• 专利附录
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    • 专利摘要:
    Compounds of formulae (XI), (XII), (XIV), (XV) and (XVI), as well as amidederivatives of compounds of formula (XIII), described herein, can be obtained fromthe cultivation products of a strain of micro-organism of the genus Streptomyces. Thecompounds are useful as medicaments in the treatment and prevention of bacterialinfections.
    公开号:EP1319666A1
    申请号:EP03004404
    申请日:1999-07-09
    公开日:2003-06-18
    发明作者:Inukai Masatoshi；Kaneko Masakatsu；Takatsu Toshio；Hotoda Hitoshi；Arai Masatoshi；Miyakoshi Shunichi；Kizuka Masaaki；Ogawa Yasumasa
    申请人:Sankyo Co Ltd；
    IPC主号:C07H19-00
    专利说明:
    [0001] The present invention relates to a compound of formula (I), (XI), (XII), (XIII),(XIV), (XV) or (XVI) and a derivative of a compound of formula (Ia) which haveexcellent antibiotic activity or a pharmaceutically acceptable salt thereof.
    [0002] The present invention is also a pharmaceutical composition comprising acompound described above as an active ingredient effective to treat or preventinfectious diseases.
    [0003] The present invention includes a use of a compound described above in order toprepare a medicament effective to treat or prevent infectious diseases.
    [0004] The present invention is concerned with a method effective to treat or preventinfectious diseases in warm-blooded animals comprising administering apharmacologically effective amount of a compound described above to them.
    [0005] The present invention includes a microorganism capable of producing a compoundof formula (I), (XI), (XII), (XIV), (XV) or (XVI).
    [0006] The present invention also includes a process for preparing a compound of formula(I), (XI), (XII), (XIV), (XV) or (XVI) using the said microorganism. [Background of the invention]
    [0007] A β-lactam antibiotic, an amino-glycoside, isoniazid or rifampicin has beenconventionally used in treatment or prophylaxis of microbial infections includingtubercule bacillus. Recently there have been a lot of bacteria resistant to theseantibiotics. It is desirable to develop new compounds which are different typeantimicrobial agents from conventional ones.
    [0008] On the other hand it has been known that capuramycin having a formula shownbelow exhibits anti-tubercule bacillus activity (J. Antibiotics, 29, (8), 1047-1053(1986)).
    [0009] We found new compounds of formula (I), (XI), (XII), (XIV), (XV) or (XVI),which do not show any cross resistance to conventional medicaments, in thecultivation products of a microorganism. We prepared the derivatives of compoundsdescribed above and capuramycin. We studied the physiological activity of thesederivatives for several years and found that these derivatives exhibit excellentantibiotic activity.
    [0010] The compounds of the present invention can provide a method effective to treatand prevent infection diseases including ones arising from bacteria resistant to theconventional antibiotics. Compounds of formula (I), (XI), (XII), (XIV), (XV) or(XVI) are also useful starting materials for preparation of the compounds of thepresent invention having excellent antibiotic activity. [Disclosure of the invention]
    [0011] The present invention includes a compound of formula (I)
    [0012] The present invention is also a pharmaceutical composition comprising acompound described above as an active ingredient effective to treat or preventinfectious diseases.
    [0013] The present invention includes the use of a compound described above in order toprepare a medicament effective to treat or prevent infectious diseases.
    [0014] The present invention is concerned with a method effective to treat or preventinfectious diseases in warm-blooded animals comprising administering apharmacologically effective amount of a compound described above to them.
    [0015] The present invention includes a microorganism capable of producing a compound offormula (I).
    [0016] The present invention also includes a process for preparing a compound of formula (I)using the said microorganism.
    [0017] In the above formulae, the protecting group of "protecting group for a hydroxy group"and "protected hydroxy group" of R2 a and the like can be removed by a chemicalprocedure such as hydrogenolysis, hydrolysis, electrolysis or photolysis (hereinafterreferred to as a general protecting group) or can be removed by biological method such ashydrolysis in vivo (with the proviso that it is not an ester residue group such as an acylgroup). "The protecting group which can be removed by biological method such ashydrolysis in vivo" can be cleaved by biologically method such as hydrolysis in thehuman body to give a corresponding free acid or a salt thereof. Whether a compound hasa protecting group removed in vivo is determined by detection of a corresponding parentcompound or a pharmaceutically acceptable salt thereof in the body fluid of a rat ormouse to which it is administered by intravenous injection.
    [0018] A general protecting group is selected from the group consisting of: "tetrahydropyranyl and tetrahydrothiopyranyl group" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yland 4-methoxytetrahydrothiopyran-4-yl; "tetrahydrofuranyl and tetrahydrothiofuranyl group" such as tetrahydrofuran-2-yl andtetrahydrothiofuran-2-yl; "tri(lower alkyl)silyl group (hereinafter a lower alkyl moiety represents a groupselected from the group consisting of C1 - C6 alkyl group such as the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl group) such as thetrimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl,diisopropylmethylsilyl, di(tert-butyl)methylsilyl and triisopropylsilyl group; "silyl group substituted with one or two aryl groups and two or one lower alkylgroups" such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, anddiisopropylphenylsilyl; "lower alkoxymethyl group" (hereinafter an alkoxy moiety represents a group selectedfrom the group consisting of C1 - C6 alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy), such asmethoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl, butoxymethyl and tert-butoxymethyl; "lower alkoxy-lower alkoxylmethyl group" such as the 2-methoxyethoxymethylgroup: "halogeno-lower-alkoxymethyl group" such as the 2.2.2-trichloroethoxymethyl andbis(2-chloroethoxy)methyl group; "substituted ethyl group", for example an ethyl group substituted with a lower alkoxygroup such as the 1-ethoxyethyl or 1-(isopropoxy)ethyl group, and for example ahalogenoethyl group such as the 2,2,2-trichloroethyl group; "aralkyl group" (aryl moiety is selected from the group consisting of C6 - C14 arylgroup such as phenyl, naphthyl, biphenyl, anthryl and phenanthryl group), for example alower alkyl group substituted with 1 to 3 aryl groups such as benzyl, α-naphthyl, β-naphthyl,diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl,and for example a lower alkyl group substituted with 1 to 3 aryl groups,which are substituted with lower alkyl, lower alkoxy, nitro, halogen or cyano group, suchas the 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyland 4-cyanobenzyl group; "alkoxycarbonyl group", for example lower alkoxycarbonyl group such asmethoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and isobutoxycarbonyl, and forexample lower alkoxycarbonyl group substituted with halogen or tri(lower alkyl)silylgroup such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; "alkenyloxycarbonyl group" (said alkenyl moiety is a C2 - C6 alkenyl group) such asthe vinyloxycarbonyl and allyloxycarbonyl group; and "aralkyloxycarbonyl group in which the aryl ring is optionally substituted with one ortwo lower alkoxy or nitro groups" such as the benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyland 4-nitrobenzyloxycarbonyl group.
    [0019] A preferable "general protecting group of hydroxy group" is the tetrahydropyranyl.tetrahydrothiopyranyl, silyl, aralkyl or aralkyloxycarbonyl group.
    [0020] A more preferable "general protecting group of hydroxy group" is thetetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, di(tert-butyl)methylsilyl,diphenylmethylsilyl, benzyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl, 4-methoxybenzyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitrobenzyloxycarbonyl or 4-nitrobenzyloxycarbonylgroup.
    [0021] A most preferable "general protecting group of hydroxy group" is thetrimethylsilyl, tert-butyldimethylsilyl, triphenylmethyl, benzyl or 4-methoxybenzylgroup.
    [0022] A hydroxy protecting group which can be removed by biological method such ashydrolysis in vivo is selected from the group consisting of   "1-aliphatic acyloxy - lower alkyl group" (hereinafter, acyl moiety is selected fromthe group consisting of C1 - C10 straight or branched chain alkanoyl group) such asformyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl,isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl,1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl,1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl,1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl,1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl,1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,1-pivaloyloxypentyl and 1-pivaloyloxyhexyl;   "1-(aliphatic-acylthio)-(lower alkyl)group" such as formylthiomethyl,acetylthiomethyl, dimethylaminoacetylthiomethyl, propionylthiomethyl,butyrylthiomethyl, pivaloylthiomethyl, valerylthiomethyl, isovalerylthiomethyl,hexanoylthiomethyl, 1-formylthioethyl, 1-acetylthioethyl, 1-propionylthioethyl, 1-butyrylthioethyl,1-pivaloylthioethyl, 1-valerylthioethyl, 1-isovalerylthioethyl, 1-hexanoylthioethyl,1-formylthiopropyl, 1-acetylthiopropyl, 1-propionylthiopropyl, 1-butyrylthiopropyl,1-pivaloylthiopropyl, 1-valerylthiopropyl, 1-isovalerylthiopropyl, 1-hexanoylthiopropyl, 1-acetylthiobutyl, 1-propionylthiobutyl, 1-butyrylthiobutyl, 1-pivaloylthiobutyl,1-acetylthiopentyl, 1-propionylthiopentyl, 1-butyrylthiopentyl, 1-pivaloylthiopentyland 1-pivaloylthiohexyl;   "1-(cycloalkylcarbonyloxy)-(lower alkyl) group" such as thecyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl,1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyland 1-cyclohexylcarbonyloxybutyl group;   "(1-aromatic acyloxy)-(lower alkyl) group (the aromatic acyl moiety is selectedfrom the group consisting of C6 - C10 arylcarbonyl groups)" such as thebenzoyloxymethyl group;   "1-(lower alkoxycarbonyloxy)-(lower alkyl) group" such asmethoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl,hexyloxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl,1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl,1-(tert-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl,1-(hexyloxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl,1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl,1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl,1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl,1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl,1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl,1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl,1-(iosobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl,1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyland 1-(ethoxycarbonyloxy)hexyl;   "1-(cycloalkyloxycarbonyloxy)-(lower alkyl) group" such ascyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl,1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl,1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclopentyloxycarbonyloxy)pentyl, 1-(cyclohexyloxycarbonyloxy)pentyl, 1-(cyclopentyloxycarbonyloxy)hexyland 1-(cyclohexyloxycarbonyloxy)hexyl;   "phthalidyl group" such as the phthalidyl, dimethylphthalidyl anddimethoxyphthalidyl group;   "oxodioxolenylmethyl group" such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyland (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl;   "carbamoyl group";   "carbamoyl group substituted with one or two lower alkyl groups";   "lower alkyl-dithioethyl group" such as methyldithioethyl, ethyldithioethyl,propyldithioethyl, butyldithioethyl, pentyldithioethyl and hexyldithioethyl group; and   "1-(acyloxy)alkyloxycarbonyl group" such as the pivaloyloxymethyloxycarbonylgroup.
    [0023] A preferable "hydroxy protecting group which can be removed by biologicalmethod such as hydrolysis in vivo" is selected from the group consisting of a 1-(aliphaticacyloxy)-(lower alkyl) group, a 1-(cycloalkylcarbonyloxy)-(lower alkyl)group, a 1-(lower alkoxycarbonyloxy)-(lower alkyl) group, a 1-(cycloalkyloxycarbonyloxy)-(loweralkyl) group, a phthalidyl and anoxodioxolenylmethyl group.
    [0024] A more preferable "hydroxy protecting group which can be removed by biologicalmethod such as hydrolysis in vivo" is selected from the group consisting ofacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl,valeryloxymethyl, 1-acetoxyethyl, butyryloxyethyl, 1-pivaloyloxyethyl,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,1-cyclohexylcarbonyloxyethyl,methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)ethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,1-(cyclohexyloxycarbonyloxy)ethyl, phthalidyl,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methylgroup.
    [0025] A most preferable "hydroxy protecting group which can be removed by biologicalmethod such as hydrolysis in vivo" is selected from the group consisting ofacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl,valeryloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl,methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl,cyclohexyloxycarbonyloxymethyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyland (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
    [0026] The term "pharmaceutically acceptable ester, ether and N-alkylcarbamoylderivatives" refers to a derivative that is a useful medicament without significanttoxicity.
    [0027] The ester residue of ester derivatives is selected from the group consisting of   "carbonyl and oxycarbonyl group to which a straight or branched chain C1 - C21alkyl group is attached", in which said alkyl group is selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl,3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl,1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl,4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl,decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl,tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl. 13,13-dimethyltetradecyl, heptadecyl. 15-methylhexadecyl,octadecyl, 1-methylheptadecyl, nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyland henicosyl groups;   "carbonyl and oxycarbonyl group to which a straight or branched chain C2 - C21alkenyl or alkynyl group is attached", in which said alkenyl or alkynyl group is selectedfrom the group consisting of ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,2-methyl-1-propenyl, 2-methyl-2-propenyl. 2-ethyl-2-propenyl, 1-butenyl.2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl,3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl.2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl. 3-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl,cis, cis, cis-8,11,14-heptadecatrienyl, cis-10-nonadecenyl, and cis-12-icosenyl;   "carbonyl and oxycarbonyl group to which a straight or branched chain C2 - C21alkenyl or alkynyl group is attached", in which said alkenyl or alkynyl group is selectedfrom the group consisting of ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl.2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl,3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl,2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl,2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl;   "carbonyl and oxycarbonyl group to which straight or branched chain C1 - C21 alkylgroup which has one or more substituents selected from the group consisting of loweralkoxy, halogen (hereinafter for example fluorine, chlorine, bromine and iodine,preferably fluorine and chlorine) and nitro groups is attached", in which said substitutedalkyl group is selected from the group consisting of methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl, trifluoromethyl, trichloromethyl, difluoromethyl,dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl,2,2-dibromoethyl, nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyl and1,2-dinitroethyl;   "carbonyl and oxycarbonyl group to which a (C6- C10 aryl)-(C1 - C21) alkyl groupwherein said aryl moiety optionally has one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halo and nitro groups is attached", inwhich said arylalkyl group is selected from the group consisting of benzyl, α-naphthylmethyl,β-naphthylmethyl, indenylmethyl, phenanthrenylmethyl,anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl,2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl,2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl,4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl,1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl,1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl,5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl,5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl,4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl;   "carbonyl and oxycarbonyl group to which a C6- C10 aryl group which optionallyhas one or more substituents selected from the group consisting of lower alkyl, loweralkoxy, halo and nitro groups is attached", in which said aryl group is selected fromthe group consisting of phenyl, naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,2,4-difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl,2,4-dichlorophenyl, 2,3,6-trifluorophenyl, 2,3,4-trifluorophenyl,3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl,2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl,2,4,6-trichlorophenyl, 1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl,1-chloro-2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naphthyl, 3,8-difluoro-1-naphthyl,2,3-difluoro-1-naphthyl, 4,8-difluoro-1-naphthyl, 5,6-difluoro-1-naphthyl,3,8-dichloro-1-naphthyl, 2,3-dichloro-1-naphthyl, 4,8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl,2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl, 3,4,5-trifluoro-1-naphthyl,4,5,6-trifluoro-1-naphthyl, 2,4,8-trifluoro-1-naphthyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl,2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl,2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl,2,6-dipropylmethylphenyl, 2,4-dipropylphenyl, 2,3,6-trimethylphenyl,2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,3,6-tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl,2,5,6-tripropylmethylphenyl, 2,4,6-tripropylphenyl, 1-methyl-2-naphthyl,2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-ethyl-2-naphthyl, 2-propyl-1-naphthyl,3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl,5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl, 2,3-dipropyl-1-naphthyl,4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-trimethyl-1-naphthyl,2,3,4-trimethyl-1-naphthyl, 3,4,5-trimethyl-1-naphthyl, 4,5,6-trimethyl-1-naphthyl,2,4,8-trimethyl-1-naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl, 2-butoxyphenyl,3-pentyloxyphenyl, 4-pentyloxyphenyl, 3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl,2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentyloxyphenyl,2,6-dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl, 2,3,6-trimethoxyphenyl,2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,5,6-trimethoxyphenyl,2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2,3,4-tripentyloxyphenyl,3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,4,6-tripropoxyphenyl,1-methoxy-2-naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl,1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1-naphthyl,2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl, 5,6-dimethoxy-1-naphthyl,3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-naphthyl, 4,8-dipentyloxy-1-naphthyl,5,6-dibutoxy-1-naphthyl, 2,3,6-trimethoxy-1-naphthyl, 2,3,4-trimethoxy-1-naphthyl,3,4,5-trimethoxy-1-naphthyl, 4,5,6-trimethoxy-1-naphthyl,2,4,8-trimethoxy-1-naphthyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-dinitrophenyl,2,5-dinitrophenyl, 2,6-dinitrophenyl, 2,4-dinitrophenyl, 2,3,6-trinitrophenyl,2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl, 2,5,6-trinitrophenyl, 2,4,6-trinitrophenyl,1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-naphthyl, 3,8-dinitro-1-naphthyl,2,3-dinitro-1-naphthyl, 4,8-dinitro-1-naphthyl, 5,6-dinitro-1-naphthyl,2,3,6-trinitro-1-naphthyl, 2,3,4-trinitro-1-naphthyl, 3,4,5-trinitro-1-naphthyl, 4,5,6-trinitro-1-naphthyland 2,4,8-trinitro-1-naphthyl;   "carboxy (C1 - C10)alkylcarbonyl group" such as succinoyl,glutaroyl, and adipoyl;   "residue of salt of a phosphate diester which independently has two lower alkylgroups"; and    "residue forming ester of amino acid which is optionally protected with a tert-butyloxycarbonyl,benzyloxycarbonyl or trityl group" such as glycine, alanine. valine.leucine, isoleucine, phenylalanine, proline, tryptophan, glutamine and glutamic acid.
    [0028] A preferable ester residue of ester derivatives is R6CO- or R6OCO- group wherein R6is selected from the group consisting of hydrogen: a C1 - C21 alkyl group: a C2 - C21alkenyl or alkynyl group having 1 to 3 double or triple bonds; a C1 - C21 alkyl groupsubstituted with 1 to 4 substituents selected from the group consisting of lower alkoxy,halo and nitro groups; a C1 - C21 alkyl group substituted with 1 to 3 C6 - C10 aryl groupswhich are optionally substituted with 1 to 4 substituents selected from the groupconsisting of lower alkyl, lower alkoxy, halo and nitro groups; and a C6 - C10 aryl groupwhich is optionally substituted with 1 to 4 substituents selected from the group consistingof lower alkyl, lower alkoxy, halo, and nitro groups.
    [0029] A more preferable ester residue of ester derivatives is R6CO- or R6OCO- groupwherein R6 is selected from the group consisting of hydrogen; a C1 - C21 alkyl group; a C2- C21 alkenyl group having 1 to 3 double bonds; a C2 - C6 alkynyl group having one triplebond; a C1 - C6 alkyl group substituted with 1 to 4 substituents selected from the groupconsisting of C1 - C4 alkoxy, halo and nitro groups; a C1 - C6 alkyl group substituted with1 to 3 C6 - C10 aryl groups which are optionally substituted with 1 to 3 substituentsselected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups;and a C6 - C10 aryl group which is optionally substituted with 1 to 3 substituents selectedfrom the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups.
    [0030] A more preferable ester residue of ester derivatives is R6CO- or R6OCO- groupwherein R6 is selected from the group consisting of a C1 - C21 alkyl group; a C6 - C20alkenyl group having 1 to 3 double bonds; a C2 - C6 alkynyl group having one triplebond; a C1 - C6 alkyl group substituted with one substituent selected from the groupconsisting of C1 - C4 alkoxy and nitro groups: a C1 - C6 alkyl group substituted with 1 to 3substituents selected from the group consisting of halogen; a C1 - C4 alkyl groupsubstituted with 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, haloand nitro groups; and a phenyl or naphthyl group which is optionally substituted with 1 to3 substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, haloand nitro groups.
    [0031] A more preferable ester residue of ester derivatives is R6CO- or R6OCO- groupwherein R6 is selected from the group consisting of a C6 - C20 alkyl group; a C10 - C20alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl group having one triplebond; a C1 - C4 alkyl group substituted with one substituent selected from the groupconsisting of C1 - C4 alkoxy and nitro groups; a C1 - C4 alkyl group substituted with 1to 3 substituents selected from the group consisting of fluoro and chloro groups; a C1 -C4 alkyl group substituted with 1 to 3 phenyl groups which are optionally substitutedwith 1 or 2 substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4alkoxy, fluoro and chloro groups; and a phenyl group which is optionally substitutedwith 1 to 3 substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4alkoxy, fluoro and chloro groups.
    [0032] A more preferable ester residue of ester derivatives is R6CO- or R6OCO- groupwherein R6 is selected from the group consisting of a C6 - C20 alkyl group; a C10 - C20alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl group having one triplebond; a C1 - C4 alkyl group substituted with one substituent selected from the groupconsisting of C1 - C4 alkoxy, fluoro, chloro and nitro groups; a C1 - C4 alkyl groupsubstituted with 1 to 3 phenyl groups which are optionally substituted with 1 or 2substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoroand chloro groups; and a phenyl group which is optionally substituted with 1 to 3substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoroand chloro groups.
    [0033] A still more preferable ester residue of ester derivatives is R6CO- or R6OCO-groupwherein R6 is selected from the group consisting of a C6 - C20 alkyl group; a C10- C20 alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl group having onetriple bond; a C1 - C4 alkyl group substituted with one substituent selected from thegroup consisting of C1 - C4 alkoxy groups; and a C1 - C4 alkyl group substituted with1 or 2 phenyl groups which are optionally substituted with 1 or 2 substituents selectedfrom the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups.
    [0034] A most preferable ester residue of ester derivatives is R6CO- or R6OCO- groupwherein R6 is selected from the group consisting of a C6 - C20 alkyl group and a C10 -C20 alkenyl group having 1 to 3 double bonds.
    [0035] An ether residue of ether derivatives is selected from the group consisting of    "straight or branched chain C1 - C21 alkyl group" such as the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl,neopentyl, 1-ethylpropyl, hexyl, isohexyl. 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1.3-dimethylbutyl. 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl.2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl.4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl. 5,5-dimethylhexyl,nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl,2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl,3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl,dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl,hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl. 13,13-dimethyltetradecyl,heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl,nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl and henicosyl groups;   "straight or branched chain C2 - C21 alkenyl or alkynyl group" such as ethenyl, 1-propenyl,2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl,3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl, cis, cis, cis-8,11,14-heptadecatrienyl,cis-10-nonadecenyl, cis-12-icosenyl, ethynyl, 2-propynyl, 1-methyl-2-propynyl,2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl,1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl,2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl;   "straight or branched chain C1 - C21 alkyl group which has one or more substituentsselected from the group consisting of lower alkoxy, halogen (hereinafter for examplefluorine, chlorine, bromine and iodine, preferably fluorine and chlorine) and nitro groups" such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl.trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl,2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl,nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyl and 1,2-dinitroethyl;   "(C6 - C10)aryl-(C1 - C21)alkyl group wherein said aryl moiety optionally has oneor more substituents selected from the group consisting of lower alkyl, lower alkoxy,halo and nitro group" such as benzyl, α-naphthylmethyl, β-naphthylmethyl,indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl,triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl,3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl,2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl,3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl,3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl,2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl,2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyland 6-naphthylhexyl; and   "C6 - C10 aryl group which optionally has one or more substituents selected fromthe group consisting of lower alkyl, lower alkoxy, halo and nitro groups" such asphenyl, naphthyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl,2,5-dibromophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl,2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl,2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl,2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl, 1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl,3-fluoro-1-naphthyl, 1-chloro-2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naphthyl,3,8-difluoro-1-naphthyl, 2,3-difluoro-1-naphthyl, 4,8-difluoro-1-naphthyl,5,6-difluoro-1-naphthyl, 3,8-dichloro-1-naphthyl, 2,3-dichloro-1-naphthyl,4,8-dibromo-1-naphthyl, 5,6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl,3,4,5-trifluoro-1-naphthyl, 4,5,6-trifluoro-1-naphthyl, 2,4,8-trifluoro-1-naphthyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl,3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl,3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dipropylmethylphenyl,2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl,2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,3,6-tributylphenyl,2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylmethylphenyl, 2,4,6-tripropylphenyl,1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-ethyl-2-naphthyl,2-propyl-1-naphthyl, 3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl,2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl,2,3-dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl,2,3,6-trimethyl-1-naphthyl, 2,3,4-trimethyl-1-naphthyl, 3,4,5-trimethyl-1-naphthyl,4,5,6-trimethyl-1-naphthyl, 2,4,8-trimethyl-1-naphthyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl,2-butoxyphenyl, 3-pentoxyphenyl, 4-pentyloxyphenyl, 3,5-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl,3,5-dibutoxyphenyl, 2,5-dipentyloxyphenyl, 2,6-dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl,2,3,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl,2,5,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl,2,3,4-tripentyloxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl,2,4,6-tripropoxyphenyl, 1-methoxy-2-naphthyl, 2-methoxy-1-naphthyl,3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl,3,8-dimethoxy-1-naphthyl, 2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl,5,6-dimethoxy-1-naphthyl, 3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-naphthyl,4,8-dipentyloxy-1-naphthyl, 5,6-dibutoxy-1-naphthyl, 2,3,6-trimethoxy-1-naphthyl,2,3,4-trimethoxy-1-naphthyl, 3,4,5-trimethoxy-1-naphthyl,4,5,6-trimethoxy-1-naphthyl, 2,4,8-trimethoxy-1-naphthyl, 2-nitrophenyl, 3-nitrophenyl,4-nitrophenyl, 3,5-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl,2,4-dinitrophenyl, 2,3,6-trinitrophenyl, 2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl,2,5,6-trinitrophenyl, 2,4,6-trinitrophenyl, 1-nitro-2-naphthyl, 2-nitro-1-naphthyl, 3-nitro-1-naphthyl,3,8-dinitro-1-naphthyl, 2,3-dinitro-1-naphthyl, 4,8-dinitro-1-naphthyl,5,6-dinitro-1-naphthyl, 2,3,6-trinitro-1-naphthyl, 2,3,4-trinitro-1-naphthyl,3,4,5-trinitro-1-naphthyl, 4,5,6-trinitro-1-naphthyl and 2,4,8-trinitro- 1-naphthyl. A preferable ether residue of ether derivatives is selected from the group consisting of aC1 - C21 alkyl group; a C2 - C21 alkenyl or alkynyl group having 1 to 3 double or triplebonds; a C1 - C21 alkyl group which has I to 4 substituents selected from the groupconsisting of lower alkoxy, halo and nitro groups; a C1 - C21 alkyl group which has I to 3C6- C10 aryl groups which are optionally substituted with I to 4 substituents selectedfrom the group consisting of lower alkyl, lower alkoxy, halo and nitro groups: and a C6 -C10 aryl group which is optionally substituted with 1 to 4 substituents selected from thegroup consisting of lower alkyl, lower alkoxy, halo and nitro groups.
    [0036] A more preferable ether residue of ether derivatives is selected from the groupconsisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl group having 1 to 3 double bonds;a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl group which has 1 to 4substituents selected from the group consisting of C1 - C4 alkoxy, halogen and nitrogroups; a C1 - C6 alkyl group which has 1 to 3 C6 - C10 aryl groups which are optionallysubstituted with 1 to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1- C4 alkoxy, halo and nitro groups; and a C6 - C10 aryl group which is optionallysubstituted with 1 to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1- C4 alkoxy, halo and nitro groups.
