US 5,175,159 AGranted

3-substituted-1,4-benzodiazepines as oxytocin antagonists

AssigneeMerck & Co., Inc.

InventorsMark G. Bock, Ben E. Evans, Roger M. Freidinger

Life of this patent

Estimating the term…

Abstract

Compounds of Formula I are antagonists of oxytocin and are useful in the treatment of preterm labor and dysmenorrhea, and for stoppage of labor prepatory to Caesarean delivery. ##STR1##

Claims7

Dependent claims

A compound of the formula:

##STR29## wherein R.sup.1 is H, C.sub.1 -C.sub.6 linear or branched alkyl, loweralkenyl, lower alkynyl, --X.sup.12 COOR.sup.6, --X.sup.11 -lower cycloalkyl, --X.sup.12 CN, or --X.sup.11 CX.sub.3.sup.10 ;
R.sup.2 is H, loweralkyl, substituted or unsubstituted phenyl (wherein the substitutents may be 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, --CF.sub.3, or hydroxy), 2-, 3-, 4-pyridyl, ##STR30## --X.sup.12 SCH.sub.3, --x.sup.12 SOCH.sub.3, --X.sup.12 SO.sub.2 CH.sub.3, or --X.sup.12 COOR.sup.6 ;
R.sup.3 is H,--X.sup.11 NR.sup.18 Xa.sup.11 R.sup.7, ##STR31## R.sup.6 is H, loweralkyl, lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylloweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF.sub.3 ;
R.sup.7 is loweralkyl, lower cycloalkyl, X.sup.12 -cycloloweralkyl, wherein lower cycloalkyl encompasses C.sub.3 -C.sub.10 and may be mono or polycyclic, including bridged units, and such lower cycloalkyl units may be unsubstituted or independently substituted at one or two of the secondary carbons with the following substituents:
##STR32## R.sup.9 and R.sup.10 are independently H, --OH, or --CH.sub.3 ;
R.sup.13 is H, loweralkyl, carboxyl, O, cycloloweralkyl, ##STR33## R.sup.14 is loweralkyl or phenylloweralkyl;
R.sup.15 is H, loweralkyl, ##STR34## or --NH.sub.2 ;
R.sup.18 is H, OH, OR.sup.13, or loweralkyl;
p is O when its adjacent is unsaturated and 1 when its adjacent is saturated except that when R.sup.13 is O, p=1 and is unsaturated;
r is 1 or 2;
X.sup.1 is H, --NO.sub.2, CF.sub.3 CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --X.sup.11 COOR.sup.6, or --X.sup.11 NR.sup.4 R.sup.5 ;
X.sup.2 and X.sup.3 are independently H, --OH, --NO.sub.2, halo, loweralkylthio, loweralkyl, or loweralkoxy;
X.sup.7 is O, S, HH, or NR.sup.15 with the proviso that X.sup.7 can be NR.sup.15 only when R.sup.1 is not H;
X.sup.9 and X.sub.a.sup.9 are independently NR.sup.18 or O;
X.sup.10 is F, Cl, or Br;
X.sup.11 and X.sub.a.sup.11 are independently absent or C.sub.1-4 linear or branched alkylidene;
X.sup.12 os C.sub.1-4 linear or branched alkyl;
is a saturated or unsaturated bond;
and the pharmaceutically acceptable salts thereof, with the proviso that R.sup.3 is H when and only when R.sup.13 is ##STR35##

16 more elements

A compound selected from the group consisting of:

(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-N'- TRICYCLO(3.3.1.1(3,7))DEC-2-YL-UREA
(+)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-N'-TR ICYCLO(3.3.1.1(3,7))DEC-2-YL-UREA
(R)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-N'-TR ICYCLO(3.3.1.1(3,7))DEC-1-YL-UREA
(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-TRI CYCLO(3.3.1.1(3,7))DECANE-1-CARBOXAMIDE
(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-TRI CYCLO(3.3.1.1(3,7))DECANE-1-ACETAMIDE)
(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-N'- TRICYCLO(3.3.1.1(3,7))DEC-1-YL-METHYL)-UREA
(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-3-M ETHYLTRICYCLO(3.3.1.1(3.7))DECANE-1-ACETAMIDE
(1S)-(1.ALPHA.(RS),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4 -BENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULF ONAMIDE
(1R-(1.ALPHA.(RS),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H1,4-B ENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULFON AMIDE
(+/-)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-N'- TRICYCLO(3.3.1.0(3,7))DEC-2-YL-UREA
ALPHA.-((((2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)AM INO)CARBONYL)AMINO)BENZENEACETIC ACID ETHYL ESTER, ALPHA ISOMER
(+/-)-1,2,3,5-TETRAHYDRO-1-METHYL-2-OXO-5-PHENYL-N-(TRICYCLO(3.3.1.1.(3,7)) DEC-1-YLMETHYL)-4H-1,4-BENZODIAZEPINE-4-CARBOXAMIDE
(+/-)-1,2,3,5-TETRAHYDRO-1-METHYL-2-OXO-5-PHENYL-N-TRICYCLO(3.3.1.1(3,7))DE C-2-YL-4H-1,4-BENZODIAZEPINE-4-CARBOXAMIDE
(1R-(1.ALPHA.(R*),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4- BENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULFO NAMIDE
(1R-(1.ALPHA.(S*),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4- BENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULFO NAMIDE
N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-2-HYDROXY -7,7-DIMETHYL-BICYCLO(2.2.1)HEPTANE-1-METHANESULFONAMIDE, ISOMER A AND ISOMER B
N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)-2-HYDROXY -7,7-DIMETHYL-BICYCLO(2.2.1)HEPTANE-1-METHANESULFONAMIDE,
[3(S)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)]-2- OXO-1,7,7-TRIMETHYL-BICYCLO(2.2.1)HEPTANE-3-ACETAMIDE
[3(R)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)]-2- OXO-1,7,7-TRIMETHYL-BICYCLO(2.2.1)HEPTANE-3-ACETAMIDE
(1S-(1.ALPHA.(S*),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4- BENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULFO NAMIDE
(1S-(1.ALPHA.(R*),4.ALPHA.))-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4- BENZODIAZEPIN-3-YL)-7,7-DIMETHYL-2-OXO-BICYCLO(2.2.1)HEPTANE-1-METHANESULFO NAMIDE
[3(S)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)]-2- HYDROXY-1,7,7-TRIMETHYL-BICYCLO(2.2.1)HEPTANE-3-ACETAMIDE, ISOMER A AND ISOMER B
[3(R)-N-(2,3-DIHYDRO-1-METHYL-2-OXO-5-PHENYL-1H-1,4-BENZODIAZEPIN-3-YL)]-2- OXO-1,7,7-TRIMETHYLBICYCLO(2.2.1)HEPTANE-3-CARBOXAMIDE

20 more elements

Dependencies are inferred from the claim text.

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