Compositions useful for treating gastrointestinal motility disorders

1 . A method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate 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 gastric acid suppressing agent is a proton pump inhibitor, an H 2 receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3 . The method of claim 1 , wherein the gastric acid suppressing agent is an acid pump antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4 . The method of claim 1 , wherein the gastrointestinal motility disorder is GERD.

5 . The method of claim 4 , wherein the GERD is nocturnal GERD.

6 . The method of claim 1 , wherein the gastrointestinal motililty disorder is gastroparesis.

7 . The method of claim 1 , wherein the subject is a human.

8 . The method of claim 1 , wherein the compound having 5-HT 3 receptor agonist activity is thieno[3,2-b]pyridine derivative.

9 . The method of claim 8 , wherein the compound having 5-HT 3 receptor agonist activity is 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 derivative thereof.

10 . The method of claim 9 , wherein the compound of Formula I is an N-oxide derivative.

11 . The method of claim 9 , 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.

12 . The method of claim 9 , 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.

13 . The method of claim 1 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

14 . The method of claim 13 , 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 . A method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof; and

b) a second amount of at least one gastric acid suppressing agent, wherein the gastric acid suppressing agent is a proton pump inhibitor or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein the first and second amounts together comprise a therapeutically effective amount.

17 . The method of claim 16 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

18 . The method of claim 16 , wherein the compound having 5-HT 3 agonist activity is (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide or a pharmaceutically acceptable salt, hydrate or solvate thereof.

19 . The method of claim 18 , wherein the compound having 5-HT 3 agonist activity is the monohydrochloride salt of (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide.

20 . A method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof; and

b) a second amount of at least one gastric acid suppressing agent, wherein the gastric acid suppressing agent is an H 2 receptor antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof,

wherein the first and second amounts together comprise a therapeutically effective amount.

21 . The method of claim 20 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

22 . The method of claim 20 , wherein the compound having 5-HT 3 agonist activity is (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide or a pharmaceutically acceptable salt, hydrate or solvate thereof.

23 . The method of claim 22 , wherein the compound having 5-HT 3 agonist activity is the monohydrochloride salt of (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide.

24 . A method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof; and

b) a second amount of at least one gastric acid suppressing, wherein the gastric acid suppressing agent is an acid pump antagonist selected from the group consisting of: soraprazan, AZD0865, YH1885 and CS-526,

wherein the first and second amounts together comprise a therapeutically effective amount.

25 . The method of claim 24 , wherein the compound having 5-HT 3 agonist activity is (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide or a pharmaceutically acceptable salt, hydrate or solvate thereof.

26 . The method of claim 25 , wherein the compound having 5-HT 3 agonist activity is the monohydrochloride salt of (R)—N-1-azabicyclo[2.2.2]oct-3-yl-4,7-dihydro-7-oxothieno[3,2-b]pyridine-6-carboxamide.

27 . A method of treating a gastrointestinal motility disorder in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula VI or a pharmaceutically acceptable salt, solvate or hydate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a C 1 -C 6 alkoxy group, carboxy, a C 1 -C 6 alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

is a phenyl ring or a naphthalene ring;

L is a direct bond or a C 1 -C 6 alkylene group;

L 1 and L 2 are defined so that one is a direct bond and the other is:

a) a C 1 -C 6 alkylene group optionally containing and interrupting oxygen or sulfur atom therein;

b) an oxygen atom or sulfur atom; or

c) a C 1 -C 6 alkenylene group;

Im represents a group having the formula:

wherein:

R 1 -R6 are the same or different each representing hydrogen or a C 1 -C 6 alkyl group; and

b) a second amount of at least one gastric acid suppressing agent, wherein the first and second amounts together comprise a therapeutically effective amount.

28 . The method of claim 27 , wherein for the compound of Formula VI,

is a phenyl ring, L 1 is a direct bond and L 2 is an alkylene group or alkenylene group.

29 . A method of claim 27 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula VII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

30 . The method of claim 27 , 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.

31 . The method of claim 30 , wherein the gastric acid suppressing agent is a proton pump inhibitor.

32 . The method of claim 31 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

33 . The method of claim 30 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.

34 . The method of claim 33 , wherein the H 2 receptor antagonists is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

35 . The method of claim 27 , wherein the gastric acid suppressing agent is an acid pump antagonist.

36 . The method of claim 35 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.

