THERAPEUTIC AGENT FOR IRRITABLE BOWEL SYNDROME
The present invention provides a therapeutic agent for irritable bowel syndrome which comprises, as an active ingredient, a compound having an adenosine uptake inhibitory activity, a therapeutic agent for irritable bowel syndrome which comprises, as an active ingredient, a tricyclic compound represented by formula (I) [wherein L represents —NHC(═O)— or the like, R 1 represents a hydrogen atom, halogen, or the like, X 1 —X 2 —X 3 represents S—CR 7 ═CR 8 (wherein R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or the like), or the like, Y represents —CH 2 SO 2 —, —SO 2 CH 2 — or the like, R 2 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or the like] or a pharmaceutically acceptable salt thereof, and the like.
1 - 37 . (canceled)
38 . A tricyclic compound represented by Formula (Ic)
{wherein L 1 represents an oxygen atom or a sulfur atom,
R 1c represents a hydrogen atom or substituted or unsubstituted lower alkyl,
X 1c —X 2c —X 3c represents O—CR 7 ═CR 8 [wherein R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted (lower alkanoyl)amino] or S—CR 7 ═CR 8 ,
Y c represents —CH 2 S—, —CH 2 SO— or —CH 2 SO 2 —, and
R 2c represents substituted or unsubstituted lower alkyl} or a pharmaceutically acceptable salt thereof.
39 . The tricyclic compound or the pharmaceutically acceptable salt thereof according to claim 38 , wherein R 1c is a hydrogen atom,
X 1c —X 2c —X 3c is S—CR 7c ═CR 8c (wherein R 7c and R 8c may be the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl),
Y c is —CH 2 SO 2 — and
R 2C is substituted or unsubstituted benzyl.
40 . A pharmaceutical composition which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 38 or 39 , and a pharmaceutically acceptable carrier.
41 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 38 or 39 to a patient in need thereof.
42 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 38 or 39 to a patient in need thereof.
43 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 38 or 39 to a patient in need thereof.
44 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 38 or 39 to a patient in need thereof.
45 . A tricyclic compound represented by Formula (Id)
[wherein R 9 represents a hydrogen atom or substituted or unsubstituted lower alkyl),
R 1d represents a hydrogen atom, or substituted or unsubstituted lower alkyl,
X 1d —X 2d —X 3d represents O—CR 7 ═CR 8 (wherein R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted (lower alkanoyl)amino) or S—CR 7 ═CR 8 ,
Y d represents —CH 2 S—, —CH 2 SO—, or —CH 2 SO 2 —, and
R 2d represents substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl] or a pharmaceutically acceptable salt thereof.
46 . The tricyclic compound or the pharmaceutically acceptable salt thereof according to claim 45 , wherein R 1d is a hydrogen atom, X 1d —X 2d —X 3d is S—CR 7d ═CR 8d (wherein R 1d and R 8d may be the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl),
Y d represents —CH 2 SO 2 — and
R 9 is a hydrogen atom.
47 . The tricyclic compound or the pharmaceutically acceptable salt thereof according to claim 46 , wherein R 2d is substituted or unsubstituted lower alkyl.
48 . The tricyclic compound or the pharmaceutically acceptable salt thereof according to claim 46 , wherein R 2d is substituted or unsubstituted aryl.
49 . A pharmaceutical composition which comprises, as an active ingredient, the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of claims 45 to 48 , and a pharmaceutically acceptable carrier.
50 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of claims 45 to 48 to a patient in need thereof.
51 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of claims 45 to 48 to a patient in need thereof.
52 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of claims 45 to 48 to a patient in need thereof.
53 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in any of claims 45 to 48 to a patient in need thereof.
54 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of a compound having an adenosine uptake inhibitory activity to a patient in need thereof.
55 . A method for treating diarrhea which comprises a step of administering an effective amount of a compound having an adenosine uptake inhibitory activity to a patient in need thereof.
56 . A method for treating constipation which comprises a step of administering an effective amount of a compound having an adenosine uptake inhibitory activity to a patient in need thereof.
57 - 77 . (canceled)
78 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of a tricyclic compound represented by Formula (I)
{wherein L represents an oxygen atom, a sulfur atom, —N(R 9 )— (wherein R 9 represents a hydrogen atom or substituted or unsubstituted lower alkyl), —NHC(═O)— or —C(═O)NH—,
R 1 represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
X 1 —X 2 —X 3 represents CR 5 ═CR 6 —CR 7 ═CR 8 [wherein R 5 , R 6 , R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted (lower alkanoyl)amino], N(O) m ═CR 6 —CR 7 ═CR 8 (wherein m represents 0 or 1), CR 5 ═CR 6 —N(O) m ═CR 8 , CR 5 ═CR 6 —CR 7 ═N(O) m , CR 5 ═CR 6 —O, CR 5 ═CR 6 —S, O—CR 7 ═CR 8 , S—CR 7 ═CR 8 or O—CR 7 ═N,
Y represents —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 O—, —CH═CH—, —(CH 2 ) p —(wherein p represents an integer of 0 to 2), —SCH 2 —, —SOCH 2 —,
—SO 2 CH 2 — or —OCH 2 —, and
R 2 represents a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, or a substituted or unsubstituted heterocyclic group} or a pharmaceutically acceptable salt thereof to a patient in need thereof.
