US 5,849,735 AGranted

Tricyclic benzazepine vasopressin antagonists

AssigneeAmerican Cyanamid Company

InventorsJay D. Albright, Aranapakam M. Venkatesan, Efren G. Delos Santos

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.

Claims40

Dependent claims

A compound selected from those of Formula I:

##STR71## wherein Y is selected from NH, NCOCH.sub.3, or N-lower alkyl (C.sub.1 -C.sub.3);
A--B is selected from ##STR72## R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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 ##STR73## wherein Ar is a moiety selected from the group:
##STR74## and X is O, S, --NCH.sub.3 or --NH, --NCH.sub.3, ##STR75## or a chemical bond;
R.sub.5 and R.sub.7 are selected from the group of hydrogen, (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:
##STR76## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
n is an integer from 0 to 2;
Ar' is selected from the group:
##STR77## R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR78## --(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, two or three;
R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower all (C.sub.1 -C.sub.3);
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
or
(b) a moiety of the formula:
--X--R.sub.10
wherein
X is O, S, NH, NCH.sub.3, ##STR79## or a chemical bond;
R.sub.10 is, lower alkenyl(C.sub.3 -C.sub.8), --(CH.sub.2)p-cycloalkyl(C.sub.3 -C.sub.6), ##STR80## and p is zero to three;
and R.sub.5 and R.sub.7 are as previously defined;
or
(c) a moiety of the formula:
##STR81## 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, tetahydrothiophene, the moieties ##STR82## or --CH.sub.2 --K', wherein K' is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR83## 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),
R.sub.8 is 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, --NH-lower alkyl(C.sub.1 -C.sub.3);
--N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
R.sub.a and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR84## 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) and OH;
Ra and Rb are as hereinbefore defined;
q and Ar' are as defined above;
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, --NH-lower alkyl(C.sub.1 -C.sub.3);
--N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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);
R.sub.25 is selected from the moieties ##STR85## the moiety:
##STR86## represents:
(1) 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;
(2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S;
(3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom;
(4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms;
(5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom;
wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C.sub.1 -C.sub.3)lower alkyl, formyl, a moiety of the formula:
##STR87## halogen or (C.sub.1 -C.sub.3)lower alkoxy;
wherein q and R.sub.b are as hereinbefore defined;
and the pharmaceutically acceptable salts thereof.

46 more elements

A compound selected from Formula I:

##STR100## wherein;
Y is selected from NH or ##STR101## A--B is ##STR102## R.sub.1 is H, halogen (chlorine, fluorine, bromine, iodine), OH, --S-lower alkyl (C.sub.1 -C.sub.3), --SH, --SO-lower allyl (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), --CHF.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 allyl (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 ##STR103## wherein Ar is a moiety selected from the group ##STR104## R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
R.sub.6 is selected from:
(a) the moieties of the formulae:
##STR105## wherein n is 0-2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR106## --(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, two or three;
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
Ar' is selected from the group:
##STR107## R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower alkyl (C.sub.1 -C.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, --NH-lower alkyl (C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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);
(b) a moiety of the formula:
--X--R.sub.10
wherein:
X is a bond, O, S, NH, ##STR108## R.sub.10 is selected from the group of 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), ##STR109## p is an integer from 0 to 3;
R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
(c) a moiety of the formula:
##STR110## 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, the moieties:
##STR111## or --CH.sub.2 --K' wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR112## 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);
R.sub.8, Ra and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR113## 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.a, R.sub.b, q, Ar', R.sub.4, R.sub.8, R.sub.9 and W' are as described above;
R.sub.25 is selected from the moieties:
##STR114## or a pharmaceutically acceptable salt thereof.

31 more elements

A compound selected from those of Formula I:

##STR115## wherein:
Y is selected from NH, NCOCH.sub.3, or N-lower alkyl (C.sub.1 -C.sub.3);
R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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;
Ar is selected from the moieties:
##STR116## R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
R.sub.6 is selected from:
(a) the moieties of the formulae:
##STR117## wherein n is 0-2,
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR118## --(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, two or three;
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
Ar' is selected from the group:
##STR119## R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower alkyl (C.sub.1 -C.sub.3);
R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 --C.sub.3), or halogen;
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, --NH-lower alkyl (C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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 allyl (C.sub.1 -C.sub.3);
or
(b) a moiety of the formula:
--X--R.sub.10
wherein:
X is a bond, O, S, NH, NCH.sub.3, or ##STR120## R.sub.10 is selected from the group of 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), ##STR121## p is an integer from 0 to 3;
R.sub.5 and R.sub.7 are as defined above;
or
(c) a moiety of the formula:
##STR122## 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, the moieties:
##STR123## or --CH.sub.2 --K' wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR124## 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);
R.sub.8, R.sub.a and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR125## 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, q, Ar', R.sub.4, R.sub.8, R.sub.9 and W' are as defined above;
R.sub.25 is selected from the moieties:
##STR126## or a pharmaceutically acceptable salt thereof.

