Thiadiazoline Derivative
A thiadiazoline derivative represented by the general formula (I), or a pharmacologically acceptable salt thereof: [wherein R 1 represents a hydrogen atom and the like, R 2 represents a hydrogen atom, —COR 5 (wherein R 5 represents lower alkyl and the like) and the like, R 3 represents lower alkyl and the like, R 4 represents aryl and the like, A represents —(CH 2 ) n — (wherein n represents an integer of 1 to 6) and the like, and B represents —NR 6 R 7 (wherein R 6 and R 7 are the same or different and represent a hydrogen atom, lower alkyl and the like) and the like] is provided.
1 . A thiadiazoline derivative represented by the general formula (I), or a pharmacologically acceptable salt thereof:
<wherein,
R 1 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl,
R 2 represents a hydrogen atom, or —COR 5 (wherein R 5 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl), or
R 1 and R 2 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group,
R 3 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl,
R 4 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group,
A represents —(CH 2 ) n — (wherein n represents an integer of 1 to 6), or a group of the formula (II)
(wherein m represents an integer of 0 to 2, and Z represents CH or a nitrogen atom capable of binding to B), and
(i) when A is —(CH 2 ) n —, and n is 1 or 2,
B represents —NR 6 R 7 {wherein R 6 represents a hydrogen atom, or lower alkyl, R 7 represents substituted lower alkyl, —COR 8 [wherein R 8 represents substituted lower alkyl (provided that R 8 is not trifluoromethyl), substituted lower alkoxy, substituted or unsubstituted aryloxy, a substituted or unsubstituted heterocyclic group, or
—NR 9 R 10 (wherein R 9 and R 10 are the same or different, and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R 9 and R 10 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group)], or R 6 and R 7 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group},
—OR 11 (wherein R 11 represents substituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkylcarbamoyl, substituted or unsubstituted di-(lower alkyl)carbamoyl, or substituted or unsubstituted heterocyclylcarbonyl),
—SR 12 (wherein R 12 has the same meaning as that of the aforementioned R 11 ), or
CH═NR 13 (wherein R 13 represents hydroxy, or substituted or unsubstituted lower alkoxy),
(ii) when A is —(CH 2 ) n —, and n is an integer of 3 to 6,
B represents —NR 14 R 15 {wherein R 14 and R 15 are the same or different, and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, —COR 16 [wherein R 16 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, or —NR 17 R 18 (wherein R 17 and R 18 are the same or different, and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or R 17 and R 18 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group)], or —SO 2 R 19 [wherein R 19 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or —NR 20 R 21 (wherein R 20 and R 21 are the same or different, and represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl, or R 20 and R 21 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group)], or R 14 and R 15 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group},
—OR 22 (wherein R 22 has the same meaning as that of the aforementioned R 11 ),
—SR 23 (wherein R 23 has the same meaning as that of the aforementioned R 11 ), or
—CH═NR 24 (wherein R 24 has the same meaning as that of the aforementioned R 13 ),
(iii) when A is a group of the formula (II),
B represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, or substituted or unsubstituted lower alkylsulfonyl>.
2 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 1 is a hydrogen atom, or lower alkyl.
3 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 2 is —COR 5 (wherein R 5 has the same meaning as that mentioned above).
4 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 3 , wherein R 5 is lower alkyl.
5 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 3 , wherein R 5 is tert-butyl.
6 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 3 is lower alkyl.
7 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 3 is tert-butyl.
8 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 4 is substituted or unsubstituted aryl.
9 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 4 is phenyl.
10 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein A is —(CH 2 ) n — (wherein n has the same meaning as that mentioned above).
11 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 10 , wherein n is 1 or 2.
12 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 11 , wherein B is —NR 6 R 7 (wherein R 6 and R 7 have the same meanings as those mentioned above, respectively).
13 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 12 , wherein R 6 is a hydrogen atom.
14 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 12 , wherein R 7 is —COR 8 (wherein R 8 has the same meaning as that mentioned above).
15 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 12 , wherein R 6 and R 7 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group.
16 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 10 , wherein n is an integer of 3 to 6.
17 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 10 , wherein n is 3.
18 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 16 , wherein B is —NR 14 R 15 (wherein R 14 and R 15 have the same meanings as those mentioned above, respectively).
19 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 18 , wherein R 14 is a hydrogen atom.
20 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 18 , wherein R 15 is substituted or unsubstituted lower alkyl.
21 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 18 , wherein R 15 is —COR 16 (wherein R 16 has the same meaning as that mentioned above).
22 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 21 , wherein R 16 is a substituted or unsubstituted heterocyclic group.
23 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 21 , wherein R 16 is —NR 17 R 18 (wherein R 17 and R 18 have the same meanings as those mentioned above, respectively).
24 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 18 , wherein R 15 is —SO 2 R 19 (wherein R 19 has the same meaning as that mentioned above).
25 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 , wherein A is a group of the formula (II).
26 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 25 , wherein Z is a nitrogen atom.
27 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 25 , wherein B is a hydrogen atom, or substituted or unsubstituted lower alkyl.
28 . A pharmaceutical composition which comprises the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
29 . A mitotic kinesin Eg5 inhibitor which comprises the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
30 . An antitumor agent which comprises the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
31 . A method for inhibiting a mitotic kinesin Eg5 which comprises administering an effective amount of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 .
32 . A method for therapeutic treatment of a malignant tumor which comprises administering an effective amount of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 .
33 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 for the manufacture of a mitotic kinesin Eg5 inhibitor.
34 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 for the manufacture of the antitumor agent.