    [0037] A more preferable ether residue of ether derivatives is selected from the groupconsisting of a C1 - C21 alkyl group; a C6 - C20 alkenyl group having 1 to 3 double bonds;a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl group which has onesubstituent selected from the group consisting of C1 - C4 alkoxy and nitro groups; a C1 -C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halogroups; a C1 - C4 alkyl group which has 1 to 3 phenyl or naphthyl groups which areoptionally substituted with 1 to 3 substituents selected from the group consisting of C1 -C4 alkyl, C1 - C4 alkoxy, halo and nitro groups; and a phenyl or naphthyl group which isoptionally substituted with 1 to 3 substituents selected from the group consisting of C1 -C4 alkyl, C1 - C4 alkoxy, halo and nitro groups.
    [0038] A more preferable ether residue of ether derivatives is selected from the groupconsisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3 double bonds;a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl group which has onesubstituent selected from the group consisting of C1 - C4 alkoxy and nitro group; a C1 - C4alkyl group which has 1 to 3 substituents selected from the group consisting of fluoro and chloro groups; a C1 - C4 alkyl group which has 1 to 3 phenylgroups which are optionally substituted with 1 or 2 substituents selected from thegroup consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro group; and aphenyl group which is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups.
    [0039] A more preferable ether residue of ether derivatives is selected from the groupconsisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3 doublebonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl group whichhas one substituent selected from the group consisting of C1 - C4 alkoxy, fluoro,chloro and nitro groups; a C1 - C4 alkyl group which has 1 to 3 phenyl groups whichare optionally substituted with 1 or 2 substituents selected from the group consistingof C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups; and a phenyl group whichis optionally substituted with 1 to 3 substituents selected from the group consisting ofC1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups.
    [0040] A still more preferable ether residue of ether derivative is selected from the groupconsisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3 doublebonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl group whichhas one substituent selected from the group consisting of C1 - C4 alkoxy groups; and aC1 - C4 alkyl group which has 1 or 2 phenyl groups optionally substituted with 1 or 2substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoroand chloro groups.
    [0041] A most preferable ether residue of ether derivatives is selected from the groupconsisting of a C6 - C20 alkyl group and a C10 - C20 alkenyl group having 1 to 3 doublebonds.
    [0042] An alkyl residue of N-alkylcarbamoyl derivatives is selected from the groupconsisting of   "straight or branched chain C1 - C21 alkyl group" such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl,neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl,4-methylheptyl, 5-methylheptyl. 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl,5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl.8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl.4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl.hexadecyl. 4,8,12-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl,heptadecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl,nonadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl and henicosyl groups:   "straight or branched chain C2 - C21 alkenyl or alkynyl group" such as ethenyl, 1-propenyl.2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl,3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl,2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,cis-8-heptadecenyl, cis, cis-8,11-heptadecadienyl, cis, cis, cis-8,11,14-heptadecatrienyl,cis-10-nonadecenyl, cis-12-icosenyl, ethynyl, 2-propynyl, 1-methyl-2-propynyl,2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, I -methyl-2-butynyl, 2-methyl-2-butynyl,1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl,2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl,2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl;   "straight or branched chain C1 - C21 alkyl group which has substituents selected fromthe group consisting of alkoxy, halogen (hereinafter example fluorine, chlorine, bromineand iodine, preferably fluorine and chlorine) and nitro" such as methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl, trifluoromethyl, trichloromethyl,difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl,6-iodohexyl, 2,2-dibromoethyl, nitromethyl, dinitromethyl, 1-nitroethyl, 2-nitroethyland 1,2-dinitroethyl; and    "(C6 - C10)aryl-(C1 - C21)alkyl group wherein said aryl moiety optionally has substituentselected from the group consisting of lower alkyl, lower alkoxy, halogen and nitrogroups" such as benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl.phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl,2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl. 3-phenylpropyl,1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl,3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl,4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl. 4-phenylpentyl,5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl. 4-naphthylpentyl,5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl. 3-phenylhexyl, 4-phenylhexyl,5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl,4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl.
    [0043] A preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from the groupconsisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl or alkynyl group having 1 to 3double or triple bonds; a C1 - C21 alkyl group which has one or more substituents selectedfrom the group consisting of lower alkoxy, halo and nitro groups; and a C1 - C21 alkylgroup which has 1 to 3 C6 - C10 aryl groups which are optionally substituted with 1 to 4substituents selected from the group consisting of lower alkyl, lower alkoxy, halo andnitro groups.
    [0044] A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from thegroup consisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl group having 1 to 3 doublebonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl group which has 1to 4 substituents selected from the group consisting of C1 - C4 alkoxy, halogen and nitrogroups; and a C1 - C6 alkyl group which has I to 3 C6- C10 aryl groups which areoptionally substituted with 1 to 3 substituents selected from the group consisting of C1 -C4 alkyl, C1 - C4 alkoxy, halo and nitro groups.
    [0045] A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected from thegroup consisting of a C1 - C21 alkyl group; a C6 - C20 alkenyl group having 1 to 3 doublebonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl group which hasone substituent selected from the group consisting of C1 - C4 alkoxy and nitro groups; aC1 - C6 alkyl group which has 1 to 3 substituents selected from the group consisting of halo group; and a C1 - C4 alkyl group which has 1 to 3 phenyl ornaphthyl groups which are optionally substituted with 1 to 3 substituents selectedfrom the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups.
    [0046] A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected fromthe group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy andnitro groups; a C1 - C4 alkyl group which has 1 to 3 substituents selected from thegroup consisting of fluoro and chloro groups; and a C1 - C4 alkyl group which has 1 to3 phenyl groups which are optionally substituted with 1 to 2 substituents selectedfrom the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups.
    [0047] A more preferable alkyl residue of N-alkylcarbamoyl derivatives is selected fromthe group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy,fluoro, chloro and nitro groups; and a C1 - C4 alkyl group which has 1 to 3 phenylgroups which are optionally substituted with 1 to 2 substituents selected from thegroup consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups.
    [0048] A still more preferable alkyl residue of N-alkylcarbamoyl derivative is selectedfrom the group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1to 3 double bonds; a C3- C5 alkynyl group having one triple bond; a C1 - C4 alkylgroup which has one substituent selected from the group consisting of C1 - C4 alkoxygroups; and a C1 - C4 alkyl group which has 1 to 2 phenyl groups optionallysubstituted with 1 to 2 substituents selected from the group consisting of C1 - C2 alkyl,C1 - C4 alkoxy, fluoro and chloro groups.
    [0049] A most preferable alkyl residue of N-alkylcarbamoyl derivatives is selected fromthe group consisting of a C6 - C20 alkyl group and a C10 - C20 alkenyl group having 1to 3 double bonds.
    [0050] In compound (Ia), there are several functional groups to which the hydroxyprotecting group, and the ester, ether and alkyl residues can be attached. Therefore aplurality of protecting groups and residues can independently exist by optionalcombination of these protecting groups and residues.
    [0051] A preferable pharmaceutically acceptable ester derivative of (Ia) is a derivativewhich has one or two of the ester residues at R2, R3 and/or R5. A more preferableester derivative is a derivative which has one or two of the ester residues at R3 and/orR5. A still more preferable ester derivative is a derivative which has one of the esterresidues at R3 or R5. A most preferable ester derivative is a derivative which has oneof the ester residue at R3.
    [0052] A preferable pharmaceutically acceptable ether derivative of (Ia) is a derivativewhich has one or two of the ether residues at R2, R3 and/or R5. A more preferableether derivative is a derivative which has one or two of the ether residues at R3 and/orR5. A still more preferable ether derivative is a derivative which has one of the etherresidues at R3 or R5. A most preferable ether derivative is a derivative which has oneof the ether residues at R3.
    [0053] A preferable pharmaceutically acceptable N-alkylcarbamoyl derivative is aderivative having one of the alkyl residues.
    [0054] The term "pharmaceutically acceptable salt" refers to a salt that is a usefulmedicament without significant toxicity.
    [0055] Where compound (I), (Ia), and pharmaceutically acceptable ester, ether and N-alkylderivatives of compound (Ia) have a basic group such as an amino group, thesecompounds can be converted into an acid addition salt by a conventional treatmentwith an acid. Such acid addition salts include inorganic acid salts such ashydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such asacetate, benzoate, oxalate, maleate, fumarate, tartrate and citrate; and sulfonic acidsalts such as methanesulfonate, benzenesulfonate and p-toluenesulfonate.
    [0056] Where compound (I) and pharmaceutically acceptable ester, ether and N-alkylderivatives of compound (Ia) have an acidic group such as a carboxy group, thesecompounds can be converted into a base addition salt by a conventional treatmentwith a base. Such base addition salts include alkali metal salts such as sodium,potassium and lithium salts; alkaline earth metal salts such as calcium and magnesiumsalts; metal salts such as aluminium, iron, zinc, copper, nickel and cobalt salts; andquaternary ammonium salts such as ammonium salt.
    [0057] When compound (I) and pharmaceutically acceptable derivative of compound (Ia)are allowed to stand in the atmosphere, these compounds may take up water to form a hydrate. The present invention includes such hydrates. Compound (I) andpharmaceutically acceptable derivative of compound (Ia) may absorb a solvent toform a solvate. The present invention includes such solvates.
    [0058] Compound (I) and pharmaceutically acceptable derivative of compound (Ia) haveseveral asymmetric carbons and therefore they can exist as several stereoisomers suchas enantiomers and diastereomers in which each carbon has R or S configuration. Thecompound of the present invention encompasses individual enantiomers anddiastereomers and mixtures of these stereoisomers in all proportions.
    [0059] A preferable configuration of the compound of the present invention is shownbelow:
    [0060] A preferable compound (I) is selected from the following compounds: (1) a compound (I) wherein R2 is a methyl group, (2) a compound (I) wherein R4 is a hydroxy group, (3) a compound (I) wherein X is a methylene group;   or a compound wherein R2, R4 and X is selected in optional   combination of (1), (2) and (3), for example: (4) a compound (I) wherein R4 is a hydroxy group and X is a methylenegroup, and (5) a compound (I) wherein R2 is a methyl group, R4 is a hydroxygroup and X is a methylene group.
    [0061] A preferable compound of formula (Ia) is selected from the following compounds: (i) a compound (Ia) wherein the protecting group for a hydroxy group is selectedfrom the group consisting of "tetrahydropyranyl or tetrahydrothiopyranyl group","silyl group", "aralkyl group", "aralkyloxycarbonyl group", "1-(aliphatic acyloxy)-(loweralkyl) group", "1-(cycloalkylcarbonyloxy)-(lower alkyl) group", "1-(loweralkoxycarbonyloxy)-(lower alkyl) group", "1-(cycloalkyloxycarbonyloxy)-(loweralkyl) group", "phthalidyl" and "oxodioxolenylmethyl group". (ii) a compound (Ia) wherein the protecting group for a hydroxy group is selectedfrom the group consisting of tetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl,tetrahydrothiopyran-2-yl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, di(tert-butyl)methylsilyl,diphenylmethylsilyl, benzyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl,4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl,benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl, butyryloxyethyl, 1-pivaloyloxyethyl,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,1-cyclohexylcarbonyloxyethyl,methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)ethyl,cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,1-(cyclohexyloxycarbonyloxy)ethyl, phthalidyl,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methylgroup. (iii) a compound (Ia) wherein the protecting group of hydroxy group is selectedfrom the group consisting of trimethylsilyl, tert-butyldimethylsilyl, triphenylmethyl,benzyl, 4-methoxybenzyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl, valeryloxymethyl, cyclopentylcarbonyloxymethyl,cyclohexylcarbonyloxymethyl, methoxycarbonyloxymethyl,ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,isobutoxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl. [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyland (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
    [0062] A preferable ester derivative of compound (Ia) is selected from the followingcompounds: (iv) an ester derivative of compound (Ia) wherein the ester residue is R6CO- or R6OCO-groupin which R6 is selected from the group consisting of hydrogen: a C1 - C21 alkylgroup; a C2 - C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds: a C1 - C21alkyl group substituted with 1 to 4 substituents selected from the group consisting oflower alkoxy, halo and nitro groups; a C1 - C21 alkyl group substituted with 1 to 3 C6 -C10 aryl groups which are optionally substituted with 1 to 4 substituents selected from thegroup consisting of lower alkyl, lower alkoxy, halo and nitro groups; and a C6 - C10 arylgroup which is optionally substituted with 1 to 4 substituents selected from the groupconsisting of lower alkyl, lower alkoxy, halo and nitro groups. (v) an ester derivative of compound (Ia) wherein the ester residue is R6CO- or R6OCO-groupin which R6 is selected from the group consisting of hydrogen; a C1 - C21 alkylgroup; a C2 - C21 alkenyl group having 1 to 3 double bonds; a C2 - C6 alkynyl grouphaving one triple bond; a C1 - C6 alkyl group substituted with I to 4 substituents selectedfrom the group consisting of C1 - C4 alkoxy, halo and nitro groups; a C1 - C6 alkyl groupsubstituted with 1 to 3 C6- C10 aryl groups which are optionally substituted with 1 to 3substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo andnitro groups; and a C6- C10 aryl group which is optionally substituted with 1 to 3substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo andnitro groups. (vi) an ester derivative of compound (Ia) wherein the ester residue is R6CO- or R6OCO-groupin which R6 is selected from the group consisting of a C1 - C21 alkyl group; a C6 -C20 alkenyl group having 1 to 3 double bonds; a C2 - C6 alkynyl group having one triplebond; a C1 - C6 alkyl group substituted with one substituent selected from the groupconsisting of C1 - C4 alkoxy and nitro groups; a C1 - C6 alkyl group substituted with 1 to 3substituents selected from the group consisting of halogen; a C1 - C4 alkyl groupsubstituted with 1 to 3 phenyl or naphthyl groups which are optionally substituted with 1to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups; and a phenyl or naphthyl groupwhich is optionally substituted with 1 to 3 substituents selected from the groupconsisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups. (vii) an ester derivative of compound (Ia) wherein the ester residue is R6CO- orR6OCO- group in which R6 is selected from the group consisting of C6 - C20 alkylgroup; a C10 - C20 alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl grouphaving one triple bond; a C1 - C4 alkyl group substituted with one substituent selectedfrom the group consisting of C1 - C4 alkoxy, and nitro groups; a C1 - C4 alkyl groupsubstituted with 1 to 3 substituents selected from the group consisting of fluoro andchloro groups; a C1 - C4 alkyl group substituted with 1 to 3 phenyl groups which areoptionally substituted with 1 or 2 substituents selected from the group consisting of C1- C2 alkyl, C1 - C4 alkoxy, fluoro, and chloro groups; and a phenyl group which isoptionally substituted with 1 to 3 substituents selected from the group consisting of C1- C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups. (viii) an ester derivative of compound (Ia) wherein the ester residue is R6CO- orR6OCO- group in which R6 is selected from the group consisting of a C6 - C20 alkylgroup; a C10 - C20 alkenyl group having 1 to 3 double bonds; a C3- C5 alkynyl grouphaving one triple bond; a C1 - C4 alkyl group substituted with one substituent selectedfrom the group consisting of C1 - C4 alkoxy, fluoro, chloro and nitro groups; a C1 - C4alkyl group substituted with 1 to 3 phenyl groups which are optionally substitutedwith 1 or 2 substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4alkoxy, fluoro, and chloro groups; and a phenyl group which is optionally substitutedwith 1 to 3 substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4alkoxy, fluoro and chloro groups. (ix) an ester derivative of compound (Ia) wherein the ester residue is R6CO- orR6OCO- group in which R6 is selected from the group consisting of a C6 - C20 alkylgroup; a C10 - C20 alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl grouphaving one triple bond; a C1 - C4 alkyl group substituted with one substituent selectedfrom the group consisting of C1 - C4 alkoxy groups; and a C1 - C4 alkyl groupsubstituted with 1 to 2 phenyl groups which are optionally substituted with 1 or 2substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoroand chloro groups. (x) an ester derivative of compound (Ia) wherein the ester residue is R6CO- or R6OCO-groupin which R6 is selected from the group consisting of a C6 - C20 alkyl group; and aC10 - C20 alkenyl group having 1 to 3 double bonds.
    [0063] A preferable ether derivative of compound (Ia) is selected from following compounds: (xi) an ether derivative of compound (Ia) wherein the ether residue is selected from thegroup consisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl or alkynyl group having 1 to3 double or triple bonds; a C1 - C21 alkyl group which has 1 to 3 substituents selectedfrom the group consisting of lower alkoxy, halo and nitro groups; a C1 - C21 alkyl groupwhich has 1 to 3 C6 - C10 aryl groups which are optionally substituted with I to 4substituents selected from the group consisting of lower alkyl, lower alkoxy, halo andnitro groups; and a C6 - C10 aryl group which is optionally substituted with 1 to 4substituents selected from the group consisting of lower alkyl, lower alkoxy, halo andnitro groups. (xii) an ether derivative of compound (Ia) wherein the ether residue is selected from thegroup consisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl group having I to 3 doublebonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl group which has 1to 4 substituents selected from the group consisting of C1 - C4 alkoxy, halo and nitrogroup; a C1 - C6 alkyl group which has 1 to 3 C6 - C10 aryl groups which is optionallysubstituted with 1 to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1- C4 alkoxy, halo and nitro groups; and a C6 - C10 aryl group which are optionallysubstituted with 1 to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1- C4 alkoxy, halo and nitro groups. (xiii) an ether derivative of compound (Ia) wherein the ether residue is selected fromthe group consisting of a C1 - C21 alkyl group; C6 - C20 alkenyl group having 1 to 3double bonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy and nitrogroups; C1 - C6 alkyl group which has 1 to 3 substituents selected from the groupconsisting of halo group; a C1 - C4 alkyl group which has 1 to 3 phenyl or naphthylgroups which are optionally substituted with 1 to 3 substituents selected from the groupconsisting of C1 - C4 alkyl, C1 - C4 alkoxy, halogen and nitro groups; and a phenyl ornaphthyl group which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitrogroups. (xiv) an ether derivative of compound (Ia) wherein the ether residue is selected fromthe group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy andnitro groups; a C1 - C4 alkyl group which has 1 to 3 substituents selected from thegroup consisting of fluoro and chloro groups; a C1 - C4 alkyl group which has 1 to 3phenyl groups which are optionally substituted with 1 or 2 substituents selected fromthe group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups; and aphenyl group which is optionally substituted with 1 to 3 substituents selected from thegroup consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups. (xv) an ether derivative of compound (Ia) wherein the ether residue is selected fromthe group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy,fluoro, chloro, and nitro groups; a C1 - C4 alkyl group which has 1 to 3 phenyl groupswhich are optionally substituted with 1 or 2 substituents selected from the groupconsisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups; and a phenylgroup which is optionally substituted with 1 to 3 substituents selected from the groupconsisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups. (xvi) an ether derivative of compound (Ia) wherein the ether residue is selected fromthe group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4 alkyl groupwhich has one substituent selected from the group consisting of C1 - C4 alkoxy group;and a C1 - C4 alkyl group which has 1 or 2 phenyl groups optionally substituted with 1or 2 substituents selected from the group consisting of C1 - C2 alkyl, C1 - C4 alkoxy,fluoro and chloro groups. (xvii) an ether derivative of compound (Ia) wherein the ether residue is selectedfrom the group consisting of a C6 - C20 alkyl group and a C10 - C20 alkenyl grouphaving 1 to 3 double bonds.
    [0064] A preferable N-alkylcarbamoyl derivative of compound (Ia) is selected from thefollowing compounds: (xviii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue ofthe N-alkylcarbamoyl derivative is selected from the group consisting of a C1 - C21 alkylgroup: a C2 - C21 alkenyl or alkynyl group having 1 to 3 double or triple bonds: a C1 - C21alkyl group which has 1 to 4 substituents selected from the group consisting of loweralkoxy, halo and nitro groups; and a C1 - C21 alkyl group which has 1 to 3 C6 - C10 arylgroups which are optionally substituted with 1 to 4 substituents selected from the groupconsisting of lower alkyl, lower alkoxy, halo and nitro groups. (xix) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue isselected from the group consisting of a C1 - C21 alkyl group; a C2 - C21 alkenyl grouphaving 1 to 3 double bonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6alkyl group which has 1 to 4 substituents selected from the group consisting of C1 - C4alkoxy, halo and nitro groups; and a C1 - C6 alkyl group which has 1 to 3 C6- C10 arylgroups which are optionally substituted with 1 to 3 substituents selected from the groupconsisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro group. (xx) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue isselected from the group consisting of a C1 - C21 alkyl group; a C6- C20 alkenyl grouphaving 1 to 3 double bonds; a C2 - C6 alkynyl group having one triple bond; a C1 - C6alkyl group which has one substituent selected from the group consisting of C1 - C4alkoxy and nitro groups; a C1 - C6 alkyl group which has 1 to 3 substituents selected fromthe group consisting of halo groups; and a C1 - C4 alkyl group which has 1 to 3 phenyl ornaphthyl groups which are optionally substituted with 1 to 3 substituents selected fromthe group consisting of C1 - C4 alkyl, C1 - C4 alkoxy, halo and nitro groups. (xxi) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue isselected from the group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl grouphaving 1 to 3 double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4alkyl group which has one substituent selected from the group consisting of C1 - C4alkoxy and nitro groups; a C1 - C4 alkyl group which has 1 to 3 substituents selected fromthe group consisting of fluoro and chloro groups; and a C1 - C4 alkyl group which has 1 to3 phenyl groups which are optionally substituted with 1 or 2 substituents selected fromthe group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups. (xxii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residue isselected from the group consisting of a C6 - C20 alkyl group; a C10 - C20 alkenyl group having 1 to 3 double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4alkyl group which has one substituent selected from the group consisting of C1 - C4alkoxy, fluoro, chloro and nitro groups; and a C1 - C4 alkyl group which has 1 to 3phenyl groups which are optionally substituted with 1 or 2 substituents selected fromthe group consisting of C1 - C2 alkyl, C1 - C4 alkoxy, fluoro and chloro groups. (xxiii) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residueis selected from the group consisting of C6 - C20 alkyl group; a C10 - C20 alkenyl grouphaving 1 to 3 double bonds; a C3 - C5 alkynyl group having one triple bond; a C1 - C4alkyl group which has one substituent selected from the group consisting of C1 - C4alkoxy groups; and C1 - C4 alkyl group which has 1 or 2 phenyl groups optionallysubstituted with 1 or 2 substituents selected from the group consisting of C1 - C2 alkyl,C1 - C4 alkoxy, fluoro and chloro groups. (xxiv) an N-alkylcarbamoyl derivative of compound (Ia) wherein the alkyl residueis selected from the group consisting of a C6 - C20 alkyl group and a C10 - C20 alkenylgroup having 1 to 3 double bonds.
    [0065] A more preferable compound (Ia) is selected from group (i) to (iii); group (iv) to(x); group (xi) to (xvii); group (xviii) to (xxiv) in optional combination of thesegroups, for example: (xxv) a compound (Ia) wherein the protecting group for a hydroxy group is (i) andthe ester residue is (iv). (xxvi) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) andthe ester residue is (v). (xxvii) a compound (Ia) wherein the protecting group for a hydroxy group is (iii)and the ester residue is (vi). (xxviii) a compound (Ia) wherein the protecting group for a hydroxy group is (i) andthe ether residue is (xi). (xxix) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) andthe ester residue is (xii). (xxx) a compound (Ia) wherein the protecting group for a hydroxy group is (iii) andthe ether residue is (xiii). (xxxi) a compound (Ia) wherein the protecting group for a hydroxy group is (i) andthe alkyl residue is (xviii). (xxxii) a compound (Ia) wherein the protecting group for a hydroxy group is (ii) andthe alkyl residue is (xix). (xxxiii) a compound (Ia) wherein the protecting group for a hydroxy group is (iii)and the alkyl residue is (xx).
    [0066] The following Tables 1 and 2 are intended to illustrate typical compounds (I) and(Ia) of the present invention and are not intended to limit the scope of this invention.
    [0067] In a compound of formula (Ib): the compound wherein R1 is a methyl group, R2 is a methyl group. R3 a is a hydrogenatom, R4 a is a hydroxy group, R5 a is a hydrogen atom and X is a methylene grouprepresents A-500359A (exemplification compound No. 1); the compound wherein R1 is a methyl group, R2 is a hydrogen atom. R3 a is ahydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogen atom and X is a methylenegroup represents A-500359C (exemplification compound No. 2); the compound wherein R1 is a methyl group, R2 is a methyl group, R3 a is a hydrogenatom, R4 a is a hydrogen atom, R5 a is a hydrogen atom and X is a methylene grouprepresents A-500359D (exemplification compound No. 3); the compound wherein R1 is a hydrogen atom, R2 is a hydrogen atom, R3 a is ahydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogen atom and X is a methylenegroup represents A-500359G (exemplification compound No. 45); and the compound wherein R1 is a methyl group, R2 is a methyl group, R3 a is ahydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogen atom and X is a sulfur atomrepresents A-500359M-2 (exemplification compound No. 396).
