US4755508A
Expired / Lapsed
US
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Benzodiazepine analogs and use as antogonists of gastrin and cholecystokinin
Assignee: Merck and Co Inc
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Filing: 1987-02-27
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Granted: 1988-07-05
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Expires: 2007-02-27
Abstract
Abstract Benzodiazepines of the formula: ##STR1## are disclosed which are antagonists of gastrin and cholecystokinin (CCK).
Inventors
- 👤 Mark G. Bock
- 👤 Ben E. Evans
- 👤 Roger M. Freidinger
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 05:03
CPC Classifications
C; C07; C07D; C07D403/00; C07D403/02; C07D403/06; A; A61; A61P; A61P1/00; A61P25/00; C07D243/00; C07D243/06; C07D243/10; C07D243/14; C07D243/16; C07D243/18; C07D243/20; C07D403/12
Claims Analysis
Total Claims: 10
Claim 1
Independent Claim
458 words
A compound of Formula I: ##STR69## wherein R 1 is --NR 16 R 17 ,; R 2 is H, loweralkyl, substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, --CF 3 , or hydroxy), 2-, 3-, 4-pyridyl, ##STR70## R 3 is ##STR71## R 4 and R 5 are independently R 6 or in combination with the N of the NR 4 R 5 group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring, or benzofused 4-7 membered heterocyclic ring or said heterocyclic ring or said benzofused heterocyclic ring which further comprises a second heteroatom selected from O and NCH 3 and the substituent(s) is/are independently selected from C 1-4 alkyl; R 6 is H, loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylloweralkyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF 3 ); R 7 is a α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents are 1 to 2 of halo, --NO 2 , --OH, --X 11 --NR 4 R 5 , loweralkyl, loweralkoxy, CF 3 , loweralkylthio, cyano, phenyl, acetylamino, acetoxy, SCF 3 , C.tbd.CH, CH 2 SCF 3 , OCHF 2 , SH or thio-phenyl) 2-, 3-, 4-pyridyl, ##STR72## (with the proviso that q is not 0 in ##STR73## R 8 is H, loweralkyl, cycloloweralkyl, --X 12 CONH 2 , --X 12 COOR 6 , --X 11 --cycloloweralkyl, ##STR74## R 11 and R 12 are independently loweralkyl or cycloloweralkyl; R 13 is O; R 14 is loweralkyl or phenylloweralkyl; R 16 and R 17 are, when separate, independently H, loweralkyl, lower alkenyl, --X 11 cycloloweralkyl, --X 12 --NR 4 R 5 ,X 12 CONR 4 R 5 , --X 12 C.tbd.N, ##STR75## --X 12 COOR 6 , or --CN; or, when joined, form with N, a heterocycle ##STR76## wherein n' is 2-6; R 18 is H or loweralkyl; p is 0 or 1; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X 11 COOR 6 or --X 11 NR 4 R 5 ; X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl or loweralkoxy; X 4 is S, O, CH 2 or NR 8 ; X 5 is H, CF 3 , CN, COOR 6 , NO 2 , or halo; X 6 is O or HH; X 8 is H or loweralkyl; X 9 and X 9 are independently NR 18 , O; X 11 is absent or C 1-4 linear or branched alkylene; X 12 is C 1-4 linear or branched alkylene. and the pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
458 words
A compound of Formula I: ##STR69## wherein R 1 is --NR 16 R 17 ,; R 2 is H, loweralkyl, substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, --CF 3 , or hydroxy), 2-, 3-, 4-pyridyl, ##STR70## R 3 is ##STR71## R 4 and R 5 are independently R 6 or in combination with the N of the NR 4 R 5 group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring, or benzofused 4-7 membered heterocyclic ring or said heterocyclic ring or said benzofused heterocyclic ring which further comprises a second heteroatom selected from O and NCH 3 and the substituent(s) is/are independently selected from C 1-4 alkyl; R 6 is H, loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylloweralkyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF 3 ); R 7 is a α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents are 1 to 2 of halo, --NO 2 , --OH, --X 11 --NR 4 R 5 , loweralkyl, loweralkoxy, CF 3 , loweralkylthio, cyano, phenyl, acetylamino, acetoxy, SCF 3 , C.tbd.CH, CH 2 SCF 3 , OCHF 2 , SH or thio-phenyl) 2-, 3-, 4-pyridyl, ##STR72## (with the proviso that q is not 0 in ##STR73## R 8 is H, loweralkyl, cycloloweralkyl, --X 12 CONH 2 , --X 12 COOR 6 , --X 11 --cycloloweralkyl, ##STR74## R 11 and R 12 are independently loweralkyl or cycloloweralkyl; R 13 is O; R 14 is loweralkyl or phenylloweralkyl; R 16 and R 17 are, when separate, independently H, loweralkyl, lower alkenyl, --X 11 cycloloweralkyl, --X 12 --NR 4 R 5 ,X 12 CONR 4 R 5 , --X 12 C.tbd.N, ##STR75## --X 12 COOR 6 , or --CN; or, when joined, form with N, a heterocycle ##STR76## wherein n' is 2-6; R 18 is H or loweralkyl; p is 0 or 1; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X 11 COOR 6 or --X 11 NR 4 R 5 ; X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl or loweralkoxy; X 4 is S, O, CH 2 or NR 8 ; X 5 is H, CF 3 , CN, COOR 6 , NO 2 , or halo; X 6 is O or HH; X 8 is H or loweralkyl; X 9 and X 9 are independently NR 18 , O; X 11 is absent or C 1-4 linear or branched alkylene; X 12 is C 1-4 linear or branched alkylene. and the pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
244 words
A compound of claim 1 wherein: R 1 is --NR 16 R 17 ; R 2 is substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, carboxyl, carboxyloweralkyl, nitro, --CF 3 , or hydroxy), 2-, 3-, 4-pyridyl --X 12 COOR 6 or or ##STR77## R 3 is ##STR78## R 4 and R 5 are independently H or loweralkyl; R 6 is H or loweralkyl; R 7 is α- or β-naphthyl, ##STR79## substituted or unsubstituted phenyl (wherein the substituents are 1 to 2 of halo, --NO 2 , --OH, --X 11 NR 4 R 5 , loweralkyl, CF 3 , loweralkoxy, loweralkylthio, CN, C.tbd.CH, SCF 3 , OCHF 2 , or thiophenyl), ##STR80## R 8 is H, loweralkyl or ##STR81## R 11 and R 12 are independently loweralkyl; R 14 is loweralkyl; R 16 and R 17 are independently H, loweralkyl, --X 11 cycloloweralkyl, --X 12 NR 4 R 5 , --X 12 CONR 4 R 5 , --X 12 CN, ##STR82## or --CN; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 , CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X 11 COOR 6 , or --X 11 NR 4 R 5 ; X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl, or loweralkoxy; X 4 is S, O, or NR 8 ; X 6 is O or HH; and the pharmaceutically acceptable salts thereof.
Claim 4
Dependent Claim
158 words
A compound of claim 2 wherein: R 1 is --NR 16 R 17 ; R 2 is substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo or carboxyl) or --(CH 2 ) 1-2 COOR 6 ; R 3 is ##STR83## R 6 is H or loweralkyl; R 7 is α- or β-naphthyl, ##STR84## substituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, or CF 3 ), or ##STR85## R 8 is H, methyl, or ethyl; R 14 is t-butyl; R 16 and R 17 are independently H, loweralkyl, --CN, --X 11 cycloloweralkyl, X 12 NR 4 R 5 ,--X 12 CONR 4 R 5 , --X 12 CN; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 CN, OH, or halo; X 2 and X 3 are independently H, --OH, --NO 2 , loweralkyl or halo; and the pharmaceutically acceptable salts thereof.
Claim 5
Dependent Claim
139 words
A compound of claim 3 wherein: R 1 is --NH 2 , --NH(CH 2 ) 0-2 CH 3 , NHCH 2 COOH, --NHCN, ##STR86## R 2 is phenyl, o-fluorophenyl, o-chlorophenyl, p-fluorophenyl, p-chlorophenyl, 2,6-difluorophenyl, --CH 2 COOEt, --CH 2 COO--t--Bu, o-carboxyphenyl, --CH 2 CH 2 COOEt, or --CH 2 CH 2 COOt--Bu; R 3 is --(CH 2 ) 1-2 R 7 , ##STR87## and the stereochemistry relates to D-tryptophan when R 3 is linked to the 7-membered ring via a methylene group; R 6 is H, methyl or ethyl; R 7 is α- or β-naphthyl, mono- or dihalophenyl, mono- or dimethylphenyl, methoxyphenyl, ##STR88## R 14 is t-butyl; r is 1; X 1 is H, chloro, fluoro, or nitro; X 2 and X 3 are independently H, --OH, fluoro or chloro or methyl or ethyl; and the pharmaceutically acceptable salts thereof.
