HK1036628A - 2"-deoxy hygromycin derivatives - Google Patents

2"-deoxy hygromycin derivatives Download PDF

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Publication number
HK1036628A
HK1036628A HK01107285.8A HK01107285A HK1036628A HK 1036628 A HK1036628 A HK 1036628A HK 01107285 A HK01107285 A HK 01107285A HK 1036628 A HK1036628 A HK 1036628A
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Hong Kong
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methyl
deoxy
amino
neoinositol
propenyl
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HK01107285.8A
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Chinese (zh)
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R‧G‧林德二世
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辉瑞产品公司
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Description

2' -deoxy hygromycin derivatives
Background
The present invention relates to novel 2' -deoxy hygromycin A derivatives which are useful as antibacterial and antiprotozoal agents in mammals, including humans, as well as in fish and birds. The invention is also directed to pharmaceutical compositions containing these novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering these novel compounds to mammals, fish and birds in need of such treatment.
The compounds of the invention may be derived from hygromycin a. Hygromycin A was a fermentation-derived natural product that was first isolated from Streptomyces hygroscopicus (Streptomyces hygroscopicus) in 1953. Hygromycin a has activity against human pathogens as an antibiotic, and it has been reported to have strong activity against treponema hyodysenteriae (serpulina (treponema)) causing swine dysentery in vitro. Several documents, including the following, are concerned with the semi-synthetic modification of hygromycin a: isono et al, in J.antibiotics 1957,10,21 and R.L.Mann and D.O.Woolf, in Proc.Chem.Soc.1957, 79,120, describe the reaction of derivatizing the 5 'ketone of hygromycin A to form 2, 4-dinitrophenylhydrazone, and K.Isono et al, in the above-mentioned reference, also mentions the 5' thiosemicarbazone; the reduction of the 5 "ketone of hygromycin a to a 5" alcohol is reported by r.l.man and d.o.woolf in the above-mentioned references and by s.j.hecker et al in bio-organic and medicinal chemistry communications (bioorg.med.chem.lett.)1992,2,533 and s.j.hecker et al in bio-organic and medicinal chemistry communications 1993,3, 295; jaynes et al report furanose analogues in bio-organic and medicinal chemistry communications 1993,3,1531 and b.h.jaynes et al in journal of antibiotics (j.antibiotic.), 1992,45, 1705; aromatic ring analogs are described in s.j.hecker et al, bio-organic and medicinal chemical communications 1993,3,289 and c.b.cooper et al, bio-organic and medicinal chemical communications 1997,7, 1747; hecker et al describe enamide analogues in bio-organic and medicinal chemistry communications 1992,2, 533; amino cyclic alcohol analogs are reported by s.j. hecker et al in bioorganic and medicinal chemistry communications 1992,2,1015 and s.j. hecker et al in bioorganic and medicinal chemistry communications 1992,2, 1043. The hygromycin derivatives of the invention are active against gram-positive and gram-negative bacteria as well as protozoa.
U.S. provisional patent application 60/084058 entitled "hygromycin A derivatives" (attorney docket number: PC10057), filed 5, 4, 1998, and entitled K.E.Brighty, R.G.Linde II, M.R.Jefson, E.L.McCormick, and S.S.Guhan, also relates to hygromycin A analogs, and is incorporated herein by reference.
Summary of The Invention
The present invention relates to compounds of the formula:wherein:
R1is H and R2is-NR3R4,-NR4C(O)R3,-OC(O)NR3R4OR-OR3；
Or R1And R2Together form = O, = N-OR3,=CR4R3,=CR4C(O)R3,=CR4C(O)OR3Or = CR4C(O)NR3R4；
R3Each independently selected from H, C1-C10Alkyl radical, C2-C10Alkenyl, - (CH)2)t(C3-C10Cycloalkyl) - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-to 10-membered hetero)Ring) wherein t is an integer from 0 to 5, said alkyl group optionally containing 1 or 2 substituents selected from O, -S (O)j- (wherein j is an integer of 0-2) and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R3The radicals being optionally substituted with benzene rings, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; r mentioned above3Of a group- (CH)2)t-the moiety optionally comprises a carbon-carbon double or triple bond when t is an integer from 2 to 5; r as defined above, other than H but including any of the optional fused rings as defined above3The radical being optionally substituted by 1 to 5R5Substituted by groups;
R4each independently is H or C1-C10An alkyl group;
R5each independently selected from C1-C10Alkyl radical, C3-C10Cycloalkyl, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR6,-C(O)R6,-C(O)OR6,-NR7C(O)OR9,-OC(O)R6,-NR7SO2R9,-SO2NR6R7,-NR7C(O)R6,-C(O)NR6R7,-NR6R7,-S(O)j(CH2)m(C6-C10Aryl radical, -S (O)j(C1-C6Alkyl) where j is an integer from 0 to 2, - (CH)2)m(C6-C10Aryl group, -O (CH)2)m(C6-C10Aryl), -NR7(CH2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle), wherein m is an integer of 0-4; said alkyl group optionally containing 1 or 2 members selected from the group consisting of O, -S (O)j- (wherein j is an integer of 0-2) and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R5The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; and the alkyl, cycloalkyl, aryl and heterocycle R5The group is optionally substituted with 1-5 substituents independently selected from: halogen, cyano, nitro, difluoromethoxy, trifluoromethyl, trifluoromethoxy, azido, -NR7SO2R9、-SO2NR6R7、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7C(O)OR9、-NR7C(O)R6、-C(O)NR6R7、-NR6R7、-OR6、C1-C10Alkyl, - (CH)2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle), wherein m is an integer of 0-4;
R6each independently selected from H, C1-C10Alkyl radical, C3-C10Cycloalkyl, - (CH)2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle), wherein m is an integer of 0-4; said alkyl group optionally containing 1 or 2 members selected from the group consisting of O, -S (O)j- (wherein j is an integer of 0-2) and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R6The radicals optionally being substituted by C6-C10Aryl radical, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; and the aforementioned R is other than H6The substituents are optionally substituted with 1-5 substituents independently selected from the group consisting of: halogen, cyano, nitro, difluoromethoxy, trifluoromethyl, trifluoromethoxy, azido, -C (O) R7、-C(O)OR7、-OC(O)R7、-NR7C(O)R8、-C(O)NR7R8、-NR7R8Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
R7and R8Each independently is H or C1-C6An alkyl group; and
R9is selected from R6Substituents in the definition, but not H.
Preferred compounds of formula 1 include those wherein R is1And R2Together form = N-OR3And R is3Is C1-C4Alkyl radical, C2-C4Alkenyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0 to 3, said heterocyclyl is optionally fused with a benzene ring, said aryl is optionally fused with a 5-or 6-membered heterocyclyl, and said R is as previously described including said optionally fused moiety3The group is optionally substituted with 1-5 substituents independently selected from: nitro, halogen, C1-C3Alkoxy radical, C1-C4Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, tert-butoxycarbonyl, -NR6R7Phenyl, cyclohexyl, carboxyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy, and thiophenyl.
Other preferred compounds of formula 1 include those wherein R is1And R2Together form = N-OR3And R is3Is- (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0 to 3, said heterocyclyl is optionally fused with a benzene ring, said aryl is optionally fused with a 5-or 6-membered heterocyclyl, and said R is as previously described including said optionally fused moiety3The group is optionally substituted with 1-5 substituents independently selected from: nitro, halogen, C1-C3Alkoxy radical, C1-C4Alkyl, difluoromethoxy, trifluoromethyl, acetylamino, tert-butoxycarbonyl, tert-butoxycarbonylamino, -NR6R7Phenyl, cyclohexyl, carboxyl, tert-butoxycarbonylaminomethyl, aminomethyl, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy and thiophenyl.
Other preferred compounds of formula 1 include those wherein R is1Is H, R2is-NR3R4,R4Is H or methyl, and R3Is- (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-2, and R3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
Other preferred compounds of formula 1 include those wherein R is1Is H, R2is-NR4C(O)R3,R4Is H, and R3Is C3-C6Cycloalkyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0-2, said aryl group being optionally fused with a 5-or 6-membered heterocyclyl group, said heterocyclyl group being optionally fused with a benzene ring, and the aforementioned R including said optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
Other preferred compounds of formula 1 include those wherein R is1And R2Together form = CR4C(O)OR3Or = CR4C(O)NR3R4,R4Is H, and R3Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl, - (CH)2)t(4-10 membered heterocycle) or- (CH)2)t(C6-C10Aryl) wherein t is an integer from 0 to 2, optionally fused with a 5-or 6-membered heterocyclic group optionally fused with a benzene ring, and the aforementioned R, excluding H but including the optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl, -NR6R7And preparation of trifluoromethylSubstituent groups.
Other preferred compounds of formula 1 include those wherein R is1Is H, R2is-OR3And R is3Is C1-C4Alkyl, - (CH)2)t(4-10 membered heterocycle) or- (CH)2)t(C6-C10Aryl) wherein t is an integer of 1 to 2, optionally fused with a 5-or 6-membered heterocyclic group optionally fused with a benzene ring, and the aforementioned R including the optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl, cyclohexyl, cyano, trifluoromethyl, benzyloxy, and trifluoromethyl.
