Pyrazolidinone CCK and gastrin antagonists and pharmaceutical formulations therof
AssigneeEli Lilly and Company
InventorsBeverley Greenwood, David R. Helton, J. Jeffry Howbert, Steven J. Mitan, Kurt Rasmussen
Life of this patent
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Abstract
Novel substituted pyrazolidinones have been found to exhibit significant binding to cholecystokinin (CCK) receptors and gastrin receptors in the brain and/or peripheral sites such as the pancreas, stomach, and ileum. The pyrazolidinones are CCK and gastrin receptor antagonists and find therapeutic application in the treatment of gastrointestinal disorders, central nervous system disorders and for appetite regulation in warm-blood vertebrates. Pharmaceutical formulations for such indications are described.
Claims19
A method for treating or preventing a condition associated with cholecystokinin modulation in a warm blooded vertebrate, comprising administering an effective amount of a compound of the formula ##STR24## wherein R and R.sup.1 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C.sub.1 -C.sub.4 alkyl), phenyl(C.sub.1 -C.sub.4 alkoxy), phenylacetyl, C.sub.1 -C.sub.6 alkanoyl, cyano, carbamyl, nitro, C.sub.1 -C.sub.6 alkoxycarbonyl, methylenedioxy, C.sub.3 -C.sub.6 alkylene, amino, --NH(C.sub.1 -C.sub.4 alkyl or benzyl), and N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
- R.sup.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, carboxymethyl, C.sub.1 -C.sub.4 alkoxycarbonylmethyl or a group of the formula ##STR25## wherein t is 1 or 0;
- A is --CH.sub.2 --, --O--, --NH-- or --N(C.sub.1 -C.sub.6 alkyl)--;
- and
- Y is phenyl or substituted phenyl as defined above;
- R.sup.4 is C.sub.1 -C.sub.6 alkyl, carboxymethyl, or C.sub.1 -C.sub.4 alkoxycarbonylmethyl;
- R.sup.3 is hydrogen or a group of the formula ##STR26## wherein B is 0 or S;
- X is selected from the phenyl substituents defined above;
- m is 0, 1 or 2;
- n is 0 or 1;
- Q is --NH--, --N(C.sub.1 -C.sub.6 alkyl)--, --S--, or --O--;
- and
- R.sup.5 is a group of the formula --[CH(R.sup.6)].sub.q --(CH.sub.2).sub.r --R.sup.7
- wherein
- R.sup.6 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- q is 0 or 1;
- r is 0, 1 or 2;
- and
- R.sup.7 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.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).sub.n R.sup.5 is 2-tetrahydroisoquinolinyl;
- and
- the pharmaceutically acceptable salts thereof;
- provided that at least one of the group R or R.sup.1 is other than hydrogen or C.sub.1 -C.sub.6 alkyl, and R or R.sup.1 is hydrogen only when the other of R and R.sup.1 is substituted phenyl in which the substituent is phenyl;
- and provided further that at least one of the groups R.sup.2 and R.sup.3 is other than hydrogen, and when R.sup.3 is a group of the formula ##STR27## R.sup.2 is other than a group of the formula ##STR28##
A method for treating or preventing a functional bowel disorder associated with motility disorders in a warm-blooded vertebrate comprising administering an effective amount of a compound of the formula ##STR29## wherein R and R.sup.1 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, naphthyl, pyridyl or substituted phenyl having 1, 2, or 3 substituents selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halo, trifluoromethyl, phenyl, phenoxy, phenyl(C.sub.1 -C.sub.4 alkyl), phenyl(C.sub.1 -C.sub.4 alkoxy), phenylacetyl, C.sub.1 -C.sub.6 alkanoyl, cyano, carbamyl, nitro, C.sub.1 -C.sub.6 alkoxycarbonyl, methylenedioxy, C.sub.3 -C.sub.6 alkylene, amino, --NH(C.sub.1 -C.sub.4 alkyl or benzyl), and N(C.sub.1 -C.sub.4 alkyl).sub.2 ;
- R.sup.2 is hydrogen, C.sub.1 -C.sub.6 alkyl, carboxymethyl, C.sub.1 -C.sub.4 alkoxycarbonylmethyl or a group of the formula ##STR30## wherein t is 1 or 0;
- A is --CH.sub.2 --, --O--, --NH-- or --N(C.sub.1 -C.sub.6 alkyl)--;
- and
- Y is phenyl or substituted phenyl as defined above;
- R.sup.4 is C.sub.1 -C.sub.6 alkyl, carboxymethyl, or C.sub.1 -C.sub.4 alkoxycarbonylmethyl;
- R.sup.3 is hydrogen or a group of the formula ##STR31## wherein B is O or S;
- X is selected from the phenyl substituents defined above;
- m is 0, 1 or 2;
- n is 0 or 1;
- Q is --NH--, --N(C.sub.1 -C.sub.6 alkyl )--, --S--, or --O--;
- and
- R.sup.5 is a group of the formula --[CH(R.sup.6)].sub.q --(CH.sub.2).sub.r --R.sup.7
- wherein
- R.sup.6 is hydrogen or C.sub.1 -C.sub.6 alkyl;
- q is 0 or 1;
- r is 0, 1 or 2;
- and
- R.sup.7 is hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.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).sub.n R.sup.5 is 2-tetrahydroisoquinolinyl;
- and
- the pharmaceutically acceptable salts thereof;
- provided that at least one of the group R or R.sup.1 is other than hydrogen or C.sub.1 -C.sub.6 alkyl, and R or R.sup.1 is hydrogen only when the other of R and R.sup.1 is substituted phenyl in which the substituent is phenyl;
- and provided further that at least one of the groups R.sup.2 and R.sup.3 is other than hydrogen, and when R.sup.3 is a group of the formula ##STR32## R.sup.2 is other than a group of the formula ##STR33## provided that the gastrointestinal disorder is not irritable bowel syndrome.
Dependencies are inferred from the claim text.