HK1036629A

HK1036629A - Hygromycin a derivatives

Info

Publication number: HK1036629A
Application number: HK01107295.6A
Authority: HK
Inventors: K‧E‧布瑞提; S‧S‧古汉; M‧R‧杰弗森; R‧G‧林德二世; E‧L‧穆考密克
Original assignee: 辉瑞产品公司
Priority date: 1998-05-04
Filing date: 1999-05-03
Publication date: 2002-01-11

Description

Hygromycin A derivatives

Background

The present invention relates to novel hygromycin a derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including humans, as well as fish and birds. The invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds in need of such treatment.

Hygromycin A is a natural product produced by fermentation and was first isolated from Streptomyces hygroscopicus in 1953. As an antibiotic, hygromycin A has activity against human pathogens and has been reported to have potent in vitro activity against swine dysentery causing little snake fungus. There are several references which mention semi-synthetic modifications of hygromycin a, including: isono et al, in journal of antibiotics 1957,10,21, and R.L.Mann and D.O.Woolf, in journal of the American society for chemical sciences 1957,79,120, mention the 5 "ketone derivatization of hygromycin A to 2, 4-dinitrophenylhydrazone. Isono et al (supra) also mention thiosemicarbazones on 5'; reduction of the 5 "ketone of hygromycin a to the 5" alcohol is mentioned in r.l.mann and d.o.woolf (supra) and s.j.hecker et al in journal of bio-organic pharmaceutical chemistry 1992,2,533 and s.j.hecker et al in journal of bio-organic pharmaceutical chemistry 1993,3, 295; jaynes et al, 1993,3,1531 in the journal of bio-organic pharmaceutical chemistry and jaynes et al, 1992,45,1705 in the journal of antibiotics; aromatic ring analogs are mentioned in s.j.hecker et al, journal of bio-organic pharmaceutical chemistry 1993,3,289 and c.b.cooper et al, journal of bio-organic pharmaceutical chemistry 1997,7, 1747; S.J. Hecker et al, in journal of Bio-organic pharmaceutical chemistry 1992,2,533, mention enamide analogues; amino cyclic alcohol analogs are mentioned by s.j.hecker et al in journal of bio-organic pharmaceutical chemistry 1992,2,1015 and by s.j.hecker et al in journal of bio-organic pharmaceutical chemistry 1992,2, 1043. The hygromycin a derivatives of the invention have activity against gram-negative and gram-positive bacteria and protozoa.

Hygromycin analogs are also mentioned in U.S. provisional patent application No. 60/084058, entitled "2" -deoxy hygromycin derivatives ", filed on 4.5.1998, and filed concurrently herewith (attorney docket No. PC 10186), assigned to the inventor R.G. Linde II, which is incorporated herein by reference in its entirety.

Summary of the inventionthe present invention relates to compounds of formula 1:and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:

R¹is H, R²is-NR³R⁴,-NR⁴C(O)R³,-OC(O)NR³R⁴OR-OR³；

Or R¹And R²Common constituent = N-OR³,=CR⁴R³,=CR⁴C(O)R³,=CR⁴C(O)OR³Or = CR⁴C(O)NR³R⁴；

Each R³Independently 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 from 0 to 5, said alkyl optionally containing 1 or 2 substituents selected from O, -S (O)_j- (wherein j is an integer of 0-2) and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R³Optionally with a benzene ring, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; r mentioned above³Of a group- (CH)₂) the t-moiety optionally comprises a carbon-carbon double or triple bond, wherein t is an integer between 2 and 5; r mentioned above³Groups, excluding H but including any optional fused rings as described above, optionally substituted with 1-5R⁵Is substituted by radicals, with the proviso that R¹Is H and R²is-OR³When R is³Is not H, methyl or ethyl;

each R⁴Independently is H or C₁-C₁₀An alkyl group;

each R⁵Independently 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 O, -S (O)_j- (wherein j is an integer of 0-2) and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R⁵Optionally with C₆-C₁₀Aryl radical, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; the alkyl, cycloalkyl, aryl and heterocycle R⁵Optionally 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;

each R⁶Independently 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 optionally comprising 1 or 2 substituents selected from O, -S (O)_j- (wherein j is an integer of 0-2) and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R⁶Optionally with C₆-C₁₀Aryl radical, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; r mentioned above⁶Substituents, other than H, 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;

each R⁷And R⁸Independently is H or C₁-C₆An alkyl group;

R⁹is selected from R⁶A substituent other than H as specified in the definition of (1).

Preferred compounds of formula 1 include those compounds, i.e., wherein R is¹And R²Common constituent = 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, heterocyclyl is optionally fused to a benzene ring, aryl is optionally fused to a 5-or 6-membered heterocyclyl, and the foregoing R³(ii) group, including the optionally fused moiety, optionally substituted with 1-5 substituents independently selected from the group consisting of: nitro, halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, tert-butoxycarbonyl, -NR⁶R⁷Phenyl, cyclohexyl, carboxyl, aminomethyl, difluoromethoxy, trifluoromethylOxy, cyano, piperidinyl, morpholino, phenoxy and thiophenyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹And R²Common constituent = 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, heterocyclyl is optionally fused to a benzene ring, aryl is optionally fused to a 5-or 6-membered heterocyclyl, and the foregoing R³(ii) group, including the optionally fused moiety, optionally substituted with 1-5 substituents independently selected from the group consisting of: nitro, halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonyl, tert-butoxycarbonylamino, -NR⁶R⁷Phenyl, cyclohexyl, carboxyl, tert-butoxycarbonylaminomethyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy and thiophenyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹Is H, R²is-NR³R⁴、R⁴Is H or methyl, R³Is- (CH)₂)_t(C₆-C₁₀Aryl) or- (CH)₂)_t(4-10 membered heterocycle), wherein t is an integer of 0-2, and R³Optionally substituted by 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl and trifluoromethyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹Is H, R²is-NR⁴C(O)R³、R⁴Is H, R³Is C₃-C₆Cycloalkyl, - (CH)₂)_t(C₆-C₁₀Aryl) or- (CH)₂)_t(4-10 membered heterocycle) wherein t is an integer of 0-2, aryl is optionally fused to a 5-or 6-membered heterocyclyl, which is optionally fused to a benzene ring, and the foregoing R³Base is composed ofSaid optionally fused moiety, optionally substituted by 1-5 moieties, is independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl and trifluoromethyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹And R²Common composition = CR⁴C(O)OR³Or = CR⁴C(O)NR³R⁴、R⁴Is H, 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, aryl optionally fused to a 5 or 6 membered heterocyclyl optionally fused to a phenyl ring and the foregoing R³And (C) a group, excluding H but including said optionally fused moiety, optionally substituted with 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, -NR⁶R⁷And trifluoromethyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹Is H, R²is-OR³、R³Is C₁-C₄Alkyl, - (CH)₂)_t(4-10 membered heterocycle) or- (CH)₂)_t(C₆-C₁₀Aryl) wherein t is an integer from 1 to 2, aryl optionally fused to a 5 or 6 membered heterocyclyl optionally fused to a phenyl ring and the foregoing R³Optionally substituted, with 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, cyclohexyl, cyano, trifluoromethyl, benzyloxy, and trifluoromethyl.

Other preferred compounds of formula 1 include those compounds, i.e., wherein R is¹Is H, R²is-OC (O) NR³R⁴、R⁴Is H, R³Is- (CH)₂)_t(C₆-C₁₀Aryl radicals) Wherein t is an integer of 0 to 2 and R³Optionally substituted by 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl and trifluoromethyl.

Particularly preferred compounds of formula 1 include those selected from the group consisting of:

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-type-hexan-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexan-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl- ] -oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (3, 4-difluorophenyl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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-galactose type-furanose-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-galactose-type-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy-5-O- [ (3, 4-dichlorophenyl) methyl ] - β -D-altrose-form-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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-arabino-hept-5- (E) -enesuranuronan-1-yl acid) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -O-propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, ethyl ester;

5-deoxy-5- [ [3- [4- [ [ N- (furan-2-yl) methyl ] - (5-methyl- β -D-arabino-hept-5- (E) -enesuranuronl-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy-5-O- [ (4-chlorophenyl) methyl ] - β -D-altrose-form-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenylamino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy-5-carbanilate- β -D-altrose-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy-5- [ (3, 4-dichlorophenyl) methyl ] carbamate- β -D-altrose-type-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -O-propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [ (2, 3-dihydrobenzofuran-6-yl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -O-propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (3-chloro-4-fluorophenyl) oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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-hexan-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl- ] -oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (2, 4-difluorophenyl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (4-phenyl-furan-3-yl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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-3-yl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenyl-furan-2-yl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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-chlorophenyl) ethyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (3-difluoromethoxy-phenyl) oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (3-difluoromethoxy-phenyl) oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- (4-difluoromethoxy-phenyl) oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- (4-difluoromethoxy-phenyl) oxime;

and pharmaceutically acceptable salts and solvates of said compounds.

In a more particular embodiment, the invention includes the following compounds:

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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;

and pharmaceutically acceptable salts and solvates of said compounds.

The invention also relates to a pharmaceutical composition which can be used for the treatment of the following diseases in mammals, fish or birds: a bacterial infection, a protozoal infection, and a disease associated with a bacterial infection or protozoal infection, the composition 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 mammal, fish or bird selected from bacterial infections, protozoal infections or diseases associated with bacterial infections or protozoal infections comprising administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

The invention also relates to a process for the preparation of a composition comprising hygromycin A and epihygromycin, the ratio of hygromycin A to epihygromycin in said composition being at least 10: 1, which comprises fermenting Streptomyces hygroscopicus in a medium having a pH of less than 6.9 at a temperature in the range of 25 ℃ to 35 ℃. In a preferred embodiment of the method, the S.hygroscopicus is S.hygroscopicus NRRL2388 or a mutant thereof, the pH ranges from 6.2 to 6.7, the temperature is about 29 ℃, and the ratio of hygromycin A to epihygromycin is at least 14: 1. In another aspect of the above method, the composition is maintained at a pH of 6.0 to 6.4, preferably about 6.0, and the temperature of the composition is maintained in the range of 25 ℃ to 35 ℃ during the purification of the hygromycin A to oil.

As used herein, unless otherwise indicated, the term "treating" or "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing the disease or condition to which it refers, or one or more symptoms of such disease or condition. The term "treatment" as used herein refers to a therapeutic action, and "treatment" in this "therapeutic action" is defined as "treatment" immediately above.

As used herein, unless otherwise indicated, the terms or phrases "bacterial infection", "protozoal infection" and "diseases associated with bacterial infection or protozoal infection" include the following: pneumonia associated with infection by streptococcus pneumoniae, haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, enterococcus faecalis, enterococcus faecium, enterococcus casseliflavus, staphylococcus epidermidis, staphylococcus haemolyticus or streptococcus digestus, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis; pharyngitis, rheumatic fever and glomerulonephritis associated with infection by streptococcus pyogenes, group C and group G streptococcus, corynebacterium diphtheriae 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, are caused by S.aureus, S.haemolyticus, E.faecalis, E.faecium, E.durans, including strains resistant to known antibacterial agents such as, but not limited to: beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines, and macrolides; uncomplicated skin and soft tissue infections and abscesses and puerperal fever associated with infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., Staphylococcus epidermidis, Staphylococcus haemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, group C-F streptococci (microcolones streptococci), Streptococcus viridans, Corynebacterium parvum, Clostridium, or Bartonella henselae; uncomplicated acute urinary tract infections associated with infections with staphylococcus aureus, coagulase-negative staphylococci or enterococci; urethritis and cervicitis; sexually transmitted diseases associated with infection by chlamydia trachomatis, haemophilus ducreyi, treponema pallidum, ureaplasma urealyticum or neisseria gonorrhoeae; toxin diseases associated with infection by staphylococcus aureus (food poisoning and toxic shock syndrome) or A, B and group C streptococci; ulcers associated with helicobacter pylori infection; systemic fever syndrome associated with recurrent borrelia infection; lyme disease associated with borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocystitis associated with infection by chlamydia trachomatis, neisseria gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, haemophilus influenzae or listeria; a mycobacterium avium complex of disseminating (MAC) disease associated with infection by mycobacterium avium or mycobacterium intracellulare; infections caused by mycobacterium tuberculosis, mycobacterium leprae, mycobacterium paratuberculosis, mycobacterium kansasii or mycobacterium cheloni; gastroenteritis associated with campylobacter jejuni subspecies jejuni infection; intestinal protozoan infections associated with cryptosporidium infection; odontogenic infections associated with streptococcus viridis infection; persistent cough associated with bordetella pertussis infection; gas gangrene associated with infection by clostridium perfringens or bacteroides; and atherosclerosis or cardiovascular diseases associated with infection by helicobacter pylori or chlamydia pneumoniae. Bacterial and protozoal infections and diseases associated with such infections in animals that may be treated or prevented include the following: bovine respiratory disease associated with infection by pasteurella haemolytica, pasteurella multocida, mycoplasma bovis, or bordetella; cow intestinal disease associated with protozoan (i.e., coccidia, cryptosporidium, etc.) infection; mastitis in dairy cows associated with infection by staphylococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, corynebacterium or enterococcus; porcine respiratory disease associated with infection by actinobacillus pleuropneumoniae (a. pleuro), pasteurella multocida or mycoplasma; porcine intestinal disease associated with infection by Lawsonia intracellularis (Lawsonia intracellularis), Salmonella, or porcine Serpentis dysentery; cow foot rot associated with clostridial infection; warts of cow hair associated with infection by fusobacterium necrophorum or arthroidal ungus; cow red eye disease associated with Moraxella bovis infection; early abortion in cows associated with protozoan (i.e. neospora) infection; skin and soft tissue infections in dogs and cats associated with staphylococcus epidermidis, staphylococcus intermedius, coagulase-negative staphylococcus or pasteurella multocida infection; and dental or oral infections of dogs and cats associated with infection by alcaligenes, bacteroides, clostridia, enterobacter, eubacterium, streptococcus digestans, porphyromonas or prevotella. Other bacterial and protozoal infections and diseases associated with such infections that can be treated or prevented according to the methods of the present invention are described in J.P.Sanford et al, Sanford Antimicrobial Therapy guidelines, 26 th edition (Antimicrobial Therapy, Inc., 1996).

The term "halogen" as used herein includes fluorine, chlorine, bromine or iodine unless otherwise specified. Preferred halo groups are fluoro, chloro and bromo.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. The hydrocarbyl group may include one or two double or triple bonds. It is understood that for the hydrocarbyl group, at least two carbon atoms are required in the hydrocarbyl group in order to include a carbon-carbon double or triple bond.

The term "aryl" as used herein, unless otherwise indicated, includes an organic radical formed from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.

The term "4-10 membered heterocyclic" as used herein, unless otherwise specified, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in the ring system, whereas aromatic heterocyclic groups necessarily have at least 5 atoms in the ring system. Heterocyclyl includes benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclyl 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, thienylalkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepinyl, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiopentanoyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, piperidino, morpholino, thiomorpholino, 2-pyrrolinyl, 3-pyrrolinyl, dihydropyranyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azab, 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, quinazolinyl, quinoxalinyl, 1, 5-diazananyl and furylpyridinyl. The aforementioned groups, when derived from the above compounds, may be attached to C or to N. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked).

The phrase "pharmaceutically acceptable salt" as used herein includes salts of acidic or basic groups that may be present in the compounds of the present invention, unless otherwise indicated. The compounds of the invention which are basic in nature are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts (i.e. salts containing pharmacologically acceptable anions), such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, acid sulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate)). In addition to the acids mentioned above, the compounds of the present invention, which include a basic moiety, such as an amino group, may also form pharmaceutically acceptable salts with various amino acids.

Those compounds of the invention that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and 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 thus 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, as well as to all pharmaceutical compositions and methods of treatment which may be applied or which contain them. In this connection, if R¹And R²Jointly form the formula = N-OR³Oxime moiety of (A), the present invention includes a nitrogen-linked-OR³E and Z configurations of the radicals. The compounds of formula 1 may also exist as tautomers. The present invention relates to the use of all of these tautomers and mixtures thereof.

The present invention also includes isotopically-labeled 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 hydrogen, carbon, nitrogen, oxygen, hydrogen,Isotopes of phosphorus, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F and³⁶and (4) Cl. 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 also within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, for example, those into which a radioactive isotope such as³H and¹⁴c, can be used in tissue distribution assays for drugs and/or substrates. Tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred because of their ease of preparation and detection. In addition, with heavier isotopes such as deuterium (i.e. deuterium)²H) Substitution may result in certain medical advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, or a reduction in the required dose, and may therefore be preferred in certain circumstances. Isotopically labeled compounds of formula 1 and prodrugs thereof according to the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The invention also includes pharmaceutical compositions containing prodrugs of the compounds of formula 1, and methods of treating bacterial infections by administering prodrugs of the compounds of formula 1. The compounds of formula 1 with free amino, amido, hydroxy or carboxy groups can be converted into prodrugs. Prodrugs include compounds in which a polypeptide chain having one amino acid residue, or two or more (e.g., two, three, or four) amino acid residues, is covalently linked via an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of the compound of formula 1. Amino acid residues include, but are not limited to, the 20 natural amino acids typically designated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine (demosine), isodesmosine, 3-methylhistidine, norvaline, β -alanine, γ -aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.

Other types of prodrugs are also included. For example, the free carboxyl groups may be derivatized as amides or alkyl esters. Amide and ester moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. The free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl, among others, as outlined in d.fleisher, r.bong, b.h. stewart, advanced drug release reviews (1996) 19, 115. Also included are carbamate prodrugs of hydroxy and amino groups, such as carbonate prodrugs of hydroxy groups and sulfate esters. Also included are derivatives of hydroxyl groups as (acyloxy) methyl and (acyloxy) ethyl ethers, where the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functionalities, or the acyl group is an amino acid ester as described above. Robinson et al in J.Med.Chem.Chem.39 (1996) 39,10 describe prodrugs of this type.

The selective introduction of the prodrug side chain can be performed on the hydroxyl group of the hygromycin a core molecule. For example, the 6 hydroxyl groups of hygromycin A can be completely silylated with tert-butyldisilyl chloride. The hexasilyl derivative is subjected to a methanolic solution of potassium carbonate at room temperature to selectively remove the phenolic silyl group, allowing further selective modification at that position. In another example, hygromycin A is incompletely silylated (see PC 10186, R. Linde,2 "-deoxy hygromycin A derivatives, U.S. provisional patent application No. 60/084,058, 1998, 5.4. sup.) to pentasilyl derivatives in which the C-2" hydroxyl group is free. This derivative can be selectively acylated, alkylated, etc., to provide a prodrug attached at C-2 ".

Detailed description of the inventionthe following scheme illustrates the preparation of the compounds of the present invention.

Flow chart

The compounds of the invention are readily prepared. According to the above scheme, the starting compound represented by formula 2 is hygromycin A, which can be prepared according to methods well known to those skilled in the art, such as by fermentation of S.hygroscopicus NRRL 2388. The methyl ketone at the 4 "position of the furanose of the hygromycin A molecule can be present in the S configuration (hygromycin A) or the R configuration (epihygromycin) on the furanose. When the published 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;. 1278,1279; -1282)), the hygromycin product was an approximately 3: 1 mixture of hygromycin A (4 "- (S) epimer) and epihygromycin with beta-oriented methyl ketones on furanose as shown. It is known from the literature (J. 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 below 6.9, and controlling the pH, temperature and solvent during purification, the ratio of hygromycin A to epihygromycin in the final recovered product can be increased to at least 14: 1. Using this starting material, essentially a single isomer derived from 4 "- (S) hygromycin can be prepared for use as a template for further synthetic modifications.

Hygromycin A enriched in the 4' - (S) epimer is produced by fermentation of S.hygroscopicus NRRL2388 or a mutant thereof, the pH of the medium being controlled to below 6.9, preferably between 6.2 and 6.7, throughout the fermentation. The medium contains assimilable sources of carbon, nitrogen and trace elements, as is well known to those skilled in the art. The fermentation is carried out at a temperature of about 25 to 35 c, preferably about 29 c. For example, fermentation is monitored using high pressure liquid chromatography. The incubation is continued until the yield of the compound is maximized, generally for about 3-10 days, preferably about 4-6 days.