Other preferred compounds of formula 1 include those wherein R is1Is H, R2is-OC (O) NR3R4,R4Is H, and R3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 0 to 2, and R3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
Particularly preferred compounds of formula 1 include compounds selected from the group consisting of:
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (benzofuran-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (benzofuran-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O-phenylmethyloxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O-phenylmethyloxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-pyridyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4- (4-morpholinyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ cyclohexylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (furan-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (furan-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-cyclohexylphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-aminophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ [ (4-aminomethyl) phenyl ] methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [3- (4-chlorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [3- (4-chlorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3- (trifluoromethoxy) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4- (1-piperidinyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [2- (phenylthio) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (benzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (benzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2-phenylpyrimidin-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluoro-4-methoxyphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-dihydro-2H-1-benzopyran-4-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (5, 6-dideoxy-5- (methyl (benzyl) amino- α -L-galactofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (5, 6-dideoxy-5-phenylamino- α -L-galactofuranose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-O- [ (3, 4-dichlorophenyl) methyl ] - β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (furan-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (5-methyl- β -D-erythro-furanhept-5- (E) -enolon-1-yluronic acid) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, ethyl ester;
5-deoxy-5- [ [3- [4- [ [ N- (furan-2-yl) methyl ] - (5-methyl- β -D-erythro-furanhept-5- (E) -enolic acid-1-yl-amide) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [3- (phenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (2-propen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (2-propen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-methylphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-methoxyphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3- (trifluoromethyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-O- [ (4-chlorophenyl) methyl ] - β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ benzhydryl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-phenylcarbamate- β -D-ribofuranose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5- [ (3, 4-dichlorophenyl) methyl ] carbamate- β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-5-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-5-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-dihydrobenzofuran-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-dihydrobenzofuran-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (1,2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (1,2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (7-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (7-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (7-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (7-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (8-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (8-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (6-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (6-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (6-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (6-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (quinolin-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (quinolin-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (quinolin-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (quinolin-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [4- (benzyl) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [4- (benzyl) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [4- (phenoxy) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [4- (phenoxy) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylthiazol-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylthiazol-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (2, 4-difluorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (2, 4-difluorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (2, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (2, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3, 5-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3, 5-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3-chloro-2, 6-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3-chloro-2, 6-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexon-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-dichlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-dichlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-afur-i-noxa-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluorophenyl) ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-dichlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-dichlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (phenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (phenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2,1, 3-benzooxadiazol-5-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2,1, 3-benzooxadiazol-5-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2,3,5, 6-tetrafluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2,3,5, 6-tetrafluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylfuran-3-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylfuran-3-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylfuran-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylfuran-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-difluoro-6-methoxyphenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-difluoro-6-methoxyphenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-thiophen-2-yl) methyl ] oxime; and pharmaceutically acceptable salts, prodrugs and solvates of said compounds.
In more specific embodiments, the invention encompasses the following compounds:
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (benzofuran-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-dichlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenyl-furan-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-5-fluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2,3,5, 6-tetrafluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-afur-ihexyl-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 4-difluorophenyl) methyl ] oxime; and pharmaceutically acceptable salts, prodrugs and solvates of said compounds.
The present invention also relates to a pharmaceutical composition for treating bacterial infections, protozoal infections or diseases associated with bacterial infections or protozoal infections in mammals, fish or birds comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a bacterial infection, a protozoal infection, or a disease associated with a bacterial infection or protozoal infection in a mammal, fish, or bird, comprising administering to the mammal, fish, or bird a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof.
As used herein, unless otherwise indicated, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing the disease to which the term applies or one or more symptoms of the disease. The term "therapeutic effect" as used herein refers to the effect of "treatment" as defined in the claims.
As used herein, the terms or phrases "bacterial infection", "protozoal infection" and "conditions associated with bacterial infection or protozoal infection" include the following, unless otherwise indicated: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis associated with infections with streptomyces pneumoniae, haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, streptococcus faecalis, enterococcus faecium, enterococcus casseliflavus, staphylococcus epidermidis, staphylococcus haemolyticus, or streptococcus digestus; pharyngitis, rheumatic fever and glomerulonephritis associated with infection by streptococcus pyogenes, group C and G streptococcus, diphtheria or actinobacillus haemolyticus; respiratory infections associated with infection by mycoplasma pneumoniae, legionella pneumophila, streptococcus pneumoniae, haemophilus influenzae or chlamydia pneumoniae; blood and tissue infections including endocarditis and osteomyelitis caused by staphylococcus aureus, staphylococcus hemolyticus, streptococcus faecalis, enterococcus faecium, streptococcus insipidus (including strains resistant to known antibacterial agents such as, but not limited to, β -lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracycline, and macrolides); uncomplicated skin and soft tissue infections and abscesses and heat of bedding associated with infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, group C-F streptococci (Microcolony streptococci), Streptococcus viridis, Corynebacterium parvum, Clostridium or Bartonella hendersoni; uncomplicated acute urinary tract infections associated with staphylococcus aureus, coagulase-negative staphylococcus, or enterococcus infections; urethritis and cervicitis; sexually transmitted diseases associated with infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, ureolytic ureaplasma or Neisseria gonorrhoeae; toxigenic diseases associated with staphylococcus aureus (food poisoning and toxic shock syndrome) or A, B and group C streptococcal infections; ulcers associated with helicobacter pylori infection; systemic fever syndrome associated with european relapsing fever borrelia infection; lyme disease associated with borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocystitis associated with chlamydia trachomatis, neisseria gonorrhoeae, staphylococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, haemophilus influenzae or listeria infections; mycobacterium avium syndrome (MAC) associated with infection by Mycobacterium avium or M.intracellulare; infections caused by mycobacterium tuberculosis, mycobacterium Jatropha, mycobacterium paratuberculosis, mycobacterium kansasii or mycobacterium cheloni; gastroenteritis associated with campylobacter jejuni infection; protozoal enteritis associated with cryptosporidium infection; odontogenic infections associated with streptococcus viridis infection; persistent cough associated with bordetella pertussis; gas gangrene associated with clostridium perfringens or bacteroides infection; and atherosclerosis or cardiovascular diseases associated with infection by helicobacter pylori or chlamydia pneumoniae. Bacterial and protozoal infections of animals that can be treated or prevented and conditions associated with these infections include the following: bovine respiratory disease associated with pasteurella haemolytica, pasteurella multocida, mycoplasma bovis, or bordetella; bovine intestinal disease associated with protozoan (i.e., coccidia, cryptosporidium, etc.) infections; bovine mastitis associated with infection by staphylococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, corynebacterium or enterococcus; porcine respiratory disease associated with infection by actinomyces macrolobae, pasteurella multocida, or mycoplasma; porcine intestinal disease associated with infection by Lawsoniainracellularis, Salmonella, or porcine dysentery venomous; cattle rotten hooves associated with clostridial infections; bovine hairy warts associated with fusobacterium necrophorum or bacteroides nodorum; bovine pinkeye associated with moraxella bovis; premature abortion in cattle associated with protozoan (i.e. neospore) infection; skin and soft tissue infections of dogs and cats with staphylococcus epidermidis, staphylococcus intermedius, coagulase-negative staphylococcus, or pasteurella multocida; and dental or oral infections of dogs and cats associated with infection by Alcaligenes, Clostridium, Enterobacter, Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial and protozoal infections and diseases associated with these infections that can be treated or prevented according To the methods of the present invention are described in "the Sanford Guide To Antimicrobial Therapy" of J.P.Sanford et al, 26 th edition (Antimicrobial Therapy, Inc., 1996).
The term "halogen" as used herein includes, unless otherwise indicated, fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.
The term "alkyl" as used herein, unless otherwise specified, includes monovalent saturated hydrocarbon radicals containing straight or branched moieties. The alkyl group may contain one or two double or triple bonds. It is understood that for the alkyl group to contain a carbon-carbon double or triple bond, the alkyl group requires at least two carbon atoms.
The term "aryl" as used herein includes, unless otherwise indicated, organic groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.
The term "4-10 membered heterocyclic" as used herein includes, unless otherwise indicated, aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group contains 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups that contain only 4 atoms in the ring system, but aromatic heteroaryl groups must contain at least 5 atoms in the ring system. Heterocyclyl includes benzo-fused ring systems as well as ring systems substituted with one or more oxo groups. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thialkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepinyl, oxazepinyl, diaza  yl, thiazepinyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiopentyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, pyrazolidinyl, thiacyl, piperazinyl, azetidinyl, morpholinyl, piperidinyl, morpholinyl, thiazepinyl, thiazinyl, and thiazinyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, 2, 3-diazananyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinoxalinyl, 1, 5-diazananyl and furopyridyl. The aforementioned groups derived from the compounds of item 1 may be C-linked or possibly linked via N. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).
The term "pharmaceutically acceptable salt" as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the invention which are basic can form a wide variety of different salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of these basic compounds are those which form non-toxic acid addition salts. By non-toxic acid addition salt is meant a salt containing a pharmaceutically acceptable anion such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate [ i.e. 1, 1' -methylene-bis (2-hydroxy-3-naphthoate) ]. The compounds of the present invention containing a basic group (e.g., amino group) can form pharmaceutically acceptable salts with various amino acids in addition to the above acids.
The compounds of the present invention, which are acidic, are capable of forming base addition salts with a variety of pharmaceutically acceptable cations. Such salts include the alkali or alkaline earth metal salts of the compounds of the invention, particularly the calcium, magnesium, sodium and potassium salts.
The compounds of the invention have asymmetric centers and can therefore exist in different enantiomeric and diastereomeric forms. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention and mixtures thereof, and to all pharmaceutical compositions and methods of treatment using or containing them. In this respect, the invention also includes the use of a compound of formula I in R1And R2Together form the formula = N-OR3-OR bound to nitrogen when oxime groups are present3E and Z configurations of the groups. The compounds of formula 1 may also exist as tautomers. The present invention relates to the use of all these tautomers and mixtures thereof.
The invention also includes isotopically-labelled compounds, and pharmaceutically acceptable salts thereof, which are identical to those recited in formula 1, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H、3H、13C、14C、15N、18O、17O、35S、18F and36and (4) Cl. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes such as3H and14c, useful in drug and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detection. Further, with heavier isotopes such as deuterium (i.e., deuterium)2H) Substitution may result in greater metabolic stability and may result in certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, and thus such isotopic substitution may be preferred in some circumstances. Isotopically labeled compounds of formula 1 of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent according to the procedures described in the schemes and/or in the examples and preparations below.
The invention also includes pharmaceutical compositions and methods of treating bacterial infections by administering prodrugs of the compounds of formula 1. The compound of formula 1 having a free amino, amido, hydroxyl or carboxyl group may be converted into a prodrug. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxyl group of a compound of formula 1. Amino acid residues include, but are not limited to, the 20 natural amino acids typically represented by three letter symbols, but also include 4-hydroxyproline, hydroxylysine, desmosine (demosine), isodesmosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
The invention also includes other types of prodrugs. For example, the free carboxyl groups may be derivatized to amides or alkyl esters. Amide and ester moieties may be incorporated into groups including, but not limited to, ether, amine, and carboxylic acid functional groups. The free hydroxyl group may be derivatized using groups described in d.fleisher, r.bong, b.h.stewart, Advanced Drug Delivery Reviews (1996)19,115, including but not limited to hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl. Like the carbonate prodrugs and sulfate esters of hydroxy groups, the present invention also includes carbamate prodrugs of hydroxy and amino groups. The invention also includes hydroxy derivatives derived as (acyloxy) methyl and (acyloxy) ethyl ethers wherein the acyl group may be an alkyl ester optionally substituted with groups including but not limited to ether, amine and carboxylic acid functional groups or wherein the acyl group is an amino acid ester as described above. Reference is made to J.medicinal Chemistry (1996)39,10 by R.P.Robinson et al.