    [0068] In Tables 1 and 2: preferable compounds include compounds of exemplification compound No.(exemp. comp. No.) 1 to 254, 280 to 283, 309 to 312, 338 to 341, 367 to 370, 396 to482, 508 to 513, 537 to 588, 592 to 704, 708 to 820, 891 to 910, 914 to 990, 1091 to1160, 1164 to 1210, 1214 to 1240, 1341 to 1390, 1394 to 1401 and 1405 to 1412; more preferable compounds include compounds of exemplification compound No.1 to 3, 7 to 11, 45, 49 to 53, 90 to 94, 131 to 135, 172 to 176, 213 to 217, 396, 400 to404, 537 to 543, 550 to 556, 563 to 569, 576 to 582, 592 to 600, 708 to 716, 891 to908, 921 to 940, 1091 to 1108, 1121 to 1158, 1171 to 1190, 1341 to 1358 and 1371 to1390; most preferable compounds include compounds of exemplification compound No.1 to 3, 7 to 11, 45, 49 to 53, 90 to 94, 131 to 135, 537 to 543, 550 to 556, 563 to 569,576 to 582, 594, 710, 891, 895, 925, 1091, 1141, 1145, 1175 and 1341; that isexemp.comp.No.1 represents the compound wherein R1 is a methyl group, R2 is a methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.2 represents the compound wherein R1 is a methyl group, R2 is ahydrogen atom, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.3 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydrogen atom, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.7 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a decanoyl group, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.8 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a lauroyl group, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.9 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a myristoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.10 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a pentadecanoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.11 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a palmitoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.45 represents the compound wherein R1 is a hydrogen atom, R2 isa hydrogen atom, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.49 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a decanoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.50 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a lauroyl group, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.51 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a myristoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.52 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a pentadecanoyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.53 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a palmitoyl group, R4 a is a hydroxy group, R5 a is a hydrogenatom and X is a methylene group; exemp.comp.No.90 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a decanoyl groupand X is a methylene group; exemp.comp.No.91 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a lauroyl groupand X is a methylene group; exemp.comp.No.92 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a myristoylgroup and X is a methylene group; exemp.comp.No.93 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a pentadecanoylgroup and X is a methylene group; exemp.comp.No.94 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a palmitoylgroup and X is a methylene group; exemp.comp.No.131 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a decanoylgroup and X is a methylene group; exemp.comp.No.132 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a lauroyl groupand X is a methylene group; exemp.comp.No.133 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a myristoylgroup and X is a methylene group; exemp.comp.No.134 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is apentadecanoyl group and X is a methylene group; exemp.comp.No.135 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is a palmitoylgroup and X is a methylene group; exemp.comp.No.537 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hexyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.538 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a heptyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.539 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is an octyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.540 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a nonyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.541 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a decyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.542 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is an undecyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.543 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a dodecyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.550 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is ahexyloxycarbonyl group and X is a methylene group; exemp.comp.No.551 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is aheptyloxycarbonyl group and X is a methylene group; exemp.comp.No.552 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anoctyloxycarbonyl group and X is a methylene group; exemp.comp.No.553 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anonyloxycarbonyl group and X is a methylene group; exemp.comp.No.554 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is adecyloxycarbonyl group and X is a methylene group; exemp.comp.No.555 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anundecyloxycarbonyl group and X is a methylene group; exemp.comp.No.556 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is adodecyloxycarbonyl group and X is a methylene group; exemp.comp.No.563 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hexyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.564 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a heptyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.565 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is an octyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.566 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a nonyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.567 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a decyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.568 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is an undecyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.569 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a dodecyloxycarbonyl group, R4 a is a hydroxy group, R5 a is ahydrogen atom and X is a methylene group; exemp.comp.No.576 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is ahexyloxycarbonyl group and X is a methylene group; exemp.comp.No.577 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is aheptyloxycarbonyl group and X is a methylene group; exemp.comp.No.578 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anoctyloxycarbonyl group and X is a methylene group; exemp.comp.No.579 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anonyloxycarbonyl group and X is a methylene group; exemp.comp.No.580 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is adecyloxycarbonyl group and X is a methylene group; exemp.comp.No.581 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is anundecyloxycarbonyl group and X is a methylene group; exemp.comp.No.582 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a hydrogen atom, R4 a is a hydroxy group, R5 a is adodecyloxycarbonyl group and X is a methylene group; exemp.comp.No.594 represents the compound wherein R1 is a methyl group, R2 is amethyl group, R3 a is a decyl group, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.710 represents the compound wherein R1 is a hydrogen atom, R2 isa methyl group, R3 a is a decyl group, R4 a is a hydroxy group, R5 a is a hydrogen atomand X is a methylene group; exemp.comp.No.891 represents the compound wherein R1 is a methyl group, R11 isa methyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom; exemp.comp.No.895 represents the compound wherein R1 is a methyl group, R11 isa methyl group, R3 is a decanoyl group, and R5 is a hydrogen atom; exemp.comp.No.925 represents the compound wherein R1 is a methyl group, R11 isa methyl group, R3 is a hydrogen atom, and R5 is a decanoyl group; exemp.comp.No.1091 represents the compound wherein R1 is a methyl group, R11is a dodecyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom; exemp.comp.No.1141 represents the compound wherein R1 is a hydrogen atom, R11is a methyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom; exemp.comp.No.1145 represents the compound wherein R1 is a hydrogen atom. R11is a methyl group, R3 is a decanoyl group, and R5 is a hydrogen atom; exemp.comp.No.1175 represents the compound wherein R' is a hydrogen atom, R11is a methyl group, R3 is a hydrogen atom, and R5 is a decanoyl group; and exemp.comp.No.1341 represents the compound wherein R1 is a hydrogen atom, R11is a dodecyl group, R3 is a hydrogen atom, and R5 is a hydrogen atom.
    [0069] Compounds of the present invention represented by the formula (I) or (Ia) canbe prepared by the process as described below.
    [0070] Compounds A-500359A (Exemp. compound No. 1), A-500359C (Exemp.compound No. 2), A-500359D (Exemp. compound No. 3), A-500359G (Exemp.compound No. 45) and A-500359M-2 (Exemp. compound No. 396) of the presentinvention each represented by the formula (I) are available by culturing amicroorganism capable of producing the above described compounds, belonging tothe Streptomyces spp. on a suitable medium and then recovering the compound fromthe cultured broth. Streptomyces griseus Strain SANK60196 (which will hereinafterbe called "Strain SANK60196"), a preferable microorganism capable of producingCompounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2 hasbeen collected and separated from the soil of Mt. Tsukuba/Ibaraki-ken in a mannerknown to those skilled in the art.
    [0071] Mycological properties of Strain SANK60196 are as follows: 1) Morphological appearance
    [0072] Strain SANK60196 showed morphological appearance as described belowafter cultivation at 28°C for 14 days on a medium specified by InternationalStreptomyces Project (which will hereinafter be abbreviated as "ISP") [refer toShirling, E.B. and Gottlieb, D.. "Int. J. Syst. Bacteriol. 16, 313-340 (1996)".]Observation through an optical microscope indicates that substrate mycelia ofSANK60196 are favourably grown and branched and show yellowish grey, yellowishbrown or pale olive colour, but unlike the strain belonging to Nocardia spp., does notshow cleavage or zigzag extension. Aerial mycelia exhibit simple branching. Theform of the spore chain is straight or curved and its chain is formed of 10 to 50 orgreater spores. Observation through a scanning electron microscope shows that thespore has an oval shape and it has a smooth surface structure. The spore is 0.6-0.8 x0.7-1.2 mm in dimension. The spore is formed only on the aerial mycelia. Formationof sporangia, axial division of aerial mycelia, cleavage of aerial mycelia and sclerotiaare not recognized. 2) Growth characteristics on various culture media
    [0073] Growth characteristics of Strain SANK60196 on an agar medium aftercultivation at 28°C for 14 days is as described below in Table 3. In the Table, thecomposition of the medium attached with ISP No. is the same as specified by ISP. Inthe item, abbreviations G, AM, R and SP stand for growth, aerial mycelia, reversecolour and soluble pigment, respectively. The colour tone is described in accordancewith "Colour Standards, ed. by Japan Colour Laboratory". The indication of thecolour tone in parentheses is a colour number in accordance with Munsell coloursystem. The pale yellow soluble pigment produced in a water-agar medium changesinto colourless by 0.05N hydrochloric acid, but shows no change by 0.05N sodiumhydroxide. Nature of Medium;    Item: characteristics Yeast extract - malt extract agar (ISP 2);    G: Excellent, flat, yellowish brown (10YR 5/6)    AM: Abundantly formed, velvety, pale brown (2.5Y 8/2)    R: Yellowish brown (10YR 5/8)    SP: Yellowish brown (10YR 6/8) Oat meal - agar (ISP 3);    G: Excellent, flat, yellowish brown (2.5Y 6/6)    AM: Abundantly formed, velvety, pale yellowish orange (5Y 9/2)    R: Dark yellow (2.5Y 8/8)    SP: Not produced Starch - inorganic salt agar (ISP 4);    G: Good, flat, yellowish brown (2.5Y 6/4)    AM: Abundantly formed, velvety, yellowish grey (7.5Y 9/2)    R: Yellowish brown (2.5Y 6/4) Glycerin - asparagine agar (ISP 5)    G: Excellent, flat, pale yellowish brown (2.5Y 7/6)    AM: Abundantly formed, velvety, yellowish grey (5Y 8/2)    R: Pale yellowish brown (2.5Y 8/6)    SP: Not produced Peptone - yeast extract - iron agar (ISP 6);   G: Excellent, flat, pale olive color (5Y 8/3)    AM: Slightly produced, velvety, yellowish grey (5Y 9/1)    R: Pale yellow (5Y 8/6)    SP: Not produced Tyrosine agar (ISP 7)    G: Good, flat, grayish yellow brown (2.5Y 5/4)    AM: Abundantly formed, velvety, light olive grey (7.5Y 8/2)    R: Yellowish brown (10YR 5/4)    SP: Grayish yellow brown (2.5Y 4/3) Sucrose - nitrate agar;    G: Not so good, flat, pale yellow (5Y 8/6)    AM: Abundantly formed, velvety, light olive grey (7.5Y 8/2)    R: Dark yellow (5Y 8/8)    SP: Pale yellow (5Y 9/6) Glucose - asparagine agar;    G: Good, flat, pale yellow (5Y 9/3)    AM: Not so good, velvety, yellowish grey (5Y 9/1)    R: Yellowish grey (7.5Y 9/3)    SP: Not produced Nutrient agar (product of Difco Laboratories)    G: Good, flat, pale yellowish brown (2.5Y 8/3)    AM: Good, velvety, yellowish grey (5Y 9/1)    R: Yellowish grey (5Y 9/4)    SP: Not produced Potato extract - carrot extract agar;    G: Not so good, flat, yellowish grey (7.5Y 9/2)    AM: Not so good, velvety, yellowish grey (5Y 9/2)    R: Yellowish grey (7.5Y 9/3)    SP: Yellowish grey (7.5Y 9/3) Water agar;    G: Not good, flat, yellowish grey (5Y 9/1)    AM: Not good, velvety, yellowish grey (5ZY 9/1)    R: Yellowish grey (7.5Y 9/4)    SP: Pale yellow (5Y 9/6) 3) Physiological characteristics
    [0074] The physiological characteristics of the present strain observed for 2 to 21days after cultivation at 28°C are as shown in Table 4. In the table. Medium 1 is ayeast extract - malt extract agar medium (ISP 2). Hydrolysis of starch positive Liquefaction of gelatin positive Reduction of nitrates positive Coagulation of milk negative Peptonization of milk positive Formation of melamine-like pigment positive Substrate decomposition:   casein positive       tyrosine positive       xanthine negative Growth temperature range (Medium 1) 6 to 35°C Optimum growth temperature (Medium 1) 18 to 30°C Growth in the presence of salt (Medium 1) 10%
    [0075] Utilisation of a carbon source by Strain SANK60196 observed aftercultivation at 28°C for 14 days on a Pridham-Gottlieb agar medium (ISP 9) is asdescribed in Table 5. In the table. "+" means utilisable, while "-" means non-utilisable. D-glucose + L-arabinose - D-xylose + Inositol - D-mannitol + D-fructose + L-rhamnose - Sucrose - Raffinose - Control - 4) Chemotaxonomic properties
    [0076] The cell wall of the present strain was investigated in accordance with themethod of Hasegawa, et al. [refer to Hasegawa. T., et al.. "The Journal of General andApplied Microbiology, 29, 319-322(1983)], resulting in the detection of LL-diaminopimelicacid. The main sugar component in the whole cells of the presentstrain was investigated in accordance with the method of M.P. Lechevalier [refer toLechevalier, M.P., "Journal of Laboratory and Clinical Medicine. 71. 934-944(1968)].As a result, no characteristic component was detected.
    [0077] The above-described mycological properties have revealed that the presentstrain belongs to Streptomyces spp. among the actinomycetes. It has been made clearthat the present strain is markedly related to Streptomyces griseus, as a result ofcomparison with the microorganism described in the ISP strains by Shirling andGottlieb [refer to Shirling, E.B. and Gottlieb, D., "International Journal of SystematicBacteriology, 18, 68―189 and 279―392 (1968); 19, 391―512 (1969); 22, 265-394(1972)"], the microorganism described in "The actinomycetes Vol. 2" written byWaksman [refer to Waksman. S.A., "The actinomycetes 2 (1961)"], with themicroorganism described in Bergey's Manual edited by Buchanan and Gibbons [referto R.E. Buchanan and N.E. Gibbons, "Bergey's Manual of DeterminativeBacteriology", 8th edition (1974)], with the microorganism described in "Bergey'sManual of Systematic Bacteriology", edited by Williams [refer to Williams. S.T., etal., "Bergey's Manual of Systematic Bacteriology 4 (1989)"] and with themicroorganism described in the recent literature about actinomycetes belonging toStreptomyces spp. It has however been recognized to be different from Streptomycesgriseus, because it produces a yellowish grey soluble pigment on a glycerin -asparagine agar medium and a pale yellowish brown soluble pigment on a peptone -yeast extract - iron agar medium but produces a soluble pigment neither on a potatoextract - carrot extract agar medium nor on a water agar medium; the maximumgrowth temperature is 40°C; and it is grown in the presence of 7% of salt.
    [0078] The present strain having such mycological characteristics is considered to bea novel strain different from Streptomyces griseus, but it is impossible to distinguishthem based on only the above-described differences. The present inventors thereforeidentified the present strain as Streptomyces griseus SANK60196.
    [0079] This strain was internationally deposited with Agency of Industrial Scienceand Technology, Ministry of International Trade and Industry (1-3. Higashi 1-chome,Tsukuba-shi, Ibaraki-ken, 305, JAPAN) as of February 22, 1996, with the accessionnumber of FERM BP-5420.
    [0080] A description was heretofore made on Strain SANK60196. It is known thatvarious properties of actinomycetes are not fixed but easily change naturally orsynthetically. The strain usable in the present invention embraces all of such variants.In other words, the present invention embraces all the strains belonging to theStreptomyces spp. and capable of producing Compounds A-500359A, A-500359C, A-500359D,A-500359G or A-500359M-2.
    [0081] Any synthetic or natural medium can be used for cultivation formicroorganisms capable of producing Compounds A-500359A. A-500359C. A-500359D,A-500359G or A-500359M-2 of the present invention, insofar as itcontains, as needed, a substance selected from carbon sources, nitrogen sources,inorganic ions and organic nutrition sources.
    [0082] Known carbon sources, nitrogen sources and inorganic salts conventionallyemployed for cultivation of the strain of the eumycetes or actinomycetes and areutilisable by a microorganism can be used as such nutrition sources.
    [0083] Specific examples of the carbon source include glucose, fructose, maltose,sucrose, mannitol, glycerol, dextrin, oats, rye, corn starch, potato, corn meal, soybeanmeal, cotton seed oil, thick malt syrup, theriac, soybean oil, citric acid and tartaricacid. They may be used either singly or in combination. The amount of the carbonsource to be added usually varies, but not limited to, within a range of from 1 to 10wt.%.
    [0084] As the nitrogen source, a substance containing protein or hydrolyzate thereofcan usually be employed. Preferred examples of the nitrogen source include soybeanmeal, wheat bran, peanut meal, cotton seed meal, casein hydrolyzate. Farmamine, fishmeal, corn steep liquor, peptone, meat extract, pressed yeast, dry yeast, yeast extract,malt extract, potato, ammonium sulfate, ammonium nitrate and sodium nitrate. It ispreferred to use the nitrogen source either singly or in combination in an amountranging from 0.2 to 6 wt.% of the amount of the medium.
    [0085] As the nutrition inorganic salt, ordinarily employed salts from which an ion isavailable, such as sodium salts, ammonium salts, calcium salts, phosphates, sulfates,chlorides and carbonates can be used. In addition, trace metals such as potassium,calcium, cobalt, manganese, iron and magnesium are usable.
    [0086] For the production of Compound A-500359A, the addition of cobalt or yeastextract is particularly effective.
    [0087] Upon culturing the microorganism capable of producing Compound A-500359A,A-500359C, A-500359D, A-500359G or A-500359M-2, an inhibitor ofantibiotic biosynthesis can be added to produce useful related compounds.Compound A500359M-2 can be produced, for example, by using, as a mediumadditive, S-(2-aminoethyl)-L-cysteine or salt thereof which is an aspartate kinaseinhibitor. The additive can be added to give its final concentration ranging from 1 to100 mM. Preferably, use of it to give a final concentration of 10 mM permitsfavorable production of Compound A-500359M-2.
    [0088] Upon liquid culture, a silicone oil, vegetable oil or surfactant can be added asan antifoamer.
    [0089] The medium used for the cultivation of Strain SANK 60196 to produceCompound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2preferably has a pH ranging from 5.0 to 8.0.
    [0090] The temperature which allows Strain SANK60196 to grow ranges from 12 to36°C. It is preferred to cultivate the strain at 18 to 28°C in order to produceCompound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2, ofwhich 19 to 23°C is more preferred.
    [0091] Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2is available by aerobic culture of Strain SANK 60196. Ordinarily-employedsolid culture, shake culture, and aeration agitation culture can be used assuch culturing method.
    [0092] For small-scale culturing, agitation of the culture for several days at 19 to23°C is preferred. Culturing is started by growing a seed culture in a single or twostage process in an Erlenmeyer flask equipped with a baffle (water flow adjustingwall) or an ordinarily-employed Erlenmeyer flask. A carbon source and a nitrogensource can be used in combination as a medium in the seed culture. The flask or seedculture may be shaken at 19 to 23°C for 5 days or until the seed cultures grow sufficiently in a thermostat incubator. The seed cultures thus grown can be used forinoculation of the second seed culture medium or a production medium. When theseed cultures are used under an intermediate growing step, they are allowed to growessentially in a similar manner, followed by inoculation of a part of them into aproduction medium. The flask into which the seed cultures has been inoculated issubjected to culturing with shaking at a constant temperature for several days andafter completion of the culturing, the cultured medium in the flask is centrifuged orfiltered.
    [0093] For large-scale cultivation, on the other hand, culturing in a jar fermenter ortank equipped with an agitator and an aeration apparatus is preferred. Prior toculturing in such a container, the culture medium is heated to 125°C for sterilization.After cooling, the seed cultures which have been allowed to grow in advance by theabove-described method are inoculated on the sterilized medium. Then, culturing iscarried out with aeration and agitation at 19 to 23°C. This method is suitable forobtaining a large amount of compounds.
    [0094] Compound A-500359M-2 can be produced by adding, as an aspartate kinaseinhibitor, an aqueous solution of S-(2-aminoethyl)-L-cysteine or salt thereof whichhas been filter sterilized in advance to a sterilized medium at the beginning time of thecultivation or during cultivation.
    [0095] The production of Compound A-500359A, A-500359C, A-500359D, A-500359Gor A-500359M-2 produced can be measured by sampling a portion of thecultured broth and subjecting it to high performance liquid chromatography. The titreof Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2usually reaches a peak in 3 to 9 days.
    [0096] After completion of the cultivation, the cell component is separated from thecultured broth by separation with the aid of diatomaceous earth or centrifugation.Compound A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2present in the filtrate or supernatant is purified by utilizing its physico-chemicalproperties with HPLC analytical data as an index. Compound A-500359A, A-500359C,A-500359D, A-500359G or A-500359M-2 present in the filtrate can bepurified by using adsorbents singly or in combination, such as activated charcoal(product of Wako Pure Chemicals) and an adsorbing resin such as "Amberlite XAD-2or XAD-4" (trade name; product of Rohm & Haas), and "Diaion HP-10, HP-20, CHP-20Por HP-50, Sepabeads SP205, SP206 or SP207" (trade name; product of Mitsubishi Chemical). Compound A-500359A, A-500359C, A-500359D, A-500359Gor A-500359M-2 in the solution can be separated from impurities bypassing a solution containing them through the layer of such adsorbents, or by elutingthe adsorbed compounds from the layer with aqueous methanol, aqueous acetone oraqueous normal butanol.
    [0097] Compounds A-500359A, A-500359C. A-500359D, A-500359G or A-500359M-2thus obtained can be purified by adsorption column chromatographyusing an adsorbent such as silica gel, "Florisil" (trade name), or "Cosmosil" (tradename; product of Nacalai Tesque); partition column chromatography using "SephadexLH-20" (trade name; product of Pharmacia Biotech); gel filtration chromatographyusing "Toyopearl HW40F" (trade name; product of TOSOH Corp); or highperformance liquid chromatography using a normal phase or reversed phase column;or the like.
    [0098] Compounds A-500359A, A-500359C, A-500359D, A-500359G or A-500359M-2according to the present invention can be separated and purified by usingthe above-exemplified separation and purification means singly or in combination asneeded, or in some cases, by using one of them in repetition.
    [0099] Compounds A-500359A, A-500359C, A-500359D, A-500359G and A-500359M-2of the present invention thus obtained are novel compounds not publishedin the literature but their antibacterial activity can be determined by a method knownto those skilled in the art.
    [0100] Ester derivatives, ether derivatives and N-alkylcarbamoyl derivatives can eachbe prepared easily by using any one of the below-described Processes A to F or usingthem in combination as necessary. (Process A)
    [0101] Process A is for the preparation of an ester derivative of Compound (Ia) andby this process, Compound (Ic) wherein R2 is a methyl group can be prepared.
    [0102] Step A1 is for the preparation of a compound having the formula (III) and it isaccomplished by protecting the hydroxy group of the compound of formula (II).
    [0103] Although the hydroxy-protecting step differs depending on the kind of theprotecting group, it is conducted by a process well known in synthetic organicchemistry.
    [0104] When the hydroxy -protecting group is a "silyl group", "alkoxymethyl group","substituted ethyl group", "aralkyl group", "alkoxycarbonyl group"."alkenyloxycarbonyl group", "aralkyloxycarbonyl group", "1-(aliphatic acyloxy)-loweralkyl group", "1-(aliphatic acylthio)-lower alkyl group". "1-(cycloalkylcarbonyloxy)-loweralkyl group", "1-(aromatic acyloxy)-lower alkylgroup", "1-(lower alkoxycarbonyloxy)-lower alkyl group", "1-(cycloalkyloxycarbonyloxy)-loweralkyl group", "phthalidyl group","oxodioxolenylmethyl group", "carbamoyl group substituted with 2 lower alkylgroups", "1-(lower alkoxycarbonyloxy)-lower alkyl group", "lower alkyl-dithioethylgroup" or "1-(acyloxy)-alkyloxycarbonyl group", this step is conducted by reactingCompound (II) with a desired hydroxy-protecting group halide in an inert solvent inthe presence of a base.
    [0105] Examples of the hydroxy-protecting group halide usable in the above reactioninclude trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldimethylsilylbromide, methyldi-t-butylsilyl chloride, methyldi-t-butylsilylbromide, diphenylmethylsilyl chloride, diphenylmethylsilyl bromide, methoxymethylchloride, 2-methoxyethoxymethyl chloride. 2,2,2-trichloroethoxymethyl chloride, 1-ethoxyethylchloride, benzyl chloride, benzyl bromide, α-naphthylmethyl chloride.diphenylmethyl chloride, diphenylmethyl bromide, triphenylmethyl chloride, 4-methylbenzylchloride, 4-methoxybenzyl chloride. 4-nitrobenzyl chloride. 4-chlorobenzylchloride, methoxycarbonyl chloride, ethoxycarbonyl chloride. 2.2.2-trichloroethoxycarbonylchloride, vinyloxycarbonyl chloride, allyloxycarbonylchloride, benzyloxycarbonyl chloride, benzyloxycarbonyl bromide. 4-methoxybenzyloxycarbonylchloride, 4-nitrobenzyloxycarbonyl chloride.acetoxymethyl chloride, propionyloxymethyl chloride, butyryloxymethyl chloride.pivaloyloxymethyl chloride, pivaloyloxymethyl bromide, valeryloxymethyl chloride, 1-acetoxyethyl chloride, butyryloxyethyl chloride, 1-pivaloyloxyethyl chloride.cyclopentylcarbonyloxymethyl chloride, cyclohexylcarbonyloxymethyl chloride, 1-cyclopentylcarbonyloxyethylchloride, 1-cyclohexylcarbonyloxyethyl chloride,methoxycarbonyloxymethyl chloride, methoxycarbonyloxymethyl bromide,ethoxycarbonyloxymethyl chloride, propoxycarbonyloxymethyl chloride,isopropoxycarbonyloxymethyl chloride, butoxycarbonyloxymethyl chloride.isobutoxycarbonyloxymethyl chloride, 1-(methoxycarbonyloxy)ethyl chloride, 1-(methoxycarbonyloxy)ethylbromide, 1-(ethoxycarbonyloxy)ethyl chloride, 1-(isopropoxycarbonyloxy)ethylchloride, cyclopentyloxycarbonyloxymethyl chloride,cyclohexyloxycarbonyloxymethyl chloride, 1-(cyclopentyloxycarbonyloxy)ethylchloride, 1-(cyclohexyloxycarbonyloxy)ethyl chloride, phthalidyl chloride, phthalidylbromide, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl chloride, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methylchloride, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylchloride, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methylchloride, dimethylcarbamoyl chloride, diethylcarbamoylchloride, methyldithioethyl chloride, ethyldithioethyl chloride andpivaloyloxymethyloxycarbonyl chloride, of which triethylsilyl chloride, t-butyldimethylsilylchloride, t-butyldimethylsilyl bromide, benzyl chloride, benzylbromide, triphenylmethyl chloride, 4-methoxybenzyl chloride, 2,2,2-trichloroethoxycarbonylchloride, allyloxycarbonyl chloride, benzyloxycarbonylchloride, benzyloxycarbonyl bromide, acetoxymethyl chloride and pivaloyloxymethylchloride are preferred.
    [0106] Examples of the base include alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates suchas lithium carbonate, sodium carbonate and potassium carbonate, alkali metalbicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metalalkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide andpotassium t-butoxide, and organic amines such as triethylamine, tributylamine, N-methylmorpholine,pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine,1,5-diazabicyclo[4.3.0]-5-nonene and 1,8-diazabicyclo[5.4.0]-7-undecene. Out ofthese, organic amines are preferred, of which triethylamine, tributylamine, pyridineand lutidine are particularly preferred. Upon use of an organic amine in the liquidform, it also serves as a solvent when used in large excess.
    [0107] There is no particular limitation on the inert solvent used in the above reaction.provided it is inert to the reaction. Examples include hydrocarbons such as hexane.benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform.carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran anddioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile.amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidoneand hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide:and mixtures thereof. Of these, hydrocarbons and amides are preferred.
    [0108] Although the reaction temperature differs with the nature of the startingcompound (II), the halide and the solvent, it usually ranges from -10°C to 100°C(preferably 0 to 50°C). Although the reaction time differs with the reaction temperatureor the like, it ranges from 30 minutes to 5 days (preferably 1 to 3 days).
    [0109] When the hydroxy-protecting group is a "tetrahydropyranyl ortetrahydrothiopyranyl group" or a "tetrahydrofuranyl or tetrahydrothiofuranyl group",Compound (II) is reacted with a cyclic ether compound such as dihydropyran, 3-bromodihydropyran,4-methoxydihydropyran, dihydrothiopyran, 4-methoxydihydrothiopyran,dihydrofuran or dihydrothiofuran in an inert solvent in thepresence of an acid.
    [0110] Examples of the acid usable in the above reaction include inorganic acids such ashydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid and organic acids suchas acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, ofwhich hydrogen chloride, hydrochloric acid, sulfuric acid and trifluoroacetic acid arepreferred, with hydrogen chloride and hydrochloric acid being particularly preferred.
    [0111] Examples of the inert solvent usable in the above reaction (which is inert to thereaction) include hydrocarbons such as hexane, benzene and toluene, halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane,ethers such as ether, tetrahydrofuran and dioxane, ketones such asacetone and methyl ethyl ketone, nitriles such as acetonitrile, amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone andhexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide; and mixturesthereof. Of these, hydrocarbons and ethers are preferred.
    [0112] Although the reaction temperature differs with the nature of the startingcompound (II), the cyclic ether compound and the solvent, it usually ranges from-10°C to 100°C (preferably 0 to 50°C). Although the reaction time differs with thereaction temperature or the like, it usually ranges from 30 minutes to 5 days(preferably 1 to 3 days).
    [0113] When the hydroxy-protecting group is a "carbamoyl group" or "carbamoylgroup substituted with one lower alkyl group", Compound (II) is reacted with anisocyanate or lower alkyl isocyanate such as methyl isocyanate or ethyl isocyanate inan inert solvent in the presence or absence of a base.
    [0114] Preferred examples of the base usable in the above reaction include the above-exemplifiedorganic amines, with triethylamine, tributylamine, pyridine and lutidinebeing particularly preferred.