34 more elements

A compound selected from those of Formula I:

##STR127## wherein:
Y is selected from NH or N-lower alkyl (C.sub.1 -C.sub.3);
R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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:
##STR128## Ar is selected from the moieties:
##STR129## R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
R.sub.6 is selected from
(a) the moieties of the formulae:
##STR130## wherein n is 0-2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR131## --(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, two or three;
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
Ar' is selected from the group;
##STR132## R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower alkyl (C.sub.1 -C.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, --NH-lower alkyl (C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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:
--X--R.sub.10
wherein:
X is a bond, O, S, NH, ##STR133## R.sub.10 is selected from the group of lower alkyl (C.sub.3 -C.sub.8), lower alkenyl (C.sub.3 -C.sub.8), --(CH.sub.2)-cycloalkyl (C.sub.3 -C.sub.6), ##STR134## p is an integer from 0 to 3;
R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
or
(c) a moiety of the formula:
##STR135## 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, the moieties:
##STR136## or --CH.sub.2 --K' wherein K is halogen, --OH, tetrahydrofuran, tehydrothiophene or the heterocyclic ring moiety:
##STR137## 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);
R.sub.8, R.sub.a and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR138## 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, q, Ar', R.sub.4, R.sub.8, R.sub.9 and W' are as defined above;
R.sub.25 is selected from the moieties:
##STR139## or a pharmaceutically acceptable salt thereof.

34 more elements

A compound selected from those of Formula I:

##STR140## wherein:
Y is selected from NH;
R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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;
Ar is selected from the moieties:
##STR141## R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
R.sub.6 is selected from
(a) the moieties of the formulae:
##STR142## wherein n is 0--2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR143## --(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, two or three;
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
Ar' is selected from the group:
##STR144## R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower alkyl (C.sub.1 -C.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, --NH-lower alkyl (C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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:
--X--R.sub.10
wherein:
X is a bond, O, S, NH, ##STR145## R.sub.10 is selected from the group of 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), ##STR146## p is an integer from 0 to 3;
R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
or
(c) a moiety of the formula:
##STR147## 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 allyl (C.sub.1 -C.sub.8) branched or unbranched, --O-lower alkenyl (C.sub.2 -C.sub.8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:
##STR148## or --CH.sub.2 --K' wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR149## 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);
R.sub.8, R.sub.a and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR150## 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, q, Ar', R.sub.4, R.sub.8, R.sub.9, and W' are as defined above;
R.sub.25 is selected from the moieties:
##STR151## or a pharmaceutically acceptable salt thereof.

33 more elements

A compound selected from those of Formula I:

##STR152## wherein:
Y is selected from NH or N-lower alkyl (C.sub.1 -C.sub.3);
R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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:
##STR153## Ar is selected from the moieties:
##STR154## R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
R.sub.25 is selected from the moieties:
##STR155## R.sub.6 is selected from:
(a) the moieties of the formulae:
##STR156## wherein n is 0-2;
cycloalkyl is defined as C.sub.3 -C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR157## --(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, two or three;
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
Ar' is selected from the group:
##STR158## R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower alkyl (C.sub.1 -C.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, --NH-lower alkyl (C.sub.1 -C.sub.3), --N-lower alkyl (C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(N.sub.b).sub.2 ;
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:
--X--R.sub.10
wherein:
X is a bond, O, S, NH, ##STR159## R.sub.10 is selected from the group of 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), ##STR160## p is an integer from 0 to 3;
R.sub.5 and R.sub.7 are independently selected from H, lower alkyl (C.sub.1 -C.sub.3), lower alkoxy (C.sub.1 -C.sub.3), or halogen;
(c) a moiety of the formula:
##STR161## 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, the moieties:
##STR162## or --CH.sub.2 --K' wherein K is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR163## 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;
or
(d) a moiety selected from those of the formulae:
##STR164## 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, Ar', R.sub.4, R.sub.8, R.sub.9 and W' are as described above;
or a pharmaceutically acceptable salt thereof.