The selective introduction of the prodrug side chain can be performed on the hydroxyl group of the hygromycin a parent nucleus. For example, the six hydroxyl groups of hygromycin A can be completely silylated with tert-butyldimethylsilyl chloride. The use of potassium carbonate in methanol at room temperature on the hexasilyl derivative enables selective removal of the phenolic silyl group, allowing further selective modification at the corresponding position. Detailed description of the invention
The preparation of the compounds of the invention is illustrated by the following reaction scheme.
Reaction scheme 1Reaction scheme 1 (continuation)Reaction scheme 2
The compounds of the invention can be prepared very simply. Referring to scheme 1 above, the starting compound of formula 2 is hygromycin A, which can be prepared according to methods well known in the art, for example, by fermentation of S.hygroscopicus NRRL 2388. The methyl ketone on the furanose of the hygromycin a molecule can exist in either the S configuration (hygromycin a) or the R configuration (epihygromycin) relative to the furanose. When the known protocol was used as a model for fermentation and recovery of hygromycin A (U.S. Pat. No. 3,100,176; Antibiotic Chemotherapy (1953) 3: 1268-. It is known from the literature (Journal of antibiotics 33 (7)), 695-one 704,1980 that pure hygromycin A will be converted to epihygromycin in alkaline solution. By carefully controlling the pH during fermentation to less than 6.9 and controlling the pH, temperature and solvent used during purification, the ratio of hygromycin A to epihygromycin in the final recovered product can be improved to 14: 1. Using this material, essentially a single isomer derived from 4 "- (S) hygromycin can be made and used as a template for further synthetic modifications.
Hygromycin A, enriched with the 4' - (S) epimer, is produced by fermentation of S.hygroscopicus NRRL2388 or a mutant thereof in a culture medium, and the pH of the culture medium is controlled to be lower than 6.9, preferably between 6.2 and 6.7, throughout the fermentation. This medium contains assimilable sources of carbon, nitrogen and trace elements known to those skilled in the art. The fermentation is carried out at a temperature of about 25-35 c (preferably about 29 c) and is monitored by chromatography (e.g., high pressure liquid chromatography). The incubation is carried out until the compound yield reaches a maximum, usually about 3-10 days, preferably about 4-6 days.
The formation of epihygromycin can be minimized during the purification process by using an aqueous buffer (rather than unbuffered water) and controlling the pH of the active stream to about 6.0. The formation of epihygromycin can also be minimized by minimizing the time that the recovered material is at an elevated temperature. Therefore, where it is desired to reduce the solvent concentration, it is preferred to dilute the active stream with an aqueous buffer, while avoiding the use of high temperature rotary evaporation. Also, as a method to avoid high temperatures, in order to reduce the volume of solution that needs to be boiled, a resin column may be used to concentrate the active solution prior to the final purification step. The final purification step of the purification process is to concentrate the active fraction to a solid using vacuum and a bath temperature of about 35-50 ℃. The time of the solution at high temperature can be minimized by fractional boiling.
The compound of formula 1 may be prepared from the compound of formula 4. In this process, the compound of formula 3 (wherein X is a protecting group described below) is prepared by protecting all of the hydroxyl groups of hygromycin A (except for the hydroxyl group at the 2 "carbon (C-2") position) in its silyl ether form with a suitable reagent such as triethylsilyl chloride (TESCl), trimethylsilyl chloride (TMSCl), or tert-butyldimethylsilyl chloride (TBDMSCl). A preferred method is to use 10eq TBDMSCl and imidazole in N, N-Dimethylformamide (DMF) at 25-40 deg.C for 12-36 hours. The hydroxy group is then removed by the method of Barton et al [ J.chem.Soc., Perkin Trans.I1975,1574] to produce the compound of formula 4. A preferred method in this case is the method disclosed by G nu-Dellac et al [ Carbohydrate Res.1991,216,249 ].
With the formula R3ONH2The compound of formula 4 can be treated with hydroxylamine(s) (either free base or salt form of such hydroxylamine can be used, but preferably free base form is used) to produce R in formula 11And R2Together form the formula = NOR3Oxime (wherein R is3As defined above). The reaction is preferably carried out in an inert solvent such as methanol, when a hydroxylamine salt such as HCl salt is used, a base such as potassium carbonate is also added and the reaction temperature is typically about 0 ℃ to 65 ℃, preferably 0 ℃ to 25 ℃. The protecting group is subsequently removed with an acid (e.g., acetic acid, hydrogen fluoride-pyridine complex) or a fluoride source such as tetrabutylammonium fluoride (TBAF). Formula R3ONH2The hydroxylamine of (a) may be prepared by one or more of the following methods: bioconjugate Chemistry (1990),2, 96; journal of pharmaceutical Science (1969)58,138; and chem.pharm.bull (1967)15,345.
Wherein R can be prepared by treating a compound of formula 4 with an acid such as acetic acid, hydrogen fluoride-pyridine complex or a fluoride source such as tetrabutylammonium fluoride (TBAF), preferably using a hydrogen fluoride-pyridine complex1And R2Compounds of formula 1 together form a ketone of formula = O.
In the formula 1R1Is H and R2is-NR3R4(wherein R is3And R4As defined above) can be synthesized by reductive amination of the C-5 "ketone moiety of the compound of formula 4.Mixing R in an inert solvent4NH2With a compound of formula 4, using a reducing agent such as NaBH4、NaBH(OAc)3(Ac is acetyl) or NaCNBH3Treatment to produce R3Product of = H. To get R3For conversion to a group other than H, a suitable formula R may be employed3C (O) H is subjected to a second reductive amination of the aldehyde (or ketone). Can be introduced as R by using Eschweiler-Clark reaction3Methyl group of the substituent. To provide amido groups such as wherein R1Is H and R2is-NR4C(O)R3Can be introduced as described above under the formula-NHR4Then the intermediate is reacted with an activated form of a carboxylic acid (e.g. R)3COCl or R3C(O)OC(O)R3) Treatment, or treatment with an amide coupling agent such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 1' Carbonyldiimidazole (CDI), or carbodiimides such as 1, 3-Dicyclohexylcarbodiimide (DCC), may incorporate the formula-C (O) R3An acyl moiety of (a). For all the above processes, the protecting group can be removed in the final step by means of an acid (e.g. acetic acid, hydrogen fluoride-pyridine complex) or a fluoride source (e.g. TBAF).
In the formula 1R1Is H and R2is-NR4C(O)R3(wherein R is4Is H and R3As defined above) can be prepared using a primary amine obtained by reductive amination of a compound of formula 4 using an ammonia equivalent (e.g., using ammonium acetate and sodium cyanoborohydride or sodium triacetoxyborohydride). On the other hand, the above-mentioned primary amines can also be prepared via the corresponding azides: (1) reducing (e.g., with sodium borohydride) the C-5' ketone of the compound of formula 4; 2) converting the resulting alcohol to a mesylate, for example by reaction with methanesulfonyl chloride and triethylamine; 3) displacement of the mesylate with azide, for example with sodium azide in DMF; and 4) reduction of the azide to a primary amine using, for example, triphenylphosphine followed by hydrolysis.
Primary amines with activated forms of R3C (O) OH (e.g. R)3C (O) Cl or R3C(O)OC(O)R3) The reaction can produce the corresponding amide. On the other hand, the method can also be usedTogether with R3C (O) OH with an amide coupling agent such as 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC), diethylphosphoryl cyanide (DEPC), DCC, CDI or EEDQ. Finally, any protecting groups are removed using an acid (e.g., acetic acid, hydrogen fluoride-pyridine complex) or a fluoride ion such as TBAF.
To introduce R other than H4The group may be alkylated after protection of the free hydroxyl group of the amide (e.g., protection in the form of a silyl ether). Alkylation may employ a base and an alkylating agent (e.g., sodium hydride and the appropriate formula R)4Br bromide). The hydroxyl groups are then deprotected with an acid (e.g., acetic acid, hydrogen fluoride-pyridine complex) or a fluoride ion such as TBAF.
On the other hand, reductive amination can be catalyzed by sodium triacetoxyborohydride or sodium cyanoborohydride from R4NH2On the compound of formula 4. The resulting secondary amines can be used as described above with the active form of R3C (O) OH acylation, or with R using an amide coupling agent3C (O) OH reaction. Deprotection of the hydroxyl groups is then carried out as described above.
Reference is made to reaction scheme 2, wherein R1Is H and R2is-OR3(wherein R is3Is alkyl or substituted alkyl) can be prepared by alkylating the corresponding R in formula 51Is hydroxy and R2An alcohol compound which is hydrogen (wherein X is a protecting group as described above). In this method, the C-5' ketone moiety of the compound of formula 4 is first reduced with a suitable reducing agent such as sodium borohydride, and then R is used in the presence of a base such as sodium hydride or potassium tert-butoxide3Alkylation of the resulting C-5' alcohol with Z (where Z is a leaving group, such as Cl, Br, I or mesylate) followed by removal of the protecting group with an acid (such as acetic acid, hydrogen fluoride-pyridine complex) or a fluoride source (such as TBAF).
Wherein R is1Is H and R2is-OR3(wherein R is3Aryl or heterocyclyl) can be prepared by a Mitsunobu reaction. In the presence of triphenylphosphine and diethyl azodicarboxylateC-5 "alcohols and R prepared as described above3OH is subjected to a Mitsunobu reaction. The resulting ether was then deprotected as described above.
On the other hand, when R1Is H and R2is-OR3When (wherein R is3Is aryl or heterocyclyl), the C-5' alcohol derived from the compound of formula 4 may be converted to a leaving group, such as a bromide or mesylate derivative. Such leaving groups can then be formed from R by a base such as sodium hydride, potassium tert-butoxide or potassium carbonate3OH is replaced.