    [0115] There is no particular limitation on the inert solvent used in the above reactionprovided that it is inert to the reaction. Examples include hydrocarbons such ashexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether,tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitrilessuch as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone and hexamethylphosphoramide, andsulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these, hydrocarbonsand ethers are preferred.
    [0116] Although the reaction temperature differs with the nature of the startingcompound (II), the cyclic ether compound and the solvent, it usually ranges from-10°C to 100°C (preferably 0 to 50°C). Although the reaction time differs with thereaction temperature or the like, it ranges from 30 minutes to 5 days (preferably 1 to 3days).
    [0117] After completion of the reaction, the desired compound in each reaction iscollected from the reaction mixture in a manner known to those skilled in the art. Thedesired compound can be obtained, for example, by filtering off any insoluble matter,as required, and then distilling off the solvent under reduced pressure; or by distillingoff the solvent under reduced pressure, adding water to the residue, extracting themixture with a water immiscible organic solvent such as ethyl acetate, drying overanhydrous magnesium sulfate or the like and then distilling off the solvent. Ifnecessary, the resulting product can be purified further in a manner known to those skilled in the art, for example, by recrystallization, column chromatography or thelike.
    [0118] Step A2 is for the preparation of a compound having the formula (Ic). Thisstep can be accomplished by esterifying Compound (III) and if desired, removing thehydroxy-protecting group from the esterified compound.
    [0119] Esterification is conducted by reacting Compound (III) with an acid halide oracid anhydride having a desired ester residue in an inert solvent in the presence of abase.
    [0120] Examples of the acid halide or acid anhydride used in the above reactioninclude compounds represented by any one of the formulae R6CO-Y, R6CO2CO2R9,R6CO-O-COR6 and R6OCO-Y [wherein R6 has the same meaning as described above,Y represents a halogen atom, preferably chlorine or bromine, R9 represents a C1-4alkyl group (preferably ethyl or isopropyl)]; a mixed acid anhydride of formic acidand acetic acid, cyclic acid anhydrides such as succinic acid anhydride, glutaric acidanhydride and adipic acid anhydride; and phosphate ester introducing agents such ascompounds represented by the formula (R7O)2PO-Y (wherein Y has the samemeaning as described above and R7 represents a lower alkyl group), of which thecompounds represented by any one of the formulas R6CO-Y, R6CO2CO2R9, R6CO-O-COR6and R6OCO-Y (wherein R6, Y and R9 have the same meanings as describedabove) are preferred.
    [0121] Examples of the base usable in the above reaction include alkali metalhydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide,alkali metal carbonates such as lithium carbonate, sodium carbonate and potassiumcarbonate, alkali metal bicarbonates such as sodium bicarbonate and potassiumbicarbonate, alkali metal alkoxides such as lithium methoxide, sodium methoxide,sodium ethoxide and potassium t-butoxide, and organic amines such as triethylamine,tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline,lutidine, collidine, 1,5-diazabicyclo[4.3.0]-5-nonene and 1,8-diazabicyclo[5.4.0]-7-undecene.Of these, organic amines are preferred, of which triethylamine,tributylamine, pyridine and lutidine are particularly preferred. Upon use of an organicamine in the liquid form, it also serves as a solvent when used in large excess.
    [0122] When the esterifying reaction is a phosphate ester introducing reaction, it canalso be conducted by reacting Compound (III) with a phosphite having a desired ester residue in an inert solvent in the presence of an acid or base. and oxidizing the reactionmixture into the corresponding phosphate ester by an oxidizing agent.
    [0123] As the phosphite, a compound represented by the formula (R7O)2-P-Z, wherein R7represents a C6-20 alkyl group and Z represents a halogen atom or a compoundrepresented by the formula -N(R8)2 (wherein R8 represents a lower C6-20 alkyl group)] canbe used.
    [0124] When, in the above formula, Z represents a halogen atom, a base is employed as acatalyst and examples of the base usable are similar to those exemplified above. When Zis not a halogen atom, on the other hand, an acid is used as a catalyst. Any acid can beused, provided that it exhibits acidity as strong as acetic acid. Tetrazole is preferred.
    [0125] Examples of the oxidizing agent usable in the above reaction include meta-chloroperbenzoicacid, t-butylhydroperoxide and peracetic acid, of which meta-chloroperbenzoicacid is preferred.
    [0126] There is no particular limitation on the inert solvent usable in the above reaction,provided that it is inert to the reaction. Examples include hydrocarbons such as hexane,benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane, ethers such as ether, tetrahydrofuran anddioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidoneand hexamethylphosphoramide, and sulfoxides such as dimethylsulfoxide;and mixtures thereof. Of these, hydrocarbons and amides are preferred.
    [0127] Although the reaction temperature differs with the nature of the startingcompound (III), the phosphite and the solvent, it usually ranges from -10°C to 100°C(preferably 0 to 50°C). The reaction time differs with the reaction temperature and thelike, but it ranges from 10 minutes to 2 days (preferably 30 minutes to 10 hours).
    [0128] Esterification can also be conducted by reacting Compound (III) with a carboxylicacid having a desired ester residue in an inert solvent in the presence of a condensingagent.
    [0129] Examples of the condensing agent usable in the above reaction includecarbodiimides such as dicyclohexylcarbodiimide, carbonyl diimidazole and 1-(N,N-dimethylaminopropyl)-3-methylcarbodiimidehydrochloride, of whichdicyclohexylcarbodiimide is preferred.
    [0130] There is no particular limitation on the inert solvent used in the above reaction.provided that it is inert to the reaction. Examples include hydrocarbons such ashexane, benzene and toluene, halogenated hydrocarbons such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane, ethers such as ether,tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, nitrilessuch as acetonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide.N-methyl-2-pyrrolidone and hexamethylphosphoramide, andsulfoxides such as dimethylsulfoxide; and mixtures thereof. Of these, hydrocarbons.halogenated hydrocarbons and amides are preferred.
    [0131] Although the reaction temperature differs with the nature of the startingcompound (III), carboxylic acid and solvent, it usually ranges from -10°C to 100°C(preferably 0 to 50°C). The reaction time differs with the reaction temperature or thelike, but it usually ranges from 10 minutes to 2 days (preferably 30 minutes to 10hours).
    [0132] After completion of the reaction, the desired compound in each reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by filtering off any insolublematter, as necessary, and then distilling off the solvent under reduced pressure; or bydistilling off the solvent under reduced pressure, adding water to the residue,extracting the mixture with a water immiscible organic solvent such as ethyl acetate,drying over anhydrous magnesium sulfate or the like and then distilling off thesolvent. If necessary, the resulting product can be purified further in a manner knownto those skilled in the art, for example, by recrystallization, column chromatographyor the like.
    [0133] Although the desired deprotection of hydroxy-protecting group differs withthe kind of protecting group, it is conducted by the process well known in syntheticorganic chemistry.
    [0134] When the hydroxy-protecting group is an "aralkyl group" or"aralkyloxycarbonyl group", deprotection is conducted by contacting thecorresponding compound with a reducing agent (including catalytic reduction) oroxidizing agent in an inert solvent.
    [0135] There is no particular limitation on the inert solvent usable in the removal bycatalytic reduction, provided that it is inert to the reaction. Examples include alcoholssuch as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene and aliphatichydrocarbons such as hexane and cyclohexane and esters such as ethyl acetate andpropyl acetate and aliphatic acids such as acetic acid: and mixtures of the above-exemplifiedorganic solvent and water, of which alcohols are preferred.
    [0136] Although there is no particular limitation on the catalyst usable in the abovereaction (provided that it is ordinarily employed for catalytic reduction), examplesinclude palladium on carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminiumoxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate,of which palladium on carbon is preferred.
    [0137] Although there is no particular limitation on the pressure of hydrogen. itusually ranges from 1 to 10 times atmospheric pressure (preferably 1 to 3 timesatmospheric pressure).
    [0138] Although the reaction temperature or reaction time differs with the nature ofthe starting substance, the solvent and the catalyst, the reaction temperature usuallyranges from -20°C to 100°C (preferably 0 to 50°C) and the reaction time usuallyranges from 30 minutes to 10 hours (preferably 1 to 5 hours).
    [0139] There is no particular limitation on the inert solvent usable upon deprotectionby an oxidizing agent, provided that it is inert to the reaction. Examples includeketones such as acetone, halogenated hydrocarbons such as methylene chloride,chloroform and carbon tetrachloride, nitriles such as acetonitrile, ethers such asdiethyl ether, tetrahydrofuran and dioxane, amides such as dimethylformamide.dimethylacetamide and hexamethylphosphoramide and sulfoxides such asdimethylsulfoxide, and mixed solvents thereof. Preferred are the amides andsulfoxides.
    [0140] There is no particular limitation imposed on the oxidizing agent usable in theabove reaction, provided that it may be employed for oxidization. Examples includealkali metal persulfates such as potassium persulfate and sodium persulfate, cericammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), ofwhich ceric ammonium nitrate (CAN) and 2,3-dichloro-5,6-dicyano-p-benzoquinone(DDQ) are preferred.
    [0141] Although the reaction temperature and reaction time differs with the nature ofthe starting substance, the solvent and the catalyst, the reaction temperature usuallyranges from -10°C to 150°C (preferably 0 to 50°C) and the reaction time usuallyranges from 10 minutes to 24 hours (preferably 30 minutes to 10 hours).
    [0142] When the hydroxy-protecting group is a t-butyl group, t-butoxycarbonylgroup, "alkoxymethyl group", "tetrahydropyranyl or tetrahydrothiopyranyl group" or"tetrahydrofuranyl or tetrahydrothiofuranyl group", deprotection is conducted byreacting the corresponding compound with an acid in an inert solvent.
    [0143] There is no particular limitation on the inert solvent used in the above reaction,provided that it is inert to the reaction. Examples include hydrocarbons such ashexane and benzene, halogenated hydrocarbons such as methylene chloride.chloroform and carbon tetrachloride, esters such as ethyl acetate, ketones such asacetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers suchas ether, tetrahydrofuran and dioxane; and mixtures thereof with water. Of these.esters, ethers and halogenated hydrocarbons are preferred.
    [0144] Examples of the acid usable here include inorganic acids such as hydrogenchloride, nitric acid, hydrochloric acid and sulfuric acid, organic acids such as aceticacid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid and Lewisacids such as boron trifluoride, of which the inorganic acids and organic acids arepreferred and hydrochloric acid, sulfuric acid and trifluoroacetic acid are particularlypreferred.
    [0145] The reaction temperature usually ranges from -10°C to 100°C (preferably -5 to50°C). Although the reaction time differs with the reaction temperature or the like, itranges from 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
    [0146] When the hydroxy-protecting group is a "silyl group", deprotection may beconducted by reacting the corresponding compound with a compound containing afluoride anion, such as tetrabutylammonium fluoride, in an inert solvent.
    [0147] There is no particular limitation on the inert solvent used in the above reactioninsofar as it is inert to the reaction. Examples include hydrocarbons such as hexaneand benzene, halogenated hydrocarbons such as methylene chloride, chloroform andcarbon tetrachloride, esters such as ethyl acetate, ketones such as acetone and methylethyl ketone, and ethers such as ether, tetrahydrofuran and dioxane; and mixturesthereof with water. Of these, ethers are preferred.
    [0148] Although there is no particular limitation imposed on the reaction temperatureor reaction time, the reaction temperature usually ranges from -10 to 50°C (preferably0 to 30°C) and the reaction time usually ranges from 2 to 24 hours (preferably 10 to18 hours).
    [0149] After completion of the reaction, the desired compound in this reaction isseparated from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate to the filtrate, washing the resulting mixture withwater and then distilling off the solvent. If necessary, the resulting product can bepurified further in a manner known to those skilled in the art, for example, byrecrystallization, reprecipitation, column chromatography or the like.
    [0150] If desired, the hydroxy group of the resulting compound can be esterified orprotected.
    [0151] Esterification of Compound (II) by using 1 to 3 molar equivalents of anesterifying agent can produce a mixture of a compound having 1 to 3 esterifiedhydroxy groups. By separating the compound from the mixture by columnchromatography or the like and then protecting its hydroxy group if desired,Compound (Ic) is also available. (Process B)
    [0152] Process B is for the preparation of an ester derivative of Compound (Ia). Bythis process. Compound (Id), wherein R2 is a methyl group, an -O- ester residue ispresent at the 2'-position, a hydroxy group or -O- ester residue is present at the 2"-positionand a hydroxy group or -O- ester residue is present at the 3"-position can beprepared.
    [0153] Step B1 is a step for preparing a compound of formula (IIIa). This step isconducted by reacting a compound of formula (IIa) with an acetonide agent in an inertsolvent in the presence of an acid catalyst.
    [0154] Examples of the acetonide agent usable in the above reaction include acetone,methoxyisopropene and 2,2-dimethoxypropane, of which acetone and 2,2-dimethoxypropaneare preferred.
    [0155] Examples of the acid catalyst usable in the above reaction include inorganicacids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid.organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonicacid, Lewis acids such as boron trifluoride and acidic resins such as"Amberlyst 15", of which organic acids and acidic resins are preferred. with p-toluenesulfonicacid and "Amberlyst 15" being more preferred.
    [0156] The reaction temperature usually ranges from -10 to 100°C (preferably 0 to50°C). Although the reaction time differs with the reaction temperature and the like,it usually ranges from 1 hour to 7 days (preferably 10 hours to 3 days).
    [0157] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate to the filtrate, washing the resulting mixture withwater and then distilling off the solvent. If necessary, the resulting product can bepurified further in a manner known to those skilled in the art, for example, byrecrystallization, reprecipitation, column chromatography or the like.
    [0158] Step B2 is for the preparation of a compound represented by the formula (Id).This step is accomplished by esterifying Compound (IIIa), removing anisopropylidene group from the esterified compound and then esterifying the hydroxygroup if desired.
    [0159] Esterification is conducted as in the corresponding reaction described in StepA2, while the reaction to remove the isopropylidene group is conducted by reactingthe corresponding compound with an acid as in Step B I while using, as an inertsolvent, water, an alcohol such as methanol or ethanol or aqueous alcohol. (Process C)
    [0160] Process C is for the preparation of an ester derivative of Compound (Ia). Bythis process, it is possible to prepare Compound (Ie) wherein R2 represents a methylgroup, a protected or unprotected hydroxy group or an -O- ester residue is present atthe 2"-poisition, and a protected or unprotected hydroxy group or an -O- ester residueis present at the 3"-position.
    [0161] Step C1 is a step for preparing Compound (Ie) and this step is accomplishedby esterifying the compound of the formula (IIb) and, if desired, protecting thehydroxy group.
    [0162] Esterification is conducted as in the corresponding reaction described in StepA2. A mixture of monoesters may be obtained by the use of an esterifying agent in an amount of about 1 molar equivalent. This mixture can be easily separated by columnchromatography or the like. Use of the esterifying agent in an amount of about 2molar equivalents yields a diester.
    [0163] The hydroxy-protecting reaction is conducted in a similar manner to thatdescribed in Step A1. (Process D)
    [0164] Process D is for the preparation of an ester derivative of Compound (Ia). Bythis process, Compound (If) having a protected or unprotected hydroxy group or anester residue at the 2'-position, a protected or unprotected hydroxy group or an esterresidue at the 3'-position, a protected or unprotected hydroxy group or an -O- esterresidue at the 2"-position and a protected or unprotected hydroxy group or an -O-esterresidue at the 3"-position can be prepared.
    [0165] Step D1 is a step for the preparation of Compound (If). It can beaccomplished by protecting the diol portion of a compound having the formula (IIc)with an isopropylidene group, esterifying the resulting compound, removing theisopropylidene group from the esterified compound and then, esterifying or protectingthe hydroxy group if desired.
    [0166] The protection of the diol portion with an isopropylidene group is conductedin a similar manner to that in Step B 1. Use of about 1 molar equivalent yields amixture of a compound protected at the 2'- and 3'-positions and a compoundprotected at the 2"- and 3"-positions. The mixture can easily be separated, forexample, by column chromatography.
    [0167] Esterification is conducted in a similar manner to the corresponding reactionin Step A2. Use of an esterifying agent in an amount of about 1 molar equivalentyields a mixture of monoesters. This mixture can easily be separated, for example, bycolumn chromatography. Use of the esterifying agent in an amount of about 2 molarequivalents yields a diester.
    [0168] The reaction to remove the isopropylidene group is conducted in a similarmanner to the corresponding reaction in Step B2.
    [0169] The esterification of the resulting compound, which is conducted as desired, isconducted in a similar manner to the corresponding reaction in Step A2. Use of anesterifying agent in an amount of about 1 molar equivalent yields a mixture ofmonoesters. This mixture can easily be separated, for example, by columnchromatography. Use of the esterifying agent in an amount of about 2 molarequivalents yields a diester. The hydroxy-protecting reaction of the compound thusobtained is conducted in a similar manner to Step A1. Use of a protecting agent in anamount of about 1 molar equivalent yields a mixture of compounds each having oneprotected hydroxy group. This mixture can easily be separated, for example, bycolumn chromatography. Use of the protecting agent in an amount of about 2 molarequivalents yields a compound having two protected hydroxy groups.
    [0170] Compound (If) is also available by esterifying the compound of the formula(IIc) with 1 to 4 molar equivalents of an esterifying agent, separating the resulting mixture, for example, by column chromatography and if desired, protecting thehydroxy group. (Process E)
    [0171] Process E is for the preparation of an ether derivative of formula (Ig) and (Ih)of Compound (Ia).
    [0172] Step E1 is a step for preparing a compound represented by formula (IV) byreacting a compound of formula (IIIa) with an alkylation protecting reagentrepresented by the formula LY (wherein L and Y have the same meanings asdescribed above) in an inert solvent in the presence of a base.
    [0173] Examples of the alkylation protecting reagent (LY) usable in the abovereaction include 4-methoxybenzyloxymethyl chloride, pivaloyloxymethyl chlorideand acetoxymethyl chloride, of which 4-methoxybenzyloxymethyl chloride ispreferred.
    [0174] Examples of the base usable in the above reaction include tertiary amines suchas 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene(DBN) and alkali metal hydrides such as sodium hydride and potassium hydride, ofwhich 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is preferred.
    [0175] Examples of the solvent usable in the above reaction include ethers such asdiethyl ether, tetrahydrofuran and dioxane and amides such as N,N-dimethylformamideand N.N-dimethylacetamide, of which N,N-dimethylformamideis preferred.
    [0176] The reaction temperature usually ranges from -30 to 100°C (preferably -10 to30°C). Although the reaction time differs with the reaction temperature and the like,it usually ranges from 30 minutes to 1 day (preferably 1 hour to 5 hours).
    [0177] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate or saturated saline, drying over anhydrous magnesiumsulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary,the resulting product can be purified further in a manner known to those skilled in theart, for example, recrystallization, reprecipitation, column chromatography or the like.
    [0178] Step E2 is a step for preparing a compound of the formula (V) by reacting acompound of the formula (IV) with an alkylating agent having a desired ether residuein an inert solvent in the presence of a base.
    [0179] Examples of the alkylating agent usable in the above reaction include alkylhalides and alkyl triflates, of which an alkyl iodide is preferred.
    [0180] Examples of the base usable in the above reaction include tertiary amines suchas 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1.5-diazabicyclo[4.3.0]non-5-ene(DBN) and alkali metal hydrides such as sodium hydride and potassium hydride, ofwhich sodium hydride is preferred.
    [0181] Examples of the solvent usable in the above reaction include ethers such asdiethyl ether, tetrahydrofuran and dioxane and amides such as N,N-dimethylformamideand N,N-dimethylacetamide, of which N,N-dimethylformamideis preferred.
    [0182] The reaction temperature usually ranges from -30 to 100°C (preferably -10 to30°C). Although the reaction time differs with the reaction temperature and the like,it usually ranges from 1 hour to 2 days (preferably 1 hour to 10 hours).
    [0183] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate or saturated saline, drying over anhydrous magnesiumsulfate or anhydrous sodium sulfate and then distilling off the solvent. If necessary,the resulting product can be purified further in a manner known to those skilled in theart, for example, recrystallization, reprecipitation, column chromatography or the like.
    [0184] Step E3 is a step for preparing a compound of the formula (Ig) by reacting acompound of the formula (V) with an agent capable of deprotecting the protecteduracil residue in an inert solvent.
    [0185] When the protecting group contained in the uracil residue in the formula (V) isa 4-methoxybenzyloxymethyl group, examples of the deprotecting agent usable hereinclude 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or cerium (IV)ammonium nitrate (CAN) [referably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ)], while examples of the solvent usable include water, alcohols such asmethanol and ethanol, and halogenated hydrocarbons such as methylene chloride andchloroform, and mixtures thereof (preferably a mixed solvent of methylene chlorideand water). The reaction temperature usually ranges from 0 to 150°C (preferably 10to 100°C). Although the reaction time differs with the reaction temperature and thelike, it usually ranges from 1 hour to 2 days (preferably 1 hour to 10 hours).
    [0186] When the protecting group contained in the uracil group in the formula (V) isa pivaloyloxymethyl or acetoxymethyl group, examples of the deprotecting agentusable here include alkali metal hydroxides such as sodium hydroxide and potassiumhydroxide, alkali metal carbonates such as sodium carbonate and potassiumcarbonate, aqueous ammonia, and amines such as methylamine and ethylamine(preferably sodium hydroxide or potassium carbonate). Examples of the solventinclude water, alcohols such as methanol and ethanol, ethers such as dioxane andtetrahydrofuran, and mixtures thereof (preferably a mixed solvent of the alcohols andethers with water). The reaction temperature usually ranges from 0 to 100°C(preferably 10 to 50°C). Although the reaction time differs with the reactiontemperature and the like, it usually ranges from 10 minutes to 1 day (preferably 1 hourto 10 hours).
    [0187] After completion of the reaction, the desired compound in the above reactionis recovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate or saturated saline as needed, drying over anhydrousmagnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. Ifnecessary, the resulting product can be purified further in a manner known to thoseskilled in the art, for example, by recrystallization, reprecipitation, columnchromatography or the like.
    [0188] Step E4 is a step for preparing a compound of the formula (Ih) by reacting acompound of the formula (Ig) with an acid catalyst in an inert solvent.
    [0189] Examples of the acid catalyst include inorganic acids such as hydrochloricacid, sulfuric acid and nitric acid, organic acids such as acetic acid, trifluoroaceticacid, trichloroacetic acid, methanesulfonic acid and p-toluenesulfonic acid, Lewisacids such as boron trifluoride and acidic resins such as "Amberlyst 15", of whichacetic acid, trifluoroacetic acid, p-toluenesulfonic acid and "Amberlyst 15" arepreferred.
    [0190] Examples of the solvent include water, alcohols such as methanol and ethanoland ethers such as dioxane and tetrahydrofuran, and mixed solvents of the alcohol orether with water, of which methanol is preferred.
    [0191] The reaction temperature usually ranges from 0 to 150°C (preferably 10 to80°C). Although the reaction time differs with the reaction temperature and the like.it usually ranges from 1 hour to 2 days (preferably 3 hours to 1 day).
    [0192] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate and saturated saline as needed, and then distilling offthe solvent. If necessary, the resulting product can be purified further in a mannerknown to those skilled in the art, for example, by recrystallization, reprecipitation, orcolumn chromatography.
    [0193] Compound (Ih) thus obtained can be converted to the corresponding hydroxy -protected compound, ester derivative or N-alkylcarbamoyl derivative by any one ofProcesses A to D and below-described Process F. (Process F)
    [0194] Process F is for the preparation of an N-alkylcarbamoyl derivative of theinvention compound (Ia).
    [0195] Step F1 is a step for preparing a compound of formula (VI) by reacting acompound of formula (II) with a benzoylating agent in an inert solvent in the presenceof a base.
    [0196] Examples of the benzoylating agent include benzoyl chloride, benzoylbromide and benzoic anhydride, of which benzoic anhydride is preferred.
    [0197] Examples of the base usable in the above reaction include organic amines suchas triethylamine, 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1.5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine and 4-dimethylaminopyridine andalkali metal hydrides such as sodium hydride and potassium hydride, of whichpyridine and 4-dimethylaminopyridine are preferred.
    [0198] Examples of the solvent usable in the above reaction include ethers such asdiethyl ether, tetrahydrofuran and dioxane, amides such as N,N-dimethylformamideand N,N-dimethylacetamide, halogenated hydrocarbons such as methylene chlorideand chloroform, and pyridine, of which pyridine is preferred.
    [0199] The reaction temperature usually ranges from -30 to 100°C (preferably -10 to30°C). Although the reaction time differs with the reaction temperature and the like,it usually ranges from 30 minutes to 1 day (preferably 1 hour to 10 hours).
    [0200] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture if necessary, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate and saturated saline as needed, drying over anhydrousmagnesium sulfate or anhydrous sodium sulfate, and then distilling off the solvent. Ifnecessary, the resulting product can be purified further in a manner known to thoseskilled in the art, for example, by recrystallization, reprecipitationor column chromatography.
    [0201] Step F2 is a step for preparing a compound of formula (VII) by reacting acompound of formula (VI) with nitrosylsulfuric acid at 0 to 30°C in an inert mixedsolvent of methylene chloride and water and then reacting diazomethane with thereaction mixture at 0 to 30°C in methylene chloride.
    [0202] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art. The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate and saturated saline as needed, drying over anhydrousmagnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. Ifnecessary, the resulting product can be purified further in a manner known to thoseskilled in the art, for example, by recrystallization, reprecipitation or columnchromatography.
    [0203] Step F3 is a step for preparing a compound of the formula (Ii) by reacting acompound of the formula (VII) with an amine in an inert solvent.
    [0204] Examples of the solvent usable in the above reaction include water, alcoholssuch as methanol and ethanol and amides such as N,N-dimethylformamide and N,N-dimethylacetamide,of which alcohols are preferred.
    [0205] The reaction temperature usually ranges from 0 to 100°C (preferably 10 to60°C). Although the reaction time differs with the reaction temperature and the like,it usually ranges from 30 minutes to 1 day (preferably 1 hour to 10 hours).
    [0206] After completion of the reaction, the desired compound in this reaction isrecovered from the reaction mixture in a manner known to those skilled in the art.The desired compound can be obtained, for example, by neutralizing the reactionmixture as needed, filtering off any insoluble matter, adding a water-immiscibleorganic solvent such as ethyl acetate or methylene chloride to the filtrate, washing theresulting mixture with a diluted aqueous solution of hydrochloric acid, an aqueoussolution of sodium bicarbonate and saturated saline as needed, drying over anhydrousmagnesium sulfate or anhydrous sodium sulfate and then distilling off the solvent. Ifnecessary, the resulting product can be purified further in a manner known to thoseskilled in the art, for example, by recrystallization, reprecipitation or columnchromatography.
    [0207] Compound (Ii) thus obtained can be converted to the corresponding hydroxy -protected compound, ester derivative or ether derivative by using any one of theabove-described Processes A to E. The present invention also provides: (1) Compound A-500359E represented by the following formula (XI):
    [0208] Compounds of the present invention represented by any one of the formulae(XI), (XII), (XIII), (XIV), (XV) and (XVI) are produced in the culture broth ofStreptomyces griseus Strain SANK60196 which belongs to the Streptomyces spp. andhas been separated from the soil collected from Mt. Tsukuba/Igaraki-ken; or produced by microbial conversion in the cultivation process or chemical conversion in theisolation and purification process.
