub.3) alkyl, --SO.sub.2 (C.sub.1 -C.sub.3) alkyl, --CO(C.sub.1 -C.sub.3)alkyl, --CF.sub.3, (C.sub.1 -C.sub.3) alkyl, --O (C.sub.1 -C.sub.3)alkyl, --NO.sub.2, --NH.sub.2, --NHCO(C.sub.1 -C.sub.3)alkyl, --N-(C.sub.1 -C.sub.3)alkyl!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH (C.sub.1 -C.sub.3)alkyl, or --SO.sub.2 N(C.sub.1 -C.sub.3)alkyl!.sub.2 ;
- R.sub.2 is H, Cl, Br, I, F, --OH, (C.sub.1 -C.sub.3) alkyl, --O--(C.sub.1 -C.sub.3)alkyl);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR200## wherein Ar is a moiety selected from the group ##STR201## 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:
- ##STR202## 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:
- ##STR203## 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, (C.sub.1 -C.sub.3) alkyl, O--(C.sub.1 -C.sub.3) alkyl, S--(C.sub.1 -C.sub.3) alkyl, --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH--(C.sub.1 -C.sub.3) alkyl;
- W' is selected from O, S, NH, N--(C.sub.1 -C.sub.3) alkyl, --NCO--(C.sub.1 -C.sub.3) alkyl, or NSO.sub.2 --(C.sub.1 -C.sub.3) alkyl;
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
13 more elements
A compound of the formula:
- ##STR204## wherein;
- Y is selected from:
- ##STR205## R.sub.1 is H, chlorine, fluorine, bromine, iodine, OH, --S--(C.sub.1 -C.sub.3) alkyl, --SH, --SO(C.sub.1 -C.sub.3) alkyl, --SO.sub.2 (C.sub.1 -C.sub.3) alkyl, --CO(C.sub.1 -C.sub.3)alkyl, --CF.sub.3, (C.sub.1 -C.sub.3) alkyl, --O (C.sub.1 -C.sub.3)alkyl, --NO.sub.2, --NH.sub.2, --NHCO(C.sub.1 -C.sub.3)alkyl, --N-(C.sub.1 -C.sub.3)alkyl!.sub.2, SO.sub.2 NH.sub.2, --SO.sub.2 NH (C.sub.1 -C.sub.3)alkyl, or --SO.sub.2 N (C.sub.1 -C.sub.3)alkyl!.sub.2 ;
- R.sub.2 is H, Cl, Br, I, F, --OH, (C.sub.1 -C.sub.3) alkyl, --O--(C.sub.1 -C.sub.3)alkyl);
- or
- R.sub.1 and R.sub.2 taken together are methylenedioxy or ethylenedioxy;
- R.sub.3 is the moiety ##STR206## wherein Ar is a moiety selected from the group ##STR207## 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:
- ##STR208## wherein cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- n is .sub.0-2;
- and wherein Ar' is selected from the moieties:
- ##STR209## 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, (C.sub.1 -C.sub.3) alkyl, O--(C.sub.1 -C.sub.3) alkyl, S--(C.sub.1 -C.sub.3)alkyl, --CF.sub.3, --CN, --OH, --SCF.sub.3, --OCF.sub.3, halogen, NO.sub.2, amino, or --NH--(C.sub.1 -C.sub.3) alkyl;
- W' is selected from O, S, NH, N--(C.sub.1 -C.sub.3) alkyl, --NCO--(C.sub.1 -C.sub.3) alkyl, or NSO.sub.2 --(C.sub.1 -C.sub.3) alkyl;
- or a pharmaceutically acceptable salt, ester or prodrug thereof.
13 more elements
Dependencies are inferred from the claim text.