The C-5' alcohol prepared from the compound of formula 5 as described above is reacted with the isocyanate R at a temperature of from 40 ℃ to 110 ℃ (preferably from 50 ℃ to 80 ℃)3NCO is reacted in toluene to give R1Is H and R2is-OC (O) NR3R4A compound of formula 1. It may be advantageous to add dimethylaminopyridine and triethylamine to the reaction. Using a base such as sodium hydride and an alkylating agent such as R4Br, it being possible to react the above reaction product (i.e. where R is4Equal to H) to R4Is equal to C1-C10Products of alkyl groups. Deprotection of the hydroxyl group can then be accomplished using fluoride ion (e.g., TBAF).
Wherein R is1And R2Together form = CR4C(O)R3，=CR4C(O)OR3Or = CR4C(O)NR3R4(wherein R is3And R4As defined above) can be prepared from the corresponding α, β -unsaturated ester intermediates obtained by Wittig or Horner-Emmons Wittig olefination of the C-5 "ketone in the compound of formula 4. For example, (ethoxycarbonylmethylene) triphenylphosphorane or (ethoxycarbonylethylene) triphenylphosphorane may be reacted with the compound of formula 4 in order to obtain an unsaturated ethyl ester. Hydrolysis of the ester (e.g., with sodium hydroxide) can yield the corresponding carboxylic acid (wherein R is1And R2Together form = chc (o) OH of the compound of formula 5). At this point, the hydroxyl group liberated in the previous step can be protected, for example, to its TES or TBDMS ether. For the preparation of the above esters, they may be prepared, for example, by DCC and DCC4-Dimethylaminopyridine (DMAP), or CDI, with a catalytic base such as sodium ethoxide3OH esterifies this carboxylic acid. Deprotection of the hydroxyl group is then carried out using an acid (e.g., acetic acid, hydrogen fluoride-pyridine complex) or a fluoride ion (e.g., TBAF).
With the aid of amide coupling agents, e.g. DCC, CDI, EEDQ, DEPC or EDC, with the formula R3NH2By treatment of the carboxylic acid intermediate (wherein R is1And R2Together form = chc (o) OH), a compound of formula 5 may be formed in which R is1And R2Together form = CR4C(O)NR3R4A compound of formula 1. For such protected derivatives, R may be introduced by alkylation4For example using a base such as sodium hydride or potassium tert-butoxide and an alkylating agent such as R4X (wherein X is Br, Cl or mesylate). Deprotection of the hydroxyl groups is then carried out as described above.
By reacting compounds of formula 4 with, for example, the corresponding R3C(O)CHR4-PPh3(Ph is phenyl) or R3C(O)CHR4-p=O(OEt)2Direct Wittig or Horner-Emmons reaction of (Et is ethyl) reagent can prepare ketone (R) of formula 11And R2Together form = CR4C(O)R3). In another aspect, wherein R1And R2The compound of formula 5, together forming = chc (O) OH, can be converted to the Weinreb amide by, for example, treatment with CDI and N, O-dimethylhydroxylamine. This amide can then be reacted with R3M (where M is a metal ion such as Li) or MgBr to form a ketone. And an aldehyde (wherein R is3A ketone structure of H) can be prepared by reacting such Weinreb amides with hydride sources such as diisobutylaluminum hydride (DIBAL) or LiAlH4And (3) reacting to obtain the product.
By R4-CH(PPh3)-R3Or R4-CH(P=O(OEt)2)-R3The ylide is subjected to Wittig or Hormer-Emmons reaction with the compound of formula 4 to obtain R in formula 11And R2Together form = CR4R3Wherein R is3And R4As defined above. The protection can then be removed as described aboveAnd (4) a base.
In another aspect, wherein R1And R2Together form = CR respectively4C(O)R3And = CR4C (O) H ketones or aldehydes of formula 5 may be used as intermediates. These compounds can be reacted with oxygen-containing triphenyl phosphonium salts or phosphoranes such as Ph by the Wittig or Horner-Emmons reaction3P-C(R3) OMe (Me is methyl) reaction. The enol ethers produced can be hydrolyzed with mild acids such as acetic acid or dilute hydrochloric acid to form aldehydes or ketones. Such aldehydes or ketones may then be reacted with organometallic derivatives R4Reaction of M (where M is, for example, Li) or MgBr to give the corresponding alcohol, which is then dehydrated by the action of methanesulfonyl chloride to give the corresponding olefin. Deprotection as described above then gives compounds in which R is1And R2Together form = CR4R3A compound of formula 1.
Wherein R is1And R2Together form = CR4R3And R is4Is aryl or heteroaryl and R3Compounds of formula 1 other than hydrogen can be prepared using palladium-catalyzed methods. In which R is3is-CH (COR)3) The compound of formula 5 is converted to an activated enol ether (e.g., enol triflate), and the resulting intermediate can then be reacted with an aryl or heteroaryl boronic acid R in a Suzuki or Stille type palladium catalyzed process4B(OH)2Or aryltin compounds such as R4SnMe3Or R4SnBu3(Bu is butyl) to give an unsaturated aryl derivative. Subsequent deprotection as described above gives the final compound.
The compounds of the present invention have asymmetric carbon atoms. Such diastereomeric mixtures can therefore be separated into their individual diastereomers on the basis of differences in their physicochemical properties using methods known to those skilled in the art, for example, chromatography or fractional crystallization. All such isomers, including mixtures of diastereomers, are considered part of the invention.
The compounds of the invention which are basic can form different salts with various inorganic and organic acids. Although such salts should necessarily be pharmaceutically acceptable for administration to animals, it is generally advisable in practice to isolate the compounds of the invention from the reaction mixture in the form of their non-pharmaceutically acceptable salts, and then to treat them with an alkaline agent so that the latter can be converted very simply into the free base compound, which is then converted into the pharmaceutically acceptable acid addition salt. The preparation of the acid addition salts of the basic compounds of the invention is readily carried out as follows: the basic compound is treated with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. The desired solid salt can be easily obtained by careful evaporation of the solvent. The desired acid addition salts may also be precipitated therefrom by addition of a suitable inorganic or organic acid to the solution of the free base/organic solvent.
The compounds of the present invention which are acidic are capable of forming base salts with a variety of different pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. These salts can be prepared by conventional methods. Chemical bases used as reagents in preparing the pharmaceutically acceptable base addition salts of the present invention can form non-toxic base addition salts with the acidic compounds of the present invention. Such non-toxic base addition salts include those derived from pharmaceutically acceptable cations such as sodium, potassium, calcium, magnesium and the like. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired alkali metal alkoxide or alkali metal hydride and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, the salts may be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide or alkali metal hydroxide and then evaporating the solution to dryness in the same manner as described above. In either case, it is preferred to use stoichiometric amounts of the reagents in order to ensure complete reaction and maximum yield of the desired end product.
The antibacterial activity of the compounds of the invention against bacterial pathogens is demonstrated by their ability to inhibit a defined strain of a particular pathogen.
Measurement of
The following assays employ conventional methodologies and data processing means in order to provide guidance for chemical structure modifications that may result in compounds having antibacterial activity against sensitive and resistant microorganisms, including but not limited to those resistant to β -lactams, macrolides, and vancomycin. In the measurement, a group of bacterial strains including various target pathogenic bacteria including representative antibiotic-resistant bacteria was first established. The chemical structure/activity relationship can be determined by using the group of strains according to activity efficacy and action spectrum. The assay was performed in microtiter plates and The results were according to The Performance Standards for Antimicrobial Laboratory Standards, published by The National Committee for Clinical Laboratory (NCCLS), 6 th edition; the Approved Standard guide is arranged; the Minimum Inhibitory Concentration (MIC) was used to compare the strains. Compounds were initially dissolved in dimethyl sulfoxide (DMSO) as stock solutions.
The activity of the compounds of the invention can also be determined according to Steers' replication gene technology, a standard in vitro bacterial test method disclosed by Steers et al [ Antibiotics and Chemotherapy 1959,9,307 ].
The in vivo activity of the compounds of the invention can be determined according to conventional animal protection studies well known to those skilled in the art, and is typically performed in rodents.
The compounds of the invention were evaluated according to an in vivo model, using a mouse model of acute bacterial infection. An example of one such in vivo system is provided below. The resulting mice (CF1 mice, mixed male and female; 18-20g) were distributed into cages and acclimated for 1-2 days prior to study. Acute infections were produced by intraperitoneal inoculation of bacteria (staphylococcus aureus strain 01a1095) suspended in 5% sterile porcine gastric mucin. The inoculum was prepared as follows: cultures were grown overnight at 37 ℃ in blood agar, the resulting surface growth was harvested from sterile brain-heart containing infusion broth, and the suspension was adjusted to turbidity that resulted in 100% lethality when diluted 1: 10 into 5% sterile porcine gastric mucin.
Mice (10 per group) were treated subcutaneously 0.5 and 4 hours post infection. Appropriate untreated controls (infected but untreated) and positive controls (vancomycin or minocycline, etc.) were included in each study. Percent survival was recorded after a 4 day observation period; determining PD by probability method50(mg/kg, calculated dose to protect 50% of infected animals).
In the treatment of bacterial and protozoal infections, the compounds of the present invention and their pharmaceutically acceptable salts (hereinafter referred to as "active compounds") may be administered by the oral, parenteral, topical or rectal route. Although the dosage to be administered will necessarily vary with the type, weight and health of the subject to be treated, and in particular the route of administration chosen, generally speaking, the most suitable dosage for the administration of these compounds is from about O.2mg per kilogram of body weight per day (mg/kg/day) to about 200 mg/kg/day, in single or divided doses < i.e. 1 to 4 doses per day >. The most preferred dosage level is from about 3 mg/kg/day to about 60 mg/kg/day. Nonetheless, the dosage will vary with the type of animal, fish or bird being treated, the response of the individual being treated to the agent, and the type of agent selected and the timing and interval of administration. In some cases, dosages below the lower limit of the above range may be satisfactory for therapeutic purposes, while in other cases, larger dosages may not produce serious side effects, provided that the large dose is first divided into several small doses for administration throughout the day.
The active compounds may be administered by the routes described above either alone or in combination with pharmaceutically acceptable carriers or diluents, and such administration may be carried out in single or divided doses. More specifically, the active compounds can be administered in a variety of different dosage forms, i.e., they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, and the like. In addition, oral pharmaceutical compositions may also be suitably sweetened and/or flavored. Generally, the concentration of active compound in these dosage forms is from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed in combination with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with particulate binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, for tableting, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful. Similar solid components may also be used as additives in gelatin capsules; such preferred materials also include lactose and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if desired, emulsifying and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various mixtures thereof.
