Compositions useful for treating gastrointestinal motility disorders
The present invention relates to method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof; and a second amount of at least one gastric acid suppressing agent (e.g., a proton pump inhibitor, an H 2 receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof; or an acid pump antagonist or pharmaceutically acceptable salt, hydrate or solvate thereof) wherein the first and second amounts together comprise a therapeutically effective amount. In particular, the method is for treating GERD, including nocturnal GERD. The invention further relates to a method of treating nocturnal GERD comprising administering to a subject in need thereof a therapeutically effective amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof. The invention further relates to a method of increasing esophageal motility in a subject in need thereof. The method of increasing esophageal motility can be achieved by administration of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof. The coadministration can also be used to increase esophageal motility.
1 . A method of treating GERD in a subject in need of treatment comprising coadministering to said subject:
a) a first amount of a compound represented by Formula I:
wherein:
R 1 represents hydrogen, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a C 3 -C 8 cycloalkyl group, a C 6 -C 12 aryl group or a C 7 -C 18 aralkyl group;
R 2 represents hydrogen, a C 1 -C 6 alkyl group, halogen, hydroxyl, a C 1 -C 6 alkoxy group, amino, a C 1 -C 6 alkylamino group, nitro, mercapto or a C 1 -C 6 alkylthio group;
Y represents —O— or
wherein R 3 represents hydrogen or a C 1 -C 6 alkyl group; and
A is represented by
wherein:
n is an integer from 1 to about 4;
R 4 represents hydrogen, a C 1 -C 6 alkyl group, a C 3 -C 8 cycloalkyl group or a C 7 -C 18 aralkyl group;
or a pharmaceutically acceptable salt, solvate, hydrate or N-oxide thereof; and
b) a second amount of at least one gastric acid suppressing agent or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein the first and second amounts together comprise a therapeutically effective amount.
2 . The method of claim 1 , wherein the GERD is nocturnal GERD.
3 . The method of claim 1 , wherein the gastric acid suppressing agent is a proton pump inhibitor, an H 2 receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
4 . The method of claim 3 , wherein the gastric acid suppressing agent is a proton pump inhibitor.
5 . The method of claim 4 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.
6 . The method of claim 3 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.
7 . The method of claim 6 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.
8 . The method of claim 1 , wherein the gastric acid suppressing agent is an acid pump antagonist.
9 . The method of claim 8 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.
10 . The method of claim 1 , wherein for the compound of Formula I
Y represents —O— or
R 1 represents hydrogen, a C 1 -C 6 alkyl group, a C 6 -C 12 aryl group or a C 7 -C 18 aralkyl group;
R 2 represents hydrogen, a C 1 -C 6 alkyl group or halogen; and
A is represented by
wherein:
n is 2 or 3; and
R 4 represents a C 1 -C 6 alkyl group.
11 . The method of claim 1 , wherein for the compound of Formula I, R 1 represents hydrogen or a C 1 -C 3 alkyl group, R 2 represents hydrogen, a C 1 -C 3 alkyl group or halogen, R 3 represents hydrogen, R 4 represents a C 1 -C 3 alkyl group and n is an integer of 2 or 3.
12 . A method of treating GERD in a subject in need of treatment comprising coadministering to said subject:
a) a first amount of a compound represented by Formula V:
or a pharmaceutically acceptable salt, solvate or hydrate thereof, and
b) a second amount of at least one gastric acid suppressing agent or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein the first and second amounts together comprise a therapeutically effective amount.
13 . The method of claim 12 , wherein the GERD is nocturnal GERD.
14 . The method of claim 12 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.
15 . The method of claim 14 , wherein the compound of Formula V is in the form of the monohydrochloride salt.
16 . The method of claim 12 , wherein the gastric acid suppressing agent is a proton pump inhibitor, an H 2 receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
17 . The method of claim 16 , wherein the gastric acid suppressing agent is a proton pump inhibitor selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.
18 . The method of claim 16 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.
19 . The method of claim 12 , wherein the gastric acid suppressing agent is an acid pump antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.
20 . The method of claim 19 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.