Bisaryl compound and medicament for cancer treatment comprising the same

A method for selectively inhibiting cancer cell proliferation by inhibiting ribonucleotide reductase comprising administering to a subject in need thereof an effective amount of a compound represented by formula (I), or a physiologically acceptable salt thereof:

• Ar1—S—R1—S—Ar2 (I)
• wherein R1 represents a nonmetal bridging group selected from —C2H4—S—C2H4—, —C2H4—S—C3H6—, —C2H4—S—C4H4—, —C2H4—S—C4H6—, —C2H4S—C4H8—, —C3H6—S—C3H6—, —C3H6—S—C4H6—, —C3H6—S—C4H8—, —C4H8—S—C4H8—, —CH2CO—S—C2H4—, —CH2CO—S—C3H6—, —CH2CO—S—C4H8—, —CH2CO—S—C4H6—, —CH2CO—S—C4H4—, —CH(CH3)CO—S—C2H4—, —C2H4CO—S—CH2CH(OH)CH2—, —CH2CO—S—C2H4NHCOCH2—, —C2H4CO—S—C2H4NHCOC2H4—, —C2H4O—C2H4—, —C2H4—O—C3H6—, —C2H4—O—C4H4—, —C2H4—O—C4H6—, —C2H4—O—C4H8—, —C3H6—O—C3H6—, —C3H6—O—C4H6—, —C3H6—O—C4H8—, —C4H8—O—C4H8—, —CH2CO—O—C2H4—, —CH2CO—O—C3H6—, —CH2CO—O—C4H8—, —CH2CO—O—C4H6—, —CH2CO—O—C4H4—, —CH(CH3)CO—O—C2H4—, —C2H4CO—O—CH2CH(OH)CH2—, —CH2CO—O—C2H4NHCOCH2, —C2H4CO—O—C2H4NHCOC2H4—;
• —R2—N(R4)—R3—, wherein R2, R3 and R4 are defined as follows:
• R2 R3 R4 —C2H4— —C2H4— —H— —C3H6— —C3H6— —H— —C4H8— —C4H8— —H— —C2H4— —C2H4— —OH— —C2H4— —C2H4— —C(═NH)NH2 —C2H4— —C2H4— —COC3H7 —C2H4— —C2H4— —COCH2CH2CO2H —C2H4— —C2H4— —COCH2CH2S—Ph—OH-p —C2H4— —C2H4— —CHO —C2H4— —C2H4— —COCH3 —C2H4— —C2H4— —SO2CH3 —C3H6— —C3H6— —CHO —C2H4— —C2H4— —CH2CH2NH2 —CH2CO— —C2H4— —H —CH2CO— —C3H6— —H —CH2CO— —C4H8— —H —CH2CO— —C4H6— —H —CH2CO— —C4H4— —H —CH2CO— —C4H4— —CHO —CH(CH3)CO— —C2H4— —H —CH(CH3)CO— —C2H4— —C2H4OH —C2H4CO— —CH2CH(OH)CH2— —C2H4OH —CH2CO— —C2H4NHCOCH2— —H —C2H4CO— —C2H4NHCOC2H4— —H —C2H4— —C2H4— —C2H5 —C2H4— —C2H4— —C3H7 —C2H4— —C2H4— —CH2—C≡CH —C2H4— —C2H4— —CH2—CH═CH2 —C2H4— —C2H4— —CH2-cyclopropyl —C2H4— —C2H4— —CH2—SO2NH2 —C2H4— —C2H4— —CH2—CN —C2H4— —C2H4— —C2H4—CO—NH2 —C2H4— —C2H4— —C2H4CO—N(CH3)2 —C2H4— —C2H4— —C2H4CO—N(C2H5)2 —C2H4— —C2H4— —CH2—CO—CH3 —C2H4— —C2H4— —C2H4—NH—CO—NH2 —C2H4— —C2H4— —C2H4—NH—CO—CH3 —C2H4— —C2H4— —CH2F —C2H4— —C2H4— —CF3 —C2H4— —C2H4— —C2H4-(N-succinimido) —C2H4— —C2H4— —C2H4—S—CH3 —C2H4— —C2H4— —CH2-ethyleneacetal —C2H4— —C2H4— —CH2-(2-thienyl) —C2H4— —C2H4— -furfuryl —C2H4— —C2H4— —CH2-(4-pyridyl) —C2H4— —C2H4— -o-hydroxybenzyl —C2H4— —C2H4— -m-hydroxybenzyl —C2H4— —C2H4— -p-hydroxybenzyl —C2H4— —C2H4— —(CH2)3—OH —C2H4— —C2H4— —CH2—NH—CO—CH3 —C2H4— —C2H4— —CH2—CO—NH2 —C2H4— —C2H4— -benzyl —C2H4— —C2H4— —CH2-(3-pyridyl) —C2H4— —C2H4— —CH2-(2-pyridyl) —C2H4— —C2H4— —CH2-(2-quinolinyl) —C2H4— —C2H4— —C2H4—OH —C2H4— —C2H4— —(CH2)3—OCH3 —C2H4— —C2H4— —C2H4—OCH3 —C2H4— —C2H4— -o-fluorobenzyl —C2H4— —C2H4— -p-fluorobenzyl —C2H4— —C2H4— —C2H4—CO-(N-morpholino) —C2H4— —C2H4— —C2H4—CO-(1-piperidyl) —C2H4— —C2H4— —C2H4—N(C2H5)2 —C2H4— —C2H4— —C2H4-(N-morpholino) —C2H4— —C2H4— —C2H4-(1-piperidyl) —C2H4— —C2H4— —CO—CH3 —C2H4— —C2H4— —CO—C2H5 —C2H4— —C2H4— —CO—C6H5 —C2H4— —C2H4— —CO-(2-pyridyl) —C2H4— —C2H4— —CO-(3-pyridyl) —C2H4— —C2H4— —CO-(4-pyridyl) —C2H4— —C2H4— —SO2—CH3 —C2H4— —C2H4— —SO2—C6H5 —C2H4— —C2H4— —CO—NH2 —C2H4— —C2H4— —CO—NH(CH3) —C2H4— —C2H4— —CO—N(CH3)2 —C2H4— —C2H4— —CO—N(C2H5)2 —C2H4— —C2H4— —CO-(N-morpholino) —C2H4— —C2H4— —CO-(1-piperidyl) —C2H4— —C2H4— —CO—NH—C6H5 —C2H4— —C2H4— —CO—NH-(2-pyridyl) —C2H4— —C2H4— —SO2—NH2 —C2H4— —C2H4— —SO2—N(C2H5)2 —C2H4— —C2H4— —SO2-(N-morpholino);
• —CH2—, —C2H4—, —C3H6—, —C4H8—, —C5H10—, —C6H12—, —C7H14—, —C8H16—, —C9H18—, —C10H20—, —C11H22, —C2H4—SO2—C2H4—SO2—C2H4—, —CH(CH3), —CH(C2H5)—, CH(n—C3H7)—, —CH(C6H5)—, —C(CH3)2—, —CH(COOH)—, CH(C2H4OH)—, —CH(CH3)—CH2—, —CH(C2H4OH)—CH2—, —CH(COOH)—CH2—, —CH(C2H5)—CH2—, —CH2—CH(OH)—CH2—, —CH2—C(CH2B)2—CH2, wherein B is p-hydroxyphenylthio, CH2—S—CH2—, —CH2—CH═CH—CH2—, —CH2—C≡C—CH2—, —CH2—C6H4—CH2— wherein —C6H4—, is an o-phenylene group, —C2H4—O—CH2—O—C2H4—, —C2H4—O—C2H4—O—C2H4—, —CH2—COO—C2H4—OCOCH2—, —CH2—COO—C3H6—OCOCH2—, —CH2CH(OH)CH2—O—C2H4—O—CH2CH(OH)CH2—, —(C2H4O)2—CO—CH2—CO—(C2H4O)2, —(C2H4O)2—CO—(trans)CH═CH—CO—(C2H4O)2—, —CH2—COO—(C2H4O)3—CO—CH2—, —CH2—COO—(C2H4O)4—CO—CH2—, —(C2H4O)3—C2H4—, —(C2H4O)4—C2H4—, —(C2H4O)5—C2H4—, —(C2H4O)3—CO—(C2H4O)3—, —(C2H4O)2—CO—C2H4—CO—(C2H4O)2, —CH2—CO—CO—CH2—, —CO—CH2—CO—,
• and Ar1 and Ar2 each represents a nonsubstituted 4-hydroxyphenyl group.

A method for treatment of ovarian or lung cancer comprising administering to a subject in need of treatment an effective amount of a compound represented by formula (I), or a physiologically acceptable salt thereof:

• Ar1—S—R1—S—Ar2 (I)
• wherein R1 represents a nonmetal bridging group selected from —C2H4—S—C2H4—, —C2H4—S—C3H6—, —C2H4—S—C4H4—, —C2H4—S—C4H6—, —C2H4S—C4H8—, —C3H6—S—C3H6—, —C3H6—S—C4H6—, —C3H6—S—C4H8—, —C4H8—S—C4H8—, —CH2CO—S—C2H4—, —CH2CO—S—C3H6—, —CH2CO—S—C4H8—, —CH2CO—S—C4H6—, —CH2CO—S—C4H4—, —CH(CH3)CO—S—C2H4—, —C2H4CO—S—CH2CH(OH)CH2—, —CH2CO—S—C2H4NHCOCH2—, —C2H4CO—S—C2H4NHCOC2H4—, —C2H4O—C2H4—, —C2H4—O—C3H6—, —C2H4—O—C4H4—, —C2H4—O—C4H6—, —C2H4—O—C4H8—, —C3H6—O—C3H6—, —C3H6—O—C4H6—, —C3H6—O—C4H8—, —C4H8—O—C4H8—, —CH2CO—O—C2H4—, —CH2CO—O—C3H6—, —CH2CO—O—C4H8—, —CH2CO—O—C4H6—, —CH2CO—O—C4H4—, —CH(CH3)CO—O—C2H4—, —C2H4CO—O—CH2CH(OH)CH2—, —CH2CO—O—C2H4NHCOCH2, —C2H4CO—O—C2H4NHCOC2H4—;
• —R2—N(R4)—R3—, wherein R2, R3 and R4 are defined as follows:
• R2 R3 R4 —C2H4— —C2H4— —H— —C3H6— —C3H6— —H— —C4H8— —C4H8— —H— —C2H4— —C2H4— —OH— —C2H4— —C2H4— —C(═NH)NH2 —C2H4— —C2H4— —COC3H7 —C2H4— —C2H4— —COCH2CH2CO2H —C2H4— —C2H4— —COCH2CH2S—Ph—OH-p —C2H4— —C2H4— —CHO —C2H4— —C2H4— —COCH3 —C2H4— —C2H4— —SO2CH3 —C3H6— —C3H6— —CHO —C2H4— —C2H4— —CH2CH2NH2 —CH2CO— —C2H4— —H —CH2CO— —C3H6— —H —CH2CO— —C4H8— —H —CH2CO— —C4H6— —H —CH2CO— —C4H4— —H —CH2CO— —C4H4— —CHO —CH(CH3)CO— —C2H4— —H —CH(CH3)CO— —C2H4— —C2H4OH —C2H4CO— —CH2CH(OH)CH2— —C2H4OH —CH2CO— —C2H4NHCOCH2— —H —C2H4CO— —C2H4NHCOC2H4— —H —C2H4— —C2H4— —C2H5 —C2H4— —C2H4— —C3H7 —C2H4— —C2H4— —CH2—C≡CH —C2H4— —C2H4— —CH2—CH═CH2 —C2H4— —C2H4— —CH2-cyclopropyl —C2H4— —C2H4— —CH2—SO2NH2 —C2H4— —C2H4— —CH2—CN —C2H4— —C2H4— —C2H4—CO—NH2 —C2H4— —C2H4— —C2H4CO—N(CH3)2 —C2H4— —C2H4— —C2H4CO—N(C2H5)2 —C2H4— —C2H4— —CH2—CO—CH3 —C2H4— —C2H4— —C2H4—NH—CO—NH2 —C2H4— —C2H4— —C2H4—NH—CO—CH3 —C2H4— —C2H4— —CH2F —C2H4— —C2H4— —CF3 —C2H4— —C2H4— —C2H4-(N-succinimido) —C2H4— —C2H4— —C2H4—S—CH3 —C2H4— —C2H4— —CH2-ethyleneacetal —C2H4— —C2H4— —CH2-(2-thienyl) —C2H4— —C2H4— -furfuryl —C2H4— —C2H4— —CH2-(4-pyridyl) —C2H4— —C2H4— -o-hydroxybenzyl —C2H4— —C2H4— -m-hydroxybenzyl —C2H4— —C2H4— -p-hydroxybenzyl —C2H4— —C2H4— —(CH2)3—OH —C2H4— —C2H4— —CH2—NH—CO—CH3 —C2H4— —C2H4— —CH2—CO—NH2 —C2H4— —C2H4— -benzyl —C2H4— —C2H4— —CH2-(3-pyridyl) —C2H4— —C2H4— —CH2-(2-pyridyl) —C2H4— —C2H4— —CH2-(2-quinolinyl) —C2H4— —C2H4— —C2H4—OH —C2H4— —C2H4— —(CH2)3—OCH3 —C2H4— —C2H4— —C2H4—OCH3 —C2H4— —C2H4— -o-fluorobenzyl —C2H4— —C2H4— -p-fluorobenzyl —C2H4— —C2H4— —C2H4—CO-(N-morpholino) —C2H4— —C2H4— —C2H4—CO-(1-piperidyl) —C2H4— —C2H4— —C2H4—N(C2H5)2 —C2H4— —C2H4— —C2H4-(N-morpholino) —C2H4— —C2H4— —C2H4-(1-piperidyl) —C2H4— —C2H4— —CO—CH3 —C2H4— —C2H4— —CO—C2H5 —C2H4— —C2H4— —CO—C6H5 —C2H4— —C2H4— —CO-(2-pyridyl) —C2H4— —C2H4— —CO-(3-pyridyl) —C2H4— —C2H4— —CO-(4-pyridyl) —C2H4— —C2H4— —SO2—CH3 —C2H4— —C2H4— —SO2—C6H5 —C2H4— —C2H4— —CO—NH2 —C2H4— —C2H4— —CO—NH(CH3) —C2H4— —C2H4— —CO—N(CH3)2 —C2H4— —C2H4— —CO—N(C2H5)2 —C2H4— —C2H4— —CO-(N-morpholino) —C2H4— —C2H4— —CO-(1-piperidyl) —C2H4— —C2H4— —CO—NH—C6H5 —C2H4— —C2H4— —CO—NH-(2-pyridyl) —C2H4— —C2H4— —SO2—NH2 —C2H4— —C2H4— —SO2—N(C2H5)2 —C2H4— —C2H4— —SO2-(N-morpholino);
• —CH2—, —C2H4—, —C3H6—, —C4H8—, —C5H10—, —C6H12—, —C7H14—, —C8H16—, —C9H18—, —C10H20—, —C11H22, —C2H4—SO2—C2H4—SO2—C2H4—, —CH(CH3), —CH(C2H5)—, CH(n—C3H7)—, —CH(C6H5)—, —C(CH3)2—, —CH(COOH)—, CH(C2H4OH)—, —CH(CH3)—CH2—, —CH(C2H4OH)—CH2—, —CH(COOH)—CH2—, —CH(C2H5)—CH2—, —CH2—CH(OH)—CH2—, —CH2—C(CH2B)2—CH2, wherein B is p-hydroxyphenylthio, CH2—S—CH2—, —CH2—CH═CH—CH2—, —CH2—C≡C—CH2—, —CH2—C6H4—CH2— wherein —C6H4—, is an o-phenylene group, —C2H4—O—CH2—O—C2H4—, —C2H4—O—C2H4—O—C2H4—, —CH2—COO—C2H4—OCOCH2—, —CH2—COO—C3H6—OCOCH2—, —CH2CH(OH)CH2—O—C2H4—O—CH2CH(OH)CH2—, —(C2H4O)2—CO—CH2—CO—(C2H4O)2, —(C2H4O)2—CO—(trans)CH═CH—CO—(C2H4O)2—, —CH2—COO—(C2H4O)3—CO—CH2—, —CH2—COO—(C2H4O)4—CO—CH2—, —(C2H4O)3—C2H4—, —(C2H4O)4—C2H4—, —(C2H4O)5—C2H4—, —(C2H4O)3—CO—(C2H4O)3—, —(C2H4O)2—CO—C2H4—CO—(C2H4O)2, —CH2—CO—CO—CH2—, —CO—CH2—CO—,
• and Ar1 and Ar2 each represents a nonsubstituted 4-hydroxyphenyl group.