The formation of epihygromycin during purification can be minimized by using an aqueous buffer solution (instead of unbuffered water) and controlling the pH of the active stream to near 6.0. The formation of epihygromycin can also be minimized by minimizing the time that the recovered material is subjected to the higher temperature. Therefore, if it is desired to reduce the solvent concentration, it is preferred to dilute the active stream with an aqueous buffer solution and avoid the use of rotary evaporation at elevated temperatures. Also, as a means to avoid higher temperatures, the active solution can be concentrated with a resin column before the final purification step to reduce the volume of solution that must be boiled. In this process, the final purification step is to concentrate the active fraction to a solid using vacuum and a water bath temperature of about 35-50 ℃. The period of time during which the solution is subjected to high temperatures can be minimized by boiling in stages.

Wherein R is¹And R²Co-formation = NOR³(wherein R is³The compound of formula 1 of oxime) as defined above can be prepared by the following method: with the formula R³ONH₂The hydroxylamine described treats hygromycin a (compound of formula 2) using the free base or salt of hydroxylamine, preferably the free base of hydroxylamine. The reaction is carried out in an inert solvent such as methanol, ethanol or pyridine, and if a salt of hydroxylamine, e.g. the hydrochloride salt, is used, a base such as Na is added to the solvent₂CO₃Or K₂CO₃The reaction is carried out at a temperature in the range of about 0 to 65 deg.C, preferably 0 to 25 deg.C. Bioconjugate chemistry (1990) 2, 96; the preparation of the formula R is disclosed in one or more of journal of pharmaceutical sciences (1969) 58,138 and Notification of chemistry and pharmacy (1967) 15,345³ONH₂Hydroxylamine is shown.

Wherein R is¹Is H, R²is-NR³R⁴And R is³And R⁴The compound of formula 1 as defined above can be synthesized by reductive amination at the C-5 "ketone site of hygromycin a. R⁴NH₂And hygromycin A in an inert solvent with a reducing agent such as NaBH₄、NaBH(OAc)₃(Ac is acetyl) or NaCNBH₃Is processed to obtain R³Product of = H. To get R³Conversion to groups other than H can be performed by a second reductive amination with an appropriate aldehyde or ketone of formula RC (O) H or RC (O) R' (if R is³Is RCH₂-or RR 'CH-, and R' and R are R³Any part within the definition that can pass through a sub-groupA methyl linkage, such as alkyl, arylalkyl, or heterocycloalkyl). An Eschweiler-Clark reaction can be used to introduce a methyl group as R³And (4) a substituent. To provide an amide group, e.g. when R is¹Is H and R²is-NR⁴C(O)R³When, as described above, one may be introduced of the formula-NHR⁴The amine represented by, then by using an activated form of a carboxylic acid, such as R³COCl or R³C(O)OC(O)R³By treatment of the intermediate to introduce a compound of formula-C (O) R³Or by using an amide coupling agent such as (2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ),1, 1' -carbonyl-diimidazole (CDI) or a carbodiimide, such as 1, 3-Dicyclohexylcarbodiimide (DCC). in the above method, K can be used in the final deprotection step₂CO₃The methanol solution of (a) releases any esterified hydroxyl groups of hygromycin a.

Wherein R can be prepared by using a primary amine produced by reductive amination of hygromycin A with an ammonia equivalent, for example by using ammonium acetate and sodium cyanoborohydride or sodium triacetoxyborohydride¹Is H, R²is-NR⁴C(O)R³And R is⁴Is H, R³A compound of formula 1 as defined above. Alternatively, the primary amine may be prepared via the corresponding azide: 1) for example, the hydroxyl groups of hygromycin A can be protected as their TBDMS (tert-butyldimethylsilyl) derivatives by the action of TBDMSCI and an amine-type base such as imidazole or pyridine; 2) the C-5 'ketone of hygromycin A is then reduced, for example, with a solution of sodium borohydride in methanol, to give the fully silylated 5' -hydroxyhygromycin; 3) converting the resulting alcohol to a mesylate, for example by the action of methanesulfonyl chloride and triethylamine; 4) replacement of the mesylate with azide, for example using sodium azide in N, N-Dimethylformamide (DMF); 5) the azide is reduced to a primary amine using, for example, triphenylphosphine followed by hydrolysis.

The primary amine and R³C (O) activated form of OH, e.g. R³C (O) Cl or R³C(O)OC(O)R³The reaction gives the corresponding amide. On the other handMay be reacted with R³C (O) OH together 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 such as acetic acid, hydrogen fluoride-pyridine complex, or fluoride ions such as tetrabutylammonium fluoride (TBAF).

To add a group R4 other than H, the amide described above can be alkylated, for example, to a silyl ether after protection of any free hydroxyl group. The alkylation may be carried out with a base and an alkylating agent such as sodium hydride and a suitable bromide of the formula R4-Br. The hydroxyl group is then deprotected with an acid such as acetic acid, hydrogen fluoride-pyridine complex, or fluoride ion such as TBAF.

Alternatively, it can be mediated by sodium triacetoxyborohydride or sodium cyanoborohydride, with R⁴NH₂The reductive amination is performed on hygromycin a or a protected version thereof. The resulting secondary amines can be substituted with R as described above³Acylation of activated form of C (O) OH, or by use of an amide coupling agent with R³C (O) OH reaction. Deprotection of the hydroxyl groups is then accomplished as described above.

Fully silylated 5' -hydroxyhygromycin A with isocyanate R in toluene³NCO is reacted at a temperature of 40-110 ℃, preferably 50-80 ℃ to obtain R¹Is H, R²is-OC (O) NR³R⁴A compound of formula 1. It may be beneficial to add dimethylaminopyridine and triethylamine to the reaction. R in the product of this reaction⁴Equal to hydrogen, can be prepared by using a base such as sodium hydride and an alkylating agent such as formula R⁴Alkylating R with a bromide represented by-Br⁴Is equal to C₁-C₁₀An alkyl group. Deprotection of the hydroxyl group can then be carried out using an acid such as acetic acid, hydrogen fluoride-pyridine complex or fluoride ions such as TBAF.

Wherein R is¹Is H, R²is-OR³And R is³Compounds of formula 1 which are alkyl or substituted alkyl may be prepared by alkylation of the corresponding alcohol of hygromycin A. In thatIn this process, the hydroxyl groups of hygromycin A are suitably protected, for example, as their silyl ethers, using a suitable reagent such as triethylsilyl chloride (TESCl), trimethylsilylchloride (TMSCil) or TBDMS and an amine type base such as imidazole or pyridine. The C-5 "ketone moiety is then reduced using a suitable reducing agent such as sodium borohydride in methanol. The resulting alcohol can be treated with R in the presence of a base such as sodium hydride or potassium tert-butoxide³Alkylation with X (where X is a leaving group such as Cl, Br or mesylate). The protecting group is then removed with an acid such as acetic acid, hydrogen fluoride-pyridine complex, or a fluorine source such as TBAF.

Wherein R is¹Is H, R²is-OR³And R is³Compounds of formula 1 that are aromatic or heterocyclic moieties may be prepared via a Mitsunobu reaction. Hughes, et al, in organic reactions (1992) 42,335, protected hygromycin alcohol, prepared as described above, was reacted with R³The Mitsunobu reaction of OH takes place mediated by triphenylphosphine and diethyl azodicarboxylate. The resulting ether was then deprotected as described above.

Or, when R is¹Is H, R²is-OR³And R is³In the case of aromatic or heterocyclic moieties, the protected hygromycin alcohol can be converted to a leaving group, such as a bromide or mesylate derivative. The leaving group is then replaced with R using a base such as sodium hydride, potassium tert-butoxide or potassium carbonate³OH。

Preparation of the alpha, beta-unsaturated ester intermediates from Wittig or Horner-EmmonsWittig olefination of the C-5 "ketone of hygromycin A¹And R²Common composition = CR⁴C(O)R³、=CR⁴C(O)OR³Or = CR⁴C(O)NR³R⁴And R is³And R⁴A compound of formula 1 as defined above. For example, (ethyloxymethylene) triphenylphosphorane or (ethyloxyethylene) triphenylphosphorane may be reacted with hygromycin A to give an unsaturated ethyl ester. The ester is hydrolyzed, for example, with aqueous sodium hydroxide to give the corresponding carboxylic acid (R)¹And R²Common structure= chc (o) OH). In this case, the hydroxyl groups of hygromycins can be protected as described above, for example, as their TES or TBDMS ethers. To prepare the above esters, R can be used, for example, by the action of DCC and DMAP, or CDI and a catalytic base such as sodium ethoxide³OH esterifies the carboxylic acid.

Wherein R is¹And R²Common composition = CR⁴C(O)NR³R⁴The compound of formula 1 can be prepared by using a compound of formula R³NH₂Amine treatment of the above carboxylic acid intermediate (R)¹And R²Co-constituent = chc (o) OH) with the use of an amide coupling agent such as DCC, CDI, EEDQ, DEPC, or EDC. With respect to the protected derivatives, R may be introduced by alkylation⁴For example with a base such as sodium hydride or potassium tert-butoxide and an alkylating agent such as R⁴-X, wherein X is Br, Cl or mesylate.

By direct Wittig or Horner Emmons reaction of hygromycin A, or by protected forms of hygromycin A with, for example, the corresponding R³C(O)CHR⁴-PPh₃(Ph is phenyl) or R³C(O)CHR⁴-P=O(OEt)₂(Et is ethyl) to prepare the compound of formula 1 (R)¹And R²Common composition = CR⁴C(O)R³). Olefination can be carried out using the methods described by j.boutag and r.thomas in chemical reviews (1974) 74,87 and b.e.maryanoff et al in chemical reviews (1989) 89,863. Alternatively, protected unsaturated carboxylic acid derivatives of hygromycin a can be converted to their Weinreb amides, for example, by treatment with CDI and N, O-dimethylhydroxylamine. The amide can then be reacted with R according to the method disclosed in the tetrahedron Kuehsen, S.NaHm. and S.M. Weinreb, 22,39 (1981)³M (where M is a metal ion such as Li or MgBr) reacts to form a ketone.

By means of R⁴-CH(PPh₃)-R³Or R⁴-CH(P=O(OEt)₂)-R³The ylide of (a) can be prepared by reaction with Wittig or Hormer-Emmons of hygromycin A or a protected derivative thereof, wherein R¹And R²Common composition = CR⁴R³And R is³And R⁴Compounds of formula 1 as defined above wherein the hydroxy groups have been modified as described above, for example, to their silyl ethers such as TES or TBDMS. The protecting group may then be removed as described above.

Alternatively, a ketone or aldehyde homologous to C-5 of hygromycin A can be used as an intermediate. These compounds can be prepared by reacting with triphenylphosphonium oxide or phosphorane such as Ph₃P-C(R³) OMe (Me is methyl) by Wittig or Hormer-Emmons reaction. The resulting enol ethers can be hydrolyzed with mild acids such as acetic acid or dilute hydrochloric acid to give aldehydes or ketones. The aldehyde or ketone may then be reacted with an organometallic derivative R⁴M (where M is, for example, Li or MgBr) gives the corresponding alcohol, which can be dehydrated under the action of methanesulfonyl chloride to give the corresponding olefin. Then deprotected as described above to give R wherein¹And R²Common composition = CR⁴R³A compound of formula 1.

Wherein R is¹And R²Common composition = CR⁴R³And R is⁴Is aryl or heteroaryl, R³Compounds of formula 1 other than hydrogen may be prepared using a palladium-catalyzed process. Protected ketone CH₃-CH(COR³) The conversion of hygro to enol triflate can be carried out using the method disclosed in p.j.stang and w.trephow, synthesis 283 (1980). Then the triflate enol ester can be reacted with aryl or heteroaryl dihydroxy methyl boric acid R by Suzuki or Stille type palladium catalysis method⁴B(OH)₂Or aryl tins, e.g. R⁴SnMe₃Or R⁴SnBu₃Coupling to give the unsaturated aryl derivative. The Suzuki coupling reaction can be performed as described in n.miyaura and a.suzuki chemical reviews (1995) 95, 2457. The Stille reaction was carried out using the conditions described in organic reactions 50,1, by V.Farina et al (1997). Deprotection as described above then gives the final compound.

The compounds of the present invention have asymmetric carbon atoms. Compounds with a mixture of isomers at one or more centers will exist as a mixture of diastereomers, which can be separated into the individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as chromatography or fractional crystallization. All such isomers, including diastereomeric mixtures, are considered as integral parts of the invention.

The compounds of the invention which are basic in nature are capable of forming a wide variety of different salts with a wide variety of inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to isolate the compounds of the invention starting from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it to the free base compound by treating the pharmaceutically unacceptable salt with a basic agent, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention can be readily prepared by treating the basic compound with substantially equivalent amounts of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. With careful evaporation of the solvent, the desired solid salt can be readily obtained. The desired acid salt may also be precipitated from a solution of the free base in an organic solvent by adding a suitable inorganic or organic acid to the solution.

Those compounds of the invention that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially sodium and potassium salts. These salts are prepared using conventional techniques. Chemical bases useful as reagents for preparing pharmaceutically acceptable basic salts of the invention are those that form non-toxic basic salts with the acidic compounds of the invention. Such non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, and magnesium. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by mixing together a lower alkanoic acid solution of an acidic compound with a desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness in the same manner as before. In both cases, it is preferred to use stoichiometric amounts of the various reagents to ensure completion of the reaction and maximum yield of the desired end product.

The antibacterial activity of the compounds of the present invention against bacterial pathogens is demonstrated by their ability to inhibit the growth of defined strains of pathogens.

Measurement of

This assay, as described below, employs conventional methods and interpretation criteria, and is designed to provide guidance on chemical modifications that may result in compounds having antibacterial activity against sensitive and resistant organisms, including but not limited to β -lactams, macrolides, and vancomycin resistance. In this assay, a set of bacterial strains is assembled to include various target pathogen species, including typical antibiotic-resistant bacteria. The use of this set of subjects enables the determination of chemical structure/activity relationships from potency and spectra of activity. The assay was performed using microtiter plates and was interpreted according to the "behavioral criteria for antimicrobial disc sensitivity tests-sixth edition, approved standards" index published by the National Committee for Clinical Laboratory Standards (NCCLS); the strains were compared with a Minimum Inhibitory Concentration (MIC). Compounds were initially dissolved in dimethyl sulfoxide (DMSO) as stock solutions.

The activity of the compounds of the invention can also be assessed according to Steers' duplicate gene technique, a standard in vitro bacterial assay described by Steers et al antibiotic and chemotherapy 1959, 9,307.

The in vivo activity of the compounds of the invention can be determined using conventional animal protection studies well known to those skilled in the art, which are typically performed in rodents.

The efficacy of the compounds was assessed using a mouse acute bacterial infection model according to an in vivo model. An example of one such in vivo system is provided below. Mice (CF1 mixed sex mice; 18-20g) were distributed to cages with arrival and allowed to acclimate to the new environment for 1-2 days before being used in the study. Acute infection was produced by intraperitoneal inoculation of bacteria suspended in 5% sterile porcine gastric mucin (staphylococcus aureus strain 01a 1095). The inoculum was prepared by the following method: the cultures were grown overnight at 37 ℃ on blood agar, the resulting surface growth with brain-heart infusion broth was harvested, and the turbidity of the suspension was adjusted so that when diluted 1: 10 to 5% in sterile porcine gastric mucin, 100% lethality would result.

Mice (10 per group) were treated subcutaneously at 0.5 and 4 hours after stimulation. Appropriate untreated (infected but untreated) and positive (vancomycin or minocycline, etc.) control mice were included in each study. After an observation period of 4 days, the percent survival was recorded; determining PD using probabilistic methods₅₀(calculated as mg/kg/dose that protected 50% of infected animals).

The compounds of the present invention and their pharmaceutically acceptable salts (hereinafter referred to as "active compounds") can be administered by the oral, parenteral, topical or rectal routes for the treatment of bacterial and protozoal infections. In general, it is most desirable to administer these compounds in a dosage range of from about 0.2mg/kg body weight per day (mg/kg/day) to about 200 mg/kg/day in a single dose or divided doses (i.e., 1-4 doses per day), although this will be adjusted depending on the species, weight and health of the subject and the particular route of administration chosen. However, dosage levels ranging from about 3 mg/kg/day to 60 mg/kg/day are most desirably employed. However, the above-described dosage ranges may vary depending upon the species of mammal, fish or bird being treated and the individual response to the drug therapy, as well as the type of pharmaceutical formulation selected and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other instances larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses and then administered within a day.

The active compounds may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent using the routes previously described, and such administration may be carried out in a single dose or in multiple 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 and formulated into tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, 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 be suitably sweetened and/or flavored. Generally, the active compound is present in such dosage forms at concentration levels ranging 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 along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting. Solid compositions in similar form may also be used as fillers in gelatin capsules; preferred materials in such combinations also include lactose or milk sugar 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, together with diluents such as water, ethanol, propylene glycol, glycerin and various like mixtures thereof.

For parenteral administration, solutions of the active compounds in sesame or peanut oil or in aqueous ethanol or propylene glycol may be employed. It may also be beneficial to use cyclodextrin derivatives such as beta-cyclodextrin sulfobutylether, sodium salt (see U.S. patent 5,134,127). The aqueous solution should be suitably buffered if necessary, while the liquid diluent is first rendered isotonic. These aqueous solutions are suitable for intravenous administration. Oily solutions are suitable for administration by intra-articular, intramuscular and subcutaneous injection. The formulation of all these solutions in sterile form is readily prepared using standard pharmaceutical techniques well known to those skilled in the art.

Furthermore, it is also possible to administer the active compounds of the invention topically, in accordance with standard pharmaceutical practice, which can be effected by means of creams, jellies, gels, pastes, patches, salves and the like.

For administration to non-human animals, such as domestic or domestic animals, the active compounds may be added to the feed of these animals or administered orally as a veterinary composition.

The active compounds may also be administered in the form of liposome 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 compound may also be associated with a soluble polymer such as a targetable drug carrier. 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 be combined with a class of biodegradable polymers useful for achieving controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polycarboxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

The invention is further described and exemplified by the following preparations and examples. In these preparations and examples, "rt" means room temperature, i.e., about 20-25 ℃.

Preparation 1

In a 2.8L Von Bashel flask, 5mL of a frozen sample of the culture S.hygroscopicus NRRL2388 (stored in 20% glycerol/80% seed culture medium at-80 ℃) were inoculated with 1L of hygromycin seed culture medium (Corn Products, Inc., cerelose)13g/L, Hubinger starch 7g/L, Roquette Corn steep solids 3g/L, Sheffield Brand Products NZ amine YTT 7g/L, Baker CoCl₂·6H₂O 0.002g/L,KH₂PO₄ 0.7g/L,MgSO₄·7H₂O1.3g/L, ammonium sulfate 0.7g/L, Dow Chemical P2000 antifoam 1 drops/bottle, Colfax soybean oil 2 drops/bottle, pH adjusted to 7.0 before being added to the autoclave). The culture was grown at 29 ℃ for 3 days on a 2 inch stroke shaker at a shaking rate of 200 rpm. The grown culture was inoculated with 8L of sterile hygromycin fermentation medium (1 g/L of Albaglos calcium carbonate, 1g/L of Sheffield Brand Products NZ amine YTT5g/L, 20g/L of Hubiner starch, 10g/L of Archer Daniels Midland nutritive soybean flour, 1ml/L of Dow Chemical P2000 antifoam, 1ml/L of Baker CoCl, in a 14-liter fermenter (New Brunswick Microferm, New Brunswick, New Jersey) equipped with two 4.75-inch Rushton impellers spaced 3.75 inches apart from each other₂·6H₂0.002g/L of O, 2ml/L of Colfax soybean oil, 10g/L of brain sugar and 5g/L of NaCl, and the pH is adjusted to 7.0 before being added into an autoclave). The culture broth was cultured at 29 ℃ at an aeration rate of 8L/min and a stirring rate of 800 rpm. To minimize the formation of epihygromycin, the pH was maintained between 6.5 and 6.9 for 126 hours, then during the rest of the time H was used₂SO₄(15%) the pH was adjusted to 6.2-6.6. The fermentations were harvested after a total of 143 hours of culture. At this time, the ratio of hygromycin A to epihygromycin was 31: 1.