For parenteral administration, solutions of the active compounds in sesame or peanut oil or in aqueous ethanol or aqueous propylene glycol may be used. It may also be advantageous to use cyclodextrin derivatives such as β -cyclodextrin sulfobutyl ether, sodium salt (see U.S. patent 5134127). If necessary, the aqueous solution should be suitably buffered and the liquid diluent should be isotonic first. These aqueous solutions are suitable for intravenous injection, while oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. All of these solutions can be readily prepared under sterile conditions according to standard pharmaceutical techniques known to those skilled in the art.
In addition, the active compounds according to the invention can also be administered topically. Such administration may be accomplished using formulations such as creams, jellies, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice.
For administration to non-human animals such as cattle or livestock, the active compounds can be administered in a mixed feed for the animal or in the form of a veterinary drench composition.
The active compounds of the present invention may also be administered in liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The active compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the active compounds may also be coupled to biodegradable polymers for the controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphiphilic block copolymers of hydrogels.
The invention is further illustrated by the following preparations and examples. In these preparations and examples, "rt" means room temperature, i.e., a temperature in the range of about 20-25 ℃.
Preparation example 1
In a 2.8L Fernbach flask, 5ml of frozen bulk S.hygroscopicus NRRL2388 culture (-80 ℃ storage, 20% glycerol/80% inoculum Medium) was inoculated with 1L of hygromycin inoculum medium (Corn Products Corp. Industrial glucose 13g/L, Hubinger starch 7g/L, Roquette Corn extract 3g/L, Sheffield Brands Products NZAmine YTT 7g/L, Baker CoCl2·6H2O 0.002g/L,KH2PO4 0.7g/L,MgSO4·7H2O1.3 g/L, ammonium sulfate 0.7g/L, Dow Chemical P2000 defoamer 1 drop/flask, Colfax soybean oil 2 drops/flask, pH adjusted to 7.0 prior to autoclaving). Cultures were grown for 3 days at 29 ℃ on 2 inch swing shake flasks with stirring at 200 rpm. In a configuration with two 4.75 inch Rush spaced 3.75 inches apartthe above-described growth culture was used to inoculate 8L of sterile hygromycin fermentation medium (1 g/L of Albaglos calcium carbonate, 1g/L of Sheffield Brand Products NZ Amine YTT 5g/L, 20g/L of Hubinger starch, 10g/L of Archer Daniels Midland Nutrisoy wheat flour, 1ml/L of Dow chemical P2000 defoamer, Backer CoCl Microferm, New Brunswick, New Jersey) in a 14-liter fermenter with a ton impeller2·6H2O0.002 g/L, Colfax soybean oil 2ml/L, industrial glucose 10g/L, NaCl 5g/L, pH adjusted to 7.0 before autoclaving). The broth was incubated at 29 ℃ with aeration at a rate of 8L/min under stirring at 800 rpm. To minimize the formation of epihygromycin, the pH was maintained between 6.5 and 6.9 for 126 hours, then H was used for the remainder of the test period2SO4(15%) the pH was adjusted to maintain 6.2-6.6. After a total cultivation period of 143 hours, the fermentate was harvested. The ratio of hygromycin A to epihygromycin was 31: 1.
6 liters of the above fermentation broth were taken and centrifuged at 8000rpm for about 15 minutes. After centrifugation, the precipitate was discarded and the supernatant (pH6.4, containing about 4.12gms hygromycin A activity by HPLC) was loaded into a column packed with 500gms XAD-16 resin (Rohm and Haas (Philadelphia, Pennsylvania)). The resin was equilibrated beforehand with two bed volumes of 25mM disodium phosphate ("buffer") pH 6.0. After loading the column, the column was washed with 2 bed volumes of buffer and 2 bed volumes of 80/20 buffer/methanol and the active eluted with 5 bed volumes of 50/50 buffer/methanol. Fractions were monitored by HPLC and fractions containing the active were pooled (2.730gms hygromycin A).
A portion of this XAD-16 eluate (approximately 800mg of hygromycin A) was diluted to 10% methanol with 1.8 liters of buffer and loaded onto a 100ml CG-161 column (TosoHaas (Montgomeryville, Pennsylvania)) previously equilibrated with 4 bed volumes of 90/10 buffer/methanol. The product was eluted with 6 bed volumes 50/50 buffer/methanol. Fractions were determined by HPLC and the active fractions were combined. The combined fractions were evaporated to dryness and a solid purity of approximately 65% by weight was measured. A small amount of these solids was taken for testing.
About 500mg of the solid was mixed with 500ml of water and 500ml of ethyl acetate, stirred for 20 minutes and separated into two layers, and then the aqueous layer portion was dried to obtain a solid and its purity was measured to be about 52% by weight. Both solids were determined by NMR and TLC (# 34945. RTM. 280-1 and 281-1), and were found to contain hygromycin A activity. In addition, NMR also showed a hygromycin A/epihygromycin ratio of approximately 15: 1.
Preparation example 2
In a 2.8L Fernbach flask, 5ml of frozen bulk S.hygroscopicus NRRL2388 culture (-80 ℃ storage, 20% glycerol/80% inoculum Medium) was inoculated with 1L of hygromycin inoculum medium (CPC International Inc. Industrial glucose 13g/L, Hubinger starch 7g/L, Roquette corn extract 3g/L, NZ AmYTine T7 g/L, Baker CoCl2·6H2O 0.002g/L,KH2PO4 0.7g/L,MgSO4·7H2O1.3 g/L, ammonium sulfate 0.7g/L, Dow Chemical P2000 defoamer 1 drop/flask, Colfax soybean oil 2 drops/flask, pH adjusted to 7.0 prior to autoclaving). Cultures were grown for 2-3 days at 29 ℃ on 2 inch swing shake flasks with stirring at 200 rpm. 380 gallons of 500 gallons hygromycin fermentation medium (Mineral Technologies 1g/L calcium carbonate, Sheffield Brand Products NZ Amine YTT 5g/L, Hubinger starch 20g/L, Archer Daniels Midland Co., 10g/L bean flour, Dow Chemical P2000 defoamer 1ml/L, Backer CoCl) was placed in two 500-gallon stainless steel fermentors2·6H2O0.002 g/L, Colfax soybean oil 2ml/L, CPC International Inc. industrial glucose 10g/L, Cargill Inc. NaCl 5 g/L). The medium was sterilized in the fermentor with 20psig steam for 60 minutes. After cooling the medium in the fermenter using a cooling coil, the pH was adjusted to 6.5-6.7. The fermentor conditions were set to a gas flow rate of 20 standard cubic feet per minute, a temperature of 28 ℃, a vent pressure of 5psig, and a pH of 6.5-6.7 maintained with 25% sodium hydroxide and 98% sulfuric acid. The stirring rate of both fermenters was varied to maintain a dissolved oxygen of more than 20% of the saturation amount measured in the broth before inoculation. Five Fernbach inoculum bottles were aseptically combined into an 8L aspirator bottle by setting the control conditions for the fermentor. This inoculum was then used to inoculate the single nominally 500 gallon fermentor described above. This procedure was repeated using 4 liters of inoculum to obtain one of themOne fermentor received 4 liters of inoculum and the other fermentor received 5 liters of inoculum. Each fermenter was allowed to ferment for approximately 114 hours and then the fermentation was stopped. The broth pH was adjusted to 6.3 with 98% sulfuric acid and removed from the fermentor for recovery.
The fermentations in the two fermentors were filtered through a ceramic filtration system (pH =6.3, hygromycin a to epihygromycin ratio of approximately 51: 1). The filtrate (1450gmsA, 506 gallons) was loaded into a 70 gallon XAD-16 resin column. The column was equilibrated beforehand with trisodium phosphate buffer ("buffer") at a bed pH of 4 at 6.0. After the column was completed, the column was washed with 2 bed volumes of buffer and 2 bed volumes of 80/20 buffer/methanol. The active was then eluted from the column with a solution of 10 fractions (approximately 50 gallons of each fraction) 50/50 buffer/methanol. The active fractions (approximately 1240gmsA) were combined and diluted to a final concentration of 10% methanol with 1200 gallons of buffer. The use of a dilution with reduced methanol concentration (non-rotary evaporation) requires the use of low temperatures in order to minimize the amount of epihygromycin (which tends to increase at high temperatures). Half of this solution was taken up into a 40 liter CG-161 column (equilibrated beforehand with 4 bed volumes of 90/10 buffer/methanol solution). After loading the column, the column was washed with 4 bed volumes 80/20 buffer/methanol and eluted with 5.5 bed volumes 50/50 buffer/methanol. After regeneration and re-equilibration of the column, the other half of the active was loaded onto the column and eluted as described above. Fractions from both runs (120L, approx. 1051gmsA) were combined and diluted to 10% methanol with buffer. It was recharged into a column of regenerated and rebalanced CG-161 resin. Once the active was absorbed in the column, elution with 4 bed volumes of methanol was started. This step serves to reduce the amount of salt and increase the sample concentration prior to final evaporation. The fractions from the final CG-161 column were combined and evaporated to dryness to give a total of approximately 1kgA hygromycin A active. The ratio of hygromycin A to epihygromycin in the final solid was about 14.5: 1.
Experimental methods of examples
Preparation of the compound of formula 3:
a solution of hygromycin A (1eq) in dimethylformamide (DMF, 0.1M) was treated with imidazole (10eq.) and tert-butyldimethylsilyl chloride (10eq) at 35 ℃ for 14-16 h. The reaction was then poured into water and extracted with ethyl acetate (EtOAc). The combined extracts were dried over magnesium sulfate and then concentrated. Chromatography (5-15% EtOAc/hexanes) provided the product.
Preparation of the compound of formula 5:
a solution of the compound of formula 3 (1eq.) in dichloroethane was treated with phenyl thiocarbonate (3eq.), pyridine (5 eq.), and dimethylaminopyridine (0.05eq.) at room temperature for 2-3 days. The reaction was then diluted with dichloromethane and washed successively with 0.5N HCl, saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate and concentrated. Chromatography (5-10% EtOAc/hexanes) provided the desired 2 "-thionocarbonate.