33 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/548,805Filed 22 Dec 1995 · continuation in part
Priority: 17 Jan 1995
Granted: 15 Dec 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 223/20
Dibenzazepines; Hydrogenated dibenzazepines: dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
C07D 223/28
With hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom: having a single bond between positions 10 and 11
C07D 243/38
Condensed with carbocyclic rings or ring systems: [b, e]- or [b, f]-condensed with six-membered rings

Family

Serial373,169Parent of this continuation-in-part · filed 17 Jan 1995
US 5,849,735 AThis patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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Abstract

A compound selected from those of Formula I:

##STR71## wherein Y is selected from NH, NCOCH.sub.3, or N-lower alkyl (C.sub.1 -C.sub.3);
A--B is selected from ##STR72## R.sub.1 is hydrogen, halogen (--Cl, --Br, --F, --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 Nlower alkyl(C.sub.1 -C.sub.3)!.sub.2 ;
R.sub.2 is hydrogen, --Cl, --Br, --F, --I, --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 ##STR73## wherein Ar is a moiety selected from the group:
##STR74## and X is O, S, --NCH.sub.3 or --NH, --NCH.sub.3, ##STR75## or a chemical bond;
R.sub.5 and R.sub.7 are selected from the group of hydrogen, (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:
##STR76## wherein cycloalkyl is defined as C.sub.3 to C.sub.6 cycloalkyl, cyclohexenyl or cyclopentenyl;
n is an integer from 0 to 2;
Ar' is selected from the group:
##STR77## R.sub.a is hydrogen, CH.sub.3, C.sub.2 H.sub.5, moieties of the formulae:
##STR78## --(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, two or three;
R.sub.4 is selected from H, lower alkyl (C.sub.1 -C.sub.3), or --CO-lower all (C.sub.1 -C.sub.3);
R.sub.b is hydrogen, --CH.sub.3 or --C.sub.2 H.sub.5 ;
or
(b) a moiety of the formula:
--X--R.sub.10
wherein
X is O, S, NH, NCH.sub.3, ##STR79## or a chemical bond;
R.sub.10 is, lower alkenyl(C.sub.3 -C.sub.8), --(CH.sub.2)p-cycloalkyl(C.sub.3 -C.sub.6), ##STR80## and p is zero to three;
and R.sub.5 and R.sub.7 are as previously defined;
or
(c) a moiety of the formula:
##STR81## 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, tetahydrothiophene, the moieties ##STR82## or --CH.sub.2 --K', wherein K' is halogen, --OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:
##STR83## 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),
R.sub.8 is 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, --NH-lower alkyl(C.sub.1 -C.sub.3);
--N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
R.sub.a and R.sub.b are as hereinbefore defined;
or
(d) a moiety selected from those of the formulae:
##STR84## 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) and OH;
Ra and Rb are as hereinbefore defined;
q and Ar' are as defined above;
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, --NH-lower alkyl(C.sub.1 -C.sub.3);
--N-lower alkyl(C.sub.1 -C.sub.3)!.sub.2, or --N(R.sub.b)(CH.sub.2).sub.q --N(R.sub.b).sub.2 ;
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);
R.sub.25 is selected from the moieties ##STR85## the moiety:
##STR86## represents:
(1) 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;
(2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S;
(3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom;
(4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms;
(5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom;
wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C.sub.1 -C.sub.3)lower alkyl, formyl, a moiety of the formula:
##STR87## halogen or (C.sub.1 -C.sub.3)lower alkoxy;
wherein q and R.sub.b are as hereinbefore defined;
and the pharmaceutically acceptable salts thereof.

46 more elements

Facts

Application

08/548,805Filed 22 Dec 1995 · continuation in part

Priority

17 Jan 1995

Granted

15 Dec 1998

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
C07D 223/20
Dibenzazepines; Hydrogenated dibenzazepines: dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
C07D 223/28
With hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom: having a single bond between positions 10 and 11
C07D 243/38
Condensed with carbocyclic rings or ring systems: [b, e]- or [b, f]-condensed with six-membered rings