The invention herein is directed to compounds and a method of treating gastrointestinal motility disorders of a mammal by administering to the mammal in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. The method can be practiced to treat gastrointestinal motility disorders such as gastroesophageal reflux, diseases characterized by delayed gastric emptying, ileus, irritable bowel syndrome, and the like. The compounds of the invention are serotonergic 5-HT.sub.3 antagonists and as such are useful for the treatment of conditions, for example, such as anxiety, psychoses and depression.
There are classes of compounds known for the treatment of such disorders. For example, azatetracycle compounds are disclosed in co-pending U.S. patent application Ser. No. 07/515,391 filed Apr. 27, 1990, and N-Azabicyclo [3.3.0] octane amides of aromatic acids are disclosed in co-pending application Ser. No. 07/406,205 filed Sep. 11, 1989. Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and are mentioned generically in U.K. Patent 2,152,049A and European application 0189002A2.
Azabicyclic nonanes are disclosed in European Patent application 0094742A2. Additional azabicyclic compounds are disclosed in U.S. Pat. Nos. 4,797,387 and 4,797,406.
Benzamides have been known as 5-HT.sub.3 antagonists and as compounds possessing gastrointestinal motility-enhancing properties. Benzamides of the following formula: ##STR1## compounds wherein X can be an azabicycloalkane moiety and which exhibit gastrointestinal motility enhancing and/or 5-HT.sub.3 antagonist properties are disclosed in EP 0094742A2 and in U.S. Pat. No. 4,797,406. In addition, UK Patent 2,152,049 discloses that certain benzamide derivatives exhibit serotonin M antagonistic activity. Indoleamides of the following formula have also been described as possessing gastrointestinal motility-enhancing and/or 5-HT.sub.3 antagonist properties: ##STR2## Compounds wherein X contains an aminergic side chain or an azabicycloalkane moiety are described in U.S. Pat. No. 4,797,406.
European patent publication number 0,230,718 discloses certain substituted benzamide derivatives, substituted with piperidinyl analogues as having gastrointestinal motility-enhancing and/or antiemetic activity and/or 5-HT receptor antagonist activity. J. Heterocyclic Chemistry (1987) 24:47 describes the preparation of the following compound: No substitution is shown in the phenyl ring and no utility is described. ##STR3##
J. Pharmaceutical Sciences (1987) 76:416 describes compounds of generic scope. Utility as anti-arrythmic agents is described. ##STR4## n=1 or 2 R.sub.1 =H, 2-Me, 4-NH.sub.2, 4-OMe, 4-NHCO.sub.2 Et, 2-OEt, 4-OEt, 3- or 4-NMe.sub.2, 3- or 4-NO.sub.2 ; R.sub.2 =H or 6-Me.
JP Patent 58083694 A2 and JP 0027355B describe anti-arrythmic agents of the following formula wherein n=1 or 2; R.sub.1 or R.sub.2 are both Me or R.sub.1 is H while R.sub.2 is nitro, di-lower alkylamino, lower alkoxycarbonylamino, or ethoxy. ##STR5##
EP Patent 39,903 and U.S. Pat. No. 4,617,401 describe compounds of the following formula wherein X is NH or O and R is H, OMe, OH, or NH.sub.2 and Z is a lone electron pair or optionally substituted alkyl group. The compounds are described as spasmolytic, antiarrythmic, and neuromuscular-blocking agents. ##STR6##
USPTO Backgrounds
USPTO Backgrounds