A toluene solution (0.1M) of the above 2 '-thiocarbonate (1eq.) was treated with α, α' -azobis (isobutyronitrile) (1eq.) and tri-n-butyltin hydride (3eq.) at 90 ℃ for 2 hours. The reaction was concentrated and chromatographed (5-10% EtOAc/hexanes) to provide the desired 2 "-deoxy compound of formula 5.
Preparation of Oxime ethers, examples 1 to 30
A solution of the compound of formula 4 (1eq.) in methanol (0.1M) is treated with the appropriate hydroxylamine at 60 ℃ for 30 minutes to 1 hour. The reaction mixture was concentrated and chromatographed (typically using 5-15% EtOAc/(toluene or hexane)) to afford the desired oxime.
The above oxime was treated with tetrabutylammonium fluoride (10eq.) in tetrahydrofuran at room temperature for 12-24 hours to remove the silyl group. The concentrated reaction mixture was then passed through a bed of ion exchange resin (Dowex 400, 35g resin per gram of starting material) and after chromatography (typically using 5-15% methanol/chloroform) the desired oxime was obtained as a mixture of E and Z isomers.
On the other hand, the removal of the silyl group can also be accomplished by adding a solution of tetrahydrofuran, pyridine, hydrogen fluoride-pyridine complex (65 ml, 16.5ml, 8.25ml, respectively) to a tetrahydrofuran (98ml) solution of the above oxime (6mmol) at room temperature. The reaction was continued for 24-96 hours and then stopped by the addition of solid sodium bicarbonate. Chromatography (typically using 5-15% methanol/chloroform) gives the desired oxime as the major E isomer.
For example 10, the deprotection of the compound of formula 4 was carried out using the hydrogen fluoride-pyridine method described above.
Synthesis examples 1-30 preparation of hydroxylamine reagent for oxime ethers
Most hydroxylamine reagents used are either commercially available (usually in the acid salt form) or are prepared from the corresponding alcohol or halide according to the following method:
1) preparation of phthalimide-protected hydroxylamine:
preparation from alcohol:
n-hydroxyphthalimide was coupled with the alcohol starting material using a Mitsunobu reaction using diethyl azodicarboxylate and triphenylphosphine according to the method of e.grohowski and j.jurczak, synthesis (1976) 682.
Preparation from bromide or chloride:
the reaction of N-hydroxyphthalimide (1 equivalent) with the halide starting material (1.2-2 equivalents) is carried out in a solution of dimethyl sulfoxide (DMSO) using potassium carbonate (0.6-2 equivalents) as the base. The reaction is carried out at room temperature, typically with stirring overnight. The reaction mixture was poured into cold water and a precipitate formed, which was filtered to give the phthalimide-protected hydroxylamine. In many cases, the species will deprotect directly; the phthalimide-protected hydroxylamine can also be purified by silica gel chromatography using an ethyl acetate-hexane mixture.
2) Removal of the phthalimide protecting group gives hydroxylamine:
the phthalimide-protected hydroxylamine was deprotected by reaction with hydrazine hydrate (1-2 eq) in ethanol solution at room temperature-reflux temperature for 30 min to overnight. The reaction mixture was filtered, and the filtrate was concentrated. The crude product can be used directly in the next reaction in the raw form obtained or can be further purified. Phthalhydrazide may be additionally removed by mixing the crude product with chloroform, filtering off the solid and removing the solvent from the filtrate. On the other hand, the crude product was dissolved in 1N hydrochloric acid and washed with diethyl ether or ethyl acetate. The aqueous layer was basified with saturated potassium carbonate solution and then extracted with ether or ethyl acetate. The final organic layer was dried and the solvent was removed to yield the hydroxylamine product.
3) Preparation of 4-phenyl-chloromethylthiazole
4-phenyl-thiazole-2-carbaldehyde was prepared in a similar manner to K.Inami and T.Shiba. Japan chemical society, journal of Bull.chem.Soc.Jpn, 1985,58, 352. The aldehyde was reduced to the corresponding alcohol using sodium borohydride in ethanol. The corresponding chloromethylthiazole is obtained by treating the alcohol with thionyl chloride (4 equivalents) in dichloromethane for 2-5 hours at room temperature.
4) Preparation of alpha-substituted benzyl alcohols
1- (3-chloro-2, 6-difluoro-phenyl) -ethanol and other phenethyl alcohol derivatives (examples 11, 14, 15, 17, 18) were prepared by treating the corresponding benzaldehyde with methylmagnesium bromide (1 equivalent) in THF at room temperature. These compounds are then converted to the corresponding benzyl bromides by treatment with 48% HBr for 1-4 hours.
1- (3-chloro-2, 6-difluoro-phenyl) -carbaldehyde was prepared from 3-chloro-2, 6-difluorobenzene with lithium diisopropylamide and N, N-dimethylformamide in a similar manner to A.S. Cantrell et al [ J.medicinal Chemistry 1996,21,4261 ].
2, 6-difluorophenethyl ketone (2, 4-difluoroiophenone) (example 16) was reduced to the corresponding alcohol using sodium borohydride in ethanol.
5) Preparation of O-aryl hydroxylamine:
substituted phenols were converted to the corresponding O-aryl hydroxylamines using 1,3, 5-trimethylbenzenesulfonylhydroxylamines as described by y.endo.k.shudo and t.okamoto, synthesis 1980,461.
The following table lists specific compounds prepared according to the above-described methods. In the table, "Ex" represents examples, "Stereo" represents oxime stereochemistry, "Mol Wt" represents molecular weight, and "Mass Spec" represents Mass spectra.
Watch (A)
Ex. Y Stereo MolWt Massspec 1H NMR Peak (CD)3OD)
1 4- (chlorophenyl) methyl group E 635 635.1 δ=7.34-7.24(m,5H),7.00(d,J=8.3Hz,1H),6.91(s,1H),6.83(d,J=8.2Hz,1H),5.06(s,2H),2.57-2.52(m,1H),2.29-2.11(m,1H),2.11(d,J=1.3Hz,3H),1.80(s,3H).
2 Benzyl radical E and Z 600.63 601.1 δ=7.36-7.24(m,6H),7.09(d,J=2.3Hz,1H),6.91(d,J.3Hz,1H),6.83(d,J=8.5Hz,1H),5.84-5.83(m,1H),5.07(s,2H),2.56-2.52(m,1H),2.29-2.24(m,1H),2.11(s,3H),1.78(s,3H).
Ex. Y Stereo Mol Wt Massspec 1H NMR Peak CD3OD)
9 (2, 4-Dimethoxyphenyl) methyl E 660.7 661.2 δ =7.22(brs,1H), 7.07-7.16(m,2H),6.88(d, J =2.3Hz,1H),6.81(dd, J =8.3 and 2.1Hz,1H),6.41-5.47(m,2H)5.82(dd, J5.2 and 1.6Hz,1H),2.50-2.60(m,1H),2.21-2.28(m,1H),2.09(d, J =1.3Hz,3H),1.73(s,3H).
10 2 "-deoxy-hygromycin A E 495.49 496.2 δ =7.22(brs,1H),7.16(d, J =8.5Hz,1H),6.89(d, J =2.1Hz,1H),6.84(dd, J =8.3 and 2.1Hz,1H),5.89(dd, J =5.2 and 2.3Hz,1H),2.44-2.50(m,1H),2.22-2.28(m,1H),2.11(s,3H),2.09(d, J =1.5Hz,3H)
11 (3-fluorobenzeneYl) ethyl E 632.65 633.2 δ=7.24-7.31(m,2H),6.81-7.11(m,6H),5.80-5.83(m,1H),5.19-5.26(m,2H),2.46-2.53(m,1H),2.20-2.62(m,1H),2.12(s,3H),1.83(s,3H),1.46-1.49(m,3H).
13 (4-Phenylthiazolyl) methyl E 683 684.2 δ=7.85-7.89(m,2H),7.74(s,1H),7.41-7.37(m,2H),7.28-7.32(m,1H),7.23(brs,1H),7.10(d,J=8.3Hz,1H),6.90(d,1.9Hz,1H),6.82(dd,J=8.5and1.9Hz,1H),5.39(m,2H),5.03(s,2H),2.55-2.60(m,1 H),2.23-2.29(m,1H),2.10(s,3H),1.86
14 (2, 4-difluorophenyl) ethyl E 650.64 651.0 δ =7.27-7.38(m,1H)7.22(brs,1H),7.07(dd, J =12.2 and 8.5Hz,1H),6.79-6.88(m,4H)5.81-5.77(m,1H),5.27-5.46(m,1H),2.43-2.50(m,1H),2.16-2.23(m,1H),2.09(s,3H),1.80(2s,3H),1.45-1.47(m,3H).
15 (3, 4-difluorophenyl) ethyl E 650.64 651.1 δ=7.24(brs,1H),7.06-7.19(m,4H),6.90(d,J=1.9Hz,1H)
Ex. Y Stereo Mol Wt Massspec 1H NMR Peak (CD)3OD)
6.81-6.84(m,1H)5.79-5.83(m,1H),5.18-5.22(m,2H),2.45-2.53(m,1H),2.18-2.26(m,1H),2.12(s,3H),1.82(2s,3H),1.45-1.48(m,3H).
16 1- (2, 4-difluorophenyl) propyl E 664.66 665.0 δ =7.25-7.29(m,1H)7.22(brs,1H),7.06(dd, J =14.8 and 8.3Hz,1H),6.78-6.88(m,4H),5.76-5.80(m,1H),5.24-5.30(m,1H),2.42-2.49(m,1H),2.16-2.23(m,1H),2.10(d, J =1.2Hz,3H),1.81(2s,3H),1.70-1.92(m,2H),0.85-0.91(m,3H).
17 (3, 5-difluorophenyl) ethyl E 650.64 651.1 δ=7.22(brs,1H),7.04-7.07(m,1H),6.74-6.88(m,5H)5.76-5.81(m,1H),5.1 7-5.21(m,2H),2.44-2.53(m,1 H),2.16-2.24(m,1H),2.08(d,J=1.4Hz,3H),1.82(2s,3H),1.43-1.45(m,3H).