    [0209] Compound A-500359E of the formula (XI), Compound A-500359F of theformula (XII), Amide derivative of Compound A-500359F of the formula (XIII),Compound A-500359H of the formula (XIV), Compound A-500359J of the formula(XV) and Compound A-500359M-3 of the formula (XVI) of the present inventioneach contain asymmetric carbons, and each may therefore exist as various opticalisomers. In the present invention, isomers of each of Compound A-500359E,Compound A-500359F, Amide derivative of Compound A-500359F, Compound A-500359H,Compound A-500359J and Compound A-500359M-3 are represented bythe same formula, but the present invention embraces all the isomers includingracemic compounds and also mixtures thereof. When a stereospecific synthesisprocess is adopted or an optically active compound is employed as a startingcompound, the isomer of each of Compound A-500359E, Compound A-5000359F,Amide derivative of Compound A-500359F, Compound A-500359H, Compound A-500359Jand Compound A-500359M-3 may be prepared directly or, if it is preparedin the form of a mixture, each isomer may be obtained in a manner known to thoseskilled in the art.
    [0210] Compound A-500359F, Compound A-500359H, Compound A-500359J andCompound A-500359M-3 of the present invention can each be converted into thecorresponding salt by a method known to those skilled in the art. The presentinvention embraces such salts of Compound A-500359F, Compound A-500359H,Compound A-500359J and Compound A-500359M-3. There is no particularrestriction on the nature of the salt of any of Compound A-500359F, Compound A-500359H,Compound A-500359J and Compound A-500359M-3, provided that it ismedically employed and is pharmacologically acceptable. When the salt ofCompound A-500359F, Compound A-500359H, Compound A-500359J orCompound A-500359M-3 is employed for the purpose other than a medicament, forexample, employed as an intermediate, no limitation is imposed. Preferred examplesof such a salt include alkali metal salts such as a sodium salt, a potassium salt, or alithium salt, alkaline earth metal salts such as a calcium salt or a magnesium salt,metal salts such as an aluminium salt, an iron salt, a zinc salt, a copper salt, a nickelsalt or a cobalt salt, inorganic salts such as an ammonium salt, organic amine saltssuch as a t-octylamine salt, a dibenzylamine salt, a morpholine salt, a glucosamine salt, a phenylglycine alkyl ester salt, an ethylenediamine salt, an N-methylglucaminesalt, a guanidine salt, a diethylamine salt, a triethylamine salt, a dicyclohexylaminesalt, an N,N'-dibenzylethylenediamine salt, a chloroprocaine salt, a procaine salt, adiethanolamine salt, a N-benzylphenethylamine salt, a piperazine salt and atetraamethylammonium salt, or a tris(hydroxymethyl)aminomethane salt, and aminoacid salts such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, or anasparagine salt. More preferred are salts preferably usable as a pharmacologicallyacceptable salt such as a sodium salt, a potassium salt and an ammonium salt.
    [0211] Compound A-500359E, Compound A-500359F, Amide derivative ofCompound A-500359F, Compound A-500359H, Compound A-500359J andCompound A-500359M-3 of the present invention and salts thereof may each exist asa solvate. For example, when they are allowed to stand in the air or recrystallized.water is adsorbed thereto by absorption or a hydrate may be formed. Such a solvate isalso embraced in the present invention.
    [0212] The present invention also embraces all the compounds, so-called prodrugs,which will be converted into Compound A-500359E, Compound A-500359F, Amidederivative of compound A-500359F, Compound A-500359H, Compound A-500359Jor Compound A-500359M-3 by metabolism in vivo.
    [0213] Compound A-500359E, Compound A-500359F, Compound A-500359H,Compound A-500359J and Compound A-500359M-3 of the present invention whichare represented by the formulae (XI), (XII), (XIV), (XV) and (XVI) respectively areavailable by culturing, in a suitable medium, a microorganism belonging to theStreptomyces spp. and recover from the cultured broth. Streptomyces griseus StrainSANK 60196 (which will hereinafter be called "Strain SANK60196"), preferred asthe microorganism capable of producing Compound A-500359E, Compound A-500359F,Compound A-500359H, Compound A-500359J and Compound A-500359M-3are, as described above, collected and isolated from the soil ofTtsukubasan/Ibaraki Prefecture in a conventional manner. Strain SANK60196 has thebiological characteristics as described above.
    [0214] The various characteristics of the actinomycetes belonging to Streptomycesspp. such as Strain SANK60196 are not stable, but as is well known, they easilychange naturally or artificially. The strains usable in the present invention include allsuch variants. The present invention embraces all the strains belonging to the Streptomyces spp. and capable of producing Compound A-500359E, Compound A-500359F,Compound A-500359H, Compound A-500359J or Compound A-500359M-3.
    [0215] Any synthetic or natural medium is usable as a medium for culturing themicroorganism capable of producing Compound A-500359E, Compound A-500359F,Compound A-500359H, Compound A-500359J or Compound A-500359M-3, insofaras it contains a source selected from carbon sources, nitrogen sources, inorganic ionsand organic nutrition sources as necessary.
    [0216] Examples of the nutrition source usable here include known carbon sources,nitrogen sources and inorganic salts which are conventionally used for the cultivationof a mycotic or actinomycete strain and are utilisable by microorganisms.
    [0217] Specific examples of the carbon source include glucose, fructose, maltose,sucrose, mannitol, glycerol, dextrin, oats, rye, corn starch, potato, corn meal, soybeanmeal, cotton seed oil, glutinous malt syrup, syrup, soybean oil, citric acid and tartaricacid. They may be used either singly or in combination. The amount of the carbonsource to be added usually varies, but is not limited to, within a range of from 1 to 10wt.% of the amount of the medium.
    [0218] A substance containing a protein or a hydrolysate thereof is generallyemployed as the nitrogen source. Preferred examples of the nitrogen source includesoybean meal, wheat bran, peanut meal, cotton seed meal, skimmed milk, caseinhydrolysate, Pharmamine (product of Sheffield Chemical), fish meal, corn steepliquor, peptone, meat extract, pressed yeast, dry yeast, yeast extract, malt extract,potato, ammonium sulfate, ammonium nitrate and sodium nitrate. It is preferred touse the above-exemplified nitrogen sources either singly or in combination in anamount ranging from 0.2 to 6 wt.% of the amount of the medium.
    [0219] Any ordinarily employed salt containing an ion such as sodium, ammonium,calcium, phosphate, sulfate, chloride or carbonate can be used as the nutrientinorganic salt. In addition, trace of metals such as potassium, calcium, cobalt,manganese, iron and magnesium are usable.
    [0220] The addition of cobalt, skimmed milk or yeast extract is particularly effectivein the production of Compound A-500359E, Compound A-500359F, Compound A-500359Hor Compound A-500359J.
    [0221] Upon culturing the microorganism, an inhibitor of antibiotic biosynthesis canbe added to produce Compound A-500359E. Compound A-500359F and CompoundA-500359H. Compound A-500359E, Compound A-500359F and Compound A-500359Hcan each be produced, for example, by using S-(2-aminoethyl)-L-cysteine orsalt thereof which is an aspartate kinase inhibitor singly or in combination with cobalt,skimmed milk and yeast extract, as a medium additive. For example, use of theabove-described additive in combination with skimmed milk improves productivity ofCompound A-500359E, Compound A-500359F and Compound A-500359H. Theadditive can be added to give its final concentration ranging from 1 to 100 mM. Forthe production of Compound A-500359E, Compound A-500359F and Compound A-500359H,the final concentration of 10 mM is preferred.
    [0222] Use of the above-described additive in combination with an amino acid or saltthereof makes it possible to produce useful compounds related to Compound A-500359Fand Compound A-500359H. In particular, by the use in combination withL-allylglycine or a salt thereof, Compound A-500359M-3 (XVI) is available. The L-allylglycinecan be added at a final concentration ranging from 1 to 100 mM. At thefinal concentration of 10 mM. Substance A-500359M-3 can be produced preferably.
    [0223] Upon liquid culture, an antifoamer such as silicone oil, vegetable oil,surfactant or the like can be used.
    [0224] The medium for cultivation of Strain SANK60196 to produce Compound A-500359E,Compound A-500359F, Compound A-500359H, or Compound A-500359Jpreferably has a pH ranging from 5.0 to 8.0.
    [0225] Although the temperature which allows growth of Strain SANK60196 rangesfrom 12 to 36°C, the strain is preferably cultured at 18 to 28°C, more preferably 19 to23°C, in order to produce Compound A-500359E, Compound A-500359F, CompoundA-500359H and Compound A-500359J.
    [0226] By in order to obtain Compound A-500359E, Compound A-500359F,Compound A-500359H, Compound A-500359J and Compound A-500359M-3, anaerobic culture of Strain SANK60196 can be used. Examples of such a cultivationmethod include ordinarily employed aerobic culture such as solid culture, shakingculture, and aeration agitation culture.
    [0227] For small-scale cultivation, shake culture for several days at 19 to 23°C ispreferred. Cultivation is started by growing a step of seed culture in a first or second stage process in a baffled Erlenmeyer flask (equipped with a water flow adjustingwall) or an ordinarily-employed Erlenmeyer flask. A carbon source and a nitrogensource can be used in combination as a medium in the seed culture. The seed cultureflask may be shaken at 19 to 23°C for 5 days in a thermostat incubator or shaken untilthe seed culture grows sufficiently. The seed culture thus grown is used forinoculation on the second seed culture medium or a production medium. When theseed cultures are used under an intermediate growing step, they are allowed to growin a similar manner, followed by partial inoculation into a production medium. Theflask into which the seeds have been inoculated is subjected to culturing with shakingat a constant temperature for several days, and after completion of the cultivation, thecultured medium in the flask is centrifuged or filtered.
    [0228] For large-scale cultivation, on the other hand, use of a jar fermenter or tankequipped with an agitator and an aeration apparatus is preferred. Prior to cultivationin such a container, a nutrient medium is heated to 121 to 130°C for sterilization.After cooling, the seed cultures which have been allowed to grow in advance by theabove-described method are inoculated on the sterilized medium. Then, cultivation iscarried out with aeration and agitation at 19 to 23°C. This method is suitable forpreparing a large amount of compounds.
    [0229] Compound A-500359E, A-500359F or A-500359H can also be produced byadding, as an aspartate kinase inhibitor, an aqueous solution of S-(2-aminoethyl)-L-cysteineor salt thereof which has been previously filter-sterilized in advance to asterilized medium at the start of, or during, cultivation.
    [0230] Compound A-500359M-3 can be produced by separately or simultaneouslyadding aqueous solutions of S-(2-aminoethyl)-L-cysteine or salt thereof, and L-allylglycine or salt thereof which have been filter sterilized in advance to the sterilizedmedium at the start of, or during, cultivation.
    [0231] The product of Compound A-500359E, A-500359F, A-500359H, A-500359Jand A-500359M-3 by cultivation can be measured by subjecting a portion of thecultured broth to HPLC analysis. The titre of Compound A-500359E, A-500359F, A-500359H,A-500359J and A-500359M-3 usually reaches a peak in 3 to 15 days.
    [0232] After completion of the cultivation, the cell component is separated from thecultured broth by filtration with the aid of diatomaceous earth or centrifugation andCompound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 present in the filtrate or supernatant is purified by utilizing their physico-chemicalproperties with HPLC analytical data as an index. As diatomaceous earth. "Celite545" (product of Celite Corporation) is preferred. Compound A-500359E, A-500359F,A-500359H, A-500359J and A-50359M-3 present in the filtrate can bepurified by using adsorbents singly or in combination, for example, activated charcoalor an adsorbing resin such as "Amberlite XAD-2 or XAD-4" (product of Rohm &Haas), and "Diaion HP-10, HP-20, CHP-20P, HP-50 or SP207" (each, product ofMitsubishi Chemical). Compound A-500359E, A-500359F, A-500359H. A-500359Jand A-500359M-3 can be separated from impurities by passing a solution containingCompound A-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3through the layer of such an adsorbent as described above, and removing theimpurities adsorbed thereto from the solution; or by eluting the adsorbed CompoundA-500359E, A-500359F, A-500359H, A-500359J and A-500359M-3 with aqueousmethanol, aqueous acetone, aqueous n-butanol, aqueous ammonia, ammonia-containingaqueous methanol or ammonia-containing aqueous acetone. When anammonia-containing solution is employed as an eluent, the amide derivative ofcompound A-500359F happens to be produced upon elution from the column orconcentration.
    [0233] Compound A-500359E, Compound A-500359F, the amide derivative ofCompound A-500359F, Compound A-500359H, Compound A-500359J andCompound A-500359M-3 thus obtained can be purified by adsorption columnchromatography using silica gel, "Florisil", "Cosmosil" (product of Nacalai Tesque),or "Diaion CHP-20P or SP207" (product of Mitsubishi Chemical); gel filtrationchromatography with "Sephadex G-10 (product of Pharmacia Biotech) or "ToyopearlHW40F" (product of TOSOH Corporation); anion exchange chromatography with"Dowex 1 or SBR-P" (product of Dow Chemical) or "Diaion PA316" (product ofMitsubishi Chemical); normal phase and reversed phase HPLC; or the like.
    [0234] Compound A-500359E, Compound A-500359F, the amide derivative ofCompound A-500359F, Compound A-500359H, Compound A-500359J andCompound A-500359M-3 of the present invention can be separated and purified byusing the above-exemplified separation and purification means singly or incombination as needed, or in some cases, by using one of them in repetition.
    [0235] Compound A-500359F can be obtained by hydrolysis of Compound A-500359E.For example, hydrolysis is preferably conducted under basic conditions,preferably in aqueous basic solution.
    [0236] Examples of the basic compound usable for hydrolysis include alkali metalhydroxides and weak acid salts thereof such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium acetate, sodium carbonate, potassium carbonateand sodium bicarbonate; alkaline earth metal hydroxides and weak acid salts thereofsuch as calcium hydroxide, magnesium hydroxide and magnesium acetate; inorganicbasic compounds and basic salts thereof such as ammonia; organic amines and basicsalts thereof such as t-octylamine, dibenzylamine, morpholine, glucosamine,phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine,diethylamine, triethylamine, dicyclohexylamine, N.N'-dibenzylethylenediamine,chloroprocaine, procaine, diethanolamine, N-benzylphenethylamine, piperazine,tetramethylammonia and tris(hydroxymethyl)aminomethane. A basic buffercontaining an alkali metal ion, an alkaline earth metal ion, an inorganic ion such asammonia, or an organic amine ion of the above-exemplified basic compounds mayalso be employed. Among them, alkali metal hydroxides are preferred, of whichsodium hydroxide is particularly preferred. In particular, hydrolysis of Compound A-500359Eby using sodium hydroxide can easily produce Compound A-500359F.
    [0237] The concentration of the basic compound used in the above-described reactionpreferably ranges from 0.001 to 1N, more preferably 0.3 to 0.1N. The reactiontemperature is preferably -20 to 40°C, more preferably 0 to 30°C. The reaction timeis preferably 30 seconds to 15 hours, more preferably 30 minutes to 2 hours.
    [0238] Use of aqueous ammonia as a base produces the amide derivative ofCompound A-500359F together with Compound A-500359F, but these compoundscan be separated and purified by the above-described method.
    [0239] The amide derivative of Compound A-500359F may be produced by reactonof Compound A-500359E with ammonia in a solvent.
    [0240] Examples of the solvent include water and alcohols such as ethanol andmethanol, of which water and methanol are preferred.
    [0241] Gaseous ammonia may be introduced into the solution of the compound, but asolution of ammonia in water or in an alcohol such as methanol or ethanol is usuallyused. Preferably, an aqueous or methanolic solution is employed.
    [0242] When aqueous ammonia is employed, its concentration preferably ranges from0.1 to 1N, more preferably 0.3 to 0.7N. The reaction temperature is preferably -20 to40°C, more preferably 0 to 30°C. The reaction time is preferably 30 minutes to 15hours, more preferably 1 to 4 hours.
    [0243] When aqueous ammonia is used, in addition to the desired amide derivative ofCompound A-500359F, Compound A-500359F is produced by the hydrolysis of theester. These compounds however can be separated and purified by the above-describedmethods.
    [0244] The amide derivative of Compound A-500359F can also be produced byreacting Compound A-500359F with a methylating reagent in a solvent, therebyconverting it to the methyl ester derivative, that is, Compound A-500359E, and thenreacting the resulting compound with ammonia as described above.
    [0245] Examples of the methylating reagent include diazomethane anddimethylsulfuric acid, of which diazomethane is preferred. The methylating reagentfor the conversion of Compound A-500359F to Compound A-500359E is preferablyadded in an amount of 1 to 5 equivalents, preferably 1.5 to 2 equivalents.
    [0246] Examples of the solvent usable for the above reaction include water andalcohols such as methanol and ethanol, of which water and methanol are preferred.
    [0247] The reaction temperature is preferably -20 to 40°C, more preferably 0 to30°C. The reaction time is preferably 30 minutes to 15 hours, more preferably 1 to 2hours.
    [0248] After completion of the reaction, Compound A-500359F, Compound A-500359E,and the amide derivative of Compound A-500359F can be isolated from thereaction mixture by the means selected as needed from those described above in theseparation and purification means for Compound A-500359E, Compound A-500359F,the amide derivative of Compound A-500359F, Compound A-500359H. CompoundA-500359J and Compound A-50359M-3.
    [0249] Typical preparation processes for Compound A-500359E, Compound A-500359F,the amide derivative of Compound A-500359F, Compound A-500359H,Compound A-500359J and Compound A-50359M-3 are described hereinabove, butpreparation processes are not limited thereto and other processes already known tothose skilled in the art may also be employed.
    [0250] Compound A-500359E, Compound A-500359F, the amide derivative ofCompound A-500359F, Compound A-500359H, Compound A-500359J andCompound A-500359M-3 of the present invention thus available are novelcompounds which have not been described in the literature. Their growth inhibitoryactivity against general gram positive bacteria or gram negative bacteria can bedetermined by the disk assay method using normal agar medium (product of EikenChemical) or heart infusion agar medium (product of Difco Laboratories). Growthinhibitory activity against Mycohacteria, gram positive bacteria belonging to theActinomycetales, can be determined similarly on the above-described medium addedfurther with glycerin.
    [0251] Typical evaluation methods of biological activity of Compound A-500359E,Compound A-500359F, the amide derivative of Compound A-500359F. CompoundA-500359H, Compound A-500359J and Compound A-500359M-3 were described sofar, but the evaluation method is not limited thereto, but other evaluation methodsalready known to those skilled in the art can also be employed.
    [0252] The compounds of the present invention or pharmacologically acceptable saltsthereof may be administered through various routes. Examples include oraladministration using tablets, capsules, granules, powders, syrups or the like: andparenteral administration using injections (intravenous, intramuscular orsubcutaneous), drops, suppositories or the like. These formulations can be preparedin a conventional manner by adding to a medicament ordinarily employed carriersknown in the field of pharmaceutical formulation technique such as an excipient.binder, disintegrator, lubricant, corrigent, adjuvant for solubilization, suspendingagent, coating agent and/or the like.
    [0253] For the formation of tablets, various carriers known conventionally in thisfield can be employed. Examples include excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose andsilicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution,starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,potassium phosphate and polyvinyl pyrrolidone; disintegrants such as dry starch,sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calciumcarbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearicmonoglyceride, starch and lactose; disintegration suppressants such as sucrose,stearin, cacao butter and hydrogenated oil; absorption facilitators such as quaternary ammonium salts and sodium lauryl sulfate: humectants such as glycerin and starch:adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; andlubricants such as purified talc, stearates, boric acid powder and polyethylene glycol.Tablets can be formed as those having ordinary coating as needed such as sugarcoated tablets, gelatin encapsulated tablets, enteric coated tablets, film coated tablets.or double or multiple layer tablets.
    [0254] For the formation of pills, various carriers conventionally known in this fieldcan be used. Examples include excipients such as glucose, lactose, cacao butter.starch, hardened vegetable oil, kaolin and talc; binders such as gum arabic powder.tragacanth powder, gelatin and ethanol: and disintegrators such as laminaran agar.
    [0255] For the formation of suppositories, various carriers conventionally known inthis field can be employed. Examples include polyethylene glycol, cacao butter.higher alcohols and esters thereof, gelatin and semi-synthetic glyceride.
    [0256] For formulation as injections, it is preferred that solutions or suspensions aresterilized and they are made isotonic with the blood. Solutions, emulsions orsuspensions can be formed using any diluent conventionally used in this field.Examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol.polyoxylated isostearyl alcohol and polyoxyethylene sorbitan esters of fatty acid. It isalso possible to incorporate, in a pharmaceutical preparation, salt, glucose or glycerinin an amount sufficient for preparing an isotonic solution, or to add an ordinarilyemployed adjuvant for solubilization, buffer, soothing agent and/or the like.
    [0257] If necessary, a colourant, preservative, flavor, sweetener or other medicamentsmay be incorporated.
    [0258] There is no particular limitation on the content of the compound incorporatedas an effective ingredient in the above-described pharmaceutical preparation. It canbe chosen suitably from a wide range. In general, it is desired to be contained in anamount of 1 to 70 wt.%, preferably 1 to 30 wt.% in the whole composition.
    [0259] There is no particular limitation on the administering method of the above-describedpharmaceutical preparation and it is determined depending on the dosageform or age, sex or other conditions of a patient to be administered or seriousness ofthe disease of the patient. For example, tablets, pills, solutions, suspensions,emulsions, granules or capsules are administered orally. Injections are administeredintravenously either singly or as a mixture with an ordinarily employed fluidreplacement such as glucose or amino acid. If necessary, they are singly administered intramuscularly, subcutaneously, intracutaneously or intraperitoneally. A suppositoryis administered rectally.
    [0260] Although the dose of the pharmaceutical composition differs with theconditions, age and weight of the patient, administration route or dosage form, dailydose usually ranges from 2000 mg (preferably 100 mg) as the upper limit to 0.1 mg(preferably 1 mg, more preferably 10 mg) as the lower limit per adult. It can beadministered once or in several portions a day according to the conditions. [Best Mode for Carrying out the Invention]
    [0261] The present invention will hereinafter be described more specifically byExamples, Tests and Formulation Examples. It should however be borne in mind thatthe present invention is not limited to or by them. The process for preparingcapuramycin, a known substance, will next be described. Preparation Example 1: Capuramycin 1) Cultivation of Streptomyces griseus Strain SANK 60196 (FERM BP-5420)
    [0262] Into each of four 2 L Erlenmeyer flasks (seed flasks), each containing 400 mlof a seed culture medium having the below-described composition, were inoculatedfour loopfuls of Strain SANK 60196 followed by shaking in a rotary shaker at 28°Cand 210 revolutions/min (revolutions per minute: which will hereinafter beabbreviated as "rpm"). Seed culture was thus conducted for 5 days. Seed culture medium Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g CaCO3 3 g Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes.
    [0263] Cultivation was conducted as described below. Described specifically, theseed culture was inoculated at 2% (v/v) into each of four 30L jar fermenters, eachcontaining 15 L of a sterilized main culture medium having the below-describedcomposition, followed by cultivation with aeration and agitation at 28°C for 8 days. Main culture medium Glucose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g CoCl2·6H2O 50 mg CaCO3 3 mg Antifoamer 50 mg("CB442"; product of NOF Corporation) Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes 2) Isolation and purification of capuramycin
    [0264] After completion of the cultivation, the cultured broth (52 L) obtained abovein 1) was filtered with the aid of"Celite 545" (product of Celite Co.) added at 4%(v/v). The filtrate (50 L) was charged on a "Diaion HP-20" column (product ofMitsubishi Chemical; 12 L). The resulting column was washed with 18 L of distilledwater and the adsorbed substance was eluted with 50 L of 10% aqueous acetone. Theeluate was concentrated by "Evapor" to give 15 L of the concentrate.
    [0265] Upon purification as described later, the active substance of each fraction wasmonitored by HPLC under the following conditions. Column: "Senshu Pak ODS-H-2151" 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - 0.04% aqueous trifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 210 nm
    [0266] The resulting concentrate was charged on a "Diaion CHP-20P" column(product of Mitsubishi Chemical; 8 L). The column was washed successively with16L each of 10% aqueous methanol and 20% aqueous methanol, followed bystepwise elution of the active substances with 16L of 30% aqueous methanol and 24Lof 40% aqueous methanol.
    [0267] On "Diaion CHP-20P" column chromatography, a peak at a retention time of17.1 minutes upon the above-described HPLC was mainly detected from a 0 to 8Lportion (which will hereinafter be called "Fraction A") of 30% aqueous methanoleluate; peaks at retention times of 13.7 minutes, 17.1 minutes and 22.6 minutes uponthe above-described HPLC were detected from a 8 to 16L portion (which willhereinafter be called "Fraction B") of 30% aqueous methanol eluate; and a peak at aretention time of 22.6 minutes upon the above-described HPLC was detected from a 0to 12 portion (which will hereinafter be called "Fraction C") of the 40% aqueousmethanol eluate. These fractions were concentrated by "Evapor", respectively, whereby 8.5 L of Fraction A, 8.5 L of Fraction B and 12.5 L of Fraction C wereobtained, each as a concentrate.
    [0268] A 16 to 24 L portion (which will hereinafter be called "Fraction D") of the40% aqueous methanol eluate was concentrated by "Evapor" and lyophilized,whereby 4.7 g of Fraction D was obtained as a crude powdery product.
    [0269] Fraction B was charged again on a "Diaion CHP-20P" column (1.5 L). Afterwashing the column with 3 L of 10% aqueous methanol, the adsorbed material waseluted stepwise with 3L each of 20% aqueous methanol, 30% aqueous methanol and40% aqueous methanol. From a combined fraction (which will hereinafter be called"Fraction E") of the 0.5 to 3 L portion of the 20% aqueous methanol eluate and the 0to 1 L portion of the 30% aqueous methanol eluate, a peak at a retention time of 17.1minutes in the above-described HPLC was mainly detected; from a combined fraction(which will hereinafter be called "Fraction F") of the 1 to 3 L portion of the 30%aqueous methanol eluate and the 0 to 0.5 L portion of the 40% aqueous methanoleluate, a peak at a retention time of 13.7 minutes in the above-described HPLC wasmainly detected; and from the 0.5 to 3 L portion (which will hereinafter be called"Fraction G") of the 40% aqueous methanol eluate, a peak at a retention time of 22.6minutes was mainly detected.
    [0270] Fraction A was combined with Fraction E (the combined one will hereinafterbe called "Fraction H"), while Fraction C was combined with Fraction G (thecombined one will hereinafter be called "Fraction I"). Fractions F, H and I wereconcentrated on "Evapor" and lyophilized, respectively, whereby 16.2 g of FractionH, 33.6 g of Fraction I and 8.6 g of Fraction F were obtained, each as a crude powderyproduct.
    [0271] The resulting crude powdery product of Fraction H (16.2 g) was dissolved in250 ml of deionised water. The resulting solution was charged on a "Toyopearl HW-40F"column (product of TOSOH Corporation; 4 L), followed by development withdeionised water. As a result of fractionation of the eluate to 75 ml portions each, theactive substance having a retention time of 17.1 minutes in the above-describedHPLC was eluted in Fraction Nos. 41 to 63. These fractions were collected andconcentrated by "Evapor" into 820 ml and the resulting concentrate was lyophilized togive 6.4 g of a crude powdery product.