37 . The method of claim 26 , wherein the gastrointestinal motililty disorder is gastroparesis.

38 . The method of claim 27 , wherein the subject is a human.

39 . 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.

40 . The method of claim 39 , wherein the GERD is nocturnal GERD.

41 . The method of claim 39 , 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.

42 . The method of claim 41 , wherein the gastric acid suppressing agent is a proton pump inhibitor.

43 . The method of claim 42 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

44 . The method of claim 41 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.

45 . The method of claim 44 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

46 . The method of claim 39 , wherein the gastric acid suppressing agent is an acid pump antagonist.

47 . The method of claim 46 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.

48 . The method of claim 39 wherein the compound of Formula I is an N-oxide derivative.

49 . The method of claim 39 , wherein for the compound of Formula I Y represents —O= 13 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.

50 . The method of claim 39 , 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.

51 . 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.

52 . The method of claim 5 1 , wherein the GERD is nocturnal GERD.

53 . The method of claim 5 1 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

54 . The method of claim 53 , wherein the compound of Formula V is in the form of S the monohydrochloride salt.

55 . The method of claim 5 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.

56 . The method of claim 55 , wherein the gastric acid suppressing agent is a proton pump inhibitor selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

57 . The method of claim 55 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

58 . The method of claim 51 , wherein the gastric acid suppressing agent is an acid pump antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

59 . The method of claim 58 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.

60 . 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 VI or a pharmaceutically acceptable salt, solvate or hydate thereof:

wherein:

R represents hydrogen, halogen, hydroxyl, a C 1 -C 6 alkoxy group, carboxy, a C 1 -C 6 alkoxycarbonyl group, nitro, amino, cyano or protected hydroxyl;

is a phenyl ring or a naphthalene ring;

L is a direct bond or a C 1 -C 6 alkylene group;

L 1 and L 2 are defined so that one is a direct bond and the other is:

a) a C 1 -C 6 alkylene group optionally containing and interrupting oxygen or sulfur atom therein;

b) an oxygen atom or sulfur atom; or

c) a C 1 -C 6 alkenylene group;

Im represents a group having the formula:

wherein:

R 1 -R 6 are the same or different each representing hydrogen or a C 1 -C 6 alkyl group; and

b) a second amount of at least one gastric acid suppressing agent,

wherein the first and second amounts together comprise a therapeutically effective amount.

61 . The method of claim 60 , wherein the GERD is nocturnal GERD.

62 . The method of claim 60 , 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.

63 . The method of claim 62 , wherein the gastric acid suppressing agent is a proton pump inhibitor selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

64 . The method of claim 62 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

65 . The method of claim 60 , wherein the gastric acid suppressing agent is an acid pump antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

66 . The method of claim 65 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1885 and CS-526.

67 . The method of claim 60 , wherein for the compound of Formula VI,

is a phenyl ring, L 1 is a direct bond and L 2 is an alkylene group or alkenylene group.

68 . The method of claim 60 , wherein the compound Formula VI is represented by Formula VII:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

69 . The method of claim 68 , wherein the gastric acid suppressing agent is a proton pump inhibitor selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

70 . The method of claim 68 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

71 . A pharmaceutical composition comprising:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof; and

b) a second amount of at least one gastric acid suppressing agent,

wherein the first and second amounts together comprise a therapeutically effective amount.

72 . The pharmaceutical composition of claim 71 , 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.

73 . The pharmaceutical composition of claim 72 , wherein the gastric acid suppressing agent is a proton pump inhibitor selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

74 . The pharmaceutical composition of claim 72 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

75 . The pharmaceutical composition of claim 71 , wherein the gastric acid suppressing agent is an acid pump antagonist or a pharmaceutically acceptable salt, hydrate or solvate thereof.

76 . The pharmaceutical composition of claim 75 , wherein the acid pump antagonist is selected from the group consisting of soraprazan, AZD0865, YH1 885 and CS-526.

77 . The pharmaceutical composition of claim 71 , wherein the compound having 5-HT 3 receptor agonist activity is 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 derivative thereof.

78 . The pharmaceutical composition of claim 77 , wherein the compound of Formula I is an N-oxide derivative.

79 . The pharmaceutical composition of claim 77 , 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.

80 . The pharmaceutical composition of claim 77 , 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.

