Pyrazolidinone CCK and gastrin antagonists and pharmaceutical formulations thereof

Claim 1

A pharmaceutical formulation comprising as an active ingredient an effective amount of a compound of A compound of the formula ##STR22## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl (C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR23## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 3 is hydrogen or a group of the formula ##STR24## wherein B is O or S; n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2, or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the groups R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR25## R 2 is other than a group of the formula ##STR26## and a pharmaceutically acceptable carrier, excipient or diluent therefor.

Claim 6

A method for inhibiting the interaction of cholecystokinin or gastrin with its receptors in a warm-blooded vertebrate thereby antagonizing the influence of endogeneous cholecystokinin or gastrin which method comprising administering to said vertebrate a compound of A compound of the formula ##STR27## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR28## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 3 is hydrogen or a group of the formula ##STR29## B is O or S n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluoroophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2, or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the groups R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR30## R 2 is other than a group of the formula ##STR31## in an amount effective to antagonize the influence of cholecystokinin or gastrin in said vertebrate.

Claim 7

A method for inhibiting the interaction of cholecystokinin or gastrin with its receptors in a warm-blooded vertebrate thereby antagonizing the influence of endogeneous cholecystokinin or gastrin which method comprising administering to said vertebrate a compound of A compound of the formula ##STR27## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR28## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 3 is hydrogen or a group of the formula ##STR29## B is O or S n is 0 or 1; Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --(CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluoroophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2, or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the groups R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR30## R 2 is other than a group of the formula ##STR31## in an amount effective to antagonize the influence of cholecystokinin or gastrin in said vertebrate.

Claim 8

A method for treating irritable bowel syndrome which comprises administering to a warm blooded vertebrate an effective amount of a compound of the formula ##STR32## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR33## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 3 is hydrogen or a group of the formula ##STR34## wherein B is O or S n is 0 or 1 Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --( CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the groups R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR35## R 2 is other than a group of the formula ##STR36##

Claim 9

A method for treating irritable bowel syndrome which comprises administering to a warm blooded vertebrate an effective amount of a compound of the formula ##STR32## wherein R and R 1 are independently hydrogen, C 1 -C 6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C 1 -C 4 alkyl), phenyl(C 1 -C 4 alkoxy), phenylacetyl, C 1 -C 6 alkanoyl, cyano, carbamyl, nitro, C 1 -C 6 alkoxycarbonyl, methylenedioxy, C 3 -C 6 alkylene, amino, --NH(C 1 -C 4 alkyl or benzyl), and N(C 1 -C 4 alkyl) 2 ; R 2 is hydrogen, C 1 -C 6 alkyl, carboxymethyl, C 1 -C 4 alkoxycarbonylmethyl or a group of the formula ##STR33## wherein t is 1 or 0; A is --CH 2 --, --O--, --NH-- or --N(C 1 -C 6 alkyl)--; and Y is phenyl or substituted phenyl as defined above; R 3 is hydrogen or a group of the formula ##STR34## wherein B is O or S n is 0 or 1 Q is --NH--, --N(C 1 -C 6 alkyl)--, --S--, or --O--; and R 5 is a group of the formula --[CH(R 6 )] q --( CH 2 ) r --R 7 wherein R 6 is hydrogen or C 1 -C 6 alkyl; q is 0 or 1; r is 0, 1 or 2; and R 7 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, pentafluorophenyl, pyridyl, tetrahydro-naphthyl, indolyl, quinolinyl, phenyl, naphthyl, or phenyl or naphthyl substituted with 1, 2 or 3 substituents as defined above for phenyl; or the group --(Q) n R 5 is 2-tetrahydroisoquinolinyl; and the pharmaceutically acceptable salts thereof; provided that at least one of the groups R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is other than hydrogen or C 1 -C 6 alkyl, and R or R 1 is hydrogen only when the other of R and R 1 is substituted phenyl in which the substituent is phenyl; and provided further that at least one of the groups R 2 and R 3 is other than hydrogen, and when R 3 is a group of the formula ##STR35## R 2 is other than a group of the formula ##STR36##