Bisaryl compound and medicament for cancer treatment comprising the same

Abstract

A medicament for treatment of cancer comprising a compound represented by the following general formula (I) or a physiologically acceptable salt thereof: Ar 1 —S—R 1 —S—Ar 2 wherein R 1 represents a nonmetal bridging group; Ar 1 and Ar 2 independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring; and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group, and said heteroaryl group may have one to three substituents other than hydroxyl group on its ring.

What is claimed is:  
     
         1 . A medicament for treatment of cancer comprising a compound represented by the following general formula (I) or a physiologically acceptable salt thereof:  
       Ar 1 —S—R 1 —S—Ar 2    wherein R 1  represents a nonmetal bridging group; Ar 1  and Ar 2  independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring; and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said heteroaryl group may have one to three substituents other than hydroxyl group on its ring.    
     
     
         2 . The medicament for treatment of cancer according to  claim 1  comprising a compound or a physiologically acceptable salt thereof, wherein R 1  is represented by the general formula (II):  
       —R 2 —N(R 4 )—R 3 —  (II)  wherein R 2  and R 3  independently represent a divalent group; R 4  represents a monovalent group; and R 4  may bind to R 2  or R 3  to form a cyclic structure which may further bind to one or two C 1-4  alkylene groups to form a divalent group.    
     
     
         3 . The medicament for treatment of cancer according to  claim 1  comprising a compound or a physiologically acceptable salt thereof, wherein R 1  is represented by the general formula (III):  
       —R 5 —X 1 —R 6 —  (III)  wherein R 5  and R 6  independently represent a single bond or a divalent group not containing a nitrogen atom; X 1  represents an oxygen atom, S(O) k  wherein k represents an integer of from 0 to 2, or [(R 9 X 2 ) m (R 10 X 3 ) n (R 11 X 4 ) p ] q  wherein R 9 , R 10  and R 11  independently represent a single bond or a divalent group not containing a nitrogen atom, and any groups selected from R 5 , R 6 , R 9 , R 10  and R 11  may bind together to form a cyclic structure, X 2 , X 3  and X 4  independently represent an oxygen atom, S(O) r  wherein r represents an integer of from 0 to 2, or a single bond, and m, n, p and q independently represent an integer of from 1 to 3.    
     
     
         4 . The medicament for treatment of cancer according to  claim 1  comprising a compound or a physiologically acceptable salt thereof, wherein R 1  is 2,6-pyridinediyldimethyl group wherein the pyridinediyldimethyl group may have one to three substituents other than hydrogen atom on its ring.  
     
     
         5 . The medicament for treatment of cancer according to  claim 2  comprising a compound or a physiologically acceptable salt thereof, wherein R 2  and R 3  are the same divalent groups; and R 4  is a C 1-4  alkyl group which may have one to three substituents other than hydrogen atom.  
     
     
         6 . The medicament for treatment of cancer according to  claim 2  comprising a compound or a physiologically acceptable salt thereof, wherein R 2  and R 3  are the same divalent groups; R 4  is represented by COR 26  wherein R 25  represents hydrogen atom, a C 1-4  alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aralkyl group, or NR 26 R 27  wherein R 26  and R 27  each represent hydrogen atom, a C 1-4  alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, or an aralkyl group, and said alkyl group, aryl group, heteroaryl group, heterocyclic group, and aralkyl group including those for R 26  and R 27  may have one to three substituents other than hydrogen atom.  
     
     
         7 . The medicament for treatment of cancer according to  claim 1  comprising a compound or a physiologically acceptable salt thereof, wherein R 1  is represented by R 1A —R 1B CO—R 1C —R 1D —R 1C —COR 1B —R 1A  wherein R 1A  represents a C 1-4  lower alkylene group; R 1B  represents NH or methylene group; R 1C  represents a single bond or methylene group; R 1D  represents a divalent bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, or heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, or heterocyclic group may have one to three substituents other than hydrogen atom.  
     
     
         8 . The medicament for treatment of cancer according to any one of claims  1  to 7 comprising a compound or a physiologically acceptable salt thereof, wherein Ar 1  and Ar 2  independently represent the aryl group.  
     
     
         9 . The medicament for treatment of cancer according to  claim 8  comprising a compound or a physiologically acceptable salt thereof, wherein both of Ar 1  and Ar 2  are 4-hydroxyphenyl groups.  
     
     
         10 . The medicament for treatment of cancer according to  claim 8  or  claim 9  comprising a compound or a physiologically acceptable salt thereof, wherein R 2  and R 3  are the same groups, and the minimum number of bridge-forming atoms of R 2  and R 3  are from 1 to 10.  
     
     
         11 . The medicament for treatment of cancer according to  claim 10  comprising a compound or a physiologically acceptable salt thereof, wherein R 2  and R 3  are the same groups, and the minimum number of bridge-forming atoms of R 2  and R 3  are from 1 to 4.  
     
     
         12 . The medicament for treatment of cancer according to  claim 10  or  claim 11  comprising a compound or a physiologically acceptable salt thereof, wherein R 2  and R 3  are the same linear or branched divalent groups which may contain one to three oxygen atoms.  
     
