Treatment of gastrointestinal disorders using 5-HT3 antagonists

Claim 2

Use of a mono or dicyclic carboxylic or heterocyclic carboxylic acid ester or amide of a alcohol or amine containing nitrogen as a ring atom in free base form or in acid addition or quaternary ammonium salt form as a 5-HT 3 antagonist in the manufacture of a medicament suitable for the treatment of serotonin induced gastrointestinal disturbances.

Claim 3

Use according to claim 1 wherein the gastrointestinal disturbance is chosen from management of one of the following:gastritis, peptic ulcer,biliary dyskinesia, spastic colon, appendicitis, irritable bowel syndrome, Crohn's disease, ulcerative colitis, carcinoid syndrome and diarrhea of different genesis, e.g. secretory diarrhea, bacteria-induced diarrhea, choleric diarrhea, traveller's diarrhea, psychogenic diarrhea or oesophageal motility disturbances, achalasia, hiatus hernia, cardia insufficiency, gastroesophageal and gastroduodenal reflux, stomach hypotonia, pylorus hyperplasia, paralytic ileus and Hirschsprung's disease.

Claim 4

Use of a compound of formula I wherein A is a group of formula wherein the free valence is attached to either fused ring in formula(II) or (IV). X-Y is -CH=CH-, -0-CH 2 - or -N=CH-, Z is -CH 2 , -NR 3 -, -0- or -S-, R 1 and R 2 are independently hydrogen, halogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, mercapto or (C 1-4 )alkylthio, R 3 is hydrogen, (C 1-4 )alkyl, (C 3-5 )alkenyl, aryl or arylalkyl, and R 4 to R 7 are, independently,hydrogen, amino, nitro, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, halogen, (C 1-4 )alkoxy, (C 1-4 )alkyl, (C 1-4 )alkanoylamino, pyrrolyl, sulfamoyl, or carbamoyl 8 is -CO- or -SO 2 -C is -0- or -NH-D is a group of formula wherein n is 2, 3 or 4 wherein R 8 is hydrogen, (C 1-7 )alkyl, (C 3-5 )alkenyl or aralkyl. and, when B is CO, additionally 0 may be a group of formula wherein t is 1 or 2, and R 8 is as defined above, wherein the bond is in the position 3 ( * ) or 4 [ * ], wherein 1 is 2 or 3, wherein Z is (C 1-4 )Alkoxy, wherein R 9 to R12 are independently hydrogen or (C 1-4 )-alkyl, m is 0, 1 or 2 and n, o, p independently are 0 or 1, with the proviso that, when A is formula III, 8 is C0 and C is NH, D is not a group of formula VI, in free base form or in acid addition or quaternary ammonium salt form as a 5-HT 3 antagonist in the manufacture of a medicament suitable for the treatment of serotonin induced gastrointestinal disturbances.

Claim 5

Use of a compound of formula I wherein A is a group of formula wherein the free valence is attached to either fused ring in formula(II) or (IV). X-Y is -CH=CH-, -0-CH 2 - or -N=CH-, Z is -CH 2 , -NR 3 -, -0- or -S-, R 1 and R 2 are independently hydrogen, halogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, mercapto or (C 1-4 )alkylthio, R 3 is hydrogen, (C 1-4 )alkyl, (C 3-5 )alkenyl, aryl or arylalkyl, and R 4 to R 7 are, independently,hydrogen, amino, nitro, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, halogen, (C 1-4 )alkoxy, (C 1-4 )alkyl, (C 1-4 )alkanoylamino, pyrrolyl, sulfamoyl, or carbamoyl 8 is -CO- or -SO 2 -C is -0- or -NH-D is a group of formula wherein n is 2, 3 or 4 wherein R 8 is hydrogen, (C 1-7 )alkyl, (C 3-5 )alkenyl or aralkyl. and, when B is CO, additionally 0 may be a group of formula wherein t is 1 or 2, and R 8 is as defined above, wherein the bond is in the position 3 ( * ) or 4 [ * ], wherein 1 is 2 or 3, wherein Z is (C 1-4 )Alkoxy, wherein R 9 to R12 are independently hydrogen or (C 1-4 )-alkyl, m is 0, 1 or 2 and n, o, p independently are 0 or 1, with the proviso that, when A is formula III, 8 is C0 and C is NH, D is not a group of formula VI, in free base form or in acid addition or quaternary ammonium salt form as a 5-HT 3 antagonist in the manufacture of a medicament suitable for the treatment of serotonin induced gastrointestinal disturbances.

Claim 6

Use of a compound as defined in claim 3 wherein A is a group of formula II in free base form or in acid addition or quaternary ammonium salt form in the manufacture of a medicament suitable for the treatment of gastrointestinal disturbances.

Claim 7

Use according to claim 4 wherein the compound has A wherein R 1 and R 2 are independently hydrogen, halogen, (C 1-4 )alkyl or (C 1-4 )alkoxy, R l is in position 4 or 5, R 3 is hydrogen or (C 1-4 )alkyl and the corresponding bond is in position 3, 4 or 5, 8 is -CO-, C is -0- or -NH- and D is a group of formula IV wherein R 8 is hydrogen, (C 1-4 ) alkyl or benzyl or a group of formula VIII wherein the corresponding bond is in the 3 position in free base form or in acid addition or in quaternary ammonium salt form.

Claim 8

Use according to claim 5 wherein the compound has Z which is S or NR 3 wherein R 3 is hydrogen or (C 1-4 )alkyl in free base form or in acid addition or quaternary ammonium salt form.

Claim 9

Use according to claim 6 wherein the compound is indol-3-yl carboxylic acid endo-8-methyl-8-aza-bicyclo-C3,2,1]oct-3-yl ester in free base form or in acid addition or quaternary ammonium salt form.

Claim 10

8 . Use according to claim 6 wherein the compound is benzo-[b]thiophen-3-y1 carboxylic acid endo-9-methyl-aza-bicyclo-[3,3,1]non-3-yl ester in free base form or in acid addition or quaternary ammonium salt form.

Claim 11

9 . Use according to claim 6 wherein the compound is 5-fluoro-1-methyl-1-indol-3-yl carboxylic acid endo-9-methyl-9-aza- bicyclo[3,3,1]non-3-yl ester in free base form or in acid addition salt or quaternary ammonium salt form.

Claim 12

Benzo[b]thiophen-3-y1 carboxylic acid endo-9-methyl- aza-bicyclo[3,3,1]non-3-yl ester hydrochloride or 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]non-3-yl ester hydrogen maleate.

Claim 13

Benzo[b]thiophen-3-y1 carboxylic acid endo-9-methyl- aza-bicyclo[3,3,1]non-3-yl ester hydrochloride or 5-fluoro-l-methyl-indol-3-yl carboxylic acid endo-9-methyl-9-aza-bicyclo[3,3,1]non-3-yl ester hydrogen maleate.