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US 5,753,648 AGranted
Tricyclic benzazepine vasopressin antagonists
AssigneeAmerican Cyanamid Company
InventorsJay Donald Albright, Aranapakam M. Venkatesan, John P. Dusza, Fuk-Wah Sum
Life of this patent
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Abstract
Tricyclic compound 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 process for preparing such compounds.
Claims36
A compound selected from those of the formula:
- ##STR449## wherein Y is CH.sub.2 ;
- A--B is a moiety selected from ##STR450## and the moiety:
- ##STR451## represents phenyl or 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:
- ##STR452## is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen 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, ##STR453## --CHO, amino, (C.sub.1 -C.sub.3)lower alkoxy, (C.sub.1 -C.sub.3)lower alkylamino, CONH-lower alkyl(C.sub.1 -C.sub.3), and --CONlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- q is one or two;
- R.sub.b is independently selected from hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R.sub.e is H, lower alkyl(C.sub.1 -C.sub.3), hydroxyethyl, --CH.sub.2 CO.sub.2 R.sup.50, --CH.sub.2 C(CH.sub.2 OH).sub.3 ;
- R.sup.50 is H or lower alkyl(C.sub.1 -C.sub.4);
- R.sup.3 is a moiety of the formula:
- ##STR454## wherein Ar is a moiety selected from the group consisting of ##STR455## R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3);
- --CO-lower alkyl(C.sub.1 -C.sub.3);
- R.sup.1 is hydroxy;
- R.sup.2 is selected from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, hydroxy and halogen;
- R.sup.6 is selected from (a) moieties of the formula:
- ##STR456## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- R.sub.a is independently selected from hydrogen, --CH.sub.3, --C.sub.2 H.sub.5, ##STR457## --(CH.sub.2)q--O-lower alkyl(C.sub.1 -C.sub.3) or --CH.sub.2 CH.sub.2 OH;
- q is one or two;
- R.sub.1, R.sub.2 and R.sub.b are as hereinbefore defined;
- or
- (b) moieties of the formula:
- ##STR458## wherein R.sup.7 is lower alkyl(C.sub.3 -C.sub.8), lower alkenyl(C.sub.3 -C.sub.8), --(CH.sub.2).sub.p -cycloalkyl(C.sub.3 -C.sub.6), ##STR459## wherein p is one to five;
- X is selected from O, S, NH, NCH.sub.3 ;
- R.sup.1 and R.sup.2 are as hereinbefore defined;
- or
- (c) a moiety of the formula:
- ##STR460## wherein J is R.sub.a, lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched, O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, --O-lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:
- ##STR461## or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR462## 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, --CO.sub.2 -lower alkyl(C.sub.1 -C.sub.3), and R.sub.a and R.sub.b are as hereinbefore defined;
- or
- (d) a moiety of the formula:
- ##STR463## 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, ##STR464## and R.sub.a and R.sub.b are as hereinbefore defined wherein Ar' is selected from moieties of the formula:
- ##STR465## 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), and NSO.sub.2 lower alkyl(C.sub.1 -C.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), --N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, --OCF.sub.3, --OH, --CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, O-lower alkyl(C.sub.1 -C.sub.3), ##STR466## --N(R.sub.b)(CH.sub.2).sub.v N(R.sub.b).sub.2, and CF.sub.3 wherein v is one to three and;
- R.sup.10 is selected from hydrogen, halogen and lower alkyl(C.sub.1 -C.sub.3);
- R.sup.14 is selected from:
- --O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, ##STR467## --NH lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, ##STR468## q is 1 or 2;
- n is 0 or 1;
- R.sub.a is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R' is hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.45 is hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.20 is hydrogen, halogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, NH.sub.2, --NH(C.sub.1 -C.sub.3)lower alkyl, --N-(C.sub.1 -C.sub.3)lower alkyl!.sub.2, ##STR469## and the pharmaceutically acceptable salts thereof.
