Thiadiazoline derivative

1 . An antitumor agent comprising a thiadiazoline derivative represented by the general formula (I), or a pharmacologically acceptable salt thereof as an active ingredient:

<wherein Z represents a sulfur atom or —S(═O)—, R 1 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or —C(═W)R 5 {wherein W represents an oxygen atom or a sulfur atom, and R 5 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl,

—YR 6 (wherein Y represents an oxygen atom or a sulfur atom, and R 6 represents 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 —NR 7 R 8 [wherein R 7 and R 8 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, —OR 9 (wherein R 9 has the same meaning as that of the aforementioned R 6 ), or —NR 10 R 11 (wherein R 10 and R 11 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 10 and R 11 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group), or R 7 and R 8 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group]}, R 2 represents a hydrogen atom, substituted or unsubstituted lower alkyl, or —C(═W 1 )R 12 [wherein W 1 represents an oxygen atom or a sulfur atom, R 12 represents 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, —Y 1 R 13 (wherein Y 1 represents an oxygen atom or a sulfur atom, and R 13 represents 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 —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, or 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)],

R 3 represents 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, and R 4 represents 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 3 and R 4 are combined together to represent —(CR 16A R 16B ) m1 -Q-(CR 16C R 16D ) m2 — {wherein Q represents a single bond, substituted or unsubstituted phenylene, or cycloalkylene, m1 and m2 are the same or different, and each represents an integer of 0 to 4, with the proviso that m1 and m2 are not 0 at the same time,

R 16A , R 16B , R 16C and R 16D are the same or different, and represent a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, —OR 17 [wherein R 17 represents 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, —CONR 18 R 19 (wherein R 18 and R 19 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 18 and R 19 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group),

—SO 2 NR 20 R 21 (wherein R 20 and R 21 have the same meanings as those of the aforementioned R 18 and R 19 , respectively), or —COR 22 (wherein R 22 represents 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)], —NR 23 R 24 [wherein R 23 and R 24 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 25 (wherein R 25 represents 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, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, amino, substituted or unsubstituted lower alkylamino, di-(substituted or unsubstituted lower alkyl)amino, or substituted or unsubstituted arylamino), or —SO 2 R 26 (wherein R 26 represents 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 23 and R 24 are combined together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group], or —CO 2 R 27 (wherein R 27 represents 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 16A and R 16B , or R 16C and R 16D are combined together to represent an oxygen atom, and when m1 or m2 is an integer of 2 or more, any of R 16A , R 16B , R 16C and R 16D may be the same or different, and any two of R 16A , R 16B , R 16C and R 16D which are bound to the adjacent two carbon atoms may combine together to form a bond}>.

2 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group.

3 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or —C(═W)R 5 (wherein W and R 5 have the same meanings as those mentioned above).

4 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group.

5 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted aryl.

6 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted lower alkynyl.

7 . The antitumor agent according to claim 1 , wherein R 1 is substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkenyl.

8 . The antitumor agent according to claim 1 , wherein R 2 is a hydrogen atom, substituted or unsubstituted lower alkyl, or —C(═W 1 )R 12 (wherein W 1 and R 12 have the same meanings as those mentioned above, respectively).

9 . The antitumor agent according to claim 1 , wherein R 2 is —C(═W 1 )R 12 (wherein W 1 and R 12 have the same meanings as those mentioned above, respectively).

10 . The antitumor agent according to claim 8 , wherein R 12 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or substituted or unsubstituted cycloalkyl.

11 . The antitumor agent according to claim 8 , wherein R 12 is substituted or unsubstituted lower alkyl.

12 . The antitumor agent according to claim 8 , wherein R 12 is lower alkyl.

13 . The antitumor agent according to claim 8 , wherein W 1 is an oxygen atom.

14 . The antitumor agent according to claim 1 , wherein R 3 is 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.

15 . The antitumor agent according to claim 1 , wherein R 3 is substituted or unsubstituted lower alkyl.

16 . The antitumor agent according to claim 1 , wherein R 3 is substituted lower alkyl.

17 . The antitumor agent according to claim 1 , wherein R 4 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group.

18 . The antitumor agent according to claim 1 , wherein R 4 is substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group.

19 . The antitumor agent according to claim 1 , wherein R 4 is substituted or unsubstituted phenyl, or substituted or unsubstituted thienyl.

20 . The antitumor agent according to claim 1 , wherein R 3 and R 4 are combined together to represent —(CR 16A R 16B ) m1 -Q-(CR 16B R 16D ) m2 — (wherein Q, R 16A , R 16B , R 16C , R 16D , m1 and m2 have the same meanings as those mentioned above, respectively).

