Indolones useful as serotonergic agents

A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula:

• ##STR25## or a pharmaceutically acceptable salt thereof wherein Z is selected from the group consisting of ##STR26## R.sub.1 and R.sub.2 are independently H, halogen, alkyl, aralkyl, amino, alkoxy, alkylthio, acylamino, hydroxy, nitro, aminocarbonyl, or aminosulfonyl;
• R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, or together comprise C.sub.2-5 cycloalkyl, optionally substituted by C.sub.1-6 alkyl;
• X is NR.sub.5 or O;
• n is 0, 1 or 2;
• R.sub.5 is hydrogen or alkyl of one to six carbon atoms;
• and
• a pharmaceutically acceptable carrier.

A pharmaceutical composition as recited in claim wherein the compound is selected from the group consisting of:

• endo-2,3-dihydro-3,3-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2- oxo-1H-indole-1-carboxamide, hydrochloride hydrate;
• endo-1',2'-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2'-oxo-spiro[ cyclopropane-1,3'-(3'H)-indole]-1'-carboxamide, hydrate hydrochloride;
• anti-N-(1-azatricyclo[3.3.1.1.sup.3,7 ]decan-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-[3'H]indole]-1'(2'H)-carboxami de, monohydrochloride;
• syn-N-(1-azatricyclo[3.3.1.1.sup.3,7 ]decan-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-[3'H]indole-1'(2'H)-carboxamid e, monohydrochloride;
• N-(1-azabicyclo[2.2.2]octan-4-ylmethyl)-2'-oxo-spiro[cyclopropane-1,3'-[3'H ]indole]-1'(2'H)-carboxamide, monohydrochloride;
• 2'-oxo-N-[(hexahydro-1H-pyrrolizin-7a(5H)-yl)-methyl]spiro[cyclopropane-1,3 '-[3'H]indole]-1'(2'H)-carboxamide, monohydrochloride;
• 2'-oxo-N-[2-(hexahydro-1H-pyrrolizin-7a(5H)-yl)ethyl]spiro[cyclopropane-1,3 '-[3H]indole]-1'(2'H)-carboxamide, monohydrochloride;
• exo-2,3-dihydro-3,3-dimethyl-N-[(hexahydro-1H-pyrrolizin-1S-yl)methyl]-2-ox o-1H-indole-1-carboxamide, hydrate hydrochloride;
• and
• 2,3-dihydro-3,3-dimethyl-N-(hexahydro-1H-2,5-methanocyclopenta[c]pyrrol-4R- yl)-2-oxo-1H-indole-1-carboxamide, hydrate hydrochloride.

A method of treating conditions responsive to 5-HT.sub.4 agonists comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula:

• ##STR27## or a pharmaceutically acceptable salt thereof wherein Z is selected from the group consisting of ##STR28## R.sub.1 and R.sub.2 are independently H, halogen, alkyl, aralkyl, amino, alkoxy, alkylthio, acylamino, hydroxy, nitro, aminocarbonyl, or aminosulfonyl;
• R.sub.3 and R4 are independently H, C.sub.1-6 alkyl, or together comprise C.sub.2-5 cycloalkyl, optionally substituted by C.sub.1-6 alkyl;
• X=NH;
• and
• n is0, 1 or2.

A method of treating conditions responsive to 5-HT.sub.3 antagonism comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula:

• ##STR29## or a pharmaceutically acceptable salt thereof wherein Z is selected from the group consisting of ##STR30## R.sub.1 and R.sub.2 are independently H, halogen, alkyl, aralkyl, amino, alkoxy, alkylthio, acylamino, hydroxy, nitro, aminocarbonyl, or aminosulfonyl;
• R.sub.3 and R.sub.4 are independently H, C.sub.1-6 alkyl, or together comprise C.sub.2-5 cycloalkyl, optionally substituted by C.sub.1-6 alkyl;
• X=NR.sub.5 or O;
• n is 0, 1 or 2;
• and
• R.sub.5 is hydrogen or alkyl of one to six carbon atoms.

A method of treating conditions responsive to 5-HT.sub.4 antagonists or mixed 5-HT.sub.4 agonist/antagonist comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula:

• ##STR31## or a pharmaceutically acceptable salt thereof wherein Z is selected from the group consisting of ##STR32## R.sub.1 and R.sub.2 are independently H, halogen, alkyl, aralkyl, amino, alkoxy, alkylthio, acylamino, hydroxy, nitro, aminocarbonyl, or aminosulfonyl;
• R.sub.3 and R.sub.4 are independently H, C.sub.1-56 alkyl, or together comprise C.sub.1-6 cycloalkyl, optionally substituted by C.sub.1-6 alkyl;
• X=NR.sub.5 or 0;
• n is 0, 1 or 2;
• and
• R.sub.5 is alkyl of one to six carbon atoms.