Compositions useful for increasing lower esophageal sphincter pressure

1 - 24 . (canceled)

25 . A method of increasing the pressure of the lower esophageal sphincter in a human subject in need thereof comprising administering to said subject from about 0.5 mg to about 50 mg per day 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 derivative thereof.

26 . The method of claim 25 , wherein the compound is administered as a single dosage.

27 . The method of claim 25 , wherein the compound in administered in multiple dosages.

28 . The method of claim 25 , wherein the compound of Formula I is an N-oxide derivative.

29 . The method of claim 25 , 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.

30 . The method of claim 25 , 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.

31 . The method of claim 25 , wherein the compound of Formula I is represented by structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

32 . The method of claim 31 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

33 . The method of claim 32 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

34 . The method of claim 25 , wherein the subject in need of treatment is suffering from GERD.

35 . The method of claim 34 , wherein the GERD is nocturnal GERD.

36 . The method of claim 25 , wherein the administration is oral.

37 . A method of increasing the pressure of the lower esophageal sphincter in a human subject in need thereof comprising administering to said subject from about 1 mg to about 25 mg per day 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 derivative thereof.

38 . The method of claim 37 , wherein the compound is administered as a single dosage.

39 . The method of claim 37 , wherein the compound in administered in multiple dosages.

40 . The method of claim 37 , wherein the compound of Formula I is an N-oxide derivative.

41 . The method of claim 37 , 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.

42 . The method of claim 37 , 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.

43 . The method of claim 37 , wherein the compound of Formula I is represented by structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

44 . The method of claim 43 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

45 . The method of claim 44 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

46 . The method of claim 37 , wherein the subject in need of treatment is suffering from GERD.

47 . The method of claim 46 , wherein the GERD is nocturnal GERD.

48 . The method of claim 37 , wherein the adminstration is oral.

49 . A method of increasing the pressure of the lower esophageal sphincter in a human subject in need thereof comprising administering to said subject about 1.5 mg per day of a compound represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

50 . The method of claim 49 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

51 . The method of claim 50 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

52 . The method of claim 49 , wherein the subject in need of treatment is suffering from GERD.

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

54 . The method of claim 49 , wherein the administration is oral.

55 . A method of increasing the pressure of the lower esophageal sphincter in a human subject in need thereof comprising administering to said subject about 2.5 mg per day of a compound represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

56 . The method of claim 55 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

57 . The method of claim 56 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

58 . The method of claim 55 , wherein the subject in need of treatment is suffering from GERD.

59 . The method of claim 59 , wherein the GERD is nocturnal GERD.

60 . The method of claim 55 , wherein the administration is oral.

61 . A method of increasing the pressure of the lower esophageal sphincter in a human subject in need thereof comprising administering to said subject about 4.0 mg per day of a compound represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

62 . The method of claim 61 , wherein for the compound of Formula V the asterisked carbon atom is in the (R) configuration.

63 . The method of claim 62 , wherein the compound of Formula V is in the form of the monohydrochloride salt.

64 . The method of claim 61 , wherein the subject in need of treatment is suffering from GERD.

65 . The method of claim 64 , wherein the GERD is nocturnal GERD.

66 . The method of claim 61 , wherein the administration is oral.