Patent EA-004374-B1 (EA)
Title: 2"-deoxy hydromycin derivatives
Inventor: LINDE ROBERT GERALD II
IPC: C07H15/203
Filed: 1999-04-08
Abstract: 1. A compound of the formula or a pharmaceutically acceptable salt, prodrug, or solvate thereof wherein: R<1> and R<2> are taken together to form =N-OR<3>, =CR<4>R<3>; each R<3> is independently selected from H, C1-10 alkyl, (CH2)t(C3-10 cycloalkyl), and -(CH2)t(C6-C10 aryl), wherein t is an integer ranging from 0 to 5, said alkyl group optionally contains 1 or 2 -O-hetero moieties with the proviso that two O atoms are not attached directly to each other and said cycloalkyl, aryl and heterocyclic R<3> groups are optionally fused to a benzene ring, a C5-8 saturated cyclic group, or a 4-10 membered heterocyclic group containing C and O atoms; and the foregoing R<3> groups, including any optional fused rings referred to above, are optionally substituted by 1 to 5 R<5> groups; each R<5> is independently selected from C1-10 alkyl, halo, -OR<6>, -NR<6>R<7>, -(CH2)m(C6-C10-aryl) and -(CH2)m(4-10 membered heterocyclic), wherein m is an integer ranging from 0 to 4; R<5> aryl groups are optionally substituted by 1 to 5 substituents independently selected from halo; each R<6> is independently selected from C1-10 alkyl. 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, -(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 halo, C1-C3 alkoxy, piperidinyl, morpholino. 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(C6-10 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 halo, C1-C3 alkoxy, piperidinyl, morpholino. 4. A compound according to claim 1 wherein said compound is selected from the group consisting of: 5-Deoxy-5-[[3-[4-[(2, 6-dideoxy-beta-D-erythro-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 (4); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 (6); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 (6); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 (2); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-phenylmethyl]oxime (2); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 (28); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-difluorophenyl) methyl] oxime (19); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(1,3-benzodioxol-5-yl) methyl] oxime (3); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(1,3-benzodioxol-5-yl) methyl] oxime (3); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-chlorophenyl) methyl] oxime (1); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 -5-yl) methyl] oxime (6); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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 -5-yl) methyl] oxime (6); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-fluoro-4-methoxyphenyl) methyl] oxime (7); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-dihydro-2H-1-benzopyran-4-yl) methyl] oxime (5); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-chloro-4-fluorophenyl) methyl] oxime (27); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-chloro-5-fluorophenyl) methyl] oxime (29); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(3,5-diflurophenyl) methyl] oxime (20); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(2,4-difluorophenyl) propyl] oxime (16); 5-Deoxy-5-[[3-[4-[(2, 6-dideoxy-beta-D-erythro-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-[1-(3,4-difluorophenyl) ethyl] oxime (15); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[1-2,4-diflourophenyl) ethyl] oxime (14); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[1-(3,5-difluorophenyl) ethyl] oxime (17); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[1-(3chloro-2,6-difluorophrnyl) ethyl] oxime (18); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-chloro-2,6-difluorophenyl) methyl] oxime (22); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(2,4-difluorophenyl) methyl] oxime (21); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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-[(3chlorophenyl] oxime (23); 5-Deoxy-5-[[3-[4-[(2,6-dideoxy-beta-D-erythro-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] oxime (24); and the pharmaceutically acceptable salts, prodrugs and solvates of said compounds. 5. A pharmaceutical composition for the treatment of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or a protozoal infection, in a mammal, fish, or birds which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 6. A method of treating a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or a protozoal infection, in a mammal, fish, or birds which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of claim 1. 7. A method of preparing a compound of claim 1 wherein R<1> and R<2> are taken together to form =N-OR<3> which comprises treating a compound of the formula 4 wherein X is a protecting group, with a hydroxylamine of the formula H2N-OR<3>, or a salt of said hydroxylamine, where R<3> is as defined above, in an inert solvent with the optional addition of base if the salt of the hydroxylamine is used, at a temperature ranging from about 0 C to 65 degree C and subsequent deprotection using a fluoride source. 8. The method of claim 7 wherein said inert solvent is methanol, ethanol or pyridine, or a mixture of the foregoing solvents, said optional bases is Na2CO3 or K2CO3, said temperature range is from 50 C to 60 degree C, and said fluoride source is tetrabutylammonium fluoride or hydrogen fluoride-pyridine complex.