    [0272] The crude powdery product thus obtained was dissolved in 400 ml of water.Each of the 80 ml portions of the resulting solution was charged on an HPLC column (YMC-Pack ODS R-3105-20 (100 x 500 mm; product of YMC Co., Ltd.))equilibrated with a 6% aqueous solution of acetonitrile, followed by columndevelopment at a flow rate of 200 ml/min. The ultraviolet absorption of the activesubstance at 210 nm was detected and a peak eluted at a retention time of 105 to 120minutes was collected by five fractionation, each in portions of 400 ml.
    [0273] The resulting fractions were combined and concentrated by "Evapor" into 330ml, followed by lyophilization, whereby 3.6 g of a substance was obtained in pureform. The substance was identified as capuramycin, a known antibiotic, by structuralanalysis. Example 1: Preparation of A-500359A (Exemplification (exemp.) Compound No. 1)
    [0274] The crude powdery product (33.6 g) of Fraction I obtained in PreparationExample 1 was dissolved in 450 ml of deionised water. The resulting solution wascharged on a "Toyopearl HW-40F" column (8 L), followed by elution with deionisedwater. As a result of fractionation of the eluate into 150 ml portions, the activesubstance exhibiting a retention time of 22.6 minutes in HPLC was eluted in FractionsNos. 47 to 73. These fractions were collected, concentrated by "Evapor" into 1.5 Land then lyophilized to give 25 g of a crude powdery product.
    [0275] The resulting crude powdery product (25 g) was dissolved in 300 ml ofdeionised water. The resulting solution was charged on a "Cosmosil 140C18-OPN"column (product of Nacalai Tesque; 1.5 L). After washing the column with 3 L ofdeionised water and 12 L of 1% aqueous acetonitrile, the active compound was elutedwith 6 L of 10% aqueous acetonitrile. The eluate was concentrated by "Evapor" into840 ml and insoluble matter was filtered from the concentrate. The filtrate waslyophilized to give 20 g of Substance A-500359A in pure form. The following dataare physico-chemical properties of the resulting substance. 1) Appearance of the substance: white powder 2) Solubility: soluble in water and methanol, insoluble in normal hexane andchloroform 3) Molecular formula: C14H33N5O12 4) Molecular weight: 583 (measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows:Found: 584.2189 Calculated: 584.2205 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   257 nm (ε 10,300) 7) Optical rotation: optical rotation measured in methanol exhibits the followingvalue:[α]D 20:+94.7° (c 1.00, MeOH) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following maximum absorption:3380, 2940, 1690, 1520, 1460, 1430, 1390, 1270, 1110, 1060 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard. 1H nuclear magnetic resonancespectrum is as follows:1.22(3H,d,J=6.7Hz), 1.29(1H,m), 1.49(1H,m), 1.78(1H,m), 1.87(1H,m), 1.92(1H,m),2.01(1H,m), 3.44(3H,s), 3.58(1H,m), 3.86(1H,br.t,J=4.6Hz),3.96 (1H,ddd,J=0.7,4.5,5.7Hz), 4.30(1H,t,J=5.2Hz), 4.37(1H,t,J=4.1Hz),4.56(1H,dd,J=2.0,11.9Hz), 4.58(1H,dd,J=2.0,4.3Hz), 4.67(1H,d,J=2.0Hz),5.23(1H,d,J=5.8Hz), 5.72(1H,d,J=8.1Hz), 5.88(1H,d,J=5.2Hz),6.02(1H,br.dd,J=0.7,3.9Hz), 7.91(1H,d,J=8.1Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard. 13C nuclear magnetic resonancespectrum is as follows:22.2(q), 28.4(t), 32.1(t), 37.9(t), 50.1(d), 53.5(d), 58.8(q), 63.6(d), 68.8(d), 74.6(d),79.2(d), 81.1(d), 83.6(d), 90.4(d), 101.3(d), 102.9(d), 109.3(d), 142.0(d), 144.4(s),152.4(s), 161.9(s), 166.1(s), 173.5(s), 175.3(s) ppm. 11) High performance liquid chromatography Column: "Senshu Pak ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - water Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 20 minutes.
    [0276] The crude powdery product (8.6 g) of Fraction F was dissolved in 500 ml ofdeionised water. The resulting solution was charged on a "Toyopearl HW-40F"column (8.5 L), which was developed with deionised water. As a result offractionation of the eluate into 150 ml portions, the active substance exhibiting aretention time of 13.7 minutes in HPLC was eluted in Fraction Nos. 44 to 82. Thesefractions were collected, concentrated by "Evapor" into 900 ml, and lyophilized,whereby 2.2 g of a crude powdery product was obtained.
    [0277] The resulting crude powdery product (2.2 g) was dissolved in 150 ml ofdeionised water. The resulting solution was charged on a "Cosmosil 140C18-OPN"column (product of Nacalai Tesque; 1.5 L). After washing the column successivelywith 3 L of deionised water, 3 L of 0.5% aqueous acetonitrile, 3 L of 1% aqueousacetonitrile and 15 L of 2% aqueous acetonitrile, the active substance was eluted with10L of 4% aqueous acetonitrile. The fraction was concentrated by "Evapor" into 500ml and then lyophilized, whereby 550 g of a crude powdery product was obtained.
    [0278] The crude powdery product was dissolved in 80 ml of deionised water. Theresulting solution was charged on an HPLC column (YMC-Pack ODS R-3105-20(100 x 500 mm; product of YMC)) equilibrated with a 6% aqueous solution ofacetonitrile, and the column was developed at a flow rate of 200 ml/min. Theultraviolet absorption of the active fraction at 210 nm was detected and the activefraction eluted at a retention time of from 167 to 180 minutes was collected byfractionation.
    [0279] The resulting fraction was concentrated into 50 ml by "Evapor", followed bylyophilization, whereby 210 mg of Compound A-500359C was obtained in pure form.The following data are physico-chemical properties of the resulting substance. 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C23H31N5O12 4) Molecular weight: 569 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB spectrometry is asfollows:Found: 570.2034 Calculated: 570.2049 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   257 nm (ε 10,700) 7) Optical rotation: optical rotation measured in water exhibits the following value:[α]D 20: +89° (c 0.44, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3390,2930, 1690, 1520, 1460, 1430, 1390, 1270, 1110, 1060 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 'H nuclear magnetic resonance spectrum is as follows:1.20(3H,d,J=6.7Hz), 1.29(1H,m), 1.62(1H,m), 1.72(1H,m), 1.75(1H,m), 1.90(1H,m),1.92(1H,m), 3.65(1H,m), 4.11(1H,dd,J=5.2,6.3Hz), 4.15(1H,ddd,J=1.4,4.2,4.3Hz),4.18(1H,dd,J=3.3,5.2Hz), 4.43(1H,dd,J=2.1,6.3Hz), 4.49(1H,dd,J=3.0,4.4Hz),4.62(1H,dd,J=1.7,10.8Hz), 4.76(1H,d,J=2.1Hz), 5.36(1H,d,J=4.0Hz),5.77(1H,d,J=3.3Hz), 5.84(1H,d,J=8.1Hz), 5.98(1H,br.dd,J=1.3,3.0Hz),7.72(1H,d,J=8.1Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard. 13C nuclear magnetic resonancespectrum is as follows:21.0(q), 26.8(t), 29.4(t), 35.4(t), 48.9(d), 52.6(d), 61.9(d), 65.3(d), 69.4(d), 73.8(d),76.7(d), 83.1(d), 89.7(d), 100.1(d), 101.9(d), 109.1(d), 141.0(d), 141.8(s), 151.6(s),161.7(s), 166.4(s), 173.5(s), 175.8(s) ppm. 11) High performance liquid chromatography Column: "Senshu Pak ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - water Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 13 minutes.
    [0280] An 800 mg portion of the crude powdery product obtained as Fraction D wasdissolved in 10 ml of deionised water. A 500 µl portion of the resulting solution wascharged on an HPLC column ("Senshu Pak Pegasil ODS " (20 x 250 mm, product ofSenshu Scientific)) which had been equilibrated with a developing solvent containingacetonitrile, methanol and 0.04% aqueous trifluoroacetic acid at 3:21:76, and thecolumn was developed with the same solvent at a rate of 9 ml/min. The ultravioletabsorption of the active fraction at 210 nm was detected and a peak eluted during 35to 38 minutes was collected by fractionation. The procedure was carried out 20 timesto elute the (in portions of 10 ml).
    [0281] The powder (15 mg) obtained by concentrating the fractions eluted during 35to 38 minutes and lyophilizing the concentrate was chromatographed again on thesame HPLC column and then, concentrated and lyophilized, whereby 7 mg ofCompound A-500359D was obtained in pure form.
    [0282] The following data are the physico-chemical properties of the resultingsubstance. 1) Appearance of the substance: white powder 2) Solubility: soluble in water and methanol, insoluble in normal hexane andchloroform 3) Molecular formula: C24H33N5O11 4) Molecular weight: 567 (as measured by FAB mass spectrometry) 5) Precise mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 568.2239 Calculated: 568.2254 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   244 nm (ε 10,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:   [α]D 20: +68° (c 0.69, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3397, 2925, 1683, 1514, 1461, 1432, 1385, 1265, 1205, 1095, 1061 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows:1.12(3H,d,J=8.1Hz), 1.17(1H,m), 1.40(1H,m), 1.67(1H,m), 1.80(1H,m), 1.88(1H,m),1.90(1H,m), 2.33(1H,m), 3.24(3H,s), 3.50(1H,m), 3.57(1H,t,J=4.7Hz),4.08(1H,t,J=4.8Hz), 4.37(m),4.40(m), 4.46(1 H,br.d,J=10.7Hz), 4.50(1H,d,J=2.0Hz),5.30(1H,br.s), 5.64(1H,d,J=8.1Hz), 5.73(1H,d,J=4.8Hz), 5.97(1H,d,J=2.4Hz),7.77(1H,d,J=8.1Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterated methanolwith the signal of methanol as 49.15 ppm. 13C nuclear magnetic resonance spectrumis as follows:22.3(q), 28.6(t), 32.3(t), 35.8(t), 38.0(t), 50.2(d), 53.6(d), 58.8(q), 60.7(d), 74.7(d),77.7(d), 80.9(d), 83.8(d), 90.7(d), 99.5(d), 103.0(d), 112.3(d), 142.0(d), 144.1(d),152.4(s), 162.4(s), 166.3(s), 173.6(s), 175.5(s) ppm. 11) High performance liquid chromatography Column: "Cosmosil 5C18-MS", 4.6 x 150 mm (product of Nacalai Tesque) Solvent: a 3:21:76 mixture of acetonitrile : methanol : 0.04% aqueoustrifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 9.2 minutes.
    [0283] Into each of three 2L Erlenmeyer flasks (seed flasks) each containing 500 mlof a medium having the below-described composition were inoculated, in a sterilecondition, four loopfuls of Strain SANK60196, followed by shaking in a rotary shakerat 23°C and 210 rpm. Seed culture was thus conducted for 5 days. Seed culture medium Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g CaCO3 3 gAntifoamer 50 mg (CB442) Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes
    [0284] Cultivation was conducted as described below. Described specifically, theseed culture was inoculated at 3% (v/v) into each of two 30 L jar fermenters, eachcontaining 15 L of a sterilized medium having the below-described composition. OnDay 1 after the commencement of cultivation at 23°C, filter sterilized S-(2-aminoethyl)-L-cysteinehydrochloride was added to give a final concentration of 8mM, and cultivation was then carried out with aeration and agitation for 7 days. Cultivation medium Maltose 30 g Yeast extract 5 g (product of Difco Laboratories) Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Cobalt chloride hexahydrate 0.5 g CaCO3 3 g Antifoamer 50 mg (CB442) Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes Example 5: Preparation of A-500359G (Exemp. compound No. 45)
    [0285] After completion of the cultivation, the cultured broth (28 L) obtained inExample 4 was filtered with the aid of "Celite 545".
    [0286] Upon purification as described later, the active fraction was monitored by thefollowing high performance liquid chromatography (HPLC). Column: "Senshu Pak ODS-H-2151" 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 4.6 minutes
    [0287] 37 L of the resulting filtrate was charged on a "Diaion HP-20" column (5.5 L).After washing the column with 11 L of deionised water, the adsorbed substance waseluted with 11 L of 10% aqueous acetone. The eluate was concentrated to removeacetone. The residue was lyophilized, whereby 40 g of a crude powdery product wasobtained.
    [0288] The resulting crude powdery product was dissolved in 1 L of distilled waterand charged on a "Diaion CHP-20P" column (3 L). The column was then washedwith 6 L of distilled water, and the adsorbed substance was eluted successively with 6L of each of 5% aqueous methanol, 10% aqueous methanol and 15% aqueousmethanol. The 15% aqueous methanol eluate was concentrated to remove methanol.The residue was lyophilized to give 1.27 g of a powder.
    [0289] The resulting powder was dissolved in 30 ml of distilled water and theresulting solution was charged on a "Toyopearl HW40F" column (500 ml), followedby elution of the column with distilled water. The eluate was collected byfractionation in portions of 10 ml, each. The active substance having a retention timeof 4.6 minutes in the above-described HPLC was eluted in fractions Nos. 41 to 46.The resulting fractions were concentrated and lyophilized to give 134 mg of a powder.
    [0290] The resulting powder was dissolved in 3 ml of water and a 750 µl portion ofthe resulting solution was charged on an HPLC column ("Senshu Pak ODS-H-5251"(20 mm x 250 mm; product of Senshu Scientific)) equilibrated with 4% aqueousacetonitrile containing 0.04% of aqueous trifluoroacetic acid. The column wasdeveloped at a flow rate of 10 ml/min. The ultraviolet absorption of the active substance of 210 nm was detected and a peak eluted during 27 to 30 minutes wascollected by fractionation. The process was carried out four times.
    [0291] These fractions eluted during 27 to 30 minutes were concentrated andlyophilized to afford 20 mg of a powder. The resulting powder was dissolved in 1.6ml of water and a 800 µl portion of the resulting solution was charged on the above-describedHPLC column using instead, as a developing solvent, a 5% aqueousacetonitrile solution containing 0.04% of TFA. The column was developed at a rateof 10 ml/min. The active substance showing ultraviolet absorption at 210 nm wasdetected and a peak eluted during 19 to 20 minutes was collected again byfractionation. The fractions were concentrated and lyophilized, whereby 14 mg ofCompound A-500359G was obtained in pure form. The substance has the followingphysico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C22H29N5O12 4) Molecular weight: 555 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 556.1891 Calculated: 556.1890 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   257 nm (ε 10,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:   [α]D 20: +109° (c 0.72, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3367, 2931, 1684, 1518, 1482, 1464, 1436, 1408, 1385, 1335, 1272, 1205, 1177,1114, 1063 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows: 1.37 (1H, m), 1.65 (1H, m), 1.71 (1H, m), 1.79 (1H, m), 1.92 (1H, m), 1.98 (1H, m),3.29 (1H, m), 3.36 (1H, m), 4.10 (1H, dd, J=5.0, 6.5 Hz), 4.14 (1H, dt, J=1.5, 4.4 Hz),4.17 (1H, dd, J=3.2, 5.0 Hz), 4.41 (1H, dd, J=2.1, 6.5 Hz), 4.47 (1H, dd, J=2.9, 4.4Hz), 4.61 (1H, dd, J=1.8, 11.4 Hz), 4.78 (1H), 5.35 (1H, d, J=4.1 Hz), 5.75 (1H, d,J=3.2 Hz), 5.82 (1H, d, J=8.2 Hz), 5.97 (1H, dd, J=1.5, 2.9 Hz), 7.71 (1H, d, J=8.2Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard. 13C nuclear magnetic resonancespectrum is as follows:28.2 (t), 28.4 (t), 30.5 (t), 42.2 (t), 53.3 (d), 62.7 (d), 66.1 (d), 70.2 (d), 74.5 (d), 77.5(d), 83.9 (d), 90.5 (d), 100.9 (d), 102.7 (d), 109.9 (d), 141.8 (d), 142.7 (s), 152.2 (s),162.6 (s), 166.9 (s), 174.3 (s), 177.6 (s) ppm. 11) High performance liquid chromatography : Column: "Senshu Pak ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 4.6 minutes
    [0292] Into each of four 2 L Erlenmeyer flasks (seed flasks) each containing 500 mlof a medium having the below-described composition were inoculated, in a sterilecondition, four loopfuls of Strain SANK60196, and cultivation was then carried outwith shaking in a rotary shaker at 23°C and 210 rpm. Seed culture was thusconducted for 3 days. Seed culture medium Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g CaCO3 3 gAntifoamer 50 mg (CB442) Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes
    [0293] The culture was conducted as described below. Described specifically, theseed culture broth was inoculated at 3% (v/v) into each of two 30 L jar fermenters,each containing 15 L of a sterilized medium having the below-described composition.Six hours after commencement of cultivation at 23°C, filter-sterilized S-(2-aminoethyl)-L-cysteinehydrochloride was added to give a final concentration of 10mM, and cultivation with aeration and agitation was then carried out for 6 days. Cultivation medium Maltose 30 g Yeast extract 5 g (product of Difco Laboratories) Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g CaCO3 3 g Antifoamer 50 mg ("CB442") Tap water 1000 ml pH before sterilization: 7.4Sterilization: at 121°C for 30 minutes Example 7: Preparation of A-500359 M-2 (Exemp. compound No. 396)
    [0294] After completion of cultivation, the cultured broth (30 L) obtained in Example6 was filtered with the aid of "Celite 545".
    [0295] Upon purification as described later, the active fraction was monitored by thefollowing high performance liquid chromatography (HPLC) method. Column: "Senshu Pak ODS-H-2151" 6 x 150 mm (product of Senshu ScientificCo.. Ltd.) Solvent: 8% acetonitrile - 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 13.6 minutes
    [0296] 30 L of the resulting filtrate was charged on a "Diaion HP-20" column (6 L).After washing the column with 12 L of deionised water, the adsorbed substance waseluted with 10% aqueous acetone. The fraction eluted in 12 to 24 L was concentrated toremove acetone. The residue was lyophilized, whereby 12 g of a crude powdery productwas obtained.
    [0297] The resulting crude powdery product was dissolved in 650 ml of distilled water.The resulting solution was charged on a "Diaion CHP-20P" column (1 L). The columnwas then washed with 2 L of distilled water, and the adsorbed substance was eluted with2 L of 20% aqueous methanol and 4 L of 30% aqueous methanol. The 2 to 4 L portion ofthe 30% aqueous methanol eluate was concentrated to remove methanol. The residuewas lyophilized to yield 2.8 g of a powder.
    [0298] The resulting powder was dissolved in 50 ml of distilled water and the resultingsolution was charged on a "Toyopearl HW40F" column (500 ml), followed bydevelopment of the column with distilled water. The eluate was fractionated in portionsof 12 ml, each. The active substance having a retention time of 13.6 minutes in theabove-described HPLC was eluted in Fraction Nos. 40 to 47. The resulting fractionswere concentrated and lyophilized to give 841 mg of a powder.
    [0299] The resulting powder was dissolved in 23 ml of water and a 1 ml portion of theresulting solution was charged on an HPLC column ("Senshu Pak ODS-H-5251" (20 mmx 250 mm; product of Senshu Scientific)) equilibrated with an aqueous solutioncontaining 0.04% trifluoroacetic acid, 4% acetonitrile and 10% methanol. The columnwas developed at a flow rate of 10 ml/min. The ultraviolet absorption of the activesubstance of 210 nm was detected and a peak eluted during 23 to 26 minutes wascollected by fractionation, the preparation being carried out 23 times.
    [0300] The fractions eluted during 23 to 26 minutes were concentrated and lyophilized toafford 421 mg of a powder. The resulting powder was dissolved in 40 ml of water againand the resulting solution was charged on the above-described HPLC column using instead, a 7% aqueous acetonitrile solution containing 0.04% ofTFA as a developing solvent. The column was developed at a rate of 10 ml/min. Theultraviolet absorption of the active substance of 210 nm was detected and a peakeluted during 33 to 35 minutes was collected again by fractionation, the process beingcarried out in 40 times. The fractions were concentrated and lyophilized, whereby190 mg of Substance A-500359 M-2 was obtained in pure form.
    [0301] The substance has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water and methanol, insoluble in normal hexane andchloroform 3) Molecular formula: C23H31N5O12S 4) Molecular weight: 601 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 602.1779 Calculated: 602.1769 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   244 nm (ε 14,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:   [α]D 20: +58° (c 0.39, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3390, 2937, 1683, 1510, 1461, 1432, 1411, 1344, 1268, 1206, 1179, 1135, 1071, 1023cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows:1.30(3H,d,J=6.8Hz), 2.63(2H,m), 2.76(1 H,dd,J=2.9, 14.4Hz),2.84(1H,dd,J=8.8,14.4Hz), 3.28(3H,s), 3.73(1H,dd,J=5.0,6.5Hz), 3.98(1H,m),4.19(1H,ddd,J=1.5,3.5,4.4Hz), 4.38(1H,dd,J=3.2,5.0Hz), 4.47(1H,dd,J=2.6,6.5Hz),4.50(1H,dd,2.6,4.4Hz), 4.73(1H,d,J=2.6Hz), 5.02(1H,dd,J=2.9,8.8Hz),5.39(1H,d,J=3.5Hz), 5.75(1H,d,J=3.2Hz), 5.85(1H,d,J=8.1Hz),6.03(1H,dd,J=1.5,2.6Hz), 7.74(1H,d,J=8.1Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard. 13C nuclear magnetic resonancespectrum is as follows:21.3(q), 30.0(t), 36.3(t),53.2(d), 55.9(d), 58.6(q), 62.7(d), 65.7(d), 72.7(d), 76.5(d),78.9(d), 82.4(d), 91.1(d), 100.3(d), 102.7(d), 110.6(d), 141.9(d), 142.3(s), 152.1(s),162.3(s), 166.9(s), 173.8(s), 174.5(s) ppm. 11) High performance liquid chromatography Column: "Senshu Pak ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 8% acetonitrile - 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 14.4 minutes
    [0302] In the below-described Examples, Me, TBS, THF, TBAF, DMAP and WSCstand for a methyl group, a tert-butyldimethylsilyl group, tetrahydrofuran,tetrabutylammonium fluoride, 4-(dimethylamino)pyridine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, respectively. Example 8 (Exemp. compound No. 135)
    [0303]
    [0304] Capuramycin (2 g) was dried by azeotropy twice with pyridine and dissolvedin 34 mL of pyridine. To the resulting solution, 1.59 g of tert-butyldimethylsilylchloride was added, followed by stirring at room temperature. Three days later, thesolvent was distilled off under reduced pressure. The residue was dissolved in 200mL of ethyl acetate. The resulting solution was washed with 200 mL of saturatedsaline and dried over anhydrous magnesium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was charged on a silica gel column(300 g), which was developed with methylene chloride - methanol (concentrationgradient from 97:3 to 90:10, which will hereinafter be described as "97:3 to 90:10"),whereby 474.6 mg of the below-described compound was obtained.
    [0305] In 3 mL of pyridine were dissolved 100 mg of the compound obtained in (8-1)and 2 mg of DMAP. To the resulting solution was added 145 mg of palmiticanhydride, followed by stirring at room temperature. Forty minutes later, the solventwas distilled off under reduced pressure, and the residue dissolved in 20 mL of ethylacetate. The resulting solution was washed with 20 mL of saturated aqueous sodiumbicarbonate and dried over anhydrous magnesium sulfate. The residue obtained bydistilling off the solvent under reduced pressure was charged on a silica gel column(14 g), which was developed with methylene chloride - methanol (98:2 to 95:5),whereby 42.7 mg of the following compound was obtained.
    [0306] In 53 µL of THF were dissolved 41 mg of the compound obtained in (8-2). A53 µL THF solution containing 1M of TBAF was added to the resulting solution andthe mixture stirred at room temperature. Four hours later, the solvent was distilled offunder reduced pressure. The residue was charged on a silica gel column (6 g), whichwas developed with methylene chloride - methanol (96:4 to 94:6), whereby 16.3 mgof the below-described compound was obtained as a desired compound ofExample 8.
    [0307]
    [0308] In 4.5 mL of pyridine were dissolved 150 mg of the compound obtained inExample (8-1), 69 µL of heptanoic anhydride and 3 mg of DMAP. In a similarmanner to that described in Example (8-2), the resulting solution was reacted,whereby 286 mg of the following compound was obtained.
    [0309] In 250 µL of THF was dissolved 286 mg of the compound obtained inExample (9-1). To the resulting solution was added 250 µL of a THF solutioncontaining 1M of TBAF. The resulting mixture was reacted in a similar manner tothat described in Example (8-3), whereby 96.3 mg of the below-described compoundwas obtained as the desired compound of Example 9.
    [0310]
    [0311] The compound shown above was synthesized in accordance with the processdescribed in Japanese Patent Application Kokai Hei 5-148293. Describedspecifically, 1 g of capuramycin was dissolved in 175 mL of acetone. To the resultingsolution were added 9.2 mL of 2,2-dimethoxypropane and 253 mg of "Amberlyst 15(H+)". The resulting mixture was stirred at room temperature. Two days later, the"Amberlyst 15 (H+)" evaporated and the solvent was distilled off under reducedpressure. The residue was dissolved in 7 mL of chloroform, followed by the additionof 30 mL of hexane. White crystals thus precipitated were collected by filtration, andcharged on a silica gel column (40 g), which was developed with methylene chloride -methanol (92:8), whereby 582.7 mg of the following compound was obtained.
    [0312] In 3 mL of pyridine were dissolved 100 mg of the compound obtained in (10-1),243 mg of palmitic anhydride and 2 mg of DMAP. The resulting solution wasstirred at room temperature. One hour later, 1 mL of methanol was added toterminate the reaction. The solvent was then distilled off under reduced pressure.The residue was dissolved in 100 mL of ethyl acetate. After washing with 100 mL ofsaturated aqueous sodium bicarbonate, drying was conducted over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. From the residue,pyridine was removed by azeotropy with toluene, whereby a mixture containing thebelow-described compound was obtained. The mixture was provided for thesubsequent reaction (10-3) without purification.
    [0313] In 10 mL of methanol was dissolved the whole amount of the mixtureobtained in (10-2). To the resulting solution was added 100 mg of "Amberlyst 15(H+)", and the mixture was stirred for 47 hours at room temperature and for 4 hours at80°C. After filtration through Celite, the solvent was distilled off under reducedpressure. The residue was charged on a silica gel column (5 g), which was developedwith methylene chloride - methanol (95:5 to 93:7), whereby 84.9 mg of the below-describedcompound was obtained as the desired compound of Example 10.
    [0314]
    [0315] In 1.5L of acetone was dissolved 8.5 g of A-500359A. To the resultingsolution were added 72.7 mL of 2,2-dimethoxypropane and 2 g of "Amberlyst 15(H+)". The resulting solution was stirred at room temperature. Three days later, the"Amberlyst 15 (H+)" was filtered off and the solvent distilled off under reducedpressure. The residue was dissolved in 50 mL of chloroform, followed by theaddition of 200 mL of hexane. White crystals thus precipitated were collected byfiltration and charged on a silica gel column (400 g) which was developed withmethylene chloride - methanol (91:9), whereby 8.83 g of the following compound wasobtained.