21 . The antitumor agent according to claim 1 , wherein R 3 and R 4 are combined together to represent —(CH 2 ) m1 -Q-(CH 2 ) m2 — (wherein Q, m1 and m2 have the same meanings as those mentioned above, respectively).

22 . The antitumor agent according to claim 20 , wherein Q is substituted or unsubstituted phenylene.

23 . A mitotic kinesin Eg5 inhibitor comprising the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.

24 . A thiadiazoline derivative represented by the formula (IA) or a pharmacologically acceptable salt thereof:

{wherein Z has the same meaning as that mentioned above,

R 1 has the same meaning as that mentioned above,

(A) when R 1 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or —C(═W)R 5 (wherein W and R 5 have the same meanings as those mentioned above, respectively), R 2A , R 3A and R 4A have the same meanings as those of the aforementioned R 2 , R 3 and R 4 (with proviso that Z A is a sulfur atom, R 1 is benzyl, R 2A is acetyl, one of R 3 and R 4A is methyl, and the other of R 3 and R 4A is not 2-oxopropyl), respectively

(B) when R 1 is substituted or unsubstituted lower alkynyl, or a substituted or unsubstituted aromatic heterocyclic group, R 2A and R 3A have the same meanings as those of the aforementioned R 2 and R 3 , respectively, and R 4A represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, and

(C) when R 1 is substituted or unsubstituted aryl, R 2A represents —C(═W)R 12 (wherein W and R 12 have the same meanings as those mentioned above, respectively), R 3A represents —(CH 2 ) k NHSO 2 R 3B [wherein k represents an integer of 1 to 6, and R 3B represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, or —NR 7B R 8B (wherein R 7B and R 8B have the same meanings as those of the aforementioned R 7 and R 8 , respectively)], —(CH 2 ) k NR 7C R 8C (wherein k has the same meaning as that mentioned above, and R 7C and R 8C have the same meanings as those of the aforementioned R 7 and R 8 , respectively), or —(CH 2 ) k NHC(═O)R 7D (wherein k has the same meaning as that mentioned above, and R 7D has the same meaning as that of the aforementioned R 7 ), and R 4A has the same meaning as that of the aforementioned R 4 }.

25 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein Z is a sulfur atom.

26 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group.

27 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is substituted or unsubstituted aryl.

28 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is substituted or unsubstituted phenyl.

29 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is substituted or unsubstituted lower alkynyl.

30 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is substituted lower alkyl.

31 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 1 is —C(═W)R 5 (wherein W and R 5 have the same meanings as those mentioned above, respectively).

32 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 31 , wherein W is an oxygen atom.

33 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 31 , wherein R 5 is —NR 7 R 8 (wherein R 7 and R 8 have the same meanings as those mentioned above, respectively).

34 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 2A is —C(═O)R 12 (wherein R 12 have the same meanings as those mentioned above).

35 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 34 , wherein R 12 is lower alkyl.

36 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 3A is substituted or unsubstituted lower alkyl.

37 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 3A is —(CH 2 ) k NHSO 2 R 3B (wherein k and R 3B have the same meanings as those mentioned above, respectively), —(CH 2 ) k NR 7B R 8C (wherein k, R 7C and R 8C have the same meanings as those mentioned above, respectively), or —(CH 2 ) k NHC(═O)R 7D (wherein k and R 7D have the same meanings as those mentioned above, respectively).

38 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 3A is —(CH 2 ) k NHSO 2 R 3B (wherein k and R 3B have the same meanings as those mentioned above, respectively).

39 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 4A is substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group.

40 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 4A is substituted or unsubstituted aryl.

41 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 4A is substituted or unsubstituted phenyl, or substituted or unsubstituted thienyl.

42 . The thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 , wherein R 4A is phenyl.

43 . A medicament comprising the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 as an active ingredient.

44 . A mitotic kinesin Eg5 inhibitor comprising the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 as an active ingredient.

45 . A therapeutic agent for a disease involving cell proliferation comprising the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 as an active ingredient.

46 . An antitumor agent comprising the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 as an active ingredient.

47 . A method for therapeutic and/or preventive 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 .

48 . 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 .

49 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 for the manufacture of an antitumor agent.

50 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 1 for the manufacture of a mitotic kinesin Eg5 inhibitor.

51 . 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 24 .

52 . A method for therapeutic and/or preventive treatment of a disease involving cell proliferation which comprises administering an effective amount of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 .

53 . A method for therapeutic and/or preventive treatment of a malignant tumor which comprises administering an effective amount of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 .

54 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 for the manufacture of a mitotic kinesin Eg5 inhibitor.

55 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 for the manufacture of a therapeutic agent for a disease involving cell proliferation.

56 . Use of the thiadiazoline derivative or a pharmacologically acceptable salt thereof according to claim 24 for the manufacture of an antitumor agent.