Claim 6
Dependent Claim
19 words
A compound of claim 1 which is 2-Phenylamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; 2-Amino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; 2-Methylamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; N-[3-(((4-Chlorophenyl)aminocarbonyl)amino)-5-phenyl-3H-1,4-benzodiazepin-2-yl]-glycine; N-[3-(((4-Chlorophenyl)aminocarbonyl)amino)-5-phenyl-3H-1,4-benzodiazepin-2-yl]-glycine ethyl ester; 2-Ethoxycarbonylmethylamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; 2-Cyanoamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; 2-n-Propylamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine; and 2-Carboxymethylamino-3(R)-(3'-indolyl)methyl-5-(2'-fluorophenyl)-2H-1,4-benzodiazepine.
Claim 7
Dependent Claim
36 words
A pharmaceutical composition useful for treating gastrointestinal disorders, central nervous system disorders, or regulating appetite in mammals, comprising a pharmaceutically effective amount of a compound of Formula I of claim 1 and an acceptable pharmaceutical carrier.
Claim 8
Dependent Claim
269 words
A pharmaceutical composition of claim 6 useful for treating gastrointestinal disorders, central nervous system disorders, or regulating appetite in mammals, comprising a pharmaceutically effective amount of a compound of Formula I wherein: R 1 is --NR 16 R 17 ; R 2 is substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, carboxyl, carboxyloweralkyl, nitro, --CF 3 , or hydroxy), 2-, 3-, 4-pyridyl --X 12 COOR 6 or ##STR89## R 3 is ##STR90## R 4 and R 5 are independently H or loweralkyl; R 6 is H or loweralkyl; R 7 is α- or β-naphthyl, ##STR91## substituted or unsubstituted phenyl (wherein the substituents are 1 to 2 of halo, --NO 2 , --OH, --X 11 NR 4 R 5 , loweralkyl, CF 3 , loweralkoxy, loweralkylthio, CN, C.tbd.CH, SCF 3 , OCHF 2 , or thiophenyl), ##STR92## R 8 is H, loweralkyl or ##STR93## R 11 and R 12 are independently loweralkyl; R 14 is loweralkyl; R 16 and R 17 are independently H, loweralkyl, --X 11 cycloloweralkyl, --X 12 NR 4 R 5 , --X 12 CONR 4 R 5 , --X 12 CN, ##STR94## or --CN; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 , CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X 11 COOR 6 , or --X 11 NR 4 R 5 ; X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl, or loweralkoxy; X 4 is S, O, or NR 8 ; X 6 is O or HH; and the pharmaceutically acceptable salts thereof.
Claim 9
Dependent Claim
34 words
A method of treating gastrointestinal disorders, central nervous system disorders, or regulating appetite in mammals which comprises administering to said mammals a pharmaceutically effective amount of a compound of Formula I of claim 1.
Claim 10
Dependent Claim
268 words
A method of claim 8 of treating gastrointestinal disorders in humans which comprises administering a pharmaceutically effective amount of a compound of Formula I wherein: R 1 is --NR 16 R 17 ; R 2 is substituted or unsubstituted phenyl (wherein the substituents are 1 or 2 of halo, loweralkyl, loweralkoxy, carboxyl, carboxyloweralkyl, nitro, --CF 3 , or hydroxy), 2-, 3-, 4-pyridyl --X 12 COOR 6 or or ##STR95## R 3 is ##STR96## R 4 and R 5 are independently H or loweralkyl; R 6 is H or loweralkyl; R 7 is α- or β-naphthyl, ##STR97## substituted or unsubstituted phenyl (wherein the substituents are 1 to 2 of halo, --NO 2 , --OH, --X 11 NR 4 R 5 , loweralkyl, CF 3 , loweralkoxy, loweralkylthio, CN, C.tbd.CH, SCF 3 , OCHF 2 , or thiophenyl), ##STR98## R 8 is H, loweralkyl or ##STR99## R 11 and R 12 are independently loweralkyl; R 14 is loweralkyl; R 16 and R 17 are independently H, loweralkyl, --X 11 cycloloweralkyl, --X 12 NR 4 R 5 , --X 12 CONR 4 R 5 , --X 12 CN, ##STR100## --X 12 COOR 6 , or --CN; q is 0-4; r is 1 or 2; X 1 is H, --NO 2 , CF 3 , CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X 11 COOR 6 , or --X 11 NR 4 R 5 ; X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl, or loweralkoxy; X 4 is S, O, or NR 8 ; X 6 is O or HH; and the pharmaceutically acceptable salts thereof.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1991-07-05 | 1992-01-04 | 1992-07-05 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1995-07-05 | 1996-01-04 | 1996-07-05 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1999-07-05 | 2000-01-04 | 2000-07-05 | $7700.00 | Window Closed / Lapsed |