     
         13 . The medicament for treatment of cancer according to any one of claims  1  to 12 comprising a compound or a physiologically acceptable salt thereof, wherein the total number of carbon atoms is 35 or less.  
     
     
         14 . The medicament for treatment of cancer according to any one of  claims 1  to  12 , which is in the form of a pharmaceutical composition comprising the compound according to any one of  claims 1  to  13  or a physiologically acceptable salt thereof as an active ingredient together with one or more pharmaceutical additives.  
     
     
         15 . Use of the compound according to any one of  claims 1  to  13  or a salt thereof for the manufacture of the medicament for treatment of cancer according to any one of  claims 1  to  14 .  
     
     
         16 . A ribonucleotide reductase inhibitor which comprises the compound according to any one of  claims 1  to  13  or a salt thereof.  
     
     
         17 . The medicament for treatment of cancer according to any one of  claims 1  to  14 , which is used for preventive and/or therapeutic treatment of a disease caused by over-expression of ribonucleotide reductase.  
     
     
         18 . A selective cancer cell proliferation inhibitor which comprises the compound according to any one of  claims 1  to  13  or a salt thereof.  
     
     
         19 . A method for treatment of a cancer which comprises the step of administering a therapeutically effective amount of the compound according to any one of  claims 1  to  13  or a salt thereof to a patient.  
     
     
         20 . A compound represented by the general formula (XII) or a salt thereof:  
       Ar 23 —S—R 22 —N(R 24 )—R 23 —S—Ar 24   
       wherein R 22  and R 23  independently represent a divalent group; R 24  represents a monovalent group or a monovalent atom; R 24  may bind to R 22  and/or R 23  to form a cyclic structure, which may further bind to one or two C 1-4  alkylene groups to form a divalent group; Ar 23  and Ar 24  independently represent a group selected from the group consisting of an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring, and a heteroaryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said heteroaryl group may have one to three substituents other than hydroxyl group on its ring, provided that R 22 —N(R 24 )—R 23  except for the part of R 24  does not contain an amide bond when R 22  and R 23  do not form a ring, and provided that when Ar 23  and Ar 24  is independently a phenyl group having one hydroxyl group on the ring, not all of said phenyl groups have a tertiary alkyl group at a position on the ring adjacent to the hydroxyl group.  
     
     
         21 . The compound or the salt thereof according to  claim 20 , wherein two or three groups selected from the group consisting of R 22,  R 23  and R 24  form a ring.  
     
     
         22 . The compound or the salt thereof, wherein R 22  and R 23  are the same divalent groups; and R 2   4  is a C 1-4  alkyl group which may have one to three substituents other than hydrogen atom.  
     
     
         23 . The compound or the salt thereof, wherein R 22  and R 23  are the same divalent groups; R 24  is represented by COR 125  wherein R 126  represents hydrogen atom, a C 1-4  alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, an aralkyl group, or NR 126 R 127  wherein R 126  and R 127  each represent hydrogen atom, a C 1-4  alkyl group, an aryl group, a heteroaryl group, a heterocyclic group, or an aralkyl group, and said alkyl group, aryl group, heteroaryl group, heterocyclic group, and aralkyl group including those for R 126  and R 127  may have one to three substituents other than hydrogen atom.  
     
     
         24 . The compound or the salt thereof, wherein R 22 —N(R 24 )—R 23  is represented by R 101A —R 101B CO—R 101C —R 101D —R 101C —COR 101B —R 101A  wherein R 101A  represents a C 1-4  lower alkylene group; R 101B  represents NH or methylene group; R 101C  represents a single bond or methylene group; R 101D  represents a divalent bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, or heterocyclic group, and said bridging cyclic hydrocarbon group, monocyclic hydrocarbon group, or heterocyclic group may have one to three substituents other than hydrogen atom.  
     
     
         25 . The compound or the salt thereof according to any one of  claims 20  to  24 , wherein Ar 23  and Ar 24  independently represent an aryl group which has, on its ring, one to three hydroxyl groups optionally substituted with a monovalent group and said aryl group may have one to three substituents other than hydroxyl group on its ring.  
     
     
         26 . The compound or the salt thereof according to  claim 25 , wherein both of Ar 23  and Ar 24  are 4-hydroxyphenyl groups.  
     
     
         27 . The compound or the salt thereof according to any one of  claims 20  to  26 , wherein R 22  and R 23  are the same groups, and the minimum number of bridge-forming atoms of R 22  and R 23  are from 1 to 10.  
     
     
         28 . The compound or the salt thereof according to  claim 27 , wherein R 22  and R 23  are the same groups, and the minimum number of bridge-forming atoms of R 22  and R 23  are from 1 to 4.  
     
     
         29 . The compound or the salt thereof according to any one of  claims 20  to  28 , wherein R22 and R 23  independently represent methylene group, ethylene group, propylene group or butylene group.  
     
     
         30 . The compound or the salt thereof according to any one of  claims 20  to  28 , wherein R 22  and R 23  are the same groups, and represent methylene group, ethylene group, propylene group or butylene group.  
     
     
         31 . The compound or the salt thereof according to any one of  claims 20  to  30 , wherein the total number of carbon atoms is 35 or less.