Patent EA-004303-B1 (EA)
Title: Hygromycin a derivatives as antibacterial agents
Inventor: HAYWARD MATTHEW MERRILL
IPC: C07H15/203
Filed: 1999-11-09
Abstract: 1. A compound of the formula or a pharmaceutically acceptable salt, prodrug or solvate thereof wherein: each X<1> is -CR<6>R<7>-, and X<2> is -O; R<1> is H or OH; R<2> is H or C1-C6 alkyl, each R<3> is independently selected from H, -(CR<6>R<7>)t(C6-C10 aryl), -(CR<6>R<7>)t(4-10 membered heterocyclic), -C(O)(CR<6>R<7>)t(C6-C10 aryl), and -C(O)NR<6>(CR<6>R<7>)t(C6-C10 aryl), wherein t is an integer ranging from 0 to 1, and aryl moieties of the foregoing R<3> groups are optionally substituted by 1 to 3 R<4> groups; each R<4> is independently selected from C1-C10 alkyl, halo, cyano, trifluoromethyl, C1-C6 alkoxy, -(CR<6>R<7>)m(C6-C10 aryl), and -C(O)(CR<6>R<7>)m(C6-C10 aryl), wherein m is 0; each R<6> and R<7> is independently H. 2. A compound according to claim 1 wherein R<3> is -(CR<6>R<7>)t(C6-C10 aryl) wherein t is as defined above, and said aryl group is optionally substituted by 1 R<4> group. 3. A compound according to claim 2 wherein said aryl group is a phenyl group optionally substituted by 1 R<4> group. 4. A compound according to claim 1 wherein R<3> is -(CR<6>R<7>)t(4-10 membered heterocyclic), wherein t is 0. 5. A compound according to claim 4 wherein said heterocyclic group is a pyridyl group. 6. A compound according to claim 1 wherein R<3> is -C(O))(CR<6>R<7>)t(C6-C10 aryl) wherein t is 0, and said aryl group is optionally substituted by 1 R<4> group. 7. A compound according to claim 6 wherein said aryl group is a phenyl group optionally substituted by 1 R<4> group. 8. A compound according to claim 1 wherein R<3> is -C(O)NR<6>(CR<6>R<7>)t(C6-C10 aryl) wherein t is 0. 9. A compound according to claim 8 wherein said aryl group is a phenyl group. 10. A compound according to claim 1 wherein said compound is selected from the group consisting of: 3-(4-((2S,3S,4S,5R)-3,4-Dihydroxy-5-(3-hydroxy-1-methyl-(1E)-propenyl)-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3) dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)5-(3-Benzyloxy-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3) dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)5-(3-(3-Chloro-benzyloxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)5-(3-(Biphenyl-2-ylmethoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)5-(3-(4-tert-Butyl-benzyloxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)5-(3-(4-Fluoro-benzyloxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; Benzoic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; 4-Methoxy-benzoic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; 2-Fluoro-benzoic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; 3-Chloro-benzoic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; 4-Trifluoromethyl-benzoic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; Benzyl-carbamic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; Phenyl-carbamic acid 3-((2S,3S,4S,5R)-3,4-dihydroxy-5-(2-hydroxy-4-(2-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-(1E)-propenyl)-phenoxy)-tetrahydro-furan-2-yl)-(2E)-but-2-enyl ester; 3-(4-((2S,3S,4S,5R)-5-(3-(3-Chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3-Fluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3,5-Difluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(4-Fluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(4-Chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2-Chloro-4-fluro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(4-Chloro-3-fluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3,5-Dichloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(pyridin-3-yloxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-{3-(3-chloro-4-fluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3-Methoxy-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2,4-Dichloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2,4-Difluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2-chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2,6-Difluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(3-chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2-Fluoro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(4-Fluoro-2-propyl-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-phenoxy-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2-Benzyl-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(2-Benzoyl-4-chloro-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(4-Cyano-phenoxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-3-hydroxy-phenyl)-2-methyl-N-((3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-yl)-(2E)-acrylamide; 3-(4-((2S,3S,4S,5R)-5-(3-(Indan-4-yloxy)-1-methyl-(1E)-propenyl)-3,4-dihydroxy-tetrahydro-