    [0316] In 2 mL of THF were dissolved 125 mg of the compound obtained in (11-1),68 mg of 3,3-diphenylpropionic acid, 6 mg of DMAP and 58 mg of WSC. Theresulting solution was stirred at room temperature. Two hours later, the solvent wasdistilled off under reduced pressure. The residue was dissolved in 20 ml of methylenechloride. The resulting solution was washed successively with 20 mL of aqueoussodium bicarbonate and 20 mL of 0.01N aqueous hydrochloric acid, and then driedover anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,whereby a mixture containing the below-described compound was obtained. Theresulting mixture was provided for the subsequent reaction (11-3) withoutpurification.
    [0317] In 5 mL of methanol was dissolved the whole amount of the mixture obtainedin (11-2). To the resulting solution was added 120 mg of "Amberlyst 15 (H+)" andthe resulting mixture was stirred at 80°C for 3 hours. After filtration through Celite,the solvent was distilled off under reduced pressure. The residue was charged on asilica gel column (15 g) which was developed with methylene chloride - methanol(94:6 to 92:8), whereby 107 mg of the below-described compound was obtained asthe desired compound of Example 11.
    [0318]
    [0319] The reaction was conducted in a similar manner to that described in Example11 by using 125 mg of the compound obtained in Example (11-1) and 72 mg of 3-(3,4,5-trimethoxyphenyl)propionicacid, whereby 113.6 mg of the below-describedcompound was obtained as the desired compound of Example 12. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.92 (d, J = 8.1 Hz, 1H), 6.53 (s, 2H), 6.01 (d, J = 3.8 Hz, 1H), 5.91 (d, J = 4.5 Hz,1H), 5.71 (d, J = 8.1 Hz, 1H), 5.45 (t, J = 4.8 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.67(d, J = 2.0 Hz, 1H), 4.52 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.01 (t, J = 4.9 Hz, 1H),3.97 (t, J = 4.9 Hz, 1H), 3.81 (s, 6H), 3.71 (s, 3H), 3.57 (m, 1H), 3.29 (s, 3H), 2.87 (t,J = 7.3 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.05-1.75 (m, 4H), 1.48 (m, 1H), 1.25 (m,1H), 1.21 (d, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3388, 2933, 1692, 1591, 1509, 1458, 1424, 1384, 1335, 1268, 1239, 1127 cm-1.
    [0320]
    [0321] The reaction was conducted in a similar manner to that described in Example11 by using 125 mg of the compound obtained in Example (11-1) and 59 mg of 2-(4-nitrophenyl)propionicacid, whereby 121.4 mg of the below-described compound wasobtained as the desired compound of Example 13. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 8.22 (m, 2H), 7.92 (m, 1H), 7.55 (d, J = 8.6 Hz, 2H), 5.97 (m, 2H), 5.72 (m, 1H),5.43 (m, 1H), 5.22 (m, 1H), 4.68-4.38 (m, 4H), 4.08-3.90 (m, 3H), 3.57 (m, 1H), 3.33 (m, 1.5H), 3.12 (s, 1.5H), 2.05-1.75 (m, 4H), 1.48 (m, 4H), 1.30 (m, 1H), 1.22 (d, J =6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3383, 2931, 1691, 1606, 1521, 1458, 1431, 1384, 1348, 1269, 1237, 1205, 1151.1108, 1077, 1020 cm-1.
    [0322]
    [0323] The reaction was conducted in a similar manner to that described in Example11 by using 125 mg of the compound obtained in Example (11-1), 145 mg ofpentadecanoic acid, 12 mg of DMAP and 116 mg of WSC, whereby 103.2 mg of thebelow-described compound was obtained as the desired compound of Example 14. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 4.9 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.8 Hz, 1H), 5.24 (d, J = 5.7 Hz, 1H), 4.68 (d, J = 1.9Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.7 Hz, 1H), 3.97 (t, J =5.0 Hz, 1H), 3.57 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.4 Hz, 2H), 2.05-1.75 (m, 4H),1.63-1.15 (m, 29H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3391, 2925, 2854, 1686, 1510, 1460, 1430, 1384, 1337, 1270, 1235, 1146, 1109,1061, 1021, 978 cm-1.
    [0324]
    [0325] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (10-1) and 129 µL ofheptanoic anhydride, whereby 63.7 mg of the compound shown above was obtainedas the desired compound of Example 15. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 3.6 Hz, 1H), 5.97 (d, J = 4.9 Hz, 1H), 5.72(d, J = 8.2 Hz, 1H), 5.42 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.68 (d, J = 2.0Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.2 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.9 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.83(m, 2H), 1.63-1.25 (m, 10H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3382, 2930, 2858, 1687, 1510, 1462, 1384, 1334, 1269, 1236, 1156, 1109, 1062 cm-1.
    [0326]
    [0327] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1), 158 mg of palmiticanhydride and 2 mg of DMAP, whereby 93.4 mg of the compound shown above wasobtained as the desired compound of Example 16. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.7 Hz, 1H), 5.98 (d, J = 4.9 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 1.7Hz, 1H), 4.55 (m, 2H), 4.41 (t, J = 4.2 Hz, 1H), 4.06 (t, J = 4.8 Hz, 1H), 3.97 (t, J =4.7 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.05-1.75 (m. 4H),1.63-1.20 (m, 31H), 0.90 (t, J = 6.9 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3390, 2925, 2854, 1744, 1689, 1509, 1459, 1432, 1384, 1337, 1269, 1235, 1147,1111, 1062, 1021 cm-1.
    [0328]
    [0329] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1) and 177 µL ofdecanoic anhydride, whereby 62.2 mg of the compound shown above was obtained asthe desired compound of Example 17. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 'H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 4.7 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.4 Hz, 1H), 4.68 (d, J = 1.7Hz, 1H), 4.55 (m, 2H), 4.41 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.8 Hz, 1H), 3.97 (t, J =5.0 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.4 Hz, 2H), 2.05-1.75 (m, 4H),1.63-1.20 (m, 19H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows: 3390, 2927, 2855, 1689, 1510, 1459, 1430, 1384, 1336, 1269, 1151, 1109, 1062, 1022cm-1.
    [0330]
    [0331] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1) and 160 µL ofpelargonic anhydride, whereby 59.9 mg of the desired compound shown above wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 4.7 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 1.6Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.8 Hz, 1H), 3.97 (t, J =4.9 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.05-1.75 (m, 4H),1.63-1.20 (m, 17H), 0.90 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3389, 2928, 2856, 1688, 1510, 1459, 1384, 1336, 1269, 1153, 1108, 1061, 1023 cm-1.
    [0332]
    [0333] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1) and 105 mg ofmyristic anhydride, whereby 81.6 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 1.8Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.8 Hz, 1H), 3.97 (t, J =4.9 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.05-1.75 (m, 4H),1.63-1.20 (m, 27H), 0.90 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3389, 2925, 2854, 1689, 1509, 1459, 1384, 1337, 1269, 1148, 1110, 1062, 1022 cm-1.
    [0334]
    [0335] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1) and 91.8 mg oflauric anhydride, whereby 69.7 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows: δ = 7.95 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.7 Hz, 1H), 5.72(d, J = 8.2 Hz, 1H), 5.44 (t, J = 4.9Hz, 1H), 5.24 (d, J = 5.7Hz, 1H), 4.69 (d, J = 1.6Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.07 (t, J = 4.8 Hz, 1H), 3.97 (t, J =4.7 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.05-1.75 (m, 4H),1.63-1.20 (m, 23H), 0.90 (t, J = 7.0 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3389, 2926, 2855, 1689, 1509, 1459, 1384, 1336, 1269, 1149, 1110, 1062, 1022 cm-1.
    [0336]
    [0337] The reaction was conducted in a similar manner to that described in Example11 by using 100 mg of the compound obtained in Example (11-1) and 92.2 ml of oleicacid, whereby 70.9 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.2 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.34 (t, J = 4.8 Hz, 2H), 5.24 (d, J = 5.7Hz, 1H), 4.68 (d, J = 1.9 Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.07 (t, J =4.8 Hz, 1H), 3.97 (t, J = 4.7 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.4 Hz,2H), 2.05-1.75 (m, 8H), 1.60 (m, 2H), 1.49 (m, 1H), 1.33 (m, 21H), 1.22 (d, J = 6.7Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3391, 2926, 2855, 1688, 1509, 1459, 1431, 1384, 1336, 1269, 1145, 1109, 1061, 1022cm-1.
    [0338]
    [0339] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (11-1) and 259 mg oflinolenic acid anhydride, whereby 65 mg of the compound shown above wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.0 Hz, 1H), 5.45 (t, J = 4.9 Hz, 1H), 5.34 (m, 6H), 5.24 (d, J = 5.7 Hz, 1H),4.68 (d, J = 1.9 Hz, 1H), 4.55 (m, 2H), 4.41 (t, J = 4.2 Hz, 1H), 4.07 (t, J = 4.8 Hz,1H), 3.97 (t, J = 4.8 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.81 (t, J = 5.9 Hz, 4H), 2.38(t, J = 7.3 Hz, 2H), 2.10-1.75 (m, 8H), 1.60 (m, 2H), 1.49 (m, 1H), 1.32 (m, 9H), 1.22(d, J = 6.7 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3389, 3011, 2928, 2855, 1688, 1509, 1459, 1430, 1385, 1337, 1269, 1144, 1108,1061, 1022 cm-1.
    [0340]
    [0341] The reaction was conducted in a similar manner to that described in Example10 by using 150 mg of the compound obtained in Example (11-1) and 326 mg oflinoleic anhydride, whereby 80.5 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 'H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.45 (t, J = 4.9 Hz, 1H), 5.35 (m, 4H), 5.24 (d, J = 5.7 Hz, 1H),4.68 (d, J = 1.9 Hz, 1H), 4.55 (m, 2H), 4.41 (t, J = 4.2 Hz, 1H), 4.07 (t, J = 4.8 Hz,1H), 3.97 (t, J = 5.0 Hz, 1H), 3.58 (m, 1H), 3.38 (s, 3H), 2.77 (t, J = 6.3 Hz, 2H), 2.38(t, J = 7.3 Hz, 2H), 2.10-1.75 (m, 8H), 1.60 (m, 2H), 1.49 (m, 1H), 1.32 (m, 15H),1.22 (d, J = 6.7 Hz, 3H), 0.97 (t, J = 6.9 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3388, 3009, 2928, 2856, 1687, 1510, 1459, 1430, 1384, 1337, 1270, 1144, 1108,1061, 1021 cm-1.
    [0342]
    [0343] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (10-1) and 125.5 mg oflauric anhydride, whereby 78.3 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.42 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.7 Hz, 1H), 4.68 (d, J = 1.6Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.8 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.84(m, 2H), 1.64-1.25 (m, 20H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3381, 2926, 2855, 1689, 1509, 1462, 1436, 1383, 1333, 1269, 1149, 1111, 1063 cm-1.
    [0344]
    [0345] The reaction was conducted in a similar manner to that described in Example10 by using 150 mg of the compound obtained in Example (10-1) and 181 µl ofdecanoic anhydride, whereby 124.3 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.9 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.42 (t, J = 4.8 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 1.7Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.2 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.8 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.84(m, 2H), 1.64-1.25 (m, 16H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3378, 2927, 2856, 1689, 1509, 1462, 1436, 1383, 1333, 1270, 1151, 1111, 1063 cm-1.
    [0346]
    [0347] The reaction was conducted in a similar manner to that described in Example10 by using 100 mg of the compound obtained in Example (10-1) and 181 mg ofmyristic anhydride, whereby 67.5 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 'H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.42 (t, J = 5.0 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 1.6Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.9 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.84(m, 2H), 1.64-1.25 (m, 24H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3378, 2926, 2855, 1689, 1509, 1464, 1435, 1383, 1333, 1269, 1147, 1111, 1063 cm-1.
    [0348]
    [0349] The reaction was conducted in a similar manner to that described in Example10 by using 150 mg of the compound obtained in Example (10-1) and 163 µl ofpelargonic acid anhydride, whereby 93.5 mg of the compound shown above wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.8 Hz, 1H), 5.97 (d, J = 5.0 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.42 (t, J = 4.8 Hz, 1H), 5.24 (d, J = 5.4 Hz, 1H), 4.68 (d, J = 1.8Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.2 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.9 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.84(m, 2H), 1.64-1.25 (m, 14H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3376, 2927, 2856, 1690, 1509, 1461, 1436, 1379, 1334, 1264, 1150, 1108, 1064 cm-1.
    [0350]
    [0351] The reaction was conducted in a similar manner to that described in Example9 by using 243 mg of the compound obtained in Example (8-1) and 130 µl ofpelargonic acid anhydride, whereby 145.5 mg of the compound shown above wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 'H nuclear magneticresonance spectrum is as follows:δ = 7.72 (d, J = 8.1 Hz, 1H), 5.99 (t, J = 2.5 Hz, 1H), 5.88 (d, J = 8.1 Hz, 1H), 5.81 (d,J = 4.5 Hz, 1H), 5.72 (m, 1H), 5.64 (m, 1H), 5.45 (d, J = 3.3 Hz, 1H), 4.68 (d, J = 2.2Hz, 1H), 4.58 (dd, J = 1.0 and 10.9 Hz, 1H), 4.46 (dd, J = 2.2 and 5.2 Hz, 1H), 4.18 (t,J = 4.8 Hz, 1H), 3.65 (t, J = 5.2 Hz, 1H), 3.34 (s, 3H), 3.25 (m, 2H), 2.37 (m, 4H),2.03 (m, 2H), 1.85 (m, 2H), 1.62 (m, 5H), 1.32 (m, 21H), 0.90 (m, 6H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3369, 2927, 2856, 1749, 1693, 1508, 1461, 1380, 1335, 1270, 1258, 1143, 1115, 1067cm-1.
    [0352]
    [0353] The reaction was conducted in a similar manner to that described in Example11 by using 153.7 mg of the compound obtained in Example (10-1) and 122.2 mg ofpentadecanoic acid, whereby 102.8 mg of the compound shown above was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.7 Hz, 1H), 5.97 (d, J = 5.0 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.42 (t, J = 4.9 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.68 (d. J = 2.0Hz, 1H), 4.55 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J =4.8 Hz, 1H), 3.37 (s, 3H), 3.25 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H), 1.84(m, 2H), 1.64-1.25 (m, 26H), 0.90 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3383, 2925, 2854, 1688, 1509, 1465, 1436, 1384, 1334, 1270, 1147, 1112, 1063 cm-1.
    [0354]
    [0355] The reaction was conducted in a similar manner to that described in Example9 by using decanoic acid anhydride instead of heptanoic acid anhydride, whereby 40.6mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.72 (d, J = 8.1 Hz, 1H), 5.99 (m, 1H), 5.87 (d, J = 8.1 Hz, 1H), 5.81 (d, J = 4.4Hz, 1H), 5.72 (m, 1H), 5.64 (m, 1H), 5.45 (d, J = 3.1 Hz, 1H), 4.68 (d, J = 2.2 Hz,1H), 4.57 (m, 1H), 4.46 (dd, J = 2.1 and 5.4 Hz, 1H), 4.18 (t, J = 5.0 Hz, 1H), 3.65 (t,J = 5.0 Hz, 1H), 3.33 (s, 3H), 3.25 (m, 2H), 2.36 (m, 4H), 2.02 (m, 2H), 1.85 (m, 2H),1.70-1.25 (m, 30H), 0.90 (t, J = 6.3 Hz, 6H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows: 3375, 2926, 2854, 1747, 1691, 1507, 1463, 1380, 1334, 1267, 1247, 1142, 1115, 1066cm-1.
    [0356]
    [0357] The reaction was conducted in a similar manner to that described in Example10 by using 187 mg of the compound obtained in Example (11-1) and 267 µl ofoctanoic acid anhydride, whereby 115 mg of the desired compound shown above wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.97 (d, J = 4.9 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.44 (t, J = 4.9 Hz, 1H), 5.23 (d, J = 5.5 Hz, 1H), 4.68 (d, J = 2.0Hz, 1H), 4.56 (m, 1H), 4.52 (m, 1H), 4.42 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.7 Hz, 1H),3.97 (t, J = 5.1 Hz, 1H), 3.57 (m, 1H), 3.38 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.05-1.75(m, 4H), 1.60 (m, 2H), 1.48 (m, 1H), 1.32 (m, 9H), 1.21 (d, J = 6.6 Hz, 3H), 0.90 (t, J= 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3399, 2930, 2857, 1686, 1511, 1459, 1430, 1385, 1335, 1268, 1231, 1152, 1107,1061, 1022 cm-1.
    [0358]
    [0359] In 3 mL of pyridine were dissolved 125 mg of the compound obtained inExample (11-1), 170 µl of nonyl chloroformate, 147 mg of dimethylaminopyridineand 3 mg of 4-pyridylpyridine. The resulting solution was stirred at roomtemperature. Three hours later, the solvent was distilled off under reduced pressure.The residue was then dissolved in 60 mL of ethyl acetate. After washing with 60 mLof each of saturated aqueous NaHCO3 and saturated saline, drying was conductedover anhydrous sodium sulfate. The solvent was distilled off under reduced pressureand the residue was dissolved in 4 mL of methanol. To the resulting solution wasadded 200 mg of "Amberlyst 15", followed by heating under reflux. Three hourslater, the insoluble matter was filtered off and the solvent was distilled off underreduced pressure. The residue was subjected to a silica gel column (8 g) and elutedwith 5% methanol - methylene chloride, whereby 108 mg of the desired compoundwas obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 5.98 (d, J = 4.6 Hz, 1H), 5.71(d, J = 8.2 Hz, 1H), 5.32 (t, J = 4.8 Hz, 1H), 5.23 (d, J = 5.7 Hz, 1H), 4.68 (d, J = 2.0Hz, 1H), 4.56 (m, 1H), 4.52 (m, 1H), 4.41 (t, J = 4.2 Hz, 1H), 4.13 (m, 3H), 3.97 (t, J= 5.0 Hz, 1H), 3.57 (m, 1H), 3.40 (s, 3H), 2.05-1.75 (m, 4H), 1.65 (m, 2H), 1.48 (m,1H), 1.32 (m, 13H), 1.22 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3385, 2929, 2855, 1753, 1691, 1510, 1458, 1431, 1393, 1259, 1144, 1101, 1076, 1021cm-1.
    [0360]
    [0361] The reaction was conducted in a similar manner to that described in Example32 except for the use of 157 µl of octyl chloroformate instead of nonyl chloroformate,whereby 91 mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.94 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H), 5.71(d, J = 8.1 Hz, 1H), 5.32 (t, J = 4.6 Hz, 1H), 5.24 (d, J = 5.6 Hz, 1H), 4.69 (d, J = 2.0Hz, 1H), 4.56 (m, 1H), 4.52 (m, 1H), 4.41 (t, J = 4.0 Hz, 1H), 4.13 (m, 3H), 3.97 (t, J= 5.0 Hz, 1H), 3.57 (m, 1H), 3.40 (s, 3H), 2.05-1.75 (m, 4H), 1.65 (m, 2H), 1.48 (m,1H), 1.32 (m, 11H), 1.22 (d, J = 6.6 Hz, 3H), 0.90 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3387, 2929, 2856, 1752, 1689, 1510, 1458, 1431, 1392, 1335, 1260, 1143, 1101,1073, 1021 cm-1.
    [0362]
    [0363]
    [0364] In 50 mL of dimethylformamide (DMF) were dissolved 4.57 g of thecompound obtained in Example (11-1) and 2.2 mL of 1,8-diazabicyclo[5.4.0]-7-undecene(DBU). To the resulting solution was added a solution obtained bydissolving 2.45 g of 4-methoxybenzyl chloromethyl ether in 50 mL of DMF. Theresulting mixture was stirred at room temperature. After 2.5 hours, the solvent wasdistilled off under reduced pressure. The residue was dissolved in 300 mL ofmethylene chloride. The resulting solution was washed successively with 300mLeach of 0.01N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate andsaturated saline, and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure and then charged on a silica gel column (200 g),which was developed with 3% methanol in methylene chloride, whereby 4.80 g of thedesired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.85 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.32 (m, 2H), 7.15 (m, 2H), 6.85 (d, J = 8.7Hz, 2H), 6.37 (d, J = 4.3 Hz, 1H), 6.06 (d, J = 6.2 Hz, 1H), 5.82 (m, 1H), 5.75 (d, J =8.2 Hz, 1H), 5.70 (m, 1H), 5.44 (m, 2H), 4.73 (m, 3H), 4.61 (s, 2H), 4.57 (s, 1H), 4.45(m, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 3.79 (s, 3H), 3.56 (s, 3H), 3.53 (m, 1H), 3.28 (d,J = 7.8 Hz, 1H), 2.35 (s, 2H), 2.15 (m, 1H), 2.02-1.75 (m, 4H), 1.49 (s, 3H), 1.42 (s,3H), 1.30 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3387, 3105, 2984, 2935, 1669, 1612, 1514, 1457, 1383, 1361, 1300, 1248, 1219,1169, 1114, 1079, 1064, 1012 cm-1.
    [0365]
    [0366] In 5 mL of DMF was dissolved 773 mg of the compound obtained in Example(34-1). The resulting solution was stirred at 0°C under a nitrogen gas stream. To thereaction mixture was added 60 mg of NaH (about 60%). Two minutes later, 2.13 mLof 1-iododecane was added. Five minutes later, the temperature was allowed to riseback to room temperature, at which stirring was conducted for further 25 minutes.The reaction mixture was then distilled under reduced pressure to remove the solvent.The residue was dissolved in 250 mL of methylene chloride. The resulting solutionwas washed successively with 300 mL each of 0.01N aqueous hydrochloric acid,saturated aqueous sodium bicarbonate and saturated saline, and then dried overanhydrous magnesium sulfate. The solvent was distilled off under reduced pressureand the residue charged on a silica gel column (200 g) which was developed with 2%methanol in methylene chloride, whereby 395 mg of the desired compound wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.89 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 5.9 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.13(br s, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.37 (m, 1H), 5.95 (s, 1H), 5.75 (br s, 1H), 5.70(d, J = 8.1 Hz, 1H), 5.57 (m, 1H), 5.45 (s, 2H), 4.78 (d, J = 8.1 Hz, 1H), 4.74 (m, 2H),4.63 (s, 2H), 4.55 (s, 1H), 4.46 (m, 1H), 4.05 (m, 2H), 3.95 (m, 1H), 3.79 (s, 3H), 3.62(m, 1H), 3.51 (m, 1H), 3.43 (s, 3H), 4.09 (m, 1H), 1.98 (m, 1H), 1.86 (m, 1H), 1.77(m, 1H), 1.49 (s, 3H), 1.44 (s, 3H), 1.40-1.20 (m, 18H), 1.19 (d, J = 6.6 Hz, 3H), 0.88(t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows: 3386, 3102, 2928, 2855, 1713, 1670, 1613, 1587, 1514, 1456, 1382, 1359, 1338.1300, 1271, 1248, 1220, 1167, 1112, 1066, 1013 cm-1.
    [0367]
    [0368] In 5 mL of methylene chloride was dissolved 390 mg of the compoundobtained in Example (34-2). To the resulting solution were added 276 µL of waterand 484 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the resulting mixturewas stirred at room temperature. After 75 minutes, the insoluble matter was filteredoff. The filtrate was diluted with 200 mL of methylene chloride, followed bysuccessive washing with 200 mL each of saturated aqueous sodium bicarbonate andsaturated saline, and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure and the residue was charged on a silica gelcolumn (50 g) which was developed with 5% methanol in methylene chloride,whereby 278 mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 9.30 (br s, 1H), 7.99 (d, J = 7.3 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.19 (br s, 1H),6.36 (d, J = 4.4 Hz, 1H), 5.98 (br s, 1H), 5.85 (br s, 1H), 5.81 (d, J = 5.1 Hz, 1H), 5.69(dd, J = 2.2 and 8.1 Hz, 1H), 4.74 (m, 2H), 4.60 (m, 2H), 4.28 (t, J = 4.7 Hz, 1H), 4.12(t, J = 6.2 Hz, 1H), 4.07 (t, J = 4.7 Hz, 1H), 3.59 (m, 3H), 4.43 (s, 3H), 2.10-1.73 (m,4H), 1.60 (m, 2H), 1.48 (s, 3H), 1.42 (s, 3H), 1.23 (m, 19H), 0.88 (t, J = 6.6 Hz, 3H)ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3387, 3227, 3098, 2928, 2855, 1692, 1506, 1457, 1431, 1382, 1337, 1296, 1268,1250, 1235, 1220, 1166, 1121, 1082, 1065, 1013 cm-1.
    [0369]
    [0370] In 15 mL of methanol was dissolved 273 mg of the compound obtained inExample (34-3). To the resulting solution was added 260 mg of "Amberlyst 15" andthe resulting mixture was stirred at 80°C. After 4 hours and 20 minutes, the insolublematter was filtered off. The filtrate was distilled under reduced pressure, and theresidue was charged on a silica gel column (15 g) which was developed with 5%methanol in methylene chloride, whereby 176 mg of the desired compound wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 3.6 Hz, 1H), 5.92 (d, J = 4.5 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.23 (d, J = 5.3 Hz, 1H), 4.67 (s, 1H), 4.59 (m, 1H), 4.52 (m, 1H),4.38 (t, J = 4.2 Hz, 1H), 4.08 (t, J = 4.6 Hz, 1H), 3.98 (t, J = 4.7 Hz, 1H), 3.94 (t, J =4.7 Hz, 1H), 3.58 (m, 3H), 3.40 (s, 3H), 2.05-1.75 (m, 4H), 1.52 (m, 3H), 1.25 (m,18H), 0.89 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3391, 3099, 2927, 2854, 1686, 1509, 1458, 1431, 1385, 1335, 1269, 1132, 1099,1063, 1020 cm-1.
    [0371]
    [0372]
    [0373] In a similar manner to that described in Example (34-2) except for the use of1.48 mL of 1-iodohexane instead of 1-iododecane, 460 mg of the desired compoundwas obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.91 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.18(d, J = 4.1 Hz, 1H), 5.92 (d, J = 4.0 Hz, 1H), 5.74 (d, J = 8.3 Hz, 1H), 5.42 (s, 2H),5.11 (d, J = 5.4 Hz, 1H), 4.80 (m, 1H), 4.70 (m, 1H), 4.55 (m, 3H), 4.37 (t, J = 5.8 Hz,1H), 4.08 (t, J = 4.3 Hz, 1H), 3.94 (t, J = 5.2 Hz, 1H), 3.76 (s, 3H), 3.60 (m, 3H), 3.41(s, 3H), 2.05-1.75 (m, 4H), 1.55 (m, 3H), 1.43 (s, 6H), 1.25 (m, 8H), 1.19 (d, J = 6.6Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3381, 3103, 2933, 2871, 2859, 1670, 1613, 1587, 1514, 1455, 1383, 1359, 1300,1271, 1249, 1220, 1167, 1130, 1112, 1066, 1013 cm-1.