6 liters of culture broth from the above fermentation was centrifuged at 8000rpm for about 15 minutes. After centrifugation, the pellet was discarded and the supernatant (pH6.4, which contained about 4.12gms hygromycin A activity as determined by HPLC) was loaded onto a chromatography column packed with 500gms XAD-16 resin (Rohm & Haas (Philadelphia, Pennsylvania)). The resin had previously been equilibrated with 2 bed volumes of 25mM disodium phosphate, pH6.0 ("buffer"). After loading, the column was washed with 2 bed volumes of buffer and 2 bed volumes of 80/20 buffer/methanol and the activity eluted with 5 bed volumes of 50/50 buffer/methanol. Fractions were assayed by HPLC and fractions containing most of the activity (2.730gms hygromycin A) were combined.

A portion of the XAD-16 eluate (approximately 800mg hygromycin a) was diluted to 10% methanol by the addition of 1.8 liters of buffer and loaded onto a 100ml CG-161 column (tosohas (Montgomeryville, Pennsylvania)) that had been equilibrated with 90/10 buffer/methanol of 4 bed volumes. The product was eluted with 6 bed volumes of 50/50 buffer/methanol. The fractions were determined by HPLC and the active fractions were combined. The combined fractions were evaporated to dryness and the purity of the solid was determined to be approximately 65% by weight. A small portion of these solids was transferred for assay.

Approximately 500mg of solid are mixed with 500ml of water and 500ml of ethyl acetate and stirred for 20 minutes. The two layers were separated and the aqueous layer was dried to give a solid which was determined to be about 52% pure by weight. These two solids (#34945-280-1 and 281-1) were subjected to NMR and TLC measurements and were found to contain hygromycin A activity. In addition, NMR showed the hygromycin A/epihygromycin ratio to be approximately 15: 1.

Preparation 2

In a 2.8L Von Bashel flask, 5mL of a frozen sample of the culture S.hygroscopicus NRRL2388 (stored in 20% glycerol/80% seed culture medium at-80 ℃) was inoculated with 1L of hygromycin seed culture medium (CPC International Inc., cerelose)13g/L, Hubinger starch 7g/L, Roquette corn steep solids 3g/L, NZ amine YTT 7g/L, BakerCoCl₂·6H₂O 0.002g/L,KH₂PO₄ 0.7g/L,MgSO₄·7H₂O1.3g/L, ammonium sulfate 0.7g/L, Dow Chemical P2000 antifoam 1 drop/bottle, Colfax soybean oil 2 drop/bottle, pH adjusted to 7.0 before being added to the autoclave). The culture was grown at 29 ℃ for 2-3 days on a 2 inch stroke shaker at a shaking rate of 200 rpm. 380-400 gallons of hygromycin fermentation medium (mineral technologies carbonic acid) was added to two 500-gallon stainless steel fermentorsCalcium 1g/L, Sheffield Brand Products NZ amine YTT5g/L, Hubinger starch 20g/L, Archer Daniels Midland, Soybean flour 10g/L, Dow Chemical P2000 antifoam agent 1ml/L, Baker CoCl₂·6H₂O0.002g/L, soybean oil 2gm/L from Colfax, brain sugar 10g/L from CPC International Inc., NaCl5g/L from Cargill). The medium was steam sterilized in the fermentor at 20psig for 60 minutes. The medium was cooled in a fermenter using a cooling coil and the pH was adjusted to 6.5-6.7. The conditions of the fermenter were set as follows: the gas flow rate was 20 standard cubic feet per minute, the temperature was 28 ℃, the vent pressure was 5psig, and the pH was maintained between 6.5 and 6.7 with 25% sodium hydroxide and 98% sulfuric acid. The stirring rate in both fermenters was varied so that the dissolved oxygen concentration in the medium, measured immediately before inoculation, remained above 20% of the saturation concentration. After setting the control conditions for the fermenter, 5 bottles of von Bach species were aseptically combined into an 8L aspirator flask. A single, nominal 500 gallon fermentor was then inoculated with this strain as described above. This operation was repeated using 4L inoculum, so that one fermentor received 4L inoculum and the other fermentor received 5L inoculum. Each fermenter was run for approximately 114 hours, at which point the fermentation was terminated. The pH of the broth was adjusted to 6.3 with 98% sulfuric acid and removed from the fermentor for recovery.

The two fermentors described above (pH =6.3, hygromycin a to epihygromycin ratio of approximately 51: 1) were filtered on a ceramic filtration system. The filtrate (1450gmsA, 506ga1) was loaded onto a 70 gallon XAD-16 resin column. The column had been equilibrated beforehand with 4 bed volumes of trisodium phosphate buffer solution, pH6.0 ("buffer"). After loading, the column was washed with 2 bed volumes of buffer and 2 bed volumes of 80/20 buffer/methanol. The activity was then eluted from the column with 10 fractions (approximately 50 gallons each) of 50/50 buffer/methanol solution. The active fractions (approximately 1240gmsA) were combined and diluted to a final concentration of 10% methanol by the addition of 1200 gallons of buffer. The use of dilution (rather than rotary evaporation) to reduce methanol concentration allows the use of lower temperatures to minimize the amount of epihygromycin that tends to increase at higher temperatures. Half of this solution was loaded onto a 40 liter CG-161 column (which had been previously equilibrated with 4 bed volumes of 90/10 buffer/methanol solution). After loading, the column was washed with 80/20 buffer/methanol at 4 bed volumes and eluted with 50/50 buffer/methanol at 5.5 bed volumes. After regeneration and re-equilibration of the column, the other half of the activity was loaded onto the column and eluted as described above. The combined fractions from these two runs (120 liters, approx. 1051gmsA) were diluted to 10% methanol by the addition of buffer. It was reloaded onto a regenerated and rebalanced CG-161 resin column. Once the activity was adsorbed onto the column, elution was performed with 4 bed volumes of methanol. This step serves to reduce the salt and increase the concentration of the sample prior to final evaporation. The combined fractions from the final CG-161 column were evaporated to dryness to give a total hygromycin A activity of about 1 kgA. In the final solid, the ratio of hygromycin A to epihygromycin was about 14.5: 1.

Experimental methods for examples

When the final purification step was completed using silica gel chromatography using an eluent system containing 10% or more methanol, the chromatography product was dissolved in 89: 10: 1 chloroform: methanol: concentrated ammonium hydroxide and filtered, or dissolved in methanol and passed through a 0.45 μ M filter. The solvent was removed in vacuo to give the final product. In the following step, t-BOC means "t-butoxycarbonyl".

5' -Oxime ether formulations

Preparation of hydroxylamine reagents for the Synthesis of Oxime ethers, examples 1-92,1A-116A

Most hydroxylamine reagents used are either commercially available (typically as acid salts) or can be prepared from the corresponding alcohols or halides by the following method:

1) preparation of phthalimide protected benzylic or aliphatic hydroxylamines:

preparation from alcohol:

a Mitsunobu reaction with diethyl azodicarboxylate and triphenylphosphine was used to couple the N-hydroxyphthalimide and the alcohol starting material according to the method disclosed in e.grohowski and j.jurczak, synthesis 682 (1976).

Preparation from bromide or chloride:

the reaction of N-hydroxyphthalimide (1 equivalent) with the halide starter (1.2-2 equivalents) is carried out in DMSO solution using potassium carbonate (0.6-2 equivalents) as the base. The reaction is generally completed by stirring overnight at room temperature. The reaction mixture was poured into cold water to produce a precipitate, which was filtered to give phthalimide-protected hydroxylamine. In many cases, this material is deprotected 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 to give a benzylic or aliphatic hydroxylamine:

deprotection of phthalimide-protected hydroxylamine is accomplished by reaction with hydrazine hydrate (1-2 equivalents) in ethanol solution, which is carried out at a temperature ranging from room temperature to reflux for a period of 30 minutes to overnight. The reaction mixture was filtered and the filtrate was concentrated. This crude product can be used as such in the next step, or can be further purified. The crude product was mixed with chloroform, the solids were removed by filtration and the solvent was removed from the filtrate, thereby removing additional phthalhydrazide. Alternatively, the crude product is dissolved in 1N hydrochloric acid and washed with diethyl ether or ethyl acetate. The aqueous layer was basified with saturated potassium carbonate solution and extracted with ether or ethyl acetate. The final organic layer was dried and the solvent was removed to give the hydroxylamine product.

3) Preparation of 0-aryl hydroxylamine:

substituted phenols were converted to the corresponding O-aryl hydroxylamines by using mesitylenesulfonylhydroxylamine as described in y.endo, k.shudo and t.okamoto, synthesis (1980) 461.

Preparation of various alcohol and halide starting materials for hydroxylamine synthesis:

in general, the benzyl alcohol derivatives can be converted to the corresponding benzyl bromides, if desired, by treatment with 48% HBr at 65 ℃ for 1 to 4 hours.

In many cases, the alcohol starting material is obtained by reducing a more highly oxidized commercially available compound. 4-Cyclohexylbenzoic acid (examples 46,47) and 3-chloro-2-fluorobenzoic acid (examples 13A,14A) were reduced with lithium aluminum hydride (2-2.3 equivalents) in tetrahydrofuran to give the corresponding alcohols. 3- (4-chlorophenyl) propionic acid (example 56,57), 3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid (example 36A,37A), 4-chloro-3-sulfamoylbenzoic acid (example 76A), 3-chlorothiophene-2-carboxylic acid (example 85A,86A), 5-chlorothiophene-2-carboxylic acid (example 91A,92A) and 2, 6-dimethylbenzoic acid (example 98A,99A) were reduced to the corresponding alcohols using diborane in tetrahydrofuran (1.1-2 equivalents) at 0 deg.C to room temperature for 5-18 hours. 2-fluoro-6-methoxybenzonitrile is hydrolyzed to 2-fluoro-6-methoxybenzoic acid by treatment with 30% aqueous KOH at reflux temperature, which is reduced to 2-fluoro-6-methoxybenzyl alcohol with diborane as described above (example 80A). 3-trifluoromethoxybenzaldehyde (examples 62,68), 3-cyanobenzaldehyde (example 63), benzofuran-2-carbaldehyde (examples 65,66), 1, 4-benzodioxan-6-carbaldehyde (examples 83,84), 3-fluoro-4-methoxybenzaldehyde (examples 85,86), 6-fluoro-4-chromanone (examples 16A,17A), 3-chloro-4-fluorobenzaldehyde (examples 19A,22A), quinoline-3-carbaldehyde (examples 23A,24A), 4-chloro-3-fluorobenzaldehyde (examples 25A,26A), 2,3- (methylenedioxy) benzaldehyde (examples 28A,29A), 2, 4-dichlorobenzaldehyde (examples 45A,47A) 2-chloro-4-fluorobenzaldehyde (examples 46A,48A), 2-fluoro-6- (trifluoromethyl) benzaldehyde (examples 66A,67A), 2, 3-difluorobenzaldehyde (examples 68A,69A), 2- (difluoromethoxy) benzaldehyde (examples 93A,94A) and 6-chlorobenzo chroman-4-one (examples 102A,103A) were reduced to the alcohol derivative using sodium borohydride (1-2 equivalents) in tetrahydrofuran or methanol at 0 ℃ or room temperature.

Magnesium sulfate (4 equiv.) in dichloromethane was treated with concentrated sulfuric acid (1 equiv.), followed by 4-chloromethylbenzoic acid (1 equiv.) and tert-butanol (5.1 equiv.). Stirring overnight at room temperature gave tert-butyl ester (example 36).

4-amino-3, 5-dichlorobenzoic acid was N-acetylated 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 give an acetamide derivative. Reduction of the carboxylic acid was performed with lithium aluminium hydride (2 eq) in tetrahydrofuran at 0 ℃ for 2h to give N- (2, 6-dichloro-4-hydroxymethylphenyl) acetamide (example 51).

3- (aminomethyl) benzyl alcohol and 4- (aminomethyl) benzyl alcohol were prepared by reducing 3-and 4-cyanobenzaldehyde with diborane (4-5 equivalents) in THF at room temperature overnight. The amino groups in 3- (aminomethyl) benzyl alcohol (examples 8A and 9A) and 4- (aminomethyl) benzyl alcohol (example 55) and 3-aminobenzol (example 54) were protected as N-t-BOC derivatives by treatment with di-tert-butyl dicarbonate (1.1 equivalents) in THF at reflux temperature until the starting amino compound was consumed.

The reaction of ethyl 4-fluorobenzoate with piperidine (3 eq) in acetonitrile was carried out at reflux for 4 days. The cooled reaction mixture was diluted with several volumes of water to give a precipitate, which was filtered to give ethyl 4- (piperidin-1-yl) benzoate. The ester was reduced with lithium aluminium hydride (2 equiv) in tetrahydrofuran to give the corresponding alcohol (examples 71, 72).

5-Hydroxymethylbenzofuran (example 79,80) was prepared according to the procedure disclosed in K.Hiroya, K.Hashimura and K.Ogasawara in heterocycles (1994) 38,2463.

2-phenylpyrimidine-5-carbaldehyde (examples 81 and 82) was prepared according to the procedure disclosed in J.T.Gupton, J.E.Gall, S.W.Riesinger et al, J.Heterocycl. chem.1991, 28,1281. The aldehyde was reduced to the corresponding alcohol using sodium borohydride in methanol.

3-hydroxymethyl-4-phenylfuran (example 6A,7A) was prepared according to the methods disclosed in B.A. Keay and J-L.J.Bontron t, J.Canadian journal of chemistry (1991) 69,1326.

5-chloro-2-fluorobenzyl bromide (example 12A,13A) was prepared using the method disclosed in A.P.Krapcho, C.E.Gallagher, A.Mammach, M.Ellis, E.Menta and A.Oliva in the journal of heterocyclic chemistry (1997) 34, 27-32.

2-chloro-3, 4-dimethoxybenzaldehyde is converted to 4-chloro-1, 3-benzodioxole-5-carbaldehyde using the method disclosed in S.T.Ross, R.G.Franz, J.W.Wilson, R.A.Hahn and H.M.Sarau, J.Chem.Chem. 23,1805 (1986). The aldehyde was then reduced with sodium borohydride (1 eq) in THF at 0 deg.C to give 4-chloro-1, 3-benzodioxole-5-methanol (examples 30A, 31A).

4-Phenylfuroic acid was prepared using the methods disclosed in M.E.Alonso, P.Jano, M.I.Hernandez, R.S.Greenberg and E.Wenkert, J.Organischen Chemie (1983) 48,3047. This was reduced to 2- (hydroxymethyl) -4-phenyl furan (example 34A,35A) as disclosed in journal of the american society for chemistry (1994) 116,4517, w.a. scans, j.m. tour, k.e. creek, l.pirisi.

3-chloro-2, 6-difluorobenzaldehyde was prepared from 1-chloro-2, 4-difluorobenzene using N-butyllithium and N, N-dimethylformamide as disclosed in A.S. Cantrell et al, journal of medicinal chemistry (1996) 21,4261. Reduction with sodium borohydride in methanol gave 3-chloro-2, 6-difluorobenzyl alcohol, which was converted to 3-chloro-2, 6-difluorobenzyl bromide by treatment with 48% HBr for 3 hours at 65 deg.C (example 38A, 39A). The analogous work-up of 2,3,5, 6-tetrafluorotoluene gave 2,3,5, 6-tetrafluoro-4-methylbenzyl bromide (examples 40A,41A), whereas 3, 5-difluorotoluene was similarly converted to 2, 6-difluoro-4-methylbenzyl bromide (examples 63A, 64A). 3, 4-difluoroanisole was similarly converted to 2, 3-difluoro-6- (methoxy) benzyl bromide (examples 74A,75A), while 1-fluoro-3- (trifluoromethoxy) benzene was converted to 2-fluoro-6- (trifluoromethoxy) benzyl bromide (examples 77A, 78A). 2-chloro-6- (trifluoromethoxy) benzyl alcohol (example 89A,90A) was prepared in a similar manner except that lithium diisopropylamide was used in the formylation reaction instead of n-butyllithium.

Vanillin was converted to 7-chloro-benzodioxole-5-carbaldehyde using the method disclosed in T-T.Jong, P.G.Williard and J.P.Porwoll, J.Organic chem.J. (1984) 49,735. Reduction with sodium borohydride (1 eq) in methanol at room temperature gave 7-chloro-1, 3-benzodioxole-5-methanol (examples 51A, 52A). In this case, the conversion to hydroxylamine reagent is mediated by a mesylate derivative prepared using the methods disclosed in r.k.crossland and k.l.servis, in the journal of organic chemistry (1970) 35,3195.

3-chloro-5-fluorobenzyl alcohol (example 53A,54A) was prepared according to the method disclosed in W.R. Meidl, E.Von anger, H.Schoenenberger and G.Ruckdeschel in journal of medicinal chemistry (1984) 27,1111.

4-phenyl-2-thiazolecarboxaldehyde was prepared in a similar manner to the method disclosed in Notification of the Japan chemical Association (1985) 58,352, K.Inami and T.Shiba. The aldehyde was reduced to the corresponding alcohol using sodium borohydride in ethanol. The corresponding 2-chloromethylthiazole derivative (examples 104A,105A) was prepared by treating the alcohol with thionyl chloride in dichloromethane (4 equivalents) at room temperature for 2-5 hours.

2, 4-difluorophenyl ethyl ketone was reduced to the corresponding alcohol using sodium borohydride in ethanol (examples 106A, 107A).

1- (3-chloro-2, 6-difluorophenyl) ethanol and other phenylethanol derivatives (examples 108A-116A) were prepared by treating the corresponding benzaldehyde derivatives with methylmagnesium bromide (1 equivalent) in THF at room temperature. These alcohols were then converted to the corresponding benzyl bromides by treatment with 48% HBr for 1-4 hours.

Preparation of oxime ethers, Process (A-I), examples 1-92,1A-116A

Method A

A solution of hygromycin a (1 eq) and the hydrochloride salt of the appropriate hydroxylamine (1-2.2 eq) in methanol (ca. 0.1M hygromycin a) is treated with sodium carbonate (1.1-1.2 eq/hydroxylamine salt eq) and heated to reflux for 15 minutes to 2 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method B

A solution of hygromycin a (1 eq) and the hydrochloride salt of the appropriate hydroxylamine (1-2.2 eq) in methanol (ca. 0.1M hygromycin a) was treated with sodium carbonate (1.1-1.2 eq/hydroxylamine salt eq) and heated to reflux for 18 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method C

A solution of hygromycin A (1 equivalent) and the appropriate free base of hydroxylamine (1-2.2 equivalents) in methanol (ca. 0.1M hygromycin A) was heated to reflux for 18 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method D

A solution of hygromycin A (1 equivalent) and the appropriate free base of hydroxylamine (1-2.2 equivalents) in methanol (ca. 0.1M hygromycin A) was heated to reflux for 5-6 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method E

Hygromycin A (1 equivalent) and a solution of the appropriate hydroxylamine free base (1-2.2 equivalents) in methanol (ca. 0.1M hygromycin A) were stirred at room temperature for 18 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method F

Hygromycin A (1 equivalent) and a solution of the appropriate hydroxylamine free base (1-2.2 equivalents) in methanol (ca. 0.1M hygromycin A) were stirred at room temperature for 1-5 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method G

The isolated methanolic hygromycin A solution (1 eq) and a methanolic solution of the appropriate free base of hydroxylamine (1-2.2 eq) are mixed at 0 deg.C (final concentration, 0.5-0.1M hygromycin A) and warmed to room temperature for 1-2 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method H

Hygromycin A (1 equiv.) and a solution of the appropriate hydroxylamine free base (1-2.2 equiv.) in methanol (final concentration, 0.5-0.1M hygromycin A) were stirred at 0 ℃ for 2-3 hours. The reaction may be followed by thin layer chromatography using methanol/chloroform or methanol/chloroform/ammonium hydroxide eluents. The reaction mixture was then concentrated in vacuo. The crude product was purified by one of the methods in J-N.

Method I

The substrate (see table for substrate used) was dissolved in trifluoroacetic acid at a concentration of about 0.1M and stirred at room temperature for 15 minutes. At which time the trifluoroacetic acid was removed in vacuo. Chloroform: methanol: concentrated ammonium hydroxide solution was added in a volume ratio of 89: 10: 1 and the volatiles were removed in vacuo. Repeated neutralization and concentration in vacuo gave the crude product.

Purification of Oxime ethers, Process (J-N-1)

Method J

Purification was performed by silica gel chromatography. The crude product was universally pre-adsorbed onto silica gel by adding dry silica gel to a solution of the crude product in methanol, followed by complete removal of the solvent. The column elution is carried out using a chloroform solution, typically 5% to 20% methanol, often in a gradient elution mode.

Method K

Purification was performed by silica gel chromatography. The crude product was universally pre-adsorbed onto silica gel by adding dry silica gel to a solution of the crude product in methanol, followed by complete removal of the solvent. The column elution is carried out using a solution of methanol in dichloromethane, typically 5% to 20%, often in a gradient elution.

Method L

Purification was performed by silica gel chromatography. The crude product was universally pre-adsorbed onto silica gel by adding dry silica gel to a solution of the crude product in methanol, followed by complete removal of the solvent. According to R of product and starting material_fThe column elution was performed using a ternary solution of chloroform, methanol and ammonium hydroxide having a composition of 289: 10: 1 to 39: 10: 1. Column elution is typically performed in a gradient fashion. In the case of example 55, the final column eluent was 73: 25: 2.

Method M

Purification was performed by silica gel chromatography. The crude product was universally pre-adsorbed onto silica gel by adding dry silica gel to a solution of the crude product in methanol, followed by complete removal of the solvent. The column elution is carried out using a ternary solution of dichloromethane: methanol: ammonium hydroxide ranging from 322: 10: 1 to 56: 10: 1, usually in a gradient elution.

Method N

Purification and utilization of C₁₈Reverse phase chromatography, according to R of the product and starting material_fValues, elution was performed with 10% to 100% methanol-water solution. Column elution is typically performed in a gradient fashion.

Method N-1

Purification and utilization of C₁₈Reverse phase chromatography was performed, eluting with a mixture of acetonitrile and 10mM potassium phosphate buffer pH 7. The isolated fraction is a minor product of the reaction mixture and is obtained from the presence of epihygromycin (alpha stereochemistry at C-4 ") in the hygromycin starting material.

5 "-amine formulation, examples 93-101

Process for preparing amine derivatives (O-R)

Process O

A solution of hygromycin A in methanol (0.1M) was treated with amine (1 eq) and allowed to stir at room temperature for 10 minutes. Acetic acid (3 equivalents) was added followed by sodium triacetoxyborohydride (3 equivalents) and the reaction mixture was stirred for an additional 24 hours. After treatment with a small amount of saturated aqueous sodium bicarbonate, the solvent was removed in vacuo. The residue is purified by chromatography on silica gel, elution being carried out with a mixture of chloroform, methanol and ammonium hydroxide having a composition ranging from 89: 10: 1 to 70: 28: 2, generally in a gradient elution.

Method P

A solution of hygromycin A in methanol (0.1M) was treated with amine (2-4 equivalents) and allowed to stir at room temperature for 1 hour. When imine formation was delayed, 3 angstrom molecular sieve was added and the mixture was stirred overnight. Sodium borohydride (1-2 equivalents) was then added and the reaction stirred for 2-24 hours. After treatment with a small amount of saturated aqueous solution of sodium bicarbonate (and removal of the molecular sieves by filtration if present), the solvent is removed in vacuo and the residue is purified by chromatography on silica gel eluting with a mixture of chloroform: methanol: ammonium hydroxide having a composition ranging from 89: 10: 1 to 80: 19: 1.

Method Q

The aminohygromycin A derivative (0.1M) in water was treated with formaldehyde (5 equivalents) and then formic acid (10 equivalents), stirred at 90 ℃ for 5 hours, then at room temperature for 48 hours. After addition of saturated aqueous sodium bicarbonate, the reaction mixture was stirred and the clear supernatant was decanted. The remaining residue was purified by column chromatography using chloroform: methanol: ammonium hydroxide as eluent in a ratio of 80: 19: 1.

Process R

A solution of hygromycin A in methanol (0.1M) was treated with aniline (4 equiv.) and crushed 3A molecular sieve and stirred at 50 ℃ for 2 hours or at 70 ℃ overnight. After the reaction mixture has cooled to room temperature, sodium borohydride (1-2 equivalents) is added and stirring is continued at room temperature for 2-48 hours. A small amount of saturated aqueous sodium bicarbonate was added, the molecular sieve was removed by filtration, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using 80: 19: 1 chloroform: methanol: ammonium hydroxide as eluent.

5 "-amide preparation, example 102-104

Preparation of amide derivatives, process S-T

Synthesis of Persilylated 5 "-aminohygromycin A

a) A solution of hygromycin A, tert-butyldisilylchloride (12 equiv.) and imidazole (12 equiv.) in DMF (hygromycin concentration 0.25M) was stirred at 80 ℃ for 20 h. After removal of DMF under reduced pressure, the residue was extracted with diethyl ether. The combined ether extracts were washed with water, then with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 10% ethyl acetate/hexane.

b) A solution of the persilylated hygromycin A in 1: 1 methanol: tetrahydrofuran (0.2M) was treated with sodium borohydride (0.5 equiv.) and stirred at room temperature for 18 hours. After removal of the solvent under reduced pressure, the residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to give crude fully silylated 5 "-alcohol. Purification was performed by column chromatography eluting with 10% to 20% ethyl acetate/hexane. Subsequent analysis of the Mosher ester showed that the stereochemistry at the 5 "position of the main product of this reaction was R.

c) A solution of 5 "-alcohol in dichloromethane (0.2M) was treated with triethylamine (3 equiv.) at 0 deg.C, then with methanesulfonyl chloride (2 equiv.) and stirred at room temperature for 24 h. The reaction mixture was then poured into water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5 "-methanesulfonate.

d) The 5 "-mesylate solution in DMF (0.2M) was treated with sodium azide (10 equiv.) and stirred at 95 ℃ for 18 h. The reaction mixture was poured into water, extracted with diethyl ether, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude 5 "-azide was purified by silica gel chromatography eluting with 10% ethyl acetate/hexanes.

e) A toluene solution of 5 "-azide and triphenylphosphine (3 equivalents) (5" -azide concentration 0.2M) was stirred at 105 ℃ for 18 h. Toluene was removed under reduced pressure and replaced with tetrahydrofuran/water (10/1) (hygromycin derivative concentration 0.1M) and stirred at 75 ℃ for 5 hours. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes to provide the fully silylated 5 "-amino hygromycin A.

Method S

a) The persilylated 5 "-aminohygromycin A and the appropriate carboxylic acid (2 equivalents) were stirred with EEDQ (1-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, 2 equivalents) in THF for 3 hours at 70 deg.C (concentration of the persilylated hygromycin was 0.1M). The reaction mixture was poured into water and extracted with ether. The combined organic layers were washed with 5% sodium carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulfate, the organic extracts were filtered and concentrated to give a residue which was chromatographed on silica gel using a mixture of ethyl acetate and hexane to give the desired amide as its per-silyl-protected derivative.

b) 5' -solution of modified hexasilyl hygromycin A (1 equiv., 0.1M) was treated with tetrabutylammonium fluoride (TBAF, 10 equiv.) in 1M THF at room temperature for 14-24 hours to remove the silyl group. THF was removed in vacuo and the crude material was dissolved in a mixture of water and methanol. The solution/suspension was applied to a Dowex (50X4-400) resin column (10-30g resin/mmoleTBAF which had been converted to the OH form by treatment with 0.1-0.2N sodium hydroxide followed by washing with 1 Column Volume (CV) of water). The column was gravity eluted with 1-3CV of water until TBAF was removed, then 50% aqueous methanol with the help of nitrogen pressure to give the desired amide product. If further purification is required, silica gel chromatography (methods J-N) can be carried out.

Method T

A solution of the appropriate carboxylic acid (1.2 equivalents) in tetrahydrofuran was treated with DEPC (diethylphosphoryl cyanide, 1.2 equivalents) and triethylamine (1.2 equivalents), and the reaction mixture was stirred for 10 minutes. Persilylated 5 "-amino hygromycin A (1 eq) was added (final hygromycin derivative concentration 0.17M) and the reaction was allowed to proceed for 48 hours at room temperature. The reaction mixture was poured into water and extracted with ether. The combined organic layers were washed with aqueous sodium carbonate, water and saturated sodium chloride solution, then dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a mixture of ethyl acetate and hexane.

The silanized amide was deprotected with TBAF according to step b in method S.

5 "-Ether, carbamate preparation, example 105-131

Method (U-Z)

The persilylated 5 "-hydroxyhygromycin A is alkylated or acylated by the processes U to Y (see example 102. sub. 104, steps a and b), followed by removal of the silyl group using step b of process S.

Process U for the preparation of 5 "-hygromycin A benzyl ether

Sodium hydride (60% dispersion in mineral oil, 10 equivalents) was weighed into an oven-dried round-bottomed flask and washed with hexaneAnd washing for 3 times. Residual hexane was removed in vacuo and Tetrahydrofuran (THF) (concentration of 0.1M per silylated 5 "-hygromycin A), per silylated 5" -hydroxyhygromycin A (1 eq) and benzyl bromide (10 eq) were added thereto at room temperature. The resultant slurry was heated at 50 ℃ for 1 to 4 hours. The reaction was cooled to room temperature, quenched by addition of water, and then quenched with chloroform (CHCl)₃) The extraction was performed twice. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to a semi-solid which was chromatographed (SiO)₂5-15% EtOAc: toluene or EtOAc: hexane) (EtOAc means ethyl acetate) to yield the desired ether.

Method V

Potassium tert-butoxide (1M in THF, 5 equiv.) was added to a solution of fully silylated 5 "-hydroxyhygromycin A (1 equiv.) and benzyl bromide (10 equiv.) in THF at room temperature (fully silylated 5" -hydroxyhygromycin A concentration of 0.1M). The reaction was complete after 15 minutes. Water was added to terminate the reaction and the product was extracted into chloroform. The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and chromatographed (SiO)₂5-15% EtOAc: toluene or EtOAc: hexane) to give the desired product.

Method W

Potassium tert-butoxide (1M in THF, 2 equivalents) was added dropwise over 5 minutes to a solution of fully silylated 5 "-hydroxyhygromycin a (1 equivalent) and benzyl bromide (5 equivalents) in dioxane at room temperature (fully silylated 5" -hydroxyhygromycin concentration of 0.1M). The reaction was complete after 15 minutes. Water was added to terminate the reaction and the product was extracted into chloroform. The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and chromatographed (SiO)₂5-15% EtOAc: toluene or EtOAc: hexane) to give the desired product.

Method X

Phenyl isocyanate (7 equivalents) was added to a solution of the fully silylated 5 "-hydroxyhygromycin A (1 equivalent) in toluene (fully silylated 5" -hydroxyhygromycin concentration of 0.05M) and heated to 60 ℃ for 12-24 hours. Will be provided withThe crude reaction mixture was concentrated and chromatographed (SiO)₂5-15% EtOAc: toluene or EtOAc: hexane) to afford the silylated product.

Method Y

Use s.th.; seeger, b.; benzyl isocyanate (7 equivalents) was prepared by the method disclosed in Kutzke, U.S. and Eckstein, journal of organic chemistry (1996) 61,3883. This was added to a toluene solution of persilylated 5 "-hydroxyhygromycin a (1 eq), dimethylaminopyridine (0.2 eq) and triethylamine (4 eq) (0.05M concentration of persilylated 5" -hydroxyhygromycin) and heated to 70 ℃ for 12-24 hours. The crude reaction mixture was concentrated and chromatographed (SiO)₂5-7% EtOAc: hexane) to afford the silylated material.

Method Z

K of Persilylated 5' -Hydroxyhygromycin A in methanol₂CO₃(1.3 equiv) (0.1M) and stirred for 14-20 h. The methanol was removed in vacuo and the residue dissolved in 1: 1 EtOAc: hexane and water. The organic phase was washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. This material was taken up with allyl bromide (1-3 equivalents) and K without further purification₂CO₃(1.4 equiv.) of DMF solution (0.1M) for 14-24 hours. The reaction mixture was poured into hexane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated to give a white foam consisting of allyl-protected phenolic hydroxyl groups, which was used without further purification. The 5 "-alcohol was alkylated with benzyloxychloromethyl ether under the conditions of method X. Allyl groups were removed using the method disclosed in Jaynes, b.h., Elliot, n.c. and Schicho, d.l. in journal of antibiotics (1992) 45,1705, followed by silyl group removal using step b of method S.

5 "-olefin preparation, example 132-

Preparation of olefin derivatives, process AA-EE

Method AA

A solution of hygromycin A and (ethyloxymethylene) triphenylphosphorane (2 equivalents) in DMF (0.1M hygromycin A) was stirred at 70 ℃ for 15 hours. DMF was removed under reduced pressure and the resulting residue was chromatographed on silica gel using a mixture of chloroform, methanol and ammonium hydroxide (80: 19: 1) to give the unsaturated ester of example 132.

Method BB

The ethyl ester of example 132 was dissolved in water and tetrahydrofuran (1: 1) (0.25M), treated with sodium hydroxide (3 equivalents) and stirred at room temperature for 6 hours. After removal of the tetrahydrofuran under reduced pressure, the pH was adjusted to pH4 by addition of 1N HCl. The aqueous solution was concentrated to dryness under reduced pressure, and the resulting residue was mixed with MeOH and filtered. The filtrate was concentrated to give the carboxylic acid of example 133.

Method CC

A solution of the carboxylic acid of example 133, DCC (dicyclohexylcarbodiimide, 1 eq) and HOBT (hydroxybenzotriazole, 1 eq) in DMF (0.25M) was treated with the appropriate amine (1 eq) and the reaction mixture was stirred at room temperature for 18 h. After removal of DMF under reduced pressure, the resulting oil was chromatographed on silica gel using a mixture of chloroform, methanol and ammonium hydroxide (80: 19: 1) to give the desired amide.

Method DD

A mixture of the carboxylic acid of example 133 and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (1 eq) in DMF (0.25M) was treated with the appropriate amine (1 eq) and the reaction mixture was stirred at room temperature for 18 h. After removal of DMF under reduced pressure, the residue was purified by chromatography on silica gel eluting with chloroform, methanol and ammonium hydroxide at a concentration ranging from 89: 10: 1 to 80: 19: 1.

Method EE

The product of example 133 (0.25M) in dimethylformamide was treated with EEDQ (1-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, 1.2-2 equivalents) and the appropriate amine (1 equivalent) and stirred at 70 ℃ overnight. After cooling, or the reaction mixture was concentrated in vacuo to give the crude product for purification; alternatively, the reaction mixture was poured into chloroform, and the resulting solid was filtered to obtain a crude product.

The specific compounds prepared according to the above procedure are set forth in the following table. In these tables, "Ex" refers to the examples, "Mol Wt" refers to molecular weight, "Stereo" refers to the stereochemistry (E or Z) of the oxime moiety, "Pro" refers to the method used to prepare the compound, and "Mass Spec" refers to Mass spectrometry.

Using the specific chemistry and general chemistry described above, the following compounds can be prepared in a similar manner. Each of the compounds listed below is part of the present invention and has activity against bacterial infections. Where the essential alcohol or halide starting materials are not commercially available, reference or preparative information is given regarding them.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 6-benzofurancarboxaldehyde can be prepared as disclosed in A.S. Tasker et al, J.Med.Chem. 40,322 (1997). The aldehyde is reduced with sodium borohydride and the double bond is hydrogenated over palladium on carbon to give 2, 3-dihydro-6-benzofuran methanol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 6-benzofurancarboxaldehyde can be prepared as disclosed in A.S. Tasker et al, J.Med.Chem. 40,322 (1997). The aldehyde is reduced with sodium borohydride and the double bond is hydrogenated over palladium on carbon to give 2, 3-dihydro-6-benzofuran methanol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. Reducing the 2, 3-dihydro-5-benzofuran carboxaldehyde with sodium borohydride to obtain the 2, 3-dihydro-5-benzofuran methanol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. Reducing the 2, 3-dihydro-5-benzofuran carboxaldehyde with sodium borohydride to obtain the 2, 3-dihydro-5-benzofuran methanol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-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. 7-chloro-3, 4-dihydro-1 (2H) -naphthalenone can be prepared by the method disclosed in W.M. Owton and M.Brunavs. synthetic letters (1991) 21,981. Reducing with sodium borohydride to obtain 7-chloro-1, 2,3, 4-tetrahydro-1-naphthalenol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 7-chloro-3, 4-dihydro-1 (2H) -naphthalenone can be prepared by the method disclosed in W.M. Owton and M.Brunavs. synthetic letters (1991) 21,981. Reducing with sodium borohydride to obtain 7-chloro-1, 2,3, 4-tetrahydro-1-naphthalenol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 7-fluoro-3, 4-dihydro-1 (2H) -naphthalenone can be prepared by the method disclosed in W.M. Owton and M.Brunavs. synthetic letters (1991) 21,981. Reducing with sodium borohydride to obtain 7-fluoro-1, 2,3, 4-tetrahydro-1-naphthalenol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 7-fluoro-3, 4-dihydro-1 (2H) -naphthalenone can be prepared by the method disclosed in W.M. Owton and M.Brunavs. synthetic letters (1991) 21,981. Reducing with sodium borohydride to obtain 7-fluoro-1, 2,3, 4-tetrahydro-1-naphthalenol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 8-chloro-2, 3-dihydro-4H-1-benzopyran-4-one may be prepared by the methods disclosed in tetrahedron letters 29,3487, G.Ariamala and K.K.Balasubramanian; then reducing the mixture by sodium borohydride to obtain 8-chloro-3, 4-dihydro-2H-1-benzopyran-4-alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 8-chloro-2, 3-dihydro-4H-1-benzopyran-4-one may be prepared by the methods disclosed in tetrahedron letters 29,3487, G.Ariamala and K.K.Balasubramanian; then reducing the mixture by sodium borohydride to obtain 8-chloro-3, 4-dihydro-2H-1-benzopyran-4-alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 8-fluoro-2, 3-dihydro-4H-1-benzopyran-4-one may be prepared by the method disclosed in J.Med.Chem. 31,230, R.Sarges et al (1988); then reducing with sodium borohydride to obtain 8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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. 8-fluoro-2, 3-dihydro-4H-1-benzopyran-4-one may be prepared by the method disclosed in J.Med.Chem. 31,230, R.Sarges et al (1988); then reducing with sodium borohydride to obtain 8-fluoro-3, 4-dihydro-2H-1-benzopyran-4-alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [4- (phenylmethyl) benzyl ] oxime. The 4- (benzyl) benzoic acid was reduced with diborane to 4- (benzyl) benzyl alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (Z) -O- [4- (phenylmethyl) benzyl ] oxime. The 4- (benzyl) benzoic acid was reduced with diborane to 4- (benzyl) benzyl alcohol.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime. Reducing the 4-phenoxybenzaldehyde into 4-phenoxybenzyl alcohol by using sodium borohydride.

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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) benzyl ] oxime. Reducing the 4-phenoxybenzaldehyde into 4-phenoxybenzyl alcohol by using sodium borohydride.

