Method of treating functional bowel disorders
The invention relates to a method of treating functional bowel disorders in a subject in need of treatment. The method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound that has 5-HT 3 receptor antagonist activity and NorAdrenaline Reuptake Inhibitor (NARI) activity. The invention further relates to a method of treating a functional bowel disorder in a subject in need thereof, comprising coadministering to said subject a first amount of a 5-HT 3 antagonist and a second amount of a NARI, wherein the first and second amounts together comprise a therapeutically effective amount or are each present in a therapeutically effective amount. In addition, the method of the invention comprises administering a NARI alone. The functional bowel disorders which can be treated according to the method of the invention include IBS, functional abdominal bloating, functional constipation and functional diarrhea.
1 - 62 . (canceled)
63 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.02 mg to about 200 mg per day of a compound of formula I:
or a pharmaceutically effective salt thereof to a human subject in need thereof,
wherein R 1 and R 2 independently represent hydrogen, halogen or a C 1 -C 6 alkyl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;
R 3 and R 4 independently represent hydrogen or a C 1 -C 6 alkyl group;
R 5 is hydrogen, C 1 -C 6 alkyl,
or —C(O)—NH—R 6
wherein m is an integer from about 1 to about 3, X is halogen and R 6 is a C 1 -C 6 alkyl group; and
Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and n is 2 or 3.
64 . The method of claim 63 , wherein said pain or discomfort is pain.
65 . The method of claim 64 , wherein said pain is visceral pain.
66 . The method of claim 63 , wherein said administering is in one, two, three, or four dosages.
67 . The method of claim 63 , wherein said administering is every day.
68 . The method of claim 63 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
69 . The method of claim 63 , wherein said administering is oral.
70 . The method of claim 63 , wherein the functional bowel disorder is irritable bowel syndrome.
71 . The method of claim 70 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
72 . The method of claim 70 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
73 . The method of claim 70 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.
74 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.02 mg to about 200 mg per day of a compound of formula II:
or a pharmaceutically effective salt thereof to a human subject in need thereof.
75 . The method of claim 74 , wherein said pain or discomfort is pain.
76 . The method of claim 75 , wherein said pain is visceral pain.
77 . The method of claim 74 , wherein said administering is in one, two, three, or four dosages.
78 . The method of claim 74 , wherein said administering is every day.
79 . The method of claim 74 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
80 . The method of claim 74 , wherein said administering is oral.
81 . The method of claim 74 , wherein the functional bowel disorder is irritable bowel syndrome.
82 . The method of claim 81 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
83 . The method of claim 81 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
84 . The method of claim 81 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.
85 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.1 mg to about 50 mg per day of a compound of formula I:
or a pharmaceutically effective salt thereof to a human subject in need thereof,
wherein R 1 and R 2 independently represent hydrogen, halogen or a C 1 -C 6 alkyl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;
R 3 and R4 independently represent hydrogen or a C 1 -C 6 alkyl group;
R 5 is hydrogen, C 1 -C 6 alkyl,
or —C(O)—NH—R 6
wherein m is an integer from about 1 to about 3, X is halogen and R 6 is a C 1 -C 6 alkyl group; and
Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and n is 2 or 3.
86 . The method of claim 85 , wherein said pain or discomfort is pain.
87 . The method of claim 86 , wherein said pain is visceral pain.
88 . The method of claim 85 , wherein said administering is in one, two, three, or four dosages.
89 . The method of claim 85 , wherein said administering is every day.
90 . The method of claim 85 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
91 . The method of claim 85 , wherein said administering is oral.
92 . The method of claim 85 , wherein the functional bowel disorder is irritable bowel syndrome.
93 . The method of claim 92 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
94 . The method of claim 92 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
95 . The method of claim 92 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.
96 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.1 mg to about 50 mg per day of a compound of formula II:
or a pharmaceutically effective salt thereof to a human subject in need thereof.
97 . The method of claim 96 , wherein said pain or discomfort is pain.
98 . The method of claim 97 , wherein said pain is visceral pain.
99 . The method of claim 96 , wherein said administering is in one, two, three, or four dosages.
100 . The method of claim 96 , wherein said administering is every day.
101 . The method of claim 96 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
102 . The method of claim 96 , wherein said administering is oral.
103 . The method of claim 96 , wherein the functional bowel disorder is irritable bowel syndrome.
104 . The method of claim 103 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
105 . The method of claim 103 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
106 . The method of claim 103 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.
107 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.5 mg to about 10 mg per day of a compound of formula I:
or a pharmaceutically effective salt thereof to a human subject in need thereof,
wherein R 1 and R 2 independently represent hydrogen, halogen or a C 1 -C 6 alkyl group; or R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;
R 3 and R 4 independently represent hydrogen or a C 1 -C 6 alkyl group;
R 5 is hydrogen, C 1 -C 6 alkyl,
or —C(O)—NH—R 6
wherein m is an integer from about 1 to about 3, X is halogen and R 6 is a C 1 -C 6 alkyl group; and
Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and n is 2 or 3.
108 . The method of claim 107 , wherein said pain or discomfort is pain.
109 . The method of claim 108 , wherein said pain is visceral pain.
110 . The method of claim 107 , wherein said administering is in one, two, three, or four dosages.
111 . The method of claim 107 , wherein said administering is every day.
112 . The method of claim 107 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
113 . The method of claim 107 , wherein said administering is oral.
114 . The method of claim 113 , wherein 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg is administered.
115 . The method of claim 107 , wherein the functional bowel disorder is irritable bowel syndrome.
116 . The method of claim 115 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
117 . The method of claim 115 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
118 . The method of claim 115 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.
119 . A method for treating pain or discomfort associated with a functional bowel disorder comprising administering from about 0.5 mg to about 10 mg per day of a compound of formula II:
or a pharmaceutically effective salt thereof to a human subject in need thereof.
120 . The method of claim 119 , wherein said pain or discomfort is pain.
121 . The method of claim 120 , wherein said pain is visceral pain.
122 . The method of claim 119 , wherein said administering is in one, two, three, or four dosages.
123 . The method of claim 119 , wherein said administering is every day.
124 . The method of claim 119 , wherein said administering is every other day, every 2 days, every 3 days, every 4 days, or every 5 days.
125 . The method of claim 119 , wherein said administering is oral.
126 . The method of claim 125 , wherein 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg is administered.
127 . The method of claim 119 , wherein the functional bowel disorder is irritable bowel syndrome.
128 . The method of claim 127 , wherein the irritable bowel syndrome is diarrhea predominant irritable bowel syndrome.
129 . The method of claim 127 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
130 . The method of claim 127 , wherein the irritable bowel syndrome is nonconstipated irritable bowel syndrome.