39 more elements
A compound selected from those of the formula:
- ##STR470## wherein Y is CH.sub.2 ;
- A--B is a moiety selected from ##STR471## and the moiety:
- ##STR472## represents phenyl or 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:
- ##STR473## is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from:
- ##STR474## q is one or two;
- R.sub.b is independently selected from hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R.sub.e is hydroxyethyl, --CH.sub.2 CO.sub.2 R.sup.50, or --CH.sub.2 C(CH.sub.2 OH).sub.3 ;
- R.sup.50 is H or lower alkyl(C.sub.1 -C.sub.4);
- R.sup.3 is a moiety of the formula:
- ##STR475## wherein Ar is a moiety selected from the group consisting of ##STR476## R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3);
- --CO-lower alkyl(C.sub.1 -C.sub.3);
- R.sup.1 and R.sup.2 are independently selected from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, hydroxy and halogen;
- R.sup.6 is selected from (a) moieties of the formula:
- ##STR477## ##STR478## lower alkyl (C.sub.3 -C.sub.8) straight or branched, ##STR479## lower alkyl (C.sub.3 -C.sub.8) straight or branched, ##STR480## lower alkyl (C.sub.1 -C.sub.8), ##STR481## lower alkenyl (C.sub.1 -C.sub.8), ##STR482## lower alkenyl(C.sub.3 -C.sub.8) straight or branched, or ##STR483## lower alkenyl (C.sub.3 -C.sub.8) straight or branched;
- wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
- R.sub.a is independently selected from hydrogen, --CH.sub.3, --C.sub.2 H.sub.5, ##STR484## --(CH.sub.2).sub.q --O-lower alkyl(C.sub.1 -C.sub.3) and --CH.sub.2 CH.sub.2 OH;
- q is one or two;
- R.sub.1, R.sub.2 and R.sub.b are as hereinbefore defined;
- or
- (b) moieties of the formula:
- ##STR485## wherein R.sup.7 is selected from lower alkyl(C.sub.3 -C.sub.8), lower alkenyl(C.sub.3 -C.sub.8), --(CH.sub.2).sub.p -cycloalkyl(C.sub.3 -C.sub.6), ##STR486## wherein p is one to five;
- X is selected from O, S, NH, NCH.sub.3 ;
- R.sup.1 and R.sup.2 are as hereinbefore defined;
- or
- (c) a moiety of the formula:
- ##STR487## wherein J is R.sub.a, lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched, O-lower alkyl(C.sub.3 -C.sub.8) branched or unbranched, --O-lower alkenyl(C.sub.3 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:
- ##STR488## or --CH.sub.2 --K' wherein K' is (C.sub.1 -C.sub.3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
- ##STR489## 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, --CO.sub.2 -lower alkyl(C.sub.1 -C.sub.3), and R.sub.a and R.sub.b are as hereinbefore defined;
- or
- (d) a moiety of the formula:
- ##STR490## 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, ##STR491## and R.sub.a and R.sub.b are as hereinbefore defined wherein Ar' is selected from moieties of the formula:
- ##STR492## 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), and NSO.sub.2 lower alkyl(C.sub.1 -C.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), --N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, --OCF.sub.3, --OH, --CN, --S--CF.sub.3, --NO.sub.2, --NH.sub.2, O-lower alkyl(C.sub.1 -C.sub.3), ##STR493## --N(R.sub.b)(CH.sub.2).sub.v N(R.sub.b).sub.2, and CF.sub.3 wherein v is one to three and;
- R.sup.10 is selected from hydrogen, halogen and lower alkyl(C.sub.1 -C.sub.3);
- R.sup.14 is ##STR494## q is 1 or 2;
- n is 0 or 1;
- R.sub.a is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R'.sbsp.hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.45 is hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.20 is hydrogen, halogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, NH.sub.2, --NH(C.sub.1 -C.sub.3)lower alkyl, --N-(C.sub.1 -C.sub.3)lower alkyl!.sub.2, ##STR495## ##STR496## and the pharmaceutically acceptable salts forms thereof.
38 more elements
A compound selected from those of the formula:
- ##STR497## wherein Y is CH.sub.2 ;
- A--B is a moiety selected from ##STR498## and the moiety:
- ##STR499## represents phenyl or 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:
- ##STR500## is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen 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, ##STR501## --CHO, amino, (C.sub.1 -C.sub.3)lower alkoxy, (C.sub.1 -C.sub.3)lower alkylamino, CONH-lower alkyl(C.sub.1 -C.sub.3), and --CONlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
- q is one or two;
- R.sub.b is independently selected from hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R.sub.e is selected from H, lower alkyl (C.sub.1 -C.sub.4), hydroxyethyl, --CH.sub.2 CO.sub.2 R.sup.50 or --CH.sub.2 C(CH.sub.2 OH).sub.3 ;
- R.sup.50 is H or lower alkyl(C.sub.1 -C.sub.4);
- R.sup.3 is a moiety of the formula:
- ##STR502## wherein Ar is the moiety:
- ##STR503## R.sup.4 is selected from hydrogen, lower alkyl(C.sub.1 -C.sub.3);
- --CO-lower alkyl(C.sub.1 -C.sub.3);
- R.sup.1 and R.sup.2 are independently selected from hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, hydroxy and halogen;
- R.sup.14 is selected from:
- ##STR504## q is 1 or 2;
- n is 0 or 1;
- R.sub.a is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
- R' is hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.45 is hydrogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy and halogen;
- R.sup.20 is hydrogen, halogen, (C.sub.1 -C.sub.3)lower alkyl, (C.sub.1 -C.sub.3)lower alkoxy, NH.sub.2, --NH(C.sub.1 -C.sub.3)lower alkyl, --N-(C.sub.1 -C.sub.3)lower alkyl!.sub.2, ##STR505## --NH--(CH.sub.2).sub.p --NHlower alkyl(C.sub.1 -C.sub.3), --NH--(CH.sub.2).sub.p --Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2, ##STR506## and the pharmaceutically acceptable salts forms thereof.
18 more elements
Dependencies are inferred from the claim text.