18 (3-chloro-2, 6-difluorophenyl) ethyl E 685.08 684.9,687.0 δ=7.31-7.39(m,1H)7.24(brs,1H),7.02-7.06(m,1H),6.79-6.94(m,4H),5.74-5.79(m,1 H),5.58-5.66(m,1H),2.40-2.49(m,1H),2.18-2.24(m,1H),2.11(s,3H),1.79(s,3H),1.59(d,J=6.8Hz,3H).
19 (3, 4-difluorophenyl) methyl E 636.6 635.0 δ=7.08-7.24(m,5H),6.90(d,J=2.0 Hz,1H),5.83-5.85(m,1H),5.04(brs,1H)2.51-2.56(m,1H),2.22-2.29(m,1H),2.11(d,J=1.4Hz,3H),1.80(s,3H).
20 (3, 5-difluorophenyl) methyl E 636.6 636.9 δ=7.23(brs,1H),7.09(d,J=8.3Hz,1H),6.90-6.94(m,3H),6.78-6.84(m,2H),5.83(dd,J=5.2 amd 1.8Hz,1H),2.52-2.57(m,1H),5.07(s,2H),2.24-2.29(m,1H),2.11(d,J=1.3Hz,3H),1.82(s,3H)
Ex. Y Stereo Mol Wt Massspec 1H NMR Peak CD3OD)
21 (2, 4-difluorophenyl) methyl E 636.6 636.9 δ =7.37-7.43(m,1H),7.22(brs,1H),7.07(d, J =8.3Hz,1H),6.86-6.91(m,3H),6.81(dd, J =8.7 and 2.3Hz,1H),5.81-5.83(m,1H),5.08(brs,2H),2.40-2.54(m,1H),2.20-2.27(m,1H),2.09(d, J =1.4Hz,3H),1.75(s,3H).
22 (3-chloro-2, 6-difluorophenyl) methyl E 671.05 670.9.673.0 δ =7.38-7.44(m,1H),7.21(s,1H),7.03(d, J =3.3Hz,1H),6.92-6.97(m,1H),6.87(d, J =2.1Hz,1H),6.78(dd, J =8.5 and 1.8Hz,1H),5.80(dd, J =5.3 and 1.8Hz,1H),5.13(m,2H),2.48-2.53(m,1H),2.19-2.26(m,1H), (d, J =1.5Hz,3H),1.70(s,3H).
23 3-chlorophenyl group E 621.04 620.9.622.2 δ =7.14-7.24(m,4H),7.01-7.08(m,1H),6.92-6.97(m,1H),6.90(d, J =1.9Hz,1H),6.84(dd, J =8.3 and 1.7Hz,1H),5.92(d, J =4.5Hz,1H),2.62-2.68(m,1H),2.28-2.35(m,1H),2.11(d, J =1.1 Hz,3H),1.97(s,3H).
24 3-fluorophenyl group E 604.59 605.0 δ=7.13-7.26(m,3H),6.83-6.95(m,4H),6.67-6.71(m,1H),5.92(d,J=5.0Hz,1H),2.63-2.68(m,1H),2.30-2.35(m,1H),2.11(s,3H),1.96(s,3H).
25 3, 5-dichlorophenyl E 655.49 654.9,657.0,659.0 δ=7.11-7.21(m,4H),6.99-7.01(m,1H),6.81-6.89(m,1H),5.89-5.91(m,1H),2.61-2.66(m,1H),2.27-2.34(m,1H),2.09(d,J=1.4Hz,3H),1.95(s,3H).
26 (3, 5-dichlorophenyl) methyl group E 669.51 668.9,670.8,672.0 δ=7.24-7.32(m,4H),7.08(d,J=8.3Hz,1H),6.90(d,J=1.7Hz,1H),6.83(d,J=8.5Hz,1H),5.83(d,J=5.2Hz,1H),
Ex. Y Stereo Mol Wt Massspec 1H NMR Peak (CD)3OD)
2.51-2.56(m,1H),5.05(s,2H),2.22-2.29(m,1H),2.11(S,3H),1.82(s,3H).
27 (3-chloro-4-fluorophenyl) methyl group E 653.06 652.9,655.1 δ =7.41(dd J =7.3 and5.2Hz,1H),7.24-7.26(m,1H),7.22(d, J =1.3Hz,1H),7.14(dd, J =8.5 and 7.1Hz,1H),7.06(d, J =8.3Hz,1H),6.88(d,1.9Hz,1H),6.79-6.82(m,1H),5.80(m,1H),5.02(s,2H),2.48-2.5(m,1H),2.24-2.25(m,1H),2.09(d,
28 (3, 4-dichlorophenyl) methyl group E 669.51 668.9.670.9672.1 δ =7.44(d, J =1.8Hz,1H),7.41(d, J =8.3Hz,1H),7.20-7.23(m,2H),7.06(d, J =1.7Hz,1H),6.88(d, J =2.1Hz,1H),6.80(dd, J =8.7 and 1.8Hz,1H),5.81(dd, J =5.2 and 1.7Hz,1H),5.03(s,2H),2.48-2.54(m,1H),2.20-2.27(m,1H),2.09(d, J =1.5Hz,1H),1.78(s,3H).
29 (3-chloro-5-fluorophenyl) methyl group E 653.06 653.0,655.0 δ=7.21(brs,1H),7.15(brs,1H),7.04-7.08(m,2H),7.00(brd,1H),6.88(d, J =1.8Hz,1H),6.81(dd, J =8.6 and 1.8Hz,1H),5.81(dd J =5.2 and 1.8Hz,1H),5.05(s,2H),2.49-2.55(m,1H),2.09-2.27(m,1H),2.09(d, J =1.4Hz,3H),1.80(s,3H).
30 (4-chloro-5-fluorophenyl) methyl group E 653.06 653.0,654.9 δ =7.36(dd, J =8.1and 7.6Hz,1H),7.22(brs,1H),7.16(dd, J =10.0 and 2.0Hz,1H),7.08(brd,1H),7.05(d, J =10.5Hz,1H),6.88(d, J =1.8Hz,1H),6.80(dd, J =8.6 and 1.9Hz,1H),5.81(dd,1.7 and5.2Hz,1H), 5.03(s,2H2.20-2.27(m,1H).
The following synthetic methods may also be used to prepare the compounds of the present invention. Preparation of various alcohol starting materials used in hydroxylamine synthesis:
the starting alcohol is obtained by reducing a commercially available compound in a high oxidation state. The corresponding alcohol can be obtained by reducing 4-cyclohexylbenzoic acid with lithium aluminium hydride (2.3 equivalents) in tetrahydrofuran. The corresponding alcohol can be formed by reducing 3- (4-chlorophenyl) propionic acid with diborane (1.1 equiv.) in tetrahydrofuran at 0 deg.C to room temperature for 5 hours. 3-trifluoromethoxybenzaldehyde, 3-cyanobenzoic acid, benzofuran-2-carbaldehyde, 1, 4-benzodioxan-6-carbaldehyde and 3-fluoro-4-methoxybenzaldehyde can be reduced to the corresponding alcohol derivatives with sodium borohydride in tetrahydrofuran.
Magnesium sulfate (4 equiv.) was treated with concentrated sulfuric acid (1 equiv.) followed by 4-chloromethylbenzoic acid (1 equiv.) and t-butanol (5.1 equiv.) in dichloromethane. Stirring overnight at room temperature gave tert-butyl ester.
The N-acetylation of 4-amino-3, 5-dichlorobenzoic acid can be carried out by treatment with acetyl chloride (1.2 eq.) in dimethylformamide at 90 ℃ for 4 hours. The cooled reaction mixture was poured into cold water, frozen and filtered to obtain an acetamide derivative. The carboxylic acid was reduced with lithium aluminum hydride (2 eq.) at 0 ℃ for 2 hours in tetrahydrofuran to give N- (2, 6-dichloro-4-hydroxymethylphenyl) acetamide.
The amino groups of 3-aminobenzyl alcohol and 4-aminomethylbenzyl alcohol can be protected as N-tert-butoxycarbonyl derivatives by treatment with di-tert-butyl dicarbonate (1.1 equivalents) in Tetrahydrofuran (THF) under reflux until the starting amino compound is completely consumed.
The reaction of ethyl 4-fluorobenzoate with piperidine (3 eq) in acetonitrile can be carried out at reflux for 4 days. The cooled reaction mixture was diluted with several volumes of water to produce a precipitate, which was then filtered to give ethyl 4- (piperidin-1-yl) benzoate. The ester was reduced with lithium aluminum hydride (2 equivalents) in tetrahydrofuran to give the corresponding alcohol.
5-hydroxymethylbenzofuran can be prepared according to the method of K.Hiroya, K.Hashimura and K.Ogasawara, Heterocycles (1994)38,2463.
2-phenylpyrimidine-5-carbaldehyde can be prepared according to the method of J.T.Gupton, J.E.Gall, S.W.Riesinger et al [ J.heterocyclic Chemistry (1991)28,1281 ]. This aldehyde can be reduced to the corresponding alcohol using sodium borohydride in methanol.
The above U.S. provisional patent application entitled "hygromycin A derivatives" (attorney docket number: PC10057) describes additional processes that may be used to prepare various compounds of the present invention.