79 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 78 to a patient in need thereof.
80 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 78 to a patient in need thereof.
81 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 78 to a patient in need thereof.
82 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of a tricyclic compound represented by Formula (Ia)
[wherein R 1 represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
X 1 —X 2 —X 3 represents CR 5 ═CR 6 —CR 7 ═CR 8 [wherein R 5 , R 6 , R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted (lower alkanoyl)amino], N(O) m ═CR 6 —CR 7 ═CR 8 (wherein m represents 0 or 1), CR 5 ═CR 6 —N(O) m ═CR 8 , CR 5 ═CR 6 —CR 7 ═N(O) m , CR 5 ═CR 6 —O, CR 5 ═CR 6 —S, O—CR 7 ═CR 8 , S—CR 7 ═CR 8 or O—CR 7 ═N,
Y a represents —CH 2 SO 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —OCH 2 —, and
when Y a is —CH 2 SO 2 —, —SCH 2 —, —SOCH 2 — or —SO 2 CH 2 —,
R 2a represents a hydrogen atom, amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, a substituted or unsubstituted heteroalicyclic group, or a substituted or unsubstituted nitrogen-containing heterocyclic group, and
when Y a is —OCH 2 —,
R 2a represents a hydrogen atom, amino, trifluoromethyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono(substituted or unsubstituted lower alkyl)-substituted amino, di(substituted or unsubstituted lower alkyl)-substituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted nitrogen-containing heterocyclic group, or Formula (II)
(wherein n is 0 or 1; R 3 and R 4 may be the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl, or R 3 and R 4 may be combined together with the adjacent carbon atom thereto to form cycloalkyl; and Q represents halogen, amino, hydroxy, or substituted or unsubstituted lower alkoxy)] or a pharmaceutically acceptable salt thereof to a patient in need thereof.
83 . The method for treating irritable bowel syndrome according to claim 82 , wherein Y a is —CH 2 SO 2 —.
84 . The method for treating irritable bowel syndrome according to claim 83 , wherein R 1 is a hydrogen atom or halogen.
85 . The method for treating irritable bowel syndrome according to claim 83 , wherein R 1 is a hydrogen atom.
86 . The method for treating irritable bowel syndrome according to any of claims 82 to 85 , wherein X 1 —X 2 —X 3 is S—CR 7 ═CR 8 .
87 . The method for treating irritable bowel syndrome according to claim 86 , wherein R 2a is Formula (II)
88 . The method for treating irritable bowel syndrome according to claim 87 , wherein n is 0.
89 . The method for treating irritable bowel syndrome according to claim 88 , wherein R 3 is methyl, R 4 is trifluoromethyl, and Q is hydroxy.
90 . The method for treating irritable bowel syndrome according to claim 82 , wherein R 1 is a hydrogen atom, Y a is —CH 2 SO 2 —, X 1 —X 2 —X 3 is S—CR 7a ═CR 8a (wherein R 7a and R 8a each represents a hydrogen atom), and R 2a is Formula (III)
91 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 82 to a patient in need thereof.
92 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 82 to a patient in need thereof.
93 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 82 to a patient in need thereof.
94 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 90 to a patient in need thereof.
95 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 90 to a patient in need thereof.
96 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 90 to a patient in need thereof.
97 . A method for treating irritable bowel syndrome which comprises a step of administering an effective amount of a tricyclic compound represented by Formula (Ib)
[wherein R 1 represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy,
X 1 —X 2 —X 3 represents CR 5 ═CR 6 —CR 7 ═CR 8 [wherein R 5 , R 6 , R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, hydroxy, nitro, amino, mono(lower alkyl)-substituted amino, di(lower alkyl)-substituted amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, or substituted or unsubstituted (lower alkanoyl)amino], N(O) m ═CR 6 —CR 7 ═CR 8 (wherein m represents 0 or 1), CR 5 ═CR 6 —N(O) m ═CR 8 , CR 5 ═CR 6 —CR 7 ═N(O) m , CR 5 ═CR 6 —O, CR 5 ═CR 6 —S, O—CR 7 ═CR 8 , S—CR 7 ═CR 8 or O—CR 7 ═N,
Y b represents —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH═CH— or
—(CH 2 ) p — (wherein p has the same meaning as defined above), and
R 2b represents Formula (III)
or a pharmaceutically acceptable salt thereof to a patient in need thereof.
98 . The method for treating irritable bowel syndrome according to claim 97 , wherein X 1 —X 2 —X 3 is S—CR 7 ═CR 8 .
99 . The method for treating irritable bowel syndrome according to claim 98 , wherein Y b is —CH 2 S—.
100 . A method for treating diarrhea which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 97 to a patient in need thereof.
101 . A method for treating constipation which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 97 to a patient in need thereof.
102 . A method for inhibiting adenosine uptake which comprises a step of administering an effective amount of the tricyclic compound or the pharmaceutically acceptable salt thereof described in claim 97 to a patient in need thereof.