TABLE 1

Most of the examples in Table 1 bear the C-4 "stereochemistry shown, with the oxime moiety being beta oriented. Some of the examples have alpha oriented oximes; these are indicated in the column "stereochemistry".

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
1	Tert-butyl radical	582.61	E	A or B, L	583.1	5.69(d,J=4.2Hz,1H),4.28(d,J=8.1Hz,1H),1.22(s,9H)
2	2-propen-1-yl	566.57	E	B,L	567.1	5.93(m,1H),5.55(d,J=4.4Hz,1H),5.20(dd,J=17.2,1.7Hz,1H),5.11(dd,J=10.4,1.7Hz,1H),4.50(d,J=5.6Hz,2H),4.23(d,J=7.9Hz,1H)
3	Ethyl radical	554.46	E	B,L	555.1	5.69(d,J=4.2Hz,1H),4.23(d,J=7.9Hz,1H),4.04(q,J=7.1Hz,2H),1.18(t,J=7.1Hz,3H)
4	Ethyl radical	554.46	Z	B,L	555.1	5.64(d,J=4.2Hz,1H),5.14(d,J=6.2Hz,2H),4.03(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H)
5	Isobutyl radical	582.61	Z	B,L	583.2	5.66(d,J=4.2Hz,1H),5.18(d,J=6.2Hz,1H),3.77(d,J=6.6Hz,2H)1.95(m,1H),0.92(d,J=6.8Hz,3H)
6	(4-Nitrophenyl) methyl group	661.63	E	B,L	862.1	8.14(d,J=8.9Hz,2H),7.49(d,J=8.9Hz,2H),5.54(d,J=4.6Hz,1H),5.17(s,2H),4.25(d,J=

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)							7.9Hz,1H)
7	(4-chlorophenyl) methyl group	651.07	Z	B,L	651.1	7.32(m,4H),5.65(d, J =4.2Hz,1H),5.20(d, J =6Hz,1H),5.02(AS quartet,. DELTA.v =10.8Hz, J =12.8Hz,2H)							7.9Hz,1H)
7	(4-chlorophenyl) methyl group	651.07	Z	B,L	651.1		8	(4-chlorophenyl) methyl group	651.07	E	B,L	651.1	7.28(s,4H),5.55(d,J=4.6Hz,1H),5.03(s,2H),4.26(d,J=7.7Hz,1H)
9	(4-methylphenyl) methyl group	630.66	Z	B,L	631.2	72(d, J =8Hz,214),7.1(d, J =8Hz,2H),5.64(d, J =4.4Hz,1H),5.18(d, J =6.4Hz,1H),4.98(AB quartet,. DELTA.v =15.7Hz, J =12.1 Hz,2H)	8	(4-chlorophenyl) methyl group	651.07	E	B,L	651.1	7.28(s,4H),5.55(d,J=4.6Hz,1H),5.03(s,2H),4.26(d,J=7.7Hz,1H)
9	(4-methylphenyl) methyl group	630.66	Z	B,L	631.2		10	(4-methylphenyl) methyl group	630.66	E	B,L	631.2	7.17(d,J=8Hz，2H),7.10(d,J=8Hz,2H),5.55(d,J=4.4 Hz,1H),4.99(s,2H),4.25(d,J=7.9Hz,1H),2.28(s,3H)
11	(4-methoxyphenyl) methyl group	646.65	Z	B,L	647.2	7.27(d, J =8.7Hz,2H),6.87(d, J =8.7Hz,2H),5.64(d, J =4.4Hz,1H),5.16(d, J =6.2Hz,1H),4.95(AB quartet,. DELTA.v =16.0Hz, J =11.7Hz,2H)	10	(4-methylphenyl) methyl group	630.66	E	B,L	631.2
11	(4-methoxyphenyl) methyl group	646.65	Z	B,L	647.2		12	(4-methoxyphenyl) methyl group	646.65	E	B,L	647.2	7.22(d,J=8.3Hz,2H),6.83(d,J=8.5Hz,2H),5.55(d,J=4.6Hz,1H),4.97(s,2H),4.26(d,J=7.9 Hz,1H)，3.75(s,3H)
13	(3, 4-dichlorophenyl) methyl group	685.52	Z	B,L	685.1,687.1	7.51(d, J =1.9Hz,1H),7.45(d, J =8.3Hz,1H),7.26(dd, J =8.3,2.1 Hz,1H),5.65(d, J =4.4Hz,1H),5.22(d, J =6.2Hz,1H),5.00(AB quartet,. DELTA.v =7.3Hz, J =13.3Hz,2H)	12	(4-methoxyphenyl) methyl group	646.65	E	B,L	647.2
13	(3, 4-dichlorophenyl) methyl group	685.52	Z	B,L	685.1,687.1		14	(3, 4-dichlorophenyl) methyl group	685.52	E	B,L	685.1,687.1	7.44(m,2H),7.23(m,1H),5.55(d,J=4.4 Hz,1H),5.02(s,2H),4.25(d,J=7.7Hz,1H)
15	4-pyridylmethyl	617.62	E	B,L	618.1	8.43(d,J=5.8Hz,2H),7.32(d,J=5.8Hz,2H),5.56(d,J=4.6Hz,1H),5.13(s,2H),4.25(d,J=7.7Hz,1H)	14	(3, 4-dichlorophenyl) methyl group	685.52	E	B,L	685.1,687.1
15	4-pyridylmethyl	617.62	E	B,L	618.1		16	Benzyl radical	616.63	Z	B,L	617.2	7.34(m,5H),5.65(d,J=4.4 Hz,1H),5.21(d,J=

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)							6.2Hz,1H),5.04(AB quartet,. DELTA.v =14.4 Hz, J =12.3 Hz,2H)
17	Benzyl radical	616.63	E	B,L	617.2	7.32(m,5H),5.55(d,J=4.6 Hz,1H),5.05(s,2H),4.26(d,J=7.7Hz)
17	Benzyl radical	616.63	E	B,L	617.2	7.32(m,5H),5.55(d,J=4.6 Hz,1H),5.05(s,2H),4.26(d,J=7.7Hz)	18	Cyclohexyl methyl radical	622.68	Z	C,L	623.2	5.65(d,J=4.2 Hz,1H),5.16(d,J=6.2 Hz,1H),3.78(m,2H),1.72(m,6H),1.22(m,3H),0.96(m,2H)
19	Cyclohexyl methyl radical	622.68	E	C,L	623.2	5.55(d,J=4.6 Hz,1H),4.24(d,J=7.9 Hz,1H),3.82(m,2H),1.68(m,6H),1.21(m,3H),0.94(m,2H)	18	Cyclohexyl methyl radical	622.68	Z	C,L	623.2
19	Cyclohexyl methyl radical	622.68	E	C,L	623.2		20	2-pyridylmethyl	617.62	Z	C,L	618.1	8.49(bd, J =4.8 Hz,1H),7.82(ddd, sharp td, J =7.7,1.7 Hz,1H),7.45(d, J =7.9Hz,1H), 7.32(m,1H),5.66(d, J =4.2Hz,1H),5.24(d, J =6.2Hz,1H),5.15(A8 quartet, Δ v =10.9Hz, J =14.1 Hz,2H)
21	2-pyridylmethyl	617.62	E	C,L	618.1	8.45(bd, J =5.0 Hz,1H),7.79(ddd, clear td, J =7.8,1.7 Hz,1H),7.40(d, J =7.9Hz,1H),7.31(dd, J =7.6Hz,4.9 Hz,1H),5.56(d, J =4.6Hz,1H), 5.15(s.2h),4.25(d, J =7.7Hz,1H)	20	2-pyridylmethyl	617.62	Z	C,L	618.1
21	2-pyridylmethyl	617.62	E	C,L	618.1		22	(4-fluorophenyl) methyl group	634.62	Z	C,L	635.1	7.36(dd, J =8, 5Hz,2H), 7.04(dd, clear triplet J =8.8Hz,2H),5.65(d, J =4.2Hz,1H),5.20(d.J =6.4Hz,1H),5.01(AB quartet,. DELTA.v =12.0Hz, J =12.6Hz,2H)
23	(4-fluorophenyl) methyl group	634.62	E	C,L	635.1	7.32(dd, J =8.5,5.4Hz,2H),7.01(dd, sharp t, J =8.9Hz,2H),5.55(d, J =4.36 Hz,1H),5.02(s,2H),4.25(d, J =7.9Hz,1H)	22	(4-fluorophenyl) methyl group	634.62	Z	C,L	635.1
23	(4-fluorophenyl) methyl group	634.62	E	C,L	635.1		24	(2, 4-dichlorophenyl) methyl group	685.52	E	C,L	685.1;687.0	7.42(d,J=2.1 Hz,1H),7.34(d,J=8.3 Hz,1H),7.26(dd,J=8.3,2.1 Hz,1H),5.56(d,J=4,6 Hz,1H),5.13(s,2H),4.26(d,J=7.7 Hz,1H)

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃0D)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃0D)	25	(2, 4-dichlorophenyl) methyl group	685.52	Z	C,L	685.1;687.0	7.46(d, J =8.3Hz,1H),7.43(d, J =1.9Hz,1H),7.30(dd, J =8.3,2.1 Hz,1H),5.66(d, J =4.2Hz,1H), 5.25(d, J =6.4Hz,1H),5.11(AB quartet,. DELTA.v =9.1 Hz, J =14.0Hz,2H)
26	(2,3,4,5, 6-Pentafluorophenyl) -methyl	706.58	E	C,L	707.2	5.54(d,J=4.6Hz,1H),5.16(s,2H),4.21(d,J=7.9Hz,1H)	25	(2, 4-dichlorophenyl) methyl group	685.52	Z	C,L	685.1;687.0
26	(2,3,4,5, 6-Pentafluorophenyl) -methyl	706.58	E	C,L	707.2	5.54(d,J=4.6Hz,1H),5.16(s,2H),4.21(d,J=7.9Hz,1H)	27	(3, 4-difluorophenyl) methyl group)	652.61	E	C,L	653.2	7.17(m,3H),5.56(d,J=4.4 Hz,1H),5.02(s,2H),4.25(d,J=7.9Hz,1H)
28	(4-trifluoromethylphenyl) methyl group	684.63	E	C,L	685.2	7.58(d,J=8.1 Hz,2H),7.46(d,J=7.9Hz,2H),5.54(d,J=4.4 Hz,1H),5.13(s,2H),4.24(d,J=7.9Hz,1H)	27	(3, 4-difluorophenyl) methyl group)	652.61	E	C,L	653.2
28	(4-trifluoromethylphenyl) methyl group	684.63	E	C,L	685.2		29	(3-trifluoromethylphenyl) methyl group	684.63	E	C,L	685.2	7.57(m,3H),7.49(m,1H),5.55(d,J=4.4 Hz,1H),5.12(s,2H),4.25(d,J=7.7 Hz,1H)
30	(2-chlorophenyl) methyl group	651.07	E	C,L	651.2;653.1	7.35(m,2H),7.24(m,2H),5.56(d,J=4.6 Hz,1H),5.17(s,2H),4.26(d,J=7.9Hz,1H)	29	(3-trifluoromethylphenyl) methyl group	684.63	E	C,L	685.2
30	(2-chlorophenyl) methyl group	651.07	E	C,L	651.2;653.1		31	(2, 3-dichlorophenyl) methyl group	685.52	E	C,L	685.1;687.1	7.42(d,J=7.7Hz,1H),7.27(m,2H),5.55(d,J=4.6Hz,1H),5.17(s,2H),4.25(d,J=7.7Hz,1H)
32	(4-Acylaminobenzophenone) methyl group	673.68	E	C,L	674.2	7.47(d,J=8.3Hz,2H),7.24(d,J=8.3Hz,2H),5.55(d,J=4.6Hz,1H),5.00(s,2H),4.25(d,J=7.9Hz,1H)	31	(2, 3-dichlorophenyl) methyl group	685.52	E	C,L	685.1;687.1
32	(4-Acylaminobenzophenone) methyl group	673.68	E	C,L	674.2		33	2-pyrazinylmethyl	618.6	E	C,L	619.2	8.59(s,1H),8.54(bs,1H),8.50(bs,1H),5.55(d,J=4.4Hz,1H),5.21(s,2H),4.24(d,J=7.7Hz,1H)
34	4-pyrimidinylmethyl	618.6	E	C,L	619.2	9.03(s,1H),8.67(bd,J=5.2Hz,1H),7.40(d,J=5.2Hz,1H),5.56(d,J=4.4 Hz,1H),5.15(s,2H),4.25(d,J=7.5Hz,1H)	33	2-pyrazinylmethyl	618.6	E	C,L	619.2
34	4-pyrimidinylmethyl	618.6	E	C,L	619.2		35	4-pyrimidinylmethyl	618.6	Z	C,L	619.2	9.07(s,1H),8.73(m,1H),7.57(d,J=5.2 Hz,1H),5.68(d,J=4.2Hz,1H),5.29(d,J=6.4Hz,1H),5.16(bs,2H)

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)							1H)
45	(4-carboxyphenyl) methyl	660.64	E	I (using the product of example 36), N	661.2	7.94(d,J=8.1 Hz,2H),7.38(d,J=8.1 Hz,2H),5.55(d,J=4.4Hz,1H),5.13(s,2H),4.26(d,J=7.7Hz,1H)							1H)
45	(4-carboxyphenyl) methyl	660.64	E	I (using the product of example 36), N	661.2		46	(4-Cyclohexylphenyl) methyl group	698.8	E	F,J	699.1	7.20(d,J=8.3 Hz,2H),7.13(d,J=8.1 Hz,2H),5.55(d,J=4.6 Hz,1H),5.01(s,2H),4.26(d,J=7.9 Hz,1H),2.46(m,1H),1.81(m,4H),1.75(m,1H),1.41(m,4H),1.28(m,1H)
47	(4-Cyclohexylphenyl) methyl group	698.8	Z	F,J	699.3	7.16(m,4H),5.65(d, J =4.2Hz,1H), 5.19(d, J =6.2Hz,1H),4.99(AB quartet,. DELTA.v =15.6Hz, J =12.0Hz, 2H),2.46(m,1H),1.82(m,4H),1.74(m,1H),1.42(m,4H),1.27(m,1H)	46	(4-Cyclohexylphenyl) methyl group	698.8	E	F,J	699.1
47	(4-Cyclohexylphenyl) methyl group	698.8	Z	F,J	699.3		48	2-furyl methyl group	606.59	Z	E,L	607.2	7.46(s,1H),6.37(m,2H),5.64(d, J =4.4Hz,1H), 5.12(d, J =6.2Hz,1H),4.95(AB quartet,. DELTA.v =9.5Hz, J =13.1 Hz,2H)
49	2-furyl methyl group	606.59	E	E,L	607.2	7.43(s,1H),6.35(m,2H),5.55(d,J=4.4Hz,1H),4.96(s,2H),4.26(d,J=7.9Hz,1H)	48	2-furyl methyl group	606.59	Z	E,L	607.2
49	2-furyl methyl group	606.59	E	E,L	607.2		50	(3-fluorophenyl) methyl group	634.62	Z	G,L	635.2	7.32(m,1H),7.15(m,1H),7.11(bd, J =8H,1H),6.99(bdd, sharp bt, J =8.3Hz,1H), 5.66(d, J =4.2Hz,1H),5.24(d, J =6.4Hz,1H),5.04(AB quartet,. DELTA.v =9.9Hz, J =13.2Hz,2H)
51	(4-acetylamino-3, 5-dichlorophenyl) methyl group	742.57	E	F,L	742.0;743.9	7.37(s,2H),5.54(d,J=4.6Hz,1H),5.00(s,2H),4.23(d,J=7.9Hz,1H),2.13(s,3H)	50	(3-fluorophenyl) methyl group	634.62	Z	G,L	635.2
51	(4-acetylamino-3, 5-dichlorophenyl) methyl group	742.57	E	F,L	742.0;743.9		52	[4- [ (tert-Butoxycarbonylamino) -methyl group]Butyl radical]Methyl radical	745.79	E	E,L	746.1	7.24(AB quartet,. DELTA.v =18.4 Hz, J =8.1Hz, 4H),5.55(d, J =4.6Hz,1H),5.03(s,2H),4.25(d, J =7.7Hz,1H), 4.19(s,2H),1.43(s,9H)
53		745.79	Z	E.L	746.1	7.27(AB quartet,. DELTA.v = C)	52		745.79	E	E,L	746.1

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)		[4- (tert-Butoxycarbonylamino) methyl group]Phenyl radical]Methyl radical					28.3 Hz, J =8.1Hz, 4H),5.64(d, J =4.4Hz,1H), 5.20(d, J =6.4Hz,1H),5.01(AB quartet Δ v =13.9Hz, J =12.3 Hz,2H),4.20(s,2H),1.44(s,9H)
54	(3-aminophenyl) methyl group	631.64	E	I (using the product from example 38), L	632.1	7.07(t,J=7.7 Hz,1H),6.76(bs,1H),6.70(m,2H),5.54(d,J=4.6 Hz,1H),4.95(s,2H),4.24(d,J=7.9 Hz,1H)
54	(3-aminophenyl) methyl group	631.64	E	I (using the product from example 38), L	632.1		55	(4-Aminomethylphenyl) methyl	645.67	E	(using the product of example 52), L	645.9	7.26(s,4H),5.52(d,J=4,6 Hz,1H),5.02(s,2H),4.22(d.J=7.9 Hz,1H),3.75(s,2H)
56	3- (4-chlorophenyl) propan-1-yl	679.13	Z	E,J	679.2;681.2	7.24(d,J=8.3 Hz,2H),7.16(d,J=8.3 Hz,2H),5.67(d,J=4.2 Hz,1H),5.17(d,J=6.4 Hz,1H),4.00(m,2H),2.68(t,J=7.6 Hz,2H),1.91(m,2H)	55	(4-Aminomethylphenyl) methyl	645.67	E	(using the product of example 52), L	645.9
56	3- (4-chlorophenyl) propan-1-yl	679.13	Z	E,J	679.2;681.2		57	3- (4-chlorophenyl) propan-1-yl	679.13	E	E,J	679.2;681.2	7.21(d,J=8.3Hz,2H),7.12(d,J=8.5 Hz,2H),5.56(d,J=4.6 Hz,1H),4.26(d,J=7.7 Hz,1H),4.02(t,J=6.3 Hz,2H),2.62(t,J=7.6 Hz,2H),1.90(m,2H)
58	2-benzimidazolylmethyl	656.65	E	E,L	657.2	7.52(m,2H),7.21(m,2H),5,57(d,J=4.6Hz,1H),5.27(s,2H),4.28(d,J=7.9 Hz,1H)	57	3- (4-chlorophenyl) propan-1-yl	679.13	E	E,J	679.2;681.2
58	2-benzimidazolylmethyl	656.65	E	E,L	657.2		59	2-benzeneBenzimidazolylmethyl group	656.65	Z	E,L	657.1	7.54(m,2H),7.22(m,2H),5.67(d,J=4.4 Hz,1H),5.33(d,J=6.8 Hz,1H),5.27(s,2H)
60	2-phenylethyl group	630.66	Z	E,J	631.1	7.22(m,5H),5.63(d,J=4.2 Hz,1H),5.09(d,J=6.2 Hz,1H),4.15(m,2H),2.90(t,J=7.0 Hz,2H)	59	2-benzeneBenzimidazolylmethyl group	656.65	Z	E,L	657.1
60	2-phenylethyl group	630.66	Z	E,J	631.1		61	2-phenylethyl group	630.66	E	E,J	631.1	7.12(m,5H),5.53(d,J=4.6 Hz,1H),4.27(d,J=7.7 Hz,1H),4.17(t,J=6.7Hz,2H),2.85(t,J=6.8 Hz,2H)
62		700.62	E	E,L	701	7.39(t,J=7.9 Hz,1H),	61	2-phenylethyl group	630.66	E	E,J	631.1

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)		[3- (trifluoromethoxy) phenyl group]Methyl radical					7.30(d,J=7.9Hz,1H),7.20(bs,1H),7.16(bd,J=8.1 Hz,1H),5.55(d,J=4.6 Hz,1H),5.09(s,2H),4.25(d,J=7.9 Hz,1H)
63	(3-cyanophenyl) methyl group	641.64	E	E,L	642.1	7.61(m,3H),7.46(dd, sharp t, J =7.7Hz,1H), 5.53(d, J =4.6Hz,1H), 5.08(s,2H),4.23(d, J =7.9Hz,1H)		[3- (trifluoromethoxy) phenyl group]Methyl radical
63	(3-cyanophenyl) methyl group	641.64	E	E,L	642.1		64	(3, 4-dimethoxyphenyl) methyl	676.68	E	E,L	677.1	6.90(m,2H),6.84(s,1H),5.53(d,J=4.6Hz,1H),4.96(s,2H),4.25(d,J=7.9 Hz,1H),3.77(s,3H),3.76(s,3H)
65	2-benzofuranylmethyl radical	656.65	E	E,L	657.1	7.51(d,J=7.7Hz,1H),7.39(d,J=8.1 Hz,1H),7.22(m,1H),7.15(m,1H),6.71(s,1H),5.53(d,J=4.6Hz,1H),5.11(s,2H),4.26(d,J=7.9 Hz,1H)	64	(3, 4-dimethoxyphenyl) methyl	676.68	E	E,L	677.1
65	2-benzofuranylmethyl radical	656.65	E	E,L	657.1		66	2-benzofuranylmethyl radical	656.65	Z	E,L	657.1	7.53(d, J =7.1 Hz,1H),7.42(d, J =8.3Hz,1H),7.24(m,1H),7.17(m,1H),6.75(s,1H),5.62(d, J =4.2Hz,1H), 5.17(d, J =6.2Hz,1H), 5.10(AB quartet,. DELTA.v =6.9Hz, J =13.7Hz,2H)
67	(3, 4-dimethoxyphenyl) methyl	676.68	Z	E,L	677.1	6.88(m,3H),5.62(d, J =4.2Hz,1H), 5.17(d, J =6.4Hz,1H), 4.94(AB quartet,. DELTA.v =17.2Hz, J =12.0Hz, 2H),3.80(s,3H),3.79(s,3H)	66	2-benzofuranylmethyl radical	656.65	Z	E,L	657.1
67	(3, 4-dimethoxyphenyl) methyl	676.68	Z	E,L	677.1		68	[3- (trifluoromethoxy) phenyl group]Methyl radical	700.63	Z	E,L	701,0	7.40(m,1H),7.34(bd, J =6.4Hz,1H), 7.27(bs,1H),7.16(m,1H),5.66(d, J =3.9Hz,1H),5.23(d, J =6.2Hz,1H),5.07(AB quartet, Δ v =92. Hz, J =13.1 Hz,2H)
69	2-anilinoethyl radical	645.67	Z	E,L	646.2	7.08(dd,J=8.5,7.5Hz,2H),6.66(dd,J=8.6,0.9Hz,2H),6.62(t,J=7.3Hz,1H),5.62(d,J=4.2Hz,1H),5.18(d,J=6.4Hz,1H),4.15(m,2H),3.27(m,2H)	68	[3- (trifluoromethoxy) phenyl group]Methyl radical	700.63	Z	E,L	701,0

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)	70	2-anilinoethyl radical	645.67	E	E,L	646.1	7.04(dd,J=8.6,7.4Hz,2H),6.60(dd,J=8.6,0.9Hz,2H),6.56(t,J=7.4Hz,1H),5.55(d,J=4.6Hz,1H),4.25(d,J=7.7Hz,1H),4.16(m,2H),3.31(m,2H)
71	[4- (1-piperidino) phenyl group]Methyl radical	699.76	E	H,J	700.1	7.15(d,J=8.5Hz,2H),6.87(d,J=8.7 Hz,2H),5.52(d,J=4.6 Hz,1H),4.92(s,2H),4.24(d,J=7.7 Hz,1H),3.06(dd,J=5.4,5.4 Hz,4H),1.65(m,4H),1.54(m,2H)	70	2-anilinoethyl radical	645.67	E	E,L	646.1
71	[4- (1-piperidino) phenyl group]Methyl radical	699.76	E	H,J	700.1		72	[4- (1-piperidino) phenyl group]Methyl radical	699.76	Z	H,J	700.1	7.23(d, J =8.8Hz,2H),6.93(d, J =8.8Hz,2H), 5.63(d, J =4.3Hz,1H), 5.15(d, J =6.4Hz,1H),4.93(AB quartet,. DELTA.v =17.3 Hz, J =11.8Hz,2H), 3.11(dd, J =5.4,5.4 Hz,4H),1.69(m,4H),1.58(m,2H)
73	3-phenylpropan-1-yl	644.68	Z	E,J	645.1	7.20(d,J=7.3 Hz,2H),7.13(m,3H),5.64(d,J=4.2Hz,1H),5.18(d,J=6.4 Hz,1H),3.97(m,2H),2.65(t,J=7.7 Hz,2H),1.90(m,2H)	72	[4- (1-piperidino) phenyl group]Methyl radical	699.76	Z	H,J	700.1
73	3-phenylpropan-1-yl	644.68	Z	E,J	645.1		74	3-phenylpropan-1-yl	644.68	E	E,J	645.1	7.18(d,J=7.3 Hz,2H),7.11(m,3H),5.54(d,J=4.4 Hz,1H),4.24(d,J=7.9 Hz,1H)4.01(t,J=6.3Hz,2H),2.61(t,J=7.7Hz,2H),1.89(m,2H)
75	(2-fluorophenyl) methyl group	634.62	Z	G,L	635.2	7.44 (clear J =7.5,1.8 Hz,1H),7.30(m,1H),7.14(m,1H),7.06(dd, J =10.2,8.3 Hz,1H),5.65(d, J =4.2Hz, H),5.20(d, J =6.4Hz,1H),5.11(AB quartet,. DELTA.v =9.1 Hz, J =12.9Hz, 1H)	74	3-phenylpropan-1-yl	644.68	E	E,J	645.1
75	(2-fluorophenyl) methyl group	634.62	Z	G,L	635.2		76	(2-fluorophenyl) methyl group	634.62	E	G,L	635.2	7.36 (clear J =7.5,1.5 Hz,1H),7.28(m,1H),7.12(m,1H),7.04(dd, J =10.1,8.4 Hz,1H),5.55(d, J =4.6Hz,1H), 5.12(s,2H),4.26(d, J =7.9Hz,

examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)
examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)		4-phenyl-3-furanylmethyl					7.59(bs,1H),7.43(bd,J=8 Hz,2H),7.31(bt,J=8Hz,2H),7.25(m,1H),5.56(d.J=4.6 Hz,1H),5.00(s,2H),4.27(d,J=7.9Hz,1H)
7A	4-phenyl-3-furanylmethyl	682.69	Z	F,L	683.1	7.66(d, J =1.7 Hz,1H),7.64(bs,1H),7.50(bd, J =8Hz,2H),7.38(bt, J =8Hz,2H),7.29(m,1H),5.64(d, J =4.2Hz,1H),5.13(d, J =6.4Hz,1H),4.98(AB quartet,. DELTA.v =21.6Hz, J =12.0 hz.2h)		4-phenyl-3-furanylmethyl
7A	4-phenyl-3-furanylmethyl	682.69	Z	F,L	683.1		8A	(3- [ (tert-Butoxycarbonyl) aminomethyl group]Phenyl) methyl	745.79	Z	F,L	746.1	7.26(m,3H),7.20(m,1H),5.66(d, J =4.4Hz,1H),5.21(d, J =6Hz,1H), 5.03(AB quartet,. DELTA.v =13.4H2, J =12.5Hz,2H),4.21(m,2H)
9A	(3- [ (tert-Butoxycarbonyl) aminomethyl group]Phenyl) methyl	745.79	E	F,L	746.1	7.24(m,2H),7.19(m,2H),5.56(d,J=4.6 Hz,1H),5.05(s,2H),4.26(d,J=7.9 Hz,1H),4.20(m,2H)	8A		745.79	Z	F,L	746.1
9A		745.79	E	F,L	746.1		10A	(3-chlorophenyl) methyl group	651.07	Z	D,L	651.1;653.1	7.35(bs,1H),7.26(m,3H),5.64(d, J =4.4Hz,1H),5.21(d, J =6.4Hz,1H),5.01(AB quartet Δ V =10.2 Hz, J =13.0Hz,2H)
11A	(3, 5-difluorophenyl) methyl	652.61	E	F,L	653.1	6.90(m,2H),6.82(m,1H),5.56(d,J=4.6 Hz,1H),5.06(s,2H),4.26(d,J=7.．9Hz,1H)	10A	(3-chlorophenyl) methyl group	651.07	Z	D,L	651.1;653.1
11A	(3, 5-difluorophenyl) methyl	652.61	E	F,L	653.1		12A	(5-chloro-2-fluorophenyl) methyl group	669.06	E	F,L	669.0;671.0	7.34(dd, J =6,2,2.6 Hz),7.27(ddd, J =8.8,4.5,3.0Hz,1H),7.05(dd, clear t, J =9.2 Hz,1H),5.54(d, J =4.4Hz,1H), 5.07(s,2H),4.24(d, J =7.7Hz,1H)
13A	(3-chloro-2-fluorophenyl) methyl group	669.06	Z	E,L	669.0;671.0	7.37 (sharp dd, J =7.7,6.9 Hz,2H),7.1(m,1H),5.64(d, J =4.4Hz,1H), 5.19(d, J =6.2Hz,1H), 5.10(bs,2H)	12A	(5-chloro-2-fluorophenyl) methyl group	669.06	E	F,L	669.0;671.0
13A	(3-chloro-2-fluorophenyl) methyl group	669.06	Z	E,L	669.0;671.0		14A	(3-chloro-2-fluorophenyl) methyl group	669.06	E	E,L	669.0;671.0	7.36(m,1H),7.28(m,1H),7.08(m,1H),5.54(d,J=4.4 Hz,1H),5.11(s,2H),

Carry out pouring	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)
Carry out pouring	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃0D)							7.7 Hz,1H)
21A	2-quinolylmethyl	667.68	Z	F,L	668.1	8.32(d, J =8.5Hz,1H), 8.12(d, J =8.3Hz,1H), 7.92(d, J =8.1Hz, 1H),7.76(m,1H),7.59(m,1H),7.53(d, J =8.5Hz,1H), 5.69(d, J =4.4Hz,1H), 5.36(AB quartet Δ v =16.4 Hz, J =14.8 Hz,2H),5.28(d, J =6.4Hz,1H)							7.7 Hz,1H)
21A	2-quinolylmethyl	667.68	Z	F,L	668.1		22A	(3-chloro-4-fluorophenyl) methyl group	669.06	Z	E,L	669.0;671.0	7.46(dd, J =7.3,2.1 Hz,1H),7.29(ddd, J =8.3,4.7,2.1 Hz, H),7.17(m,1H),5.64(d, J =4.2Hz,1H), 5.19(d, J =5.6 Hz,1H),4.98(AB quartet Δ v =7.7, J =13.2Hz,2H)
23A	3-quinolylmethyl	667.68	Z	F,L	668.1	8.84(bd,J=1.9 Hz,1H),8.30(bs,1H),7.99(d,J=8.7 Hz,1H),7.91(d,J=8.1 Hz,1H),7.73(m,1H),7.58(m,1H),5.63(d,J=4.4 Hz,1H),5.24(m,3H)	22A	(3-chloro-4-fluorophenyl) methyl group	669.06	Z	E,L	669.0;671.0
23A	3-quinolylmethyl	667.68	Z	F,L	668.1		24A	3-quinolylmethyl	667.68	E	F,L	668.1	8.80(bd,J=2.1 Hz,1H),8.26(ba,J=1.5Hz,1H),7.98(d,J=8.5 Hz,1H),7.89(bd,J=8.3Hz,1H),7.73(m,1H),7.58(m,1H),5.53(d,J=4.6 Hz,1H),5.27(s,2H),4.25(d,J=7.7Hz,1H)
25A	(4-chloro-3-fluorophenyl) methyl group	669.06	Z	F,L	669.1,671.1	7.39(dd, sharp t, J =7.9Hz,1H), 7.23(m,1H),7.14(m,1H),5.64(d, J =4.4Hz,1H),5.21(d, J =6.4Hz,1H), 5.00(AB quartet,. DELTA.v =7.7Hz, J =13.3Hz,2H)	24A	3-quinolylmethyl	667.68	E	F,L	668.1
25A	(4-chloro-3-fluorophenyl) methyl group	669.06	Z	F,L	669.1,671.1		26A27A	(4-chloro-3-fluorophenyl) methyl (3,4, 5-trifluorophenyl)	669.06670.6	EE	F,LE,L	669.1,671.1671.1	7.42(dd, sharp t, J =7.9Hz,1H), 7.20(dd, J =10.1,1.8 Hz,1H),7.14(m,1H),5.59(d, J =4.6Hz,1H), 5.07(s,2H),4.28(d, J =7.8Hz,1H)7.04(dd, sharp t, J = 1H)
	Methyl radical					7.6Hz,2H),5.54(d,J=4.6 Hz,1H),4.99(s,2H),4.23(d,J=7.9 Hz,1H)	26A27A	(4-chloro-3-fluorophenyl) methyl (3,4, 5-trifluorophenyl)	669.06670.6	EE	F,LE,L	669.1,671.1671.1

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD							6.2 Hz,1H)
44A	(2, 6-dichlorophenyl) methyl group	685.52	E	F,J	685.0;687.0	7.34(m,2H),7.24(dd,J=8.8,7.2 Hz,1H),5.54(d,J=4.6 Hz,1H),5.32(s,2H),4.24(d,J=7.9Hz,1H)							6.2 Hz,1H)
44A	(2, 6-dichlorophenyl) methyl group	685.52	E	F,J	685.0;687.0		45A	(2, 4-dichlorophenyl) methyl group	685.52	Z	F,L	685.0;687.0	7,51(d,J=8.2Hz,1H),7.47(d,J=2.3Hz,1H),7.34(dd,J=8.2,2.3Hz,1H),5.70(d,J=4.3 Hz,1H),5.29(d,J=6.3 Hz,1H),5.15(bs,2H)
46A	(2-chloro-4-fluorophenyl) methyl group	669.06	Z	F,L	669.1;671.1	7.54(dd, J =8.6,6.3 Hz,1H),7.24(dd, J =8.6,2.6Hz,1H),7.09(ddd, clear td, J =8.6,2.6,1H),5.70(d, J =4.3Hz,1H), 5.28(d, J =6.3Hz,1H), 5.15(A8 quartet,. DELTA.v =6.8Hz, J =13.5 Hz,2H)	45A	(2, 4-dichlorophenyl) methyl group	685.52	Z	F,L	685.0;687.0
46A	(2-chloro-4-fluorophenyl) methyl group	669.06	Z	F,L	669.1;671.1		47A	(2, 4-dichlorophenyl) methyl group	685.52	E	F,L	685.1;687.0	7.45(d,J=2.0 Hz,1H),7.37(d,J=8.2Hz,1H),7.29(dd,J=8.6,2.3 Hz,1H),5.59(d,J=4.6Hz,1H),5.17(s,2H),4.29(d,J=7.6 Hz,1H)
48A	(2-chloro-4-fluorophenyl) methyl group	669.06	E	F,L	669.1;671.1	7.42(dd, J =8.6,5.9 Hz,1H),7.22(dd, J =8.6,2.6Hz,1H),7.05(ddd, clear, J =8.6, 2.6H)Hz,1H),5.59(d,J=4,6Hz,1H),5.16(s,2H),4.29(d,J=7.9Hz,1H)	47A	(2, 4-dichlorophenyl) methyl group	685.52	E	F,L	685.1;687.0
48A	(2-chloro-4-fluorophenyl) methyl group	669.06	E	F,L	669.1;671.1		49A	(2-chloro-6-fluorophenyl) methyl group	669.06	Z	F,J	669.1;671.1	7.33(ddd, sharp td, J =8.3,6.0 Hz,1H),7.25 (presumed bd, J-blurred 1H),7.08(bdd, sharp bt, J =8.3Hz,1H),5.63(d, J =4.2Hz,1H),5.20(bs,2H),5.12(d, J =62Hz,1H)
50A	(2-chloro-6-fluorophenyl) methyl group	669.06	E	F,J	669.1;671.1	7.31(ddd, sharp td, J =8.1,6.0,1H),7.22 (presumed bd, J-blurred 1H),7.05 (presumed bt, J =8.3Hz,1H), 5.55(d, J =4.6Hz,1H), 5.22(s,2H),4.25(d, J =7.9Hz,1H)	49A	(2-chloro-6-fluorophenyl) methyl group	669.06	Z	F,J	669.1;671.1

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)		(2,3, 6-trifluorophenyl) methyl group					5.55(d,J=4.6 Hz,1H),5.15(s,2H),4.23(d,J=7.9Hz,1H)
61A	(2, 4-difluorophenyl) methyl	652.61	Z	F,L	653.2	7.50(m,1 H),6.95(m,2H),5.68(d,J=4.0Hz,1H),5.22(d,J=6.3Hz,1H),5.09(bs,2H)		(2,3, 6-trifluorophenyl) methyl group					5.55(d,J=4.6 Hz,1H),5.15(s,2H),4.23(d,J=7.9Hz,1H)
61A	(2, 4-difluorophenyl) methyl	652.61	Z	F,L	653.2		62A	(2, 4-difluorophenyl) methyl	652.61	E	F,L	653.2	7.39(m,1 H),6.91(m,2H),5.58(d,J=4.6Hz,1H),5.09(s,2H),4.30(d,J=7.9Hz,1H)
63A	(2, 6-difluoro-4-tolyl) methyl group	666.64	Z	F,L	667.1	6.77(d,J=8.1 Hz,2H),5.60(d,J=4.2Hz,1H),5.08(d,J=6.2 Hz,1H),5.04(bs,2H),2.32(s,3H)	62A	(2, 4-difluorophenyl) methyl	652.61	E	F,L	653.2
63A	(2, 6-difluoro-4-tolyl) methyl group	666.64	Z	F,L	667.1		64A	(2, 6-difluoro-4-tolyl) methyl group	666.64	E	F,L	667.1	6.75(d,J=8.1 Hz,2H),5.52(d,J=4.6Hz,1H),5.06(s,2H),4.22(d,J=7.9 Hz,1H),2.30(s,3H)
65A	(2,3,4,5, 6-pentafluorophenyl) methyl group	706.58	Z	F,L	707.1	5.62(d,J=4.O Hz,1H),5.11(bs,2H),5.08(d,J=6.2Hz,1H)	64A	(2, 6-difluoro-4-tolyl) methyl group	666.64	E	F,L	667.1
65A	(2,3,4,5, 6-pentafluorophenyl) methyl group	706.58	Z	F,L	707.1	5.62(d,J=4.O Hz,1H),5.11(bs,2H),5.08(d,J=6.2Hz,1H)	66A	(2-fluoro-6-trifluoromethylphenyl) methyl group	702.62	Z	F,L	703.1	7.54(m,2H),7.40(m,1H),5.60(d, J =4.2Hz,1H),5.20(AB quartet, Δ V =15.4Hz, J =11.5Hz,2H),5.07(d, J =6.4Hz,1H)
67A	(2-fluoro-6-trifluoromethylphenyl) methyl group	702.62	E	F,L	703.1	7.54(m,2H),7.40(m,1H),5.55(d,J=4.6Hz,1H),5.24(s,2H),4.25(d,J=7.9Hz,1H)	66A	(2-fluoro-6-trifluoromethylphenyl) methyl group	702.62	Z	F,L	703.1
67A	(2-fluoro-6-trifluoromethylphenyl) methyl group	702.62	E	F,L	703.1		68A	(2, 3-difluorophenyl) methyl	652.61	Z	F,L	653.1	7.25(m,1H),7.17(m,2H),5.69(d, J =4.0Hz,1H),5.24 (presumed d, J fuzzy, 1H),5.16(bs,2H)
69A	(2, 3-difluorophenyl) methyl	652.61	E	F,L	653.1	7.16(m,3H),5.59(d,J=4.6 Hz,1H),5.17(bs,2H),4.28(d,J=7.9Hz,1H)	68A	(2, 3-difluorophenyl) methyl	652.61	Z	F,L	653.1
69A	(2, 3-difluorophenyl) methyl	652.61	E	F,L	653.1		70A	(2,3, 4-trifluorophenyl) methyl group	670.6	E	F,L	671.1	7.17(m,1H),7.03(m,1H),5.53(d,J=4.6Hz,1H),5.08(s,2H),4.22(d,J=7.7Hz,1H)
71A	(2,3, 4-trifluorophenyl) methyl group	670.6	Z	F,L	671.1	7.22(m,1H),7.09(m,1H),5.65(d,J=4.2Hz,1H),5.18(d,J=6.2Hz,1H),5.08(bs,2H)	70A	(2,3, 4-trifluorophenyl) methyl group	670.6	E	F,L	671.1
71A	(2,3, 4-trifluorophenyl) methyl group	670.6	Z	F,L	671.1		72A	(2,3,5, 6-tetrafluorophenyl) methyl group	688.59	Z	F,L	688.9	7.27(m,1H),5.69(d,J=4.0HZ,1H),53.4(d,J=

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)		I					6.6 Hz,1H),5.12(bs,2H)
73A	(2,3,5, 6-tetrafluorophenyl) methyl group	688.59	E	F,L	689.0	7.17(m,1H),5.58(d,J=4.3 HZ,1H),5.13(bs,2H),4.27(d,J=7.6Hz,1H)		I					6.6 Hz,1H),5.12(bs,2H)
73A	(2,3,5, 6-tetrafluorophenyl) methyl group	688.59	E	F,L	689.0		74A	2, 3-difluoro-6-methoxyphenyl) methyl	682.64	E	F,L	683.0	7.20(m,1H),6.76(ddd,J=9.2,3.6,2.3Hz,1H),5.58(d,J=4.6 Hz,1H),5.16(d,J=2.O Hz,2H),4.28(d,J=7.9Hz,1H),3.83(s,3H)
75A	2, 3-difluoro-6-methoxyphenyl) methyl	682.64	Z	F,L	683.0	7.22(m,1H),6.80(ddd,J=92.3,3.2,0,1H),5.65(d,J=3.6Hz,1H),5.14(m,2H),5.09(d,J=5.6Hz,1H),3.88(s,3H)	74A	2, 3-difluoro-6-methoxyphenyl) methyl	682.64	E	F,L	683.0
75A	2, 3-difluoro-6-methoxyphenyl) methyl	682.64	Z	F,L	683.0		76A	(4-chloro-3-sulfonylaminophenyl) methyl group	730.15	E	F,L	730.0	8.21(m,1H),7.90(m,1H),7.52(m,1H),5.58(d,J=4.6 Hz,1H),5.13(s,2H),4.28(d,J=7.9Hz,1H)
77A	(2-fluoro-6-trifluoromethoxyphenyl) methyl	718.616	E	F,L	719.0	7.48(ddd, sharp td, J =8.2,6.3 Hz,1H),7.18(m,2H),5.58(d, J =4.3Hz,1H),5.19(d, J =1.0Hz,2H),4.27(d, J =7.9Hz,1H)	76A	(4-chloro-3-sulfonylaminophenyl) methyl group	730.15	E	F,L	730.0
77A	(2-fluoro-6-trifluoromethoxyphenyl) methyl	718.616	E	F,L	719.0		78A	(2-fluoro-6-trifluoromethoxyphenyl) methyl	718.616	Z	F,L	719.0	7.49(ddd, clear, J =8.6,6.3 Hz,1H),7.19(m,2H),5.65(d, J =4.3Hz,1H), 5.16(bs,2H),5.14(d, J =6.3Hz,1H)
79A	3-chloro-4-fluorophenyl	655.04	E	E,J	654.8	7.28(dd, J =6.2,2.7Hz,1H),7.11(dd, sharp t, J =9Hz,1H),7.02(m,1H),5.65(d, J =4.4Hz,1H), 4.28(dd, J =8.3,4.6Hz,1H)	78A	(2-fluoro-6-trifluoromethoxyphenyl) methyl	718.616	Z	F,L	719.0
79A	3-chloro-4-fluorophenyl	655.04	E	E,J	654.8		80A	(2-fluoro-6-methoxyphenyl) methyl	664.65	E	F,L	665.1	7.26(ddd, sharp td, J =8.5,6.9 Hz,1H),6.76(d, J =8.5Hz,1H), 6.65(dd, sharp t, J =8.5Hz,1H),5.53(d, J =4.6Hz,1H),5.09(d, J =1.4Hz, 2H), andH),4.24(d,J=7.9Hz,1H),3.79(s,3H)
81A	4- (methoxycarbonyl) phenyl	660.64	E	E,J	661.1	7.88(d,J=8.5Hz,2H),7.12(d,J=8.5Hz,2H),5.65(d,J=4.4Hz,1H),4.29(dd,J=8.1,5Hz,1H),3.84(s,3H)	80A	(2-fluoro-6-methoxyphenyl) methyl	664.65	E	F,L	665.1

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)	82A	3-chlorophenyl group	637.04	E	E,J	637.3;639.4	7.19(dd, sharp t, J =8.2 Hz,1H),7.18(dd, sharp t, J =2.2Hz,1H),6.99(ddd, J =8.3,2.3,1.0 Hz,1H),6.95(ddd, J =8.1,1.9,1.0Hz,1H),5.62(d, J =4.6Hz,1H),4.25(dd, J =8.1,4.6Hz,1H)
83A	2-fluorophenyl group	620.58	E	E,J	621.0	7.34(ddd, clear, J =8.1,1.7 Hz,1H),7.05(m,1H),7.00(m,1H),6.94(m,1H),5.62(d, J =4.6Hz,1H), 4.26(dd, J =8.2,4.7Hz,1H)	82A	3-chlorophenyl group	637.04	E	E,J	637.3;639.4
83A	2-fluorophenyl group	620.58	E	E,J	621.0		84A	3, 5-dichlorophenyl	671.49	E	E,J	670.7;673,2	7.14(d,J=1.9Hz,2H),7.04(bs,1H),5.65(d J=4.4Hz,1H),4.29(dd,J=8.1,4.6Hz,1H)
85A	(3-chloro-2-thiapan-yl) methyl group	657.098	Z	F,L	656.8;658,9	7.46(d,J=5.3Hz,1H),6.95(d,J=5.3Hz,1H),5.68(d,J=4.3 Hz,1H),5.19(m,2H),5.17(d,J=6.3 Hz,1H)	84A	3, 5-dichlorophenyl	671.49	E	E,J	670.7;673,2
85A	(3-chloro-2-thiapan-yl) methyl group	657.098	Z	F,L	656.8;658,9		86A	(3-chloro-2-thienyl) methyl	657.098	E	F,L	656.9;658.9	7,43(d,J=5.3 Hz,tH),6.93(d,J=5.3Hz,1H),5.59(d,J=4.6Hz,1H),5.20(s,2H),4.31(d,J=7.6Hz,1H)
87A	(2-thienyl) methyl	622.653	Z	F,L	622.9	7.38(dd,J=5.3,1.3Hz,1H),7.08(bd,J=3.6Hz,1H),6.99(dd,J=5.3,3.6Hz,1H),5.67(d,J=4.3Hz,1H),5.20(bs,2H),5.16(d,J=6.3Hz,1H)	86A	(3-chloro-2-thienyl) methyl	657.098	E	F,L	656.9;658.9
87A	(2-thienyl) methyl	622.653	Z	F,L	622.9		88A	(2-thienyl) methyl	622.653	E	F,L	622.9	7.35(dd,J=5.3,1.3 Hz,1H),7.05(bd,J=3.3Hz,1H),6.97(dd,J=4.9,3.3Hz,1H),5.59(d,J=4.6HZ,1H),5.22(s,2H),4.31(d,J=7.9Hz,1H)
89A	(2-chloro-6-trifluoromethoxyphenyl) methyl	735.07	Z	F,L	734.8;737.0	7.46(m,2H),7.33(m, 1H),5.66(d, J =4.3Hz,1H),525(AB quartet, Ay =4.9Hz, J =11.5Hz,2H),5.14(d, J =6.3Hz,1H)	88A	(2-thienyl) methyl	622.653	E	F,L	622.9
89A	(2-chloro-6-trifluoromethoxyphenyl) methyl	735.07	Z	F,L	734.8;737.0		90A	(2-chloro-6-trifluoromethoxyphenyl) methyl	735.07	E	F,L	734.8;736.9	7.45(m,2H),7.31(m,1H),5.58(d,J=4.3HZ,1H),5.28(s,2H),4,28(d,J=

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)							7.9Hz，1H)
91A	(5-chloro-2-thienyl) methyl	657.098	Z	F，L	656.9：658.9	6.89(d，J=4．0Hz，1H)，6.85(d，J=4.0 Hz，1H)，5.68(d，J=4.0 Hz，1H)．5.15(d，J=6.3 Hz，1H)．5.10(s，2H)							7.9Hz，1H)
91A	(5-chloro-2-thienyl) methyl	657.098	Z	F，L	656.9：658.9		92A	(5-chloro-2-thienyl) methyl	657.098	E	F，L	656.9：658.9	6.86(bd，J=3.6Hz，1H)．6.82(bd，J=3．6 Hz，1H)，5.59(d，J=4．3Hz，1H)，5.12(s，2H)，4.31(d，J=7.2Hz，1H)
93A	(2-difluoromethoxyphenyl) methyl group	682.635	Z	F，L	683.1	7.49(bd, J =7.7Hz,1H), 7.33(dd, sharp bt, J =8Hz, 1H),7.22(dd, sharp bt, J =7.5 hz.1H), 7.16(bd, J =8Hz, 1H), 6.79(t, J =74.4 Hz,1H),5.65(d, J =4.2Hz,1H), 5.22(d, J =6.4Hz,1H),5.11(AB quartet. Δ ν =9.2 Hz, J =13.2Hz,2H)	92A	(5-chloro-2-thienyl) methyl	657.098	E	F，L	656.9：658.9
93A	(2-difluoromethoxyphenyl) methyl group	682.635	Z	F，L	683.1		94A	(2-difluoromethoxyphenyl) methyl group	682.635	E	F，L	683.1	7.37(d, J =7.1 HZ,1H),7.29(dd, sharp bt, J = 7HZ,1H), 7.16(dd, sharp bt, J =7.5HZ, 1H), 7.10 (m.1h), 6.72 (t.J =74 HZ,1H),5.54(d, J =4.4HZ, 1H). 5.11(s, 2H),4.24 fd, J =7.9Hz,1H)
95A	(3-fluorophenyl) methyl group	634.618	E; 4' alpha-stereochemistry	F：N-1	634.9	7.36 (ddd, clear td, J =7.9, 5.9 Hz,1H),7.18(m, 1H), 7.10(m, 1H),7.02(m,1H), 5.73(d, J =4.3Hz,1H), 5.12(s,2H), 4.79(d, J =6.9Hz, 1H)	94A	(2-difluoromethoxyphenyl) methyl group	682.635	E	F，L	683.1
95A	(3-fluorophenyl) methyl group	634.618	E; 4' alpha-stereochemistry	F：N-1	634.9		96A	(3-chlorophenyl) methyl group	651.073	E: alpha-stereochemistry at position 4 ″	F：N-1	650.8	7.32(bs，1 H)．7.27(m，3H)，5.68(d，J=4.4 Hz，1H)，5.05(s，2H)，4.74(d，J=7.1 Hz，1H)
97A	(3, 4-dichlorophenyl) methyl group	685.518	E	F，L	684.9；686.9	7.42(m，2H)，7.20(dd，J=8．3，2.1 Hz，1H)．5.53(d，J=4.6 Hz，1H)．5.00(s，2H)，423(d，J=7.9 Hz，1H)	96A	(3-chlorophenyl) methyl group	651.073	E: alpha-stereochemistry at position 4 ″	F：N-1	650.8
97A	(3, 4-dichlorophenyl) methyl group	685.518	E	F，L	684.9；686.9		98A	(2.6-dimethylphenyl) methyl	644.682	Z	F，L	644.9	7.05(dd, J =8.3, 6.4Hz,1H) 6.97(bd, J =7.5Hz, 2H), 5.59(d, J =4.4Hz,1H), 5.11(AB quartet, Δ ν =18.3Hz, J =10.9Hz, 2H), 5.09(d.J =6.4Hz,

examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)				S			2H),0.89(m,3H).
107A	1- (2, 4-difluorophenyl) propyl	680.66	E, mixtures of diastereomers	G,L	681.0	7.25(m,1H),6.83(m,2H),5.52 and 5.51(2d, J =4.5 and 4.5Hz,1H),5.23(m,1H),1.86 and 1.72(2m,2H),0.86(m,3H).				S			2H),0.89(m,3H).
107A	1- (2, 4-difluorophenyl) propyl	680.66	E, mixtures of diastereomers	G,L	681.0		108A	1- (3, 4-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.0,689.0	7.28(m,1H),7.15(m,1H),5.64(d,J4.2 HZ,1H),5.29(d,J=6.6Hz,1H),5.09(q,J=6.6HZ,1H),1.43(d,J=6.6 HZ,3H).
109A	1- (3, 4-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.0,689.0	7.13(m,3H),5.52(m,1H),5.14(m,1H),1.43 and 1.42(2d, J =6.4 and 6.6Hz,3H).	108A	1- (3, 4-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.0,689.0
109A	1- (3, 4-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.0,689.0		110A	1- (2, 4-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.1	7.51 and 7.37(m,1H),8.85(m,1H),5.65(m,1H),5.38(m,1H),5.30 and 5.24(2d, J =6.6 and 6.4Hz,1H),1.45 and 1.44(2d, J =6.6 and 6.6Hz,3H).
111A	1- (2, 4-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.1	7.29(m,1H),6.85(m,2H),5.52(m,1H),5.40(m,1H),1.47 and 1.46(2d, J =6.6 and 6.6Hz,3H)	110A	1- (2, 4-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.1
111A	1- (2, 4-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.1		112A	1- (3, 5-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.0	6/97(m,2H),6.76(m,1H),5.65(d,J4.2Hz,1H),5.30(d,J6.6Hz,1H),5.10(q,J=6.6Hz,1H),1.4(d,J=6.6Hz,3H).
113A	1- (3, 5-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.0	6.83(m,2H),6.75(m,1H),5.52(2 d, J =4.8 and 4.6Hz,1H), 5.15(m,1H),1.43 and 1.42(2d, J =6.6 and 6.6Hz,3H)	112A	1- (3, 5-difluorophenyl) ethyl	666.64	Z, mixtures of diastereomers	G,L	667.0
113A	1- (3, 5-difluorophenyl) ethyl	666.64	E, mixtures of diastereomers	G,L	667.0		114A	1- (3-chloro-2, 6-difluorophenyl) ethyl	701.081	Z, mixtures of diastereomers	G,L	701.0,703.0	7.39(m,1H),6.94(m,1H),5.64(brd,J=3.9 Hz,1H),5.49(q,6.8Hz),5.18(m,1H),1.60(d,6.9 Hz).

Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Examples	Y	Molecular weight	Stereochemistry	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)	115A	1- (3-chloro-2, 6-difluorophenyl) ethyl	701.081	E, mixtures of diastereomers	G.L	701.0,703.0	7.35(m,1H),6.89(m,1H),5.58(m,1H),5.49(m,1H),1.56 and 1.55(2d, J =6.8 and 6.8Hz, 3H).
116A	1- (3-chlorophenyl) ethyl	665.10	E	E,L	665.1,667.1	7.25(m,1H),7.20(m,1H),5.54 and 5.53(2d, J =4.8 and 4.8 Hz,1H),5.17(m,1H),1.47 and 1.45(2d, J =6.2 and 6.6Hz,3H).	115A	1- (3-chloro-2, 6-difluorophenyl) ethyl	701.081	E, mixtures of diastereomers	G.L	701.0,703.0

TABLE 2

In the examples listed in Table 2 below, except for Y in example 97¹Y in all the examples, other than methyl¹Are all H.

Examples	Y	Molecular weight	Method	Preparation method	1HNMR value (CD)₃OD)
Examples	Y	Molecular weight	Method	Preparation method	1HNMR value (CD)₃OD)	93	Benzyl radical	602.64	O	603.2	7,17(m,3H),7.08(m,2H),5.53(d,J=4.6Hz,1H),3.87(dd,J=7.5,4.4)Hz,1H),3.79(d,J=13.1 Hz,1H),3.61(d,J=13.1 Hz,1H),2.90(m,1H),1.09(d,J=6.6HZ,3H)
94	(3, 4-dimethoxyphenyl) methyl	662.7	O	663.3	7.07(s,1H),6.92(m,2H),5.61(d, J =3.7Hz,1H), 4.07 (the right half is AB quartet; left hand signal blur, J =13.1 Hz,1H),3.80(s,3H),3.79(s,3H),3.41(m,1H), 1.26(d,	93	Benzyl radical	602.64	O	603.2

examples	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
examples	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)						J=6．9 Hz,3H)
95	[2- (trifluoromethyl) phenyl group]Methyl radical	670.64	P	671.2	7.56(bd,J=7.9Hz，1H),7.41(m,2H),7.33(bt,J=7.5Hz,1H),5.53(d,J=4.6Hz,1H),3.87(dd,J=7.5,4.4 Hz,1H),2.92(m．1H),1．09(d,J=6.6 Hz,3H)						J=6．9 Hz,3H)
95	[2- (trifluoromethyl) phenyl group]Methyl radical	670.64	P	671.2		96	(4-tert-butylphenyl) methyl group	658.75	P	659.3	7.20(d,J=8.3 Hz,2H),6.97(d,J=8.3 Hz,2H),5.51(d,J=4.6 Hz,1H),3.84(dd,J=7.5,4.4 Hz,1H),3.73(d,J=13.1Hz,1H),3.55(d，J=13.1 Hz,1H),2.86(m,1H),1.24(s，9H)，1.07(d,J=6.4Hz,3H)
97	Benzyl radical	616.67	O (using the product of example 93 as starting material:	617.2	7.30(m,5H),5.55(d, J =3.9Hz,1H), 4.04(dd, J = 7.1.4.9 Hz,1H), 3.54 (AB quartet,. DELTA.v =49.0 Hz, J =13.2Hz,2H), 2.88(m,1H),2.16(s, 3H),0.91(d, J =6.6 Hz,3H)	96	(4-tert-butylphenyl) methyl group	658.75	P	659.3
97	Benzyl radical	616.67	O (using the product of example 93 as starting material:	617.2		98	Phenyl radical	588.62	R	589.2	7.02(dd,J=8.6,7.4 Hz，2H),6.58(dd,J=8.7,1.0Hz,2H),6.54(dd,J=7.3．1.0 Hz,1H),5.57(d,J=4.4 HZ,1H),3.86(dd,J=6.8,5.4 Hz,1H),3.59(m，1H),1.04(d,J=6.4 Hz,3H)
99	2-phenylethyl group	616.67	P	617.3	7.19(m,2H)．7.08(m,3H),5.52(d,J=4.4 HZ,1H),3.87(dd,J=7.2,3.8 Hz,1H), 2.88(m,3H),2.67(m，2H),1.03(d,J=6.4Hz，3H)	98	Phenyl radical	588.62	R	589.2
99	2-phenylethyl group	616.67	P	617.3		100	4-fluorophenyl group	606.61	R	607.2	6.76(dd, sharp t, J =8.8Hz,2H),6.56(dd, J =9.0,4.5Hz,2H),5.58(d, J =4.4Hz,1H),3.53(m,1H),1.04(d, J =6.4Hz,3H)
101	2- (4-chlorophenyl) ethyl	651.12	P	651.2：6532	7.19(d,J=8.3 Hz,2H),7.08(d,J=8.3 Hz,2H),5.53(d,J=4.4 Hz,1H),2.9(m,3H),2.7(m,2H),	100	4-fluorophenyl group	606.61	R	607.2

Examples	Y	Molecular weight	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
					1.07(d,J=6.4Hz,3H)

TABLE 3TABLE 4

Examples	Y	Molecular weight	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)	105	Benzyl radical	603.63	U	604.1	7.25(brs,1H),7.2-7.13(m,6H),6.92(d, J =1.3 Hz,1H),6.84(dd, J =8.5 and 1.9Hz,1H), 5.56(d, J =3.7Hz,1H),4.42(AB quartet, Δ v =16Hz, J =11.8Hz,2H),2.08(d, J =1.5Hz,3H),1.16(d, J =6.4Hz,3H).
106	(3, 4-dichlorophenyl) methyl group	672.52	U	672.1,674.1	7.30-7.26(m,2H), 7.22(s,1H), 7.13(d, J =8.5Hz,1H), 7.03(dd, J =8.3 and 2.0Hz,1H), 6.89(d, J =2Hz,1H), 6.85(dd, J =8.5,1.9Hz,1H), 5.56(br dd,1H), 4.34(AB quartet,. DELTA./. nu =34.7Hz, J =12.7Hz, 12H),2.05(d, J =1.5Hz,3H),1.16(d, J =6.2Hz,1H).	105	Benzyl radical	603.63	U	604.1
106	(3, 4-dichlorophenyl) methyl group	672.52	U	672.1,674.1		107	(4-fluorophenyl) methyl group	621.62	U	622.2	7.22(brs,1H),7.16-7.12(m,3H),6.90-6.81(m,4H),5.54(d, J =4.0Hz,1H),4.38(AB quartet,. DELTA.v =25.1Hz, J =11.7Hz,2H),2.06(d, J =1.4hz.3h),1.14(d, J =6.2Hz)
108	(4-methylphenyl) methyl group	617.66	U	618.3	7.25(s,1H),7.17(d, J =8.3Hz,1H), 7.04-6.99(m,4H),6.93(d, J =1.8 Hz,1H),6.84(dd, J =8.5 and 2.1 Hz,1H),5.55(d, J =3.9Hz,1H), 4.37(AB quartet,. DELTA.v =16.0Hz, J =11.7Hz,2H), 2.25(s,3H),2.08(d, J =2.2Hz, 3H),1.15(d, J =6.2Hz,3H)	107	(4-fluorophenyl) methyl group	621.62	U	622.2
108	(4-methylphenyl) methyl group	617.66	U	618.3		109	(3-fluorophenyl) methyl group	621.62	U	622	7.22(d,J=5.4Hz,1H),7.2-7.16(m,1H)7.16(d,J=8.5Hz,1H).

Implement and apply	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Implement and apply	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)	116	(2-fluorophenyl) methyl group	621.6	U	621.8	7.28-7.19(m,3H),7.17(d, J =8.3Hz,1H),7.01-6.95(m,2H),6.90(d, J =1.9Hz,1H), 6.81(dd, J =8.3 and 1.8Hz,1H),5.54(d, J =4.2Hz,1H),4.48(brs,2H),1.19(d, J =6.5Hz,3H).
117	(4-methoxyphenyl) methyl group	633.7	V	634．2	7.25(s,1H),7.17(d, J =8.5Hz,1H),7.06(d, J =8.5Hz,2H),6.93(d, J =1.9Hz,1H), 6.85(dd, J =8.5 and 2.0Hz,1H), 6.73(d, J =8.5Hz,2H), 5.55(d, J =3.3Hz,1H), 4.35(AB quartet. Δ v =20.5 Hz, J =11.4Hz,2H),1.14(d, J =6.3Hz, 3H).	116	(2-fluorophenyl) methyl group	621.6	U	621.8
117	(4-methoxyphenyl) methyl group	633.7	V	634．2		118	(3-cyanophenyl) methyl group	628.6	W	629.2	7.54(d, J =62Hz,1H),7.46-7.35(m,2H),7.23(s,1H),7.15(d, J =8.3Hz,1H),6.91(d, J =2.1 Hz,1H),6.84(dd, J =8.4 and 1.9Hz,1H), 5.6(d, J =3.7Hz,1H),4.45(AB quartet,. DELTA.v =42.3, J =12.3,2H),1.20(d, J =6.2Hz, 3H).
119	[ (4-trifluoromethyl) phenyl]Methyl radical	671.6	W	672.1	7.47(d, J =8.1Hz,2H),7.33(d, J =8.1Hz,2H), 7.24(s,1H),7.15(d, J =8.3Hz,1H),6.91(d, J =1.9Hz,1H), 6.84(dd, J =8.4 and 1.9Hz,1H),5.59(d, J =3.7Hz,1H), 4.50(AB quartet. Δ v =27.1 Hz, J =12.7Hz,2H), 1.20(d, J =6.5Hz,3H)	118	(3-cyanophenyl) methyl group	628.6	W	629.2
119	[ (4-trifluoromethyl) phenyl]Methyl radical	671.6	W	672.1		120	(4-cyanophenyl) methyl group	628.6	W	629.2	7.52(d, J =8.1Hz, 1H),7.31(d, J =8.1,2H),7.24(s,1H),7.15(d, J =8.5Hz,1H), 6.91(d, J =1.9Hz,1H), 6.83(dd, J =8.5 and 1.9Hz,1H),5.59(d, J =3.7Hz,1H), 4.48(AB quartet, Δ v =32.3Hz, J =13.4Hz,2H),1.21(d, J =6.4Hz,3H).
121	(3-methylphenyl) methyl group	617.6	W	618.3	7.25(s,1H),7.18(d, J =8.5Hz,1H), 7.15-6.95(3m,3H),6.93(d, J =2.1 Hz,1H),6.85(dd, J =8.5 and 2.1 Hz,1H),5.55(d, J =3.5Hz,1H) 4.38(AB quartet, Av =14.1 Hz, J =11.7Hz,2H),2.24(s,3H)1.15(d, J =6.4Hz,3H).	120	(4-cyanophenyl) methyl group	628.6	W	629.2
121	(3-methylphenyl) methyl group	617.6	W	618.3		122	(3, 4-dimethylphenyl) methyl	631.7	W	632.2	7.25(s.1h),7.18(d, J =8.5Hz,1H),6.96-6.93(m,2H),6.87-6.83(m,3H),5.54(d, J =3.3Hz,1H),4.34(AB quartet,. DELTA.v =12.9Hz, J =11.5Hz,2H), 2.17(s,3H),2.15(s,3H),1.13(d, J =6.2Hz, 3H).
123	Phenylaminocarbonyl	632.63	X	633.1	7,35-7.19(2m,5H),7.11(d,J=8.6	122	(3, 4-dimethylphenyl) methyl	631.7	W	632.2

Examples	Y	Molecular weight	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)
Examples	Y	Molecular weight	Preparation method	Mass spectrometry	1HNMR Peak (CD)₃OD)						Hz,1H)6.96(t, J =7.4 Hz,1H)6.91 (d, J =2.1 Hz,1H),6.73(dd, J =8.5 and 2.1 Hz,1H),5.56(d, J =3.5Hz,1H), 1.22(d, J =6.4Hz,3H),
124	3-fluorophenylaminocarbonyl	650.62	X	651.1	7.26-7.20(m,3H),7.15, (d, J =8.5Hz,1H),7.05(dd, J =8.1 and 1.8Hz,1H),6.93(d, J =2.1 Hz,1H),6.76-6.68(m,2H),5.58(d, J =3.5Hz,1H),1.24(d, J =6.4Hz,3H),
124	3-fluorophenylaminocarbonyl	650.62	X	651.1		125	3, 4-Dichloroanilinocarbonyl	701.52	X	701,703	7.62(s,1H),7.33(d, J =8.9Hz, 1H),7.23-7.20(m,2H),7.11(d, J =8.5Hz,1H), 6.92(d, J =2.1 Hz,1H),6.74(dd, J =8.5 and 2.1 Hz,1H),5.56(d, J =3.1 Hz,1H),4.91-4.8(m,1H),1.25(d, J =6.4Hz,3H).
126	4-chlorophenylaminocarbonyl	667.07	X	667.669	7.35-7.32(m,2H),7.20-7.19(m,3H),7.12(d, J =8.5Hz,1H), 6.93(d, J =2.1 Hz,1H),6.75(dd, J =8.5 and 2.1 Hz,1H),5.57(d, J =3.1 Hz,1H),1.24(d, J =6.4Hz,3H).	125	3, 4-Dichloroanilinocarbonyl	701.52	X	701,703
126	4-chlorophenylaminocarbonyl	667.07	X	667.669		127	4-Methoxyphenylaminocarbonyl group	662.65	X	663	7.23-7.21(m,3H),7.13(d,J=8.5Hz,1H),6.93,(d,J=1.9 Hz,1H),6.80-6.76(m,3H),5.58(brs,1H),1.23,(d,J=6.4 Hz,3H).
128	[ (4-fluorophenyl) methyl]Aminocarbonyl group	664.5	Y	665.1	7.24(brs,3H),7.10(d,J=8.3 Hz,1H), 7.00(m,2H),6.6(brs,1H),6.77(br d,J=8.1 Hz,1H),5.52(brs,1H),4.9-4.80(m,1H),1.19(br d,J=6.4Hz,1H).	127	4-Methoxyphenylaminocarbonyl group	662.65	X	663
128	[ (4-fluorophenyl) methyl]Aminocarbonyl group	664.5	Y	665.1		129	(benzyl) aminocarbonyl	646.6	Y	647.2	7.73-7.1(m,6H),7.5(d,J=8.3 Hz1H),6.82(brs,1H),6.66(d,J=8.3,1H),5.50(d,J=5.2 Hz,1H),4.83-4.80(m,1H),1.20(d,J=6.9Hz,3H).
130	[ (3, 4-dichlorophenyl) methyl]Aminocarbonyl group	715.5	Y	715,717	7.39(s,1H),723(s,1H),7.18-7.01(m,3H),6.86(d,J=1.6Hz,1H),6.77-6.72(m,1H),5.52(d,J=2.5Hz,1H),4.85-4.82(m,1H),1.20(d,J=6.5Hz,3H).	129	(benzyl) aminocarbonyl	646.6	Y	647.2
130	[ (3, 4-dichlorophenyl) methyl]Aminocarbonyl group	715.5	Y	715,717		131	[ (4-chlorophenyl) methyl]Aminocarbonyl group	681.1	Y	681.1,683.1	7.3-7.2(m,4H)7.11(d,J=8.5Hz,1H),6.77(d,J=7.7,1H),5.5(br s,1H),4.84-4.80(m,1H),1.19(d,J=6.4Hz).

TABLE 5

Examples	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)
Examples	Y	Molecular weight	Preparation method	Mass spectrometry	Peak 1H NMR (CD)₃OD)	132	Ethoxy radical	581.58	AA	582.2	5.80(bs,1H),5.59(d,J=4.6Hz,1H),4.02(q,J=7.1 Hz,2H),2.04(d,J=1.2 Hz,3H),1.15(t,J=7.1 Hz,3H)
133	Hydroxy radical	553.52	BB	554.1	5.84(bs,1H),5.56(d,J=3.9Hz,1H),1.95(d,J=1.2Hz,3H)	132	Ethoxy radical	581.58	AA	582.2
133	Hydroxy radical	553.52	BB	554.1	5.84(bs,1H),5.56(d,J=3.9Hz,1H),1.95(d,J=1.2Hz,3H)	134	(benzyl) amino	642.67	CC	643.3	7.21(m,5H),5.90(s,1H),5.60(d,J=2.3Hz,1H),4.32(s,2H),1.99(s,3H)
135	[ (3-fluorophenyl) methyl]Amino group	660.66	DD	661.2	7.30(m,1H),7.03(d,J=7.9Hz,1H),6.94(m,2H),5.93(s,1H),5.61(d,J=3.8Hz,1H),4.34(s,2H),2.00(d,J=1.3Hz,3H)	134	(benzyl) amino	642.67	CC	643.3
135	[ (3-fluorophenyl) methyl]Amino group	660.66	DD	661.2		136	Cyclohexylamino group	634.69	EE,L	635.1	5.82(s,1H),5.60(d,J=3.9Hz,1H),3.59(m,1H),1.95(d,J=1.2Hz,3H),1.78(bd,J=11.8 Hz,2H),1.70(bd,J=13.3Hz,2H),1.59(bd,J=12.7Hz,1H),1.31(m,2H),1.14(m,3H)
137	4-pyridylmethylamino	643.65	EE,J	644.3	8.39(m,2H),7.23(m,2H),5.93(bs,1H),5.60(d, J =3.7Hz,1H), 4.36(AB quartet,. DELTA.v =20.3 Hz, J =16.2Hz,2H),1.99(d, J =1.2 Hz,3H)	136	Cyclohexylamino group	634.69	EE,L	635.1

Claims

1. A compound of formula 1:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:

R¹is H, R²is-NR³R⁴,-NR⁴C(O)R³,-OC(O)NR³R⁴OR-OR³；

Each R³Independently 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 from 0 to 5, said alkyl optionally containing 1 or 2 substituents selected from O, -S (O)_j-, where j is an integer of 0 to 2, and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R³Optionally with a benzene ring, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; r mentioned above³Of a group- (CH)₂)_t-the moiety optionally comprises a carbon-carbon double or triple bond, wherein t is an integer between 2 and 5; r mentioned above³Groups, excluding H but including any optional fused rings as described above, optionally substituted with 1-5R⁵Is substituted by radicals, with the proviso that R¹Is H and R²is-OR³When R is³Is not H, methyl or ethyl;

each R⁴Independently is H or C₁-C₁₀An alkyl group;

each R⁵Independently selected from: c₁-C₁₀Alkyl radical, C₃-C₁₀Cycloalkyl, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR⁶,-C(O)R⁵,-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 O, -S (O)_j-, where j is an integer of 0 to 2, and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R⁵Optionally with a group C₆-C₁₀Aryl radical, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; the alkyl, cycloalkyl, aryl and heterocycle R⁵Optionally 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;

each R⁶Independently 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 optionally comprising 1 or 2 substituents selected from O, -S (O)_j-, where j is an integer of 0 to 2, and-N (R)⁷) -with the proviso that two O atoms, two S atoms or O and S atoms are not directly connected to each other; the cycloalkyl, aryl and heterocycle R⁶Optionally with a group C₆-C₁₀Aryl radical, C₅-C₈A saturated cyclic group or a 4-to 10-membered heterocyclic fused group; r mentioned above⁶Substituents, other than H, are optionally substituted with 1-5 substituents independently selected from the group consisting of: halogen, cyano, nitro, trifluoromethyl, difluoromethylOxy, 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;

each R⁷And R⁸Independently is H or C₁-C₆An alkyl group;

2. A compound according to claim 1, wherein R is¹And R²Common constituent = 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, heterocyclyl is optionally fused to a benzene ring, aryl is optionally fused to a 5-or 6-membered heterocyclyl, and the foregoing R³(ii) group, including the optionally fused moiety, optionally substituted with 1-5 substituents independently selected from the group consisting of: 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 R is¹And R²Common constituent = 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, heterocyclyl optionally fused to a benzene ring, aryl optionally fused to a 5 or 6 membered heterocyclyl and the foregoing R³Including said optionally fused moiety, optionally substituted by 1-5Substituted with substituents independently selected from: nitro, halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, trifluoromethyl, acetylamino, tert-butoxycarbonyl, tert-butoxycarbonylamino, -NR⁶R⁷Phenyl, cyclohexyl, carboxyl, tert-butoxycarbonylaminomethyl, aminomethyl, difluoromethoxy, trifluoromethoxy, cyano, piperidinyl, morpholino, phenoxy and thiophenyl.

4. A compound according to claim 1, wherein R is¹Is H, R²is-NR³R⁴,R⁴Is H or methyl, R³Is- (CH)₂)_t(C₆-C₁₀Aryl) or- (CH)₂)_t(4-10 membered heterocycle), wherein t is an integer of 0-2, and R³Optionally substituted by 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl and trifluoromethyl.

5. A compound according to claim 1, wherein R is¹Is H, R²is-NR⁴C(O)R³,R⁴Is H, R³Is C₃-C₆Cycloalkyl, - (CH)₂)_t(C₆-C₁₀Aryl) or- (CH)₂) t (4-10 membered heterocycle), wherein t is an integer of 0-2, aryl optionally fused to a 5 or 6 membered heterocyclyl optionally fused to a benzene ring and the foregoing R³Optionally substituted, with 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl and trifluoromethyl.

6. A compound according to claim 1, wherein R is¹And R²Common composition = CR⁴C(O)OR³Or = CR⁴C(O)NR³R⁴,R⁴Is H, 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, aryl optionally fused to a 5 or 6 membered heterocyclyl optionally fused to a phenyl ring and the foregoing R³And (C) a group, excluding H but including said optionally fused moiety, optionally substituted with 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, -NR⁶R⁷And trifluoromethyl.

7. A compound according to claim 1, 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 from 1 to 2, aryl optionally fused to a 5 or 6 membered heterocyclyl optionally fused to a phenyl ring and the foregoing R³Optionally substituted, with 1-5 substituents independently selected from halogen, C₁-C₃Alkoxy radical, C₁-C₄Alkyl, cyclohexyl, cyano, trifluoromethyl, benzyloxy, and trifluoromethyl.

8. A compound according to claim 1, wherein R is¹Is H, R²is-OC (O) NR³R⁴,R⁴Is H, R³Is- (CH)₂)_t(C₆-C₁₀Aryl) group, wherein t is an integer of 0 to 2 and R³Optionally substituted by 1-5 substituents 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- [ (5-methyl- β -D-arabino-hept-5- (E) -enesuranuronan-1-yl 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- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -O-propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-methylphenyl) methyl ] oxime;

5-deoxy-5- [ [3- [4- [ (6-deoxy-5-O- [ (4-chlorophenyl) methyl ] - β -D-altrose-form-furanose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol;

5-deoxy-5- [ [3- [4- [ (6-deoxy- β -D-arabino-hexofuran-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- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -O-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- [ (6-deoxy- β -D-arabino-hexofuran-5-ulose-1-yl) oxy ] -3-hydroxyphenyl ] -2-methyl-1-oxo-2- (E) -propenyl ] amino ] -1, 2-O-methylene-D-neoinositol, (E) -O- [ (4-phenyl-furan-3-yl) methyl ] oxime;

and pharmaceutically acceptable salts and solvates of said compounds.

10. The compound according to claim 1, wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts and solvates of said compounds.

11. 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 1 and a pharmaceutically acceptable carrier.

12. 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.

13. A process for the preparation of a composition comprising hygromycin a and epihygromycin, wherein the ratio of hygromycin a to epihygromycin is at least 10: 1, which comprises fermenting streptomyces hygroscopicus in a medium having a pH of less than 6.9 at a temperature in the range of 25 ℃ to 35 ℃.

14. The process according to claim 12, wherein said S.hygroscopicus is S.hygroscopicus NRRL2388 or a mutant thereof, said pH ranges from 6.2 to 6.7, said temperature is about 29 ℃, and the ratio of hygromycin A to epihygromycin is at least 14: 1.

15. The method of claim 12, further comprising maintaining said composition at about ph6.0-6.4 and maintaining the temperature of said composition in the range of 25 ℃ to 35 ℃ during the purification of said hygromycin a to oil.

16. The method of claim 14, wherein the pH is maintained at about 6.0.

17. Wherein R is¹And R²Common constituent = N-OR³A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula H₂N-OR³Of hygromycin A, or a salt of said compound, when R is³The reaction is carried out in an inert solvent, optionally in the presence of a base, as defined above, at a temperature ranging from about 0 ℃ to 65 ℃, if a salt of hydroxylamine is used.

18. The process of claim 17, wherein the inert solvent is methanol, ethanol or pyridine, or a mixture of the foregoing solvents, the base is Na₂CO₃Or K₂CO₃And said temperature range is from 0 ℃ to 25 ℃.