Claims (13)

1. A compound of the formula:wherein:
R1is H and R2is-NR3R4,-NR4C(O)R3,-OC(O)NR3R4OR-OR3；
Or R1And R2Together form = O, = N-OR3,=CR4R3,=CR4C(O)R3,=CR4C(O)OR3Or = CR4C(O)NR3R4；
R3Each independently selected from H, C1-C10Alkyl radical, C2-C10Alkenyl, - (CH)2)t(C3-C10Cycloalkyl) - (CH)2)t(C6-C10Aryl) and- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0-5, said alkyl optionally containing 1 or 2-S (O) selected from O, wherein j is an integer of 0-2j-and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R3The radicals being optionally substituted with benzene rings, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; r mentioned above3Of a group- (CH)2)t-the moiety optionally comprises a carbon-carbon double or triple bond when t is an integer from 2 to 5; r as defined above, other than H but including any of the optional fused rings as defined above3The radical being optionally substituted by 1 to 5R5Substituted by groups;
R4each independently is H or C1-C10An alkyl group;
R5each independently selected from C1-C10Alkyl radical, C3-C10Cycloalkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6,-C(O)R6,-C(O)OR6,-NR7C(O)OR9,-OC(O)R6,-NR7SO2R9,-SO2NR6R7,-NR7C(O)R6,-C(O)NR6R7,-NR6R7,-S(O)j(CH2)m(C6-C10Aryl radical, -S (O)j(C1-C6Alkyl) where j is an integer from 0 to 2, - (CH)2)m(C6-C10Aryl group, -O (CH)2)m(C6-C10Aryl), -NR7(CH2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle) wherein m isAn integer of 0 to 4; said alkyl group optionally containing 1 or 2-S (O) selected from O, wherein j is an integer from 0 to 2j-and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R5The radicals being optionally substituted with C6-C10Aryl radical, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; and said alkyl, cycloalkyl, aryl and heterocyclic R5 groups are optionally substituted with 1-5 substituents independently selected from the group consisting of: halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR7SO2R9、-SO2NR6R7、-C(O)R6、-C(O)OR6、-OC(O)R6、-NR7C(O)OR9、-NR7C(O)R6、-C(O)NR6R7、-NR6R7、-OR6、C1-C10Alkyl, - (CH)2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle), wherein m is an integer of 0-4;
R6each independently selected from H, C1-C10Alkyl radical, C3-C10Cycloalkyl, - (CH)2)m(C6-C10Aryl) and- (CH)2)m(4-10 membered heterocycle), wherein m is an integer of 0-4; said alkyl group optionally containing 1 or 2-S (O) selected from O, wherein j is an integer from 0 to 2j-and-N (R)7) -a heteroatom moiety with the proviso that two O atoms, two S atoms or O and S atoms are not directly bonded to each other; the cycloalkyl, aryl and heterocycle R6The radicals optionally being substituted by C6-C10Aryl radical, C5-C8A saturated cyclic group or a 4-to 10-membered heterocyclyl fused; and the aforementioned R is other than H6The substituents are optionally substituted with 1-5 substituents independently selected from the group consisting of: halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R7、-C(O)OR7、-OC(O)R7、-NR7C(O)R8、-C(O)NR7R8、-NR7R8Hydroxy, C1-C6Alkyl and C1-C6An alkoxy group;
R7and R8Each independently is H or C1-C6An alkyl group; and
R9is selected from R6Substituents in the definition, but not H.
2. A compound according to claim 1, wherein R1And R2Together form = N-OR3And R is3Is C1-C4Alkyl radical, C2-C4Alkenyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0 to 3, said heterocyclyl is optionally fused with a benzene ring, said aryl is optionally fused with a 5-or 6-membered heterocyclyl, and said R is as previously described including said optionally fused moiety3The group is optionally substituted with 1-5 substituents independently selected from: nitro, halogen, C1-C3Alkoxy radical, C1-C4Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, tert-butoxycarbonyl, -NR6R7Phenyl, cyclohexyl, carboxyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy, and thiophenyl.
3. A compound according to claim 1, wherein R1And R2-form = N-OR3And R is3Is- (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0 to 3, said heterocyclyl is optionally fused with a benzene ring, said aryl is optionally fused with a 5-or 6-membered heterocyclyl, and said R is as previously described including said optionally fused moiety3The group is optionally substituted with 1-5 substituents independently selected from: nitro, halogen, C1-C3Alkoxy radical, C1-C4Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonyl, tert-butoxycarbonylamino, -NR6R7Phenyl, cyclohexyl, carboxyl, t-butoxycarbonylaminomethyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy and thiophenyl.
4. A compound according to claim 1, wherein R1Is H, R2is-NR3R4，R4Is H or methyl, and R3Is- (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle), wherein t is an integer of 0-2, and R3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
5. A compound according to claim 1, wherein R1Is H, R2is-NR4C(O)R3,R4Is H, and R3Is C3-C6Cycloalkyl, - (CH)2)t(C6-C10Aryl) or- (CH)2)t(4-10 membered heterocycle) wherein t is an integer of 0 to 2, said aryl group being optionally fused with a 5-or 6-membered heterocyclyl group, said heterocyclyl group being optionally fused with a benzene ring, and the aforementioned R including said optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
6. A compound according to claim 1, wherein R1And R2Together form = CR4C(O)OR3Or = CR4C(O)NR3R4,R4Is H, and R3Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl, - (CH)2)t(4-10 membered heterocycle) or- (CH)2)t(C6-C10Aryl) wherein t is an integer of 0 to 2, optionally fused with a 5-or 6-membered heterocyclic group optionally fused with a benzene ring, and the aforementioned R in addition to H but including the optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl, -NR6R7And trifluoromethyl.
7. A compound according to claim 1, wherein R1Is H, R2is-OR3And R is3Is C1-C4Alkyl, - (CH)2)t(4-10 membered heterocycle) or- (CH)2)t(C6-C10Aryl) wherein t is an integer of 1 to 2, optionally fused with a 5-or 6-membered heterocyclic group optionally fused with a benzene ring, and the aforementioned R including the optionally fused moiety3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl, cyclohexyl, cyano, trifluoromethyl, benzyloxy, and trifluoromethyl.
8. A compound according to claim 1, wherein R1Is H, R2is-OC (O) NR3R4,R4Is H, and R3Is- (CH)2)t(C6-C10Aryl) group, wherein t is an integer of 0 to 2, and R3The radicals are optionally substituted by 1 to 5 radicals independently selected from halogen, C1-C3Alkoxy radical, C1-C4Alkyl and trifluoromethyl.
9. The compound according to claim 1, wherein the compound is selected from the group consisting of:
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (benzofuran-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (benzofuran-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O-phenylmethyloxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O-phenylmethyloxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-pyridyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4- (4-morpholinyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ cyclohexylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-dichlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (furan-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (furan-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-cyclohexylphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-aminophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ [ (4-aminomethyl) phenyl ] methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [3- (4-chlorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [3- (4-chlorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3- (trifluoromethoxy) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4- (1-piperidinyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [2- (phenylthio) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (benzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (benzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2-phenylpyrimidin-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluoro-4-methoxyphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-dihydro-2H-1-benzopyran-4-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (5, 6-dideoxy-5- (methyl (benzyl) amino- α -L-galactofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (5, 6-dideoxy-5-phenylamino- α -L-galactofuranose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-O- [ (3, 4-dichlorophenyl) methyl ] - β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (furan-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (5-methyl- β -D-erythro-furanhept-5- (E) -enolon-1-yluronic acid) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, ethyl ester;
5-deoxy-5- [ [3- [4- [ [ N- (furan-2-yl) methyl ] - (5-methyl- β -D-erythro-furanhept-5- (E) -enolic acid-1-yl-amide) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [3- (phenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (2-propen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (2-propen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-methylphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-methoxyphenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3- (trifluoromethyl) phenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-O- [ (4-chlorophenyl) methyl ] - β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ benzhydryl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5-phenylcarbamate- β -D-ribofuranose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy-5- [ (3, 4-dichlorophenyl) methyl ] carbamate- β -D-ribofuranosyl-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chlorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-4-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-5-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-5-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-2-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-3-fluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-1, 3-benzodioxol-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-chloro-1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-chloro-1, 3-benzodioxol-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-dihydrobenzofuran-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-dihydrobenzofuran-6-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-dihydrobenzofuran-5-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (1,2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (1,2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (7-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (7-chloro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (7-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (7-fluoro-1, 2,3, 4-tetrahydronaphthalen-1-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (8-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (8-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (6-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (6-chloro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (6-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (6-fluoro-3, 4-dihydro-2H-1-benzopyran-4-yl) oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (quinolin-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (quinolin-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (quinolin-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (quinolin-3-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [4- (benzyl) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [4- (benzyl) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [4- (phenoxy) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [4- (phenoxy) phenylmethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylthiazol-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylthiazol-2-yl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (2, 4-difluorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (2, 4-difluorophenyl) propyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (2, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (2, 4-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3, 5-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3, 5-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [1- (3-chloro-2, 6-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [1- (3-chloro-2, 6-difluorophenyl) ethyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-2, 6-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (2, 6-dideoxy- β -D-erythro-hexofuranose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 4-difluorophenyl) methyl ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-dichlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-dichlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-afur-i-noxa-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chlorophenyl) ] oxime;
5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofurano-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-fluorophenyl) ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3, 5-dichlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 5-dichlorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (phenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (phenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (3-chloro-4-fluorophenyl) oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2,1, 3-benzooxadiazol-5-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2,1, 3-benzooxadiazol-5-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2,3,5, 6-tetrafluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2,3,5, 6-tetrafluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-difluorophenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylfuran-3-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylfuran-3-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenylfuran-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (4-phenylfuran-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 3-difluoro-6-methoxyphenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-difluoro-6-methoxyphenyl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (3-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-furanose-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (5-chloro-thiophen-2-yl) methyl ] oxime;
5-deoxy-5 [4- [ (2, 6-dideoxy- β -D-erythro-hexo-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (5-chloro-thiophen-2-yl) methyl ] oxime; and pharmaceutically acceptable salts, prodrugs and solvates of said compounds.
10. A pharmaceutical composition for treating a bacterial infection, a protozoal infection, or a disease associated with a bacterial infection or protozoal infection in a mammal, fish, or bird, comprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable carrier.
11. A method of treating a bacterial infection, a protozoal infection, or a disease associated with a bacterial infection or protozoal infection in a mammal, fish, or bird, comprising administering to the mammal, fish, or bird a therapeutically effective amount of a compound of claim 1.
12. Preparation of R in claim 11And R2Together form = N-OR3The process of (a), which comprises reacting a compound of formula H with an inert solvent at a temperature of about 0 ℃ to 65 ℃2N-OR3Or a salt of said hydroxylamine, wherein R3Treating a compound of formula 4, as defined above:wherein X is a protecting group, wherein when a salt of hydroxylamine is used, it is optionally carried out with the addition of a base; deprotection is then achieved using a fluoride source.
13. The process of claim 12, wherein the inert solvent is methanol, ethanol, or pyridine, or a mixture of the foregoing solvents, and the optional base is Na2CO3Or K2CO3The temperature is 50-60 ℃, and the fluoride source is tetrabutylammonium fluoride or a hydrogen fluoride-pyridine complex.
HK01107285.8A 1998-05-04 1999-04-08 2"-deoxy hygromycin derivatives HK1036628A (en)

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Application Number Priority Date Filing Date Title
US60/084,058 1998-05-04

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