US 4,735,941 AGranted

1,4-benzodiazepines with 5- and 6-membered heterocyclic rings, useful as gastrointestinal and CNS agents

AssigneeMerck & Co., Inc.

InventorsRoger M. Freidinger, Mark G. Bock, Ben E. Evans

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Abstract

Aromatic 1,4-benxodiazepines with fused 5- or 6-membered heterocyclic rings which are antagonists of cholecystokinins and/or gastrin, and are useful in the treatment or prevention of CCK-related and/or gastrin-related disorders of the gastrointestinal, central nervous and appetite regulatory systems; compositions comprising these compounds; and methods of treatment employing these compounds.

Claims15

Dependent claims

A compound of the formula:

##STR30## wherein R.sup.1 is H, or C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
R.sup.2 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, mono- or disubstituted or unsubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, carboxyl, carboxyl-C.sub.1 -C.sub.4 -alkyl, nitro, --CF.sub.3, ##STR31## and hydroxy, 2-, 3-, or 4-pyridyl, or --(CH.sub.2).sub.m COOR.sup.6 ;
R.sup.3 is ##STR32## R.sup.4 and R.sup.5 are independently H, C.sub.1 -C.sub.4 -straight- or branched-chain-alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, or are connected to nitrogen to form a hetero ring of the form ##STR33## where k is 2 to 6;
R.sup.6 is H, C.sub.1 -C.sub.4 -straight or branched-chain alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, unsubstituted or mono- or disubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, nitro, and CF.sub.3, or unsubstituted or mono- or disubstituted phenyl-C.sub.1 -C.sub.4 -straight or branched-chain alkyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, nitro, and CF.sub.3 ;
R.sup.7 is .alpha.- or .beta.-naphthyl, unsubstituted or mono- or disubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, --NO.sub.2, --OH, --NR.sup.4 R.sup.5, ##STR34## as defined above, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, cyano, phenyl, trifluoromethyl, acetylamino, acetyloxy, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, SCF.sub.3, C.tbd.CH, CH.sub.2 SCF.sub.3, OCHF.sub.2, S-phenyl, and C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, ##STR35## R.sup.8 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, --(CH.sub.2).sub.n -cyclo-C.sub.3 -C.sub.7 -alkyl, ##STR36## or branched-chain alkyl, or ##STR37## R.sup.10 is H, --OH, or --CH.sub.3 ;
R.sup.11 and R.sup.12 are independently C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or cyclo-C.sub.3 -C.sub.7 -alkyl;
R.sup.14 is C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or phenyl-C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
R.sup.18 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or formyl, acetyl, propionyl or butyryl;
m is 1-to-4;
n is 0-to-4;
q is 0-to-4;
r is 1 or 2;
X.sup.1 is H, --NO.sub.2, CF.sub.3, CN, OH, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, halo, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, --(CH.sub.2).sub.n COOR.sup.6, --NR.sup.4 R.sup.5, or ##STR38## X.sup.2 and X.sup.3 are independently H, --OH, --NO.sub.2, halo, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, or ##STR39## X.sup.4 is S, O, CH.sub.2, or NR.sup.8 ;
X.sup.6 is O;
X.sub.8 is H or C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
X.sup.9 and X.sub.a.sup.9 are independently NR.sup.18 or O;
Y=CH.sub.2 or NR.sup.1 ;
and
Z=N or CH.sub.2,
or a pharmaceutically-acceptable salt thereof.

17 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

##STR30## wherein R.sup.1 is H, or C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
R.sup.2 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, mono- or disubstituted or unsubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkylthio, carboxyl, carboxyl-C.sub.1 -C.sub.4 -alkyl, nitro, --CF.sub.3, ##STR31## and hydroxy, 2-, 3-, or 4-pyridyl, or --(CH.sub.2).sub.m COOR.sup.6 ;
R.sup.3 is ##STR32## R.sup.4 and R.sup.5 are independently H, C.sub.1 -C.sub.4 -straight- or branched-chain-alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, or are connected to nitrogen to form a hetero ring of the form ##STR33## where k is 2 to 6;
R.sup.6 is H, C.sub.1 -C.sub.4 -straight or branched-chain alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, unsubstituted or mono- or disubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, nitro, and CF.sub.3, or unsubstituted or mono- or disubstituted phenyl-C.sub.1 -C.sub.4 -straight or branched-chain alkyl, where the substituent(s) is/are independently selected from the group consisting of halo, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, nitro, and CF.sub.3 ;
R.sup.7 is .alpha.- or .beta.-naphthyl, unsubstituted or mono- or disubstituted phenyl, where the substituent(s) is/are independently selected from the group consisting of halo, --NO.sub.2, --OH, --NR.sup.4 R.sup.5, ##STR34## as defined above, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, cyano, phenyl, trifluoromethyl, acetylamino, acetyloxy, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, SCF.sub.3, C.tbd.CH, CH.sub.2 SCF.sub.3, OCHF.sub.2, S-phenyl, and C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, ##STR35## R.sup.8 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, cyclo-C.sub.3 -C.sub.7 -alkyl, --(CH.sub.2).sub.n -cyclo-C.sub.3 -C.sub.7 -alkyl, ##STR36## or branched-chain alkyl, or ##STR37## R.sup.10 is H, --OH, or --CH.sub.3 ;
R.sup.11 and R.sup.12 are independently C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or cyclo-C.sub.3 -C.sub.7 -alkyl;
R.sup.14 is C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or phenyl-C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
R.sup.18 is H, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl or formyl, acetyl, propionyl or butyryl;
m is 1-to-4;
n is 0-to-4;
q is 0-to-4;
r is 1 or 2;
X.sup.1 is H, --NO.sub.2, CF.sub.3, CN, OH, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, halo, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, --(CH.sub.2).sub.n COOR.sup.6, --NR.sup.4 R.sup.5, or ##STR38## X.sup.2 and X.sup.3 are independently H, --OH, --NO.sub.2, halo, C.sub.1 -C.sub.4 -straight- or branched-chain alkylthio, C.sub.1 -C.sub.4 -straight- or branched-chain alkyl, C.sub.1 -C.sub.4 -straight- or branched-chain alkoxy, or ##STR39## X.sup.4 is S, O, CH.sub.2, or NR.sup.8 ;
X.sup.6 is O;
X.sub.8 is H or C.sub.1 -C.sub.4 -straight- or branched-chain alkyl;
X.sup.9 and X.sub.a.sup.9 are independently NR.sup.18 or O;
Y=CH.sub.2 or NR.sup.1 ;
and
Z=N or CH.sub.2,
or a pharmaceutically-acceptable salt thereof.

17 more elements