    [0374]
    [0375] The reaction was conducted in a similar manner to that described in Example(34-3) using 458 mg of the compound obtained in Example (35-1), 313 mg of thedesired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 9.28 (br s, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.19 (br s, 1H),6.36 (d, J = 4.4 Hz, 1H), 5.98 (br s, 1H), 5.85 (br s, 1H), 5.81 (d, J = 5.1 Hz, 1H), 5.69(dd, J = 2.2 and 8.1 Hz, 1H), 4.74 (m, 2H), 4.60 (m, 3H), 4.28 (t, J = 4.7 Hz, 1H), 4.12(t, J = 6.9 Hz, 1H), 4.07 (t, J = 4.7 Hz, 1H), 3.59 (m, 3H), 4.42 (s, 3H), 2.10-1.73 (m,4H), 1.60 (m, 2H), 1.48 (s, 3H), 1.42 (s, 3H), 1.23 (m, 11H), 0.87 (t, J = 6.6 Hz, 3H)ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3386, 3097, 2933, 2872, 2859, 1692, 1507, 1457, 1432, 1383, 1337, 1268, 1235,1220, 1166, 1129, 1082, 1065, 1012 cm-1.
    [0376]
    [0377] In 15 mL of methanol was dissolved 273 mg of the compound obtained inExample (35-2). To the resulting solution was added 260 mg of "Amberlyst 15". Theresulting mixture was stirred at 80°C. After 4 hours and 20 minutes, the insoluble matter was filtered off. The filtrate was distilled under reduced pressure. The residuewas subjected to a silica gel column (15 g) and then eluted with 5% methanol inmethylene chloride, whereby 176 mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.9 Hz, 1H), 5.92 (d, J = 4.5 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.23 (d, J = 5.6 Hz, 1H), 4.66 (d, J = 2.0 Hz, 1H), 4.59 (m, 1H),4.50 (m, 1H), 4.38 (t, J = 3.9 Hz, 1H), 4.08 (t, J = 4.7 Hz, 1H), 3.99 (t, J = 4.9 Hz,1H), 3.93 (t, J = 4.7 Hz, 1H), 3.58 (m, 3H), 3.40 (s, 3H), 2.05-1.75 (m, 4H), 1.52 (m,3H), 1.25 (m, 7H), 1.22 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3387, 3098, 2931, 2859, 1687, 1509, 1458, 1431, 1385, 1335, 1268, 1131, 1098,1063, 1020 cm-1.
    [0378]
    [0379]
    [0380] In pyridine was dissolved 300 mg of Compound A-500359A. To the resultingsolution were added 696 mg of benzoic anhydride and 6.4 mg ofdimethylaminopyridine. The resulting mixture was stirred at room temperature. Fourhours later, the solvent was distilled off under reduced pressure and the residuedissolved in 200 mL of ethyl acetate. The resulting solution was washed successively with 200 mL each of saturated aqueous sodium bicarbonate and saturated and thendried over anhydrous sodium sulfate. The solvent was distilled off under reducedpressure and the residue was charged on a silica gel column (50 g), which wasdeveloped with 3% methanol in methylene chloride, whereby 423 mg of the desiredcompound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 9.40 (br s, 1H), 8.06 (m, 4H), 7.92 (m, 4H), 7.55 (m, 5H), 7.40 (m, 5H), 7.15 (brs, 1H), 6.45 (br s, 1H), 6.32 (d, J = 3.7 Hz, 1H), 6.13 (m, 1H), 6.09 (br s, 1H), 5.96 (d,J = 3.7 Hz, 1H), 5.83 (m, 2H), 5.62 (m, 2H), 4.69 (m, 1H), 4.61 (m, 1H), 4.56 (m,1H), 4.36 (t, J = 5.9 Hz, 1H), 3.54 (m, 1H), 3.34 (s, 3H), 2.12 (m, 1H), 2.00-1.50 (m,4H), 1.32 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H) ppm.
    [0381]
    [0382] In 6.3 mL of methylene chloride was dissolved 418 mg of the compoundobtained in Example (36-1). To the resulting solution was added 5 mL of water,followed by stirring at room temperature. To the reaction mixture, 4.74 g ofnitrosylsulfuric acid was gradually added over 30 minutes. After stirring for a further10 minutes, the resulting mixture was diluted with 30 mL of methylene chloride. Theorganic layer separated was washed with 10 mL each of water and saturated salineand the solvent was then distilled off under reduced pressure. The residue wasdissolved in 10 mL of methylene chloride. To the resulting solution was added anether solution of diazomethane prepared by mixing 144 mg of N-methyl-N-nitrosourea,90 mg of potassium hydroxide, 2.8 mL of ether and 2.8 mL of water andthe resulting mixture was stirred at room temperature. One hour later, the solvent wasdistilled off under reduced pressure. The residue was charged on a silica gel column(20 g) which was developed with 1.5% methanol in methylene chloride, whereby 99mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated chloroformwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 8.28 (s, 1H), 8.06 (d, J = 7.3 Hz, 2H), 7.99 (d, J = 7.3 Hz, 2H), 7.95 (m, 3H), 7.60-7.32(m, 11H), 6.33 (s, 1H), 6.20 (t, J = 3.6 Hz, 1H), 6.06 (d, J = 4.4 Hz, 1H), 5.94 (d.J = 5.9 Hz, 1H), 5.88 (t, J = 4.0 Hz, 1H), 5.70 (d, J = 3.7 Hz, 1H), 5.54 (m, 2H), 4.79(m, 1H), 4.63 (m, 1H), 4.17 (t, J = 5.5 Hz, 1H), 3.83 (s, 3H), 3.80 (m, 1H), 3.72 (m,1H), 3.35 (m, 1H), 3.30 (s, 3H), 2.19 (m, 1H), 2.02-1.75 (m, 3H), 1.52 (m, 1H), 1.32(m, 1H), 1.24 (d, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3388, 3093, 3069, 2933, 2855, 1729, 1697, 1658, 1602, 1584, 1551, 1509, 1452,1383, 1336, 1315, 1270, 1177, 1115, 1070, 1026 cm-1.
    [0383]
    [0384] In 2 mL of a 40% methylamine - methanol solution was dissolved 98 mg ofthe compound obtained in Example (36-2). The resulting solution was hermeticallysealed and then stirred. Forty-five minutes later, the solvent was distilled off underreduced pressure. The residue was subjected to reverse-phase preparative HPLC(Inertsil Prep-ODS), followed by elution with 16% acetonitrile - water, whereby 30mg of the desired compound was obtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.86 (d, J = 8.0 Hz, 1H), 5.98 (m, 1H), 5.83 (m, 1H), 5.74 (dd, J = 2.9 and 8.1 Hz,1H), 5.24 (d, J = 4.9 Hz, 1H), 4.73 (dd, J = 2.1 and 10.9 Hz, 1H), 4.50 (m, 2H), 4.38(t, J = 4.0 Hz, 1H), 4.25 (m, 1H), 4.04 (m, 2H), 3.75 (m, 1H), 3.39 (d, J = 2.8 Hz, 3H),2.74 (d, J = 2.4 Hz, 3H), 1.65 (m, 1H), 1.25 (m, 2H), 1.00 (m, 3H), 0.92 (m, 1H), 0.75(m, 2H) ppm.
    [0385]
    [0386] The reaction was conducted in a similar manner to that described in Example(36-3) by using 120 mg of the compound obtained in Example (36-2), 0.4 mL of n-propylamineand 2 mL of methanol, whereby 16 mg of the desired compound wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.91 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 4.2 Hz, 1H), 5.89 (d, J = 5.5 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.16 (d, J = 6.4 Hz, 1H), 4.67 (d, J = 2.0 Hz, 1H), 4.55 (m, 2H),4.37 (t, J = 4.3 Hz, 1H), 4.33 (t, J = 5.2 Hz, 1H), 3.92 (m, 2H), 3.60 (m, 1H), 3.45 (s,3H), 3.25 (m, 2H), 2.05-1.75 (m, 4H), 1.53 (m, 3H), 1.25 (m, 1H), 1.22 (d, J = 6.6 Hz,3H), 0.91 (t, J = 7.5 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3369, 3098, 2964, 2934, 2878, 1683, 1515, 1459, 1432, 1385, 1335, 1269, 1140,1080, 1062, 1022, 981 cm-1.
    [0387]
    [0388] The reaction was conducted in a similar manner to that described in Example(36-3) using 270 mg of the compound obtained in Example (36-2), 1.92 g ofdodecylamine and 6.9 mL of methanol, whereby 15 mg of the desired compound wasobtained. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.92 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 4.4 Hz, 1H), 5.91 (d, J = 5.9 Hz, 1H), 5.73(d, J = 8.1 Hz, 1H), 5.15 (d, J = 5.9 Hz, 1H), 4.67 (d, J = 2.2 Hz, 1H), 4.55 (m, 2H),4.36 (t, J = 4.4 Hz, 1H), 4.32 (t, J = 5.5 Hz, 1H), 3.92 (m, 2H), 3.60 (m, 1H), 3.47 (s,3H), 3.35 (m, 1H), 3.20 (m, 1H), 2.05-1.75 (m, 4H), 1.50 (m, 3H), 1.28 (m, 19H),1.22 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3351, 3098, 2926, 2854, 1685, 1512, 1459, 1432, 1385, 1335, 1264, 1139, 1090,1063, 1022, 993 cm-1.
    [0389]
    [0390]
    [0391] In 4 mL of pyridine was dissolved 125 mg of the compound obtained inExample (11-1). Under a nitrogen gas stream, 147 mg of dimethylaminopyridine and3.9 mg of 4-pyrrolidinopyridine were added to the solution. After cooling to 0°C,209.1 mg of 2,2-dimethyldodecanoyl chloride (B.D. Roth, et al, Journal of MedicinalChemistry, 35, 1609-1617 (1992)) was added. The resulting mixture was stirred atroom temperature for 28 hours. After cooling to 0°C, 2 mL of methanol was added tothe reaction mixture. The resulting mixture was stirred for 10 minutes, followed byconcentration under reduced pressure. To the residue were added 20 mL of 0.02Nhydrochloric acid and 20 mL of methylene chloride to separate it into layers. Theorganic layer thus obtained was washed three times with saturated saline, dried overanhydrous sodium sulfate and concentrated under reduced pressure, whereby 307 mgof a crude product was obtained. The product was purified by Lobar's silica gelcolumn (eluted first with a 3:7 mixture of hexane and ethyl acetate, followed by ethylacetate), whereby 132 mg of the desired compound was obtained as a white powder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.90 (d, J = 8.1 Hz, 1H), 6.16 (d, J = 3.7 Hz, 1H), 6.03 (d, J = 5.4 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.32 (t, J = 5.2 Hz, 1H), 5.14 (d, J = 5.3 Hz, 1H), 4.90 (m, 1H),4.75 (d, J = 2.1 Hz, 1H), 4.59-4.55 (m, 2H), 4.38 (t, J = 5.8 Hz, 1H), 4.05 (t, J = 4.4Hz, 1H), 3.64-3.55 (m, 1H), 3.40 (s, 3H), 2.01-1.77 (m, 4H), 1.59-1.47 (m, 3H), 1.45(s, 6H), 1.34-1.10 (m, 26H), 0.89 (t, J = 6.7 Hz, 3H) ppm.
    [0392]
    [0393] To 125 mg of the compound obtained in Example (39-1) was added 50 mL ofa 5% trifluoroacetic acid - methylene chloride solution, and the resulting mixture wasstirred at room temperature for 5 hours. Concentration of the reaction mixture andazeotropy with toluene yielded 147 mg of a crude product. The resulting product waspurified by thin-layer chromatography (elution with a 8% methanol in methylenechloride mixture), whereby 64.8 mg of the desired compound was obtained as a whitepowder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 3.9Hz, 1H), 5.98 (d, J = 4.8 Hz, 1H), 5.71 (d,J = 8.1 Hz, 1H), 5.39 (t, J = 4.8 Hz, 1H), 5.24 (d, J = 5.4 Hz, 1H), 4.69 (d, J = 2.1 Hz,1H), 4.57-4.56 (m, 1H), 4.54-4.50 (m, 1H), 4.42 (t, J = 4.1 Hz, 1H), 4.06 (t, J = 4.8Hz, 1H), 3.98 (t, J = 4.9 Hz, 1H), 3.61-3.53 (m, 1H), 3.37 (s, 3H), 2.04-1.76 (m, 4H),1.56-1.43 (m, 2H), 1.33-1.16 (m, 27H), 0.89 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3390, 2927, 2854, 1688, 1510, 1459, 1387, 1336, 1269, 1144, 1108, 1062 cm-1.
    [0394]
    [0395]
    [0396] In a similar manner to that described in Example (39-1) except for the use of122 mg of the compound obtained in Example (10-1) instead of the compoundobtained in Example (11-1), the reaction was conducted, whereby 126.9 mg of thedesired compound was obtained as a white powder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.90 (d, J = 8.1 Hz, 1H), 6.16 (d, J = 3.7 Hz, 1H), 6.03 (d, J = 5.7 Hz, 1H), 5.72(d, J = 8.1 Hz, 1H), 5.30 (t, J = 5.3 Hz, 1H), 5.15 (d, J = 5.4 Hz, 1H), 4.90 (m, 1H),4.75 (d, J = 2.1 Hz, 1H), 4.59-4.57 (m, 2H), 4.39 (t, J = 5.9 Hz, 1H), 4.03 (t, J = 4.4Hz, 1H), 3.39 (s, 3H), 3.31-3.28 (m, 2H), 2.02 (d, J = 11 Hz, 2H), 1.87-1.77 (m, 2H),1.60-1.49 (m, 2H), 1.44 (s, 6H), 1.40-1.20 (m, 18H), 1.17 (s, 6H), 0.89 (t, J = 6.9 Hz,3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3377, 2929, 2856, 1695, 1507, 1459, 1382, 1334, 1269, 1140, 1116, 1064 cm-1.(40-2)
    [0397] In a similar manner to that described in Example (39-2) except for the use of95.3 mg of the compound obtained in Example (40-1) instead of the compoundobtained in Example (39-1), whereby 72.4 mg of the desired compound was obtainedas a white powder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.2 Hz, 1H), 6.02 (d, J = 3.8 Hz, 1H), 5.98 (d, J = 4.8 Hz, 1H), 5.72(d, J = 8.2 Hz, 1H), 5.37 (t, J = 5.0 Hz, 1H), 5.24 (d, J = 5.4 Hz, 1H), 4.68 (d, J = 2.1Hz, 1H), 4.57-4.52 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.04 (t, J = 4.9 Hz, 1H), 3.98 (t, J= 4.8 Hz, 1H), 3.37 (s, 3H), 3.27-3.22 (m, 2H), 2.04-1.89 (m, 2H), 1.86-1.77 (m, 2H),1.58-1.46 (m, 2H), 1.43-1.19 (m, 18H), 1.16 (d, J = 6.2 Hz, 6H), 0.89 (t, J = 6.9 Hz,3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) tablet method exhibits absorption maxima as follows:3369, 2927, 2854, 1689, 1509, 1463, 1389, 1332, 1269, 1143, 1110, 1062 cm-1.
    [0398]
    [0399] In a similar manner to that described in Example 25 except for the use of 2-methyldodecanoylchloride [synthesized by chlorinating 2-methyldodecanoic acid which was synthesized by the process described in Organic Synthesis. 4, 616, by themethod as described in B.D. Roth, et al., Journal of Medicinal Chemistry. 35, 1609-1617(1992)] instead of 2,2-dimethyldodecanoyl chloride, 82.5 mg of the desiredcompound was obtained as a white powder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.96 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 5.98 (dd, J = 4.5 and 3.4 Hz,1H), 5.71 (d, J = 8.1 Hz, 1H), 5.46-5.43 (m, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.68 (d, J =1.9 Hz, 1H), 4.57 (dd, J = 4.8 and 1.7 Hz, 1H), 4.52 (dd, J = 11 and 1.5 Hz, 1H), 4.42(t, J = 4.1 Hz, 1H), 4.08-4.05 (m, 1H), 3.97 (t, J = 5.0 Hz, 1H), 3.61-3.54 (m, 1H),3.38 (s, 3H), 2.53-2.48 (m, 1H), 2.04-1.37 (m, 6H), 1.28 (s, 18H), 1.22 (d, J = 6.6 Hz,3H), 1.15-1.13 (m, 3H), 0.89 (t, J = 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3389, 2927, 2854, 1689, 1510, 1459, 1384, 1335, 1269, 1145, 1108, 1061 cm-1.
    [0400]
    [0401] In a similar manner to that described in Example 40 except for the use of 2-methyldodecanoylchloride instead of 2,2-dimethyldodecanoyl chloride, 77.5 mg ofthe desired compound was obtained as a white powder. 1) 1H nuclear magnetic resonance spectrum was measured in deuterated methanolwith tetramethylsilane as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:δ = 7.95 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 3.7 Hz, 1H), 5.98 (dd, J = 4.5 and 3.6 Hz,1H), 5.72 (d, J = 8.1 Hz, 1H), 5.44-5.40 (m, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.68 (d, J =1.8 Hz, 1H), 4.57-4.52 (m, 2H), 4.42 (t, J = 4.1 Hz, 1H), 4.04 (t, J = 4.8 Hz, 1H), 3.98 (t, J = 5.0 Hz, 1H), 3.37 (s, 3H), 3.29-3.23 (m, 2H), 2.23-2.48 (m, 1H), 2.03-1.99 (m,2H), 1.89-1.76 (m, 2H), 1.67-1.32 (m, 2H), 1.28 (s, 18H), 1.15-1.13 (m, 3H), 0.89 (t. J= 6.8 Hz, 3H) ppm. 2) Infrared absorption spectrum: The infrared absorption spectrum as measured bythe potassium bromide (KBr) disk method exhibits absorption maxima as follows:3369, 2927, 2854, 1689, 1509, 1461, 1382, 1333, 1269, 1144, 1110, 1062 cm-1.
    [0402] Into each of four 2 L Erlenmeyer flasks (seed flasks), each containing 500 mlof the seed culture medium described below, were inoculated aseptically four loopfulsof Strain SANK60196 followed by shaking in a rotary shaker at 23°C and 210 rpm,and the seed culture was thus conducted for 3 days.
    [0403] Medium for seed culture: containing the following components in 1000 ml oftap water: Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g Antifoamer "CB442" 50 mg (product of NOF Corporation)
    [0404] After adjustment of pH to 7.4, sterilization was conducted at 121°C for 30minutes.
    [0405] Cultivation was conducted as described below. Described specifically, theseed culture was inoculated at 3% (volume/volume: which will hereinafter beabbreviated as "v/v") into two 30 L jar fermenters, each containing 15 L of acultivation medium. Six hours later after the initiation of cultivation at 23°C, filter-sterilizedS-(2-aminoethyl)-L-cysteine hydrochloride was added to give a finalconcentration of 10 mM, followed by cultivation with aeration and agitation for 6days.
    [0406] Medium for cultivation: containing the following components in 1000 ml oftap water: Maltose 30 g Yeast extract 5 g (product of Difco Laboratories) Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g Antifoamer "CB442" 50 mg (product of NOF Corporation)
    [0407] After adjustment of pH to 7.4, sterilization was conducted at 125°C for 30minutes. Example 44 Purification of Compound A-500359E
    [0408] The cultured broth (30 L) obtained in Example 43 was filtered with the aid of"Celite 545" (product of Celite Corporation).
    [0409] Upon purification as described later, the active fraction was monitored byHPLC using the column and analytical conditions described below. Column : "Senshu Pak ODS-H-2151" 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid containing 4% acetonitrile Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 21.2 minutes
    [0410] 30 L of the resulting filtrate was charged on a column (6 L) packed with"Diaion HP-20" (product of Mitsubishi Chemical). After washing the column with 12L of deionised water, the non-adsorbed fraction and washing fraction were combined(the combined fraction will hereinafter be called "non-adsorbed·washing fraction").The adsorbed substance was eluted with 12 L of 10% aqueous acetone. The eluatewas concentrated to remove acetone and lyophilized, whereby 39 g of a crudepowdery product was obtained.
    [0411] The resulting crude powdery product was dissolved in 200 mL of deionisedwater and charged on a column (2 L) packed with "Diaion CHP-20P" (product of Mitsubishi Chemical). The column was then washed with 4 L of deionised water and4 L of 10% aqueous methanol, while the adsorbed substance was eluted with 4 L of15% aqueous methanol and 4 L of 20% aqueous methanol. A 2 to 4 L portion of the15% aqueous methanol eluate and the 20% aqueous methanol eluate were combined,followed by concentration. After removal of methanol by distillation, the residue waslyophilized to give 8.9 g of a powder.
    [0412] The resulting powder was dissolved in 200 ml of deionised water and theresulting solution was charged on a column (1 L) packed with "Toyopearl HW40F"(product of TOSOH Corporation), followed by development of the column withdeionised water. As a result of fractionation of the eluate into portions of 100 mleach, the active substance having a retention time of 21.2 minutes upon the above-describedHPLC was eluted in Fraction Nos. 5 to 10. The resulting fractions wereconcentrated and lyophilized to give 2.7 g of a powder.
    [0413] The resulting powder was dissolved in 200 ml of deionised water and chargedon an HPLC column ("YMC-Pack ODS-1050-20-SR": 100 x 500 mm; product ofYMC) equilibrated with 0.04% aqueous trifluoroacetic acid containing 4%acetonitrile. The column was developed at a flow rate of 208 ml/min with 0.04%aqueous trifluoroacetic acid containing 4% acetonitrile. As a result of fractionation ofthe eluate into portions of 1 L each, the active substance was eluted in Fraction Nos. 6and 7.
    [0414] These fractions were combined, followed by concentration to 200 ml by"Evapor" (product of Okawara Seisakujo) and lyophilization, whereby 99 mg of apowder was obtained. The resulting powder was suspended in 5 ml of distilled waterand insoluble matter was then filtered off. The filtrate was concentrated to 2 ml by arotary evaporator, followed by lyophilization, whereby 87 mg of Compound A-500359Ewas obtained as a pure product.
    [0415] The compound A-500359E has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C18H23N3O12 4) Molecular weight: 473 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 474.1349 Calculated: 474.1359 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   251 nm (ε 10,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:[α]D 20: +115° (c 0.28) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3410, 2955, 1683, 1464, 1441, 1396, 1309, 1267, 1206, 1138, 1115, 1088, 1062, 1023cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterated dimethylsulfoxide with tetramethylsilane as an internal standard substance. 1H nuclearmagnetic resonance spectrum is as follows:3.24 (3H, s), 3.52 (1H, dd, J=4.5, 6.1Hz), 3.72 (3H, s), 3.98 (1H, m), 4.10 (1H, m),4.25 (1H, m), 4.29 (1H, d, J=2.0Hz), 4.33 (1H, dd, J=2.0, 6.1Hz), 5.05 (1H, d, J=3.9Hz), 5.16 (1H, d, J=6.8Hz), 5.45 (1H, d, J=4.2Hz), 5.54 (1H, d, J=5.9Hz), 5.61 (1H, d,J=3.3Hz), 5.61 (1H, d, J=8.1Hz), 5.93 (1H, dd, J=1.3, 2.9 Hz), 7.56 (1H, br. s), 7.69(1H, br. s), 7.74 (1H, d, J=8.1 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterated dimethylsulfoxide with tetramethylsilane as an internal standard substance. 13C-nuclearmagnetic resonance spectrum is as follows:52.0 (q), 57.3 (q), 61.5 (d), 64.9 (d), 72.1 (d), 75.4 (d), 78.2 (d), 81.3 (d), 89.0 (d),99.2 (d), 101.2 (d), 114.2 (d), 139.2 (s), 139.8 (d), 150.3 (s), 161.8 (s), 163.1 (s),170.1 (s) ppm. 11) High performance liquid chromatography (which will hereinafter be abbreviatedas "HPLC") analysis: Column: "Senshu Pack ODS-H-2151"6 x 150 mm (product of Senshu Scientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid containing 4% acetonitrile Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 21 minutes
    [0416] In the purification described below, the active fraction was monitored byHPLC using the following column and analytical conditions. Column : "Senshu Pak ODS-H-2151" 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 8 minutes (Compound A-500359H)18 minutes (Compound A-500359F)
    [0417] After 42 L of non-adsorbed washing fraction obtained in Example 44 wasadjusted to pH 9 with 6N sodium hydroxide, this fraction was charged on a column(8.5 L) packed with "Diaion PA316 (Cl-)" (product of Mitsubishi Chemical). Thecolumn was washed with 27 L of deionised water and the adsorbed substance wasthen eluted with 27 L of 0.1N hydrochloric acid.
    [0418] The eluate was adjusted to pH 7 with 6N sodium hydroxide and then chargedon an activated charcoal column (2 L). The column was washed with 8 L ofdeionised water and the active substance was then eluted with 8 L of 0.5N aqueousammonia containing 10% acetone. Concentration and lyophilization of the resultingeluate yielded 28 g of a powder.
    [0419] The resulting powder was dissolved in 400 ml of distilled water. Afteradjustment to pH 3.0, the resulting solution was charged on a column (2 L) which hadbeen adjusted with water and packed with "Diaion CHP-20P" (product of MitsubishiChemical). The non-adsorbed liquid and washing fractions were collected,concentrated and lyophilized, whereby 12 g of a viscous substance was obtained.
    [0420] This viscous substance was dissolved in 200 ml of distilled water. Afteradjustment to pH 3.3 with trifluoroacetic acid, the resulting solution was then chargedon a column (1 L) equilibrated with 0.04% aqueous trifluoroacetic acid and packedwith "Diaion CHP-20P" (product of Mitsubishi Chemical). After development of thecolumn with 2 L of 0.04% aqueous trifluoroacetic acid and pooling of the fraction (Fraction H) eluted between 0.8 and 1.4 L, the eluting solution was changed to 2 L ofdistilled water. Concentration and lyophilization of 2 L of the fraction (Fraction F)eluted with distilled water yielded 605 mg of a powder.
    [0421] 600 ml of Fraction H was diluted with distilled water to 1 L and its pHadjusted to 2.8 with trifluoroacetic acid, and the resulting solution was then chargedagain on a column (1 L) packed with "Diaion CHP-20P" (product of MitsubishiChemical) equilibrated with 0.04% aqueous trifluoroacetic acid. The column waseluted with 2.2 L of 0.04% aqueous trifluoroacetic acid. Fractions 8 to 11 obtained byfractionation of the eluate in portions of 200 ml each were concentrated andlyophilized, whereby 233 mg of a powder was obtained.
    [0422] A 100 mg portion of the resulting powder was dissolved in 5 ml of water and 1ml portions of the resulting solution were charged on an HPLC column ("Senshu PakODS-H-5251": 20 x 250 mm; product of Senshu Scientific) equilibrated with 0.04%aqueous trifluoroacetic acid. The column was developed at a flow rate of 10 ml/min.The ultraviolet absorption of the active fraction at 210 nm was detected and a peakeluted during a retention time of 14 to 16 minutes was collected, the process beingcarried out 5 times. The fractions thus obtained were concentrated by a rotaryevaporator, followed by lyophilization, whereby 23 mg of Compound A-500359Hwas obtained as a pure product.
    [0423] In 15 ml of water were dissolved 605 mg of lyophilized powder of Fraction Fand 1 ml portions of the resulting solution were charged on an HPLC column("Senshu Pak ODS-H-5251": 20 x 250 mm; product of Senshu Scientific)equilibrated with 0.04% aqueous trifluoroacetic acid. The column was developed at aflow rate of 10 ml/min. The absorption of the active fraction at the ultraviolet portionof 210 nm was detected and a peak eluted during a retention time of 29 to 31 minuteswas collected 15 times by fractionation. The fractions thus obtained wereconcentrated by a rotary evaporator, followed by lyophilization, whereby 134 mg ofCompound A-500359F was obtained as a pure product.
    [0424] The compound A-500359F has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C17H21N3O12 4) Molecular weight: 459 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 460.1201 Calