US 5,618,812 AGranted

Benzodiazepine derivatives

AssigneeMerck Sharp & Dohme Corp.

InventorsJose L. Castro Pineiro, William R. Carling, Mark S. Chambers, Stephen R. Fletcher, Sarah C. Hobbs, Victor G. Matassa, Kevin W. Moore, Graham A. Showell, Michael G. Russell

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Abstract

Compounds of Formula (I), and salts and prodrugs thereof, wherein R.sup.1 represents H, optionally substituted C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl; R.sup.2 is NHR.sup.12 or (CH.sub.2).sub.s R.sup.13 where 5 is 0, 1 or 2; R.sup.3 represents C.sub.1-6 alkyl, halo or NR.sup.6 R.sup.7 ; R.sup.4 and R.sup.5 are H, C.sub.1-12 alkyl optionally substituted by NR.sup.9 R.sup.9' or an azacyclic or azabicyclic group, optionally substituted C.sub.4-9 cycloalkyl, C.sub.4-9 cycloalkyl C.sub.1-4 alkyl, aryl, arylC.sub.1-6 alkyl or azacyclic or azabicyclic groups, or R.sup.4 and R.sup.5 together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0, 1, 2 or 3; R.sup.12 is optionally substituted phenyl or pyridyl; R.sup.13 represents a group (A) wherein R.sup.14 is H or C.sub.1-6 alkyl; R.sup.15 is H, C.sub.1-6 alkyl, halo or NR.sup.6 R.sup.7 ; and the dotted line is an optional covalent bond; are CCK and/or gastrin antagonists useful in therapy. ##STR1##

Claims18

Dependent claims

A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:

##STR28## wherein:
R.sup.1 represents C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, cyclopropylmethyl, CH.sub.2 CO.sub.2 R.sup.11 (wherein R.sup.11 is C.sub.1-4 alkyl) or a group CH.sub.2 CONR.sup.6 R.sup.7 (where R.sup.6 and R.sup.7 each independently represents H or C.sub.1-4 alkyl, or R.sup.6 and R.sup.7 together from a chain (CH.sub.2)p where p is 4 or 5);
R.sup.2 represents NHR.sup.12 ;
R.sup.12 represents a phenyl group optionally substituted by one or more substituents selected from C.sub.1-6 alkyl, halo, hydroxy, (CH.sub.2).sub.q -tetrazolyl optionally substituted in the tetrazole ring by C.sub.1-4 alkyl, (CH.sub.2)q-imidazolyl, (CH.sub.2)q-triazolyl (where q is 0, 1, 2 or 3), 5-hydroxy-4-pyrone, NR.sup.6 R.sup.7, NR.sup.9 COR.sup.11, NR.sup.9 CONR.sup.9 'R.sup.11 (where R.sup.9 and R.sup.9 ' are each independently H or C.sub.1-4 alkyl and R.sup.11 is as previously defined), CONR.sup.6 R.sup.7 (where R.sup.6 and R.sup.7 are as previously defined), SO(C.sub.1-6 alkyl), SO.sub.2 (C.sub.1-6 alkyl), trifluoromethyl, CONHSO.sub.2 R.sup.8, SO.sub.2 NHCOR.sup.8 (where R.sup.8 is C.sub.1-6 alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl), SO.sub.2 NHR.sup.10 (where R.sup.10 is a nitrogen containing heterocycle), B(OH).sub.2, (CH.sub.2).sub.t CO.sub.2 H, where t is zero, 1 or 2;
or
R.sup.12 represents a group ##STR29## where W represents CH.sub.2 or NR.sup.9, where R.sup.9 is as previously defined and W.sup.1 represents CH.sub.2, or W and W.sup.1 both represent oxygen;
R.sup.3 represents C.sub.1-6 alkyl, halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are as previously defined;
x is 0, 1, 2, or 3
and NR.sup.4 R.sup.5 represents a group ##STR30## wherein each R.sup.16 independently represents C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, oxo, SR.sup.11, NR.sup.6 R.sup.7, NR.sup.9 C.sub.1-4 alkylR.sup.17, =NOR.sup.9 or ##STR31## where R.sup.11, R.sup.6, R.sup.7 and R.sup.9 are as previously defined, R.sup.17 is halo or trifluoromethyl, and d is 2 or 3;
v is 1, 2, 3, 4, 5, 6, 7 or 8;
and w is 4, 5, 6, 7, 8, 9, 10 or 11.

8 more elements

A compound of formula (I), or a salt or prodrug thereof:

##STR34## wherein:
R.sup.1 represents H, C.sub.1-6 alkyl, C.sub.3-7 cloalkyl, cyclopropylmethyl, (CH.sub.2).sub.r imidazolyl, (CH.sub.2).sub.r triazolyl, (CH.sub.2)tetrazolyl (where r is 1, 2 or 3), CH.sub.2 CO.sub.2 R.sup.11 (where R.sup.11 is C.sub.1-4 alkyl) or a group CH.sub.2 CONR.sup.6 R.sup.7 (where R.sup.6 and R.sup.7 each independently represents H or C.sub.1-4 alkyl, or R.sup.6 and R.sup.7 together form a chain (CH.sub.2).sub.p where p is 4 or 5);
R.sup.2 represents NHR.sup.12 ;
R.sup.12 represents a phenyl group optionally substituted by one or more substituents selected from C.sub.1-6 alkyl, halo, hydroxy, C.sub.1-4 alkoxy, (CH.sub.2).sub.q -tetrazolyl optionally substituted in the tetrazole ring by C.sub.1-4 alkyl, (CH.sub.2).sub.q -imidazolyl, (CH.sub.2).sub.q -triazolyl (where q is 0, 1, 2 or 3), 5-hydroxy-4-pyrone, NR.sup.6 R.sup.7, NR.sup.9 COR.sup.11, NR.sup.9 CONR.sup.9 'R.sup.11 (where R.sup.9 and R.sup.9 ' are each independently H or C.sub.1-4 alkyl and R.sup.11 is as previously defined), CONR.sup.6 R.sup.7 (where R.sup.6 and R.sup.7 are as previously defined), SO(C.sub.1-6 alkyl), SO.sub.2 (C.sub.1-6 alkyl), trifluoromethyl, CONHSO.sub.2 R.sup.8, SO.sub.2 NHCOR.sup.8 (where R.sup.8 is C.sub.1-6 alkyl, optionally substituted aryl, 2,2-difluorocyclopropane or trifluoromethyl), SO.sub.2 NHR.sup.10 (where R.sup.10 is a nitrogen containing heterocycle), B(OH).sub.2, (CH.sub.2).sub.q CO.sub.2 H, where q is as previously defined;
or
R.sup.12 represents a group ##STR35## where W represents CH.sub.2 or NR.sup.9, and R.sup.9 is as previously defined, and W.sup.1 represents CH.sub.2, or W and W.sup.1 each represent oxygen;
R.sup.3 represents C.sub.1-6 alkyl, halo or NR.sup.6 R.sup.7, where R.sup.6 and R.sup.7 are as previously defined;
R.sup.4 and R.sup.5 together with the nitrogen to which they are attached form a residue of a bridged azabicyclic system;
x is 0, 1, 2 or 3.

6 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/374,748Filed 26 Jan 1995
Priority: GB 921612329 Jul 1992
Granted: 8 Apr 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals