Patent EA-003305-B1 (EA)
Title: Hygromycin a derivatives
Inventor: BRIGHTY KATHERINE ELIZABETH
IPC: C07H15/203
Filed: 1999-05-03
Abstract: 1. A compound of the formula. or a pharmaceutically acceptable salt, prodrug or solvate thereof wherein: R<1> is H and R<2> is -NR<3>R<4>, -NR<4>C(O)R<3>, -OC(O)NR<3>R<4> or -OR<3>;or R<1> and R<2> are taken together to form =N-OR<3>, =CR<4>R<3>, =CR<4>C (O) R<3>, =CR<4>C (O) OR<3>, or =CR<4>C (O) NR<3>R<4>; each R<3> is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl,- (CH2)t (C3-C10cycloalkyl), -(CH2)t(C6-C10 aryl), and -(CH2)t (4-10-membered heterocyclic), wherein t is an integer ranging from 0 to 5, said alkyl group optionally contains 1 or 2 hetero moieties selected from O,-S (O)J- wherein j is an integer ranging from 0 to 2, and-N (R<7>)- with the proviso, that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R<3> groups are optionally fused to a benzene ring, a C5-C6 saturated cyclic group, or a 4-10-membered heterocyclic group; the- (CH2)t moieties of the foregoing R<3> groups optionally include a carbon-carbon double or triple bond where t is an integer between 2 and 5; and the foregoing R<3> groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 5 R<5> groups, with the proviso that R<3> is not H, methyl or ethyl where R<1> is H and R<2> is -OR<3>; each R<4> is independently H or C1-C10 alkyl; each R<5> is independently selected from C1-C10 alkyl, C3-C10 cycloalkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-OR<6>,-C (O) R<6>,-C (O) OR<6>, -NR<7>SO2R<9>,-SO2NR<6>R<7>,-NR<7>C(O)R<6>, -C(O)NR<6>R<7>, -NR<6>R<7>, NR<7>C(O)OR<9>,-OC(O)R<6>, -S (O)j (CH2)m (C10-C10 aryl),-S (O)j (C1-C6 alkyl), wherein j is an integer ranging from 0 to 2, -(CH2)m(C6-C10aryl), -O(CH2)m(C6-C10aryl), -NR<7>(CH2)m(C6-C10aryl),and-(CH2)m(4-10-membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally contains 1 or 2 hetero moieties selected from O,-S (O)j-, wherein j is an integer ranging from 0 to 2, and-N (R<7>)- with the proviso that two O atoms, two S atoms, or an O and S atoms are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R<5> groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10-membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R5 groups are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-NR<7>SO2R<9>,-SO2NR<6>R<7>,-C (O) R<6> , -C (O) OR<6>, -OC (O) R<6>, -NR<7>C (O) OR<6>,-NR<7>C (O) R<6>, -C (O) NR<6>R<7>, -NR<6>R<7>, -OR<6>, C1-C10 alkyl, -(CH2)m(C6-C10 aryl), and -(CH2)m(4-10-membered heterocyclic), wherein m is an integer ranging from 0 to 4; each R<6> is independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl,- (CH2)m(C6-C10 aryl), and- (CH2)m(4-10-membered heterocyclic), wherein m is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O,-S (O)j- , wherein j is an integer ranging from 0 to 2, and-N (R<7>)- with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said cycloalkyl, aryl and heterocyclic R<6> groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10-membered heterocyclic group; and the foregoing R<6> substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-C (O) R<7>, -C (O) OR<7>, -OC (O) R<7>, -NR<7>C (O) R<8>, -C (O) NR<7>R<8>, -NR<7>R<8>, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; each R<7> and R<8> is independently H or C1-C6 alkyl; and, R<9> is selected from the substituents provided in the definition of R<6> except H. 2. A compound according to claim 1 wherein R<1>and R<2> are taken together to form =N-OR<3>, and R<3> is C1-C4 alkyl, C2-C4 alkenyl, -(CH2)t(C6-C10 aryl) or -(CH2)t(4-10 membered heterocyclic), wherein t is an integer ranging from 0 to 3, the heterocyclic group is optionally fused to a benzene ring, the aryl group is optionally fused to a 5 or 6 membered heterocyclic group, and the foregoing R<3> groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from nitro, halo, C1-C3 alkoxy, C1-C4 alkyl, trifluoromethyl, acetamido, tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, tert-butoxycarbonyl, -NR<6>R<7>, phenyl, cyclohexyl, carboxy, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy, and phenylthio. 3. A compound according to claim 1 wherein R<1>and R<2> are taken together to form = N-OR<3>, and R<3> is - (CH2)t(C6-C10 aryl) or -(CH2)t(4-10-membered heterocyclic), wherein t is an integer ranging from 0 to 3, the heterocyclic group is optionally fused to a benzene ring, the aryl group is optionally fused to a 5 or 6 membered heterocyclic group, and the foregoing R3 groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from nitro, halo, C1-C3 alkoxy, C1-C4 alkyl, trifluoromethyl, acetamido, tert-butoxycarbonyl, tert-butoxycarbonylamino, -NR<6>R<7>, phenyl, cyclohexyl, carboxy, tert-butoxycarbonylaminomethyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy, and phenylthio. 4. A compound according to claim 1 wherein R<1> is H and R<2> is -NR<3>R<4>, R<4>is H or methyl, and R<3> is -(CH2)t(C6-C10 aryl) or -(CH2)t(4-10-membered heterocyclic), wherein t is an integer ranging from 0 to 2, and the R<3> group is optionally substituted by 1 to 5 substituents independently selected from halo, C1-C3 alkoxy, C1-C4 alkyl, and trifluoromethyl. 5. A compound according to claim 1 wherein R<1> is H and R<2> is -NR<4> C (O) R<3>, R<4> is H or methyl, and R<3> is C3-C6 cycloalkyl, -(CH2)t(C6-C10 aryl) or -(CH2)t (4-10-membered heterocyclic), wherein t is an integer ranging from 0 to 2, the aryl group is optionally fused to a 5 or 6-membered heterocyclic group, the heterocyclic group is optionally fused to a benzene ring, and the foregoing R<3> groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from halo, C1-C5 alkoxy, C1-C4 alkyl, and trifluoromethyl. 6. A compound according to claim 1 wherein R<1>and R<2> are taken together to form =CR<4>C (O) OR<3> or =CR<4>C (O) NR<3>R<4>, R<4> is H, and R<3> is H, Cl-C6 alkyl, C3-C5 cycloalkyl, -(CH2)t(4-10-membered heterocyclic), or -(CH2)t(C6-C10 aryl) wherein t is an integer ranging from 0 to 2, the aryl group is optionally fused to a 5 or 6-membered heterocyclic group, the heterocyclic group is optionally fused to a benzene ring, and the foregoing R<3> groups, except H but including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from halo, C1-C3 alkoxy, C1-C4 alkyl, -NR<6>R<7> and trifluoromethyl. 7. A compound according to claim 1 wherein R<1> is H, R<2> is -OR<3>, and R<3> is C1-C4 alkyl, - (CH2)t(4-10-membered heterocyclic), or- (CH2)t(C6-C10 aryl) wherein t is an integer ranging from 1 to 2, the aryl group is optionally fused to a 5 or 6 membered heterocyclic group, the heterocyclic group is optionally fused to a benzene ring, and the foregoing R<3> groups, including said optionally fused moieties, are optionally substituted by 1 to 5 substituents independently selected from halo, C1-C3 alkoxy, C1-C4 alkyl, cyclohexyl, cyano, trifluoromethyl, benzyloxy and trifluoromethyl. 8. A compound according to claim 1 wherein R<1> is H, R<2> -OC (O) NR<3>R<4>, R<4> is H, and R<3> is- (CH2)t (C6-C10 aryl) wherein t is an integer ranging from 0 to 2, and the R<3> group is optionally substituted by 1 to 5 substituents independently selected from halo, C1-C3 alkoxy, C1-C4 alkyl, and trifluoromethyl. 9. A compound according to claim 1 wherein said compound is selected from the group consisting of: 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2- (E)-propenyl] amino]-1,2-O-methylene-D-neo-inositoi, (Z)-O-[ (3-fluorophenyl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (E)-O-[ (3-fluorophenyl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3 hydroxyphenyl]-2-methyl-1-oxo-2- (E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (E)-O [(benzofuran-2-yl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (Z)-O- [ (benzofuran-2-yl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2- (E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (Z)-O-phenylmethyloxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2- (E)-propenyl](E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (E)-O- phenylmethyloxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-propenyl]amino]-1,2-O-methylene-D-neo-inositol,(Z)-O[ (4-chlorophenyl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-propenyl] amino]-1,2-O-methylene-D-neo-inositol, (Z)-O- [ (3, 4-dichlorophenyl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-propenyl]amino]-1,2-O-methylene-D-neo-inositol,(E)-O[ (3, 4-dichlorophenyl) methyl] oxime; 5-Deoxy-5-[[3-[4-[(6-deoxy-beta-D-arabino-hexofuranos-5-ulos-1-yl)oxy]-3-hydroxyphenyl]-2-methyl-1-oxo-2-(E)-p