81 . The pharmaceutical composition of claim 71 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

82 . The pharmaceutical composition of claim 81 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

83 . The pharmaceutical composition of claim 82 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

84 . A kit comprising a compound having 5-HT 3 receptor agonist activity, instructions for use with at least one gastric acid suppressing agent and optionally a device for administering the compounds.

85 . The kit of claim 84 , 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.

86 . The kit of claim 85 , wherein the gastric acid suppressing agent is a proton pump inhibitor.

87 . The kit of claim 86 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

88 . The kit of claim 85 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.

89 . The kit of claim 88 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

90 . The kit of claim 84 , wherein the 5-HT 3 receptor agonist is present in the kit in a sub-therapeutic dose.

91 . The kit of claim 84 , wherein the instructions specify that the gastric acid suppressing agent is used in a sub-therapeutic dose.

92 . The kit of claim 84 , wherein the compound having 5-HT 3 receptor agonist activity is 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 derivative thereof.

93 . The kit of claim 92 , wherein the compound of Formula I is an N-oxide derivative.

94 . The kit of claim 92 , 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.

95 . The kit of claim 92 , 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.

96 . The kit of claim 92 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

97 . The kit of claim 96 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

98 . The kit of claim 97 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

99 . A kit comprising at least one compound which is a gastric acid suppressing agent, instructions for use with a compound having 5-HT 3 receptor agonist activity, and optionally a device for administering the compounds.

100 . The kit of claim 99 , 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.

101 . The kit of claim 100 , wherein the gastric acid suppressing agent is a proton pump inhibitor.

102 . The kit of claim 101 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

103 . The kit of claim 100 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.

104 . The kit of claim 103 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

105 . The kit of claim 100 , wherein the instructions specify that the compound having 5-HT 3 receptor agonist activity is used in a sub-therapeutic dose.

106 . The kit of claim 100 , wherein the gastric acid suppressing agent is present in the kit in a sub-therapeutic dose.

107 . The kit of claim 99 , wherein the compound having 5-HT 3 receptor agonist activity is 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 2 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 derivative thereof.

108 . The kit of claim 107 , wherein the compound of Formula I is an N-oxide derivative.

109 . The kit of claim 107 , 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.

110 . The kit of claim 107 , 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.

111 . The kit of claim 107 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

112 . The kit of claim 111 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

113 . The kit of claim 112 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

114 . A kit comprising a compound having 5-HT 3 receptor agonist activity, at least one gastric acid suppressing agent, instructions for coadministering the compound having 5-HT 3 receptor agonist activity and the gastric acid suppressing agent, and optionally a device for administering the compounds.

115 . The kit of claim 114 , 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.

116 . The kit of claim 115 , wherein the gastric acid suppressing agent is a proton pump inhibitor.

117 . The kit of claim 116 , wherein the proton pump inhibitor is selected from the group consisting of esomeprazole, omeprazole, lansoprazole, rabeprazole and pantoprazole.

118 . The kit of claim 115 , wherein the gastric acid suppressing agent is an H 2 receptor antagonist.

119 . The kit of claim 118 , wherein the H 2 receptor antagonist is selected from the group consisting of nizatidine, ranitidine, famotidine, roxatidine and cimetidine.

120 . The kit of claim 114 , wherein the compound having 5-HT 3 receptor agonist activity is present in the kit in a sub-therapeutic dose.

121 . The kit of claim 114 , wherein the gastric acid suppressing agent is present in the kit in a sub-therapeutic dose.

122 . The kit of claim 114 , wherein the compound having 5-HT 3 receptor agonist activity is 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 derivative thereof.

123 . The kit of claim 122 , wherein the compound of Formula I is an N-oxide derivative.

124 . The kit of claim 122 , 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.

125 . The method of claim 122 , 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.

126 . The kit of claim 122 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

127 . The kit of claim 125 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

128 . The kit of claim 127 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

129 . A method of treating nocturnal GERD in a subject in need thereof comprising administering a therapeutically effective amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof.

130 . The method of claim 129 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

131 . A method of increasing esophageal motility in a subject in need thereof comprising administering a therapeutically effective amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate thereof.

132 . The method of claim 131 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

133 . A method of increasing esophageal motility in a subject in need of treatment comprising coadministering to said subject:

a) a first amount of a compound having 5-HT 3 receptor agonist activity or a pharmaceutically acceptable salt, hydrate or solvate 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.

134 . The method of claim 133 , wherein the compound having 5-HT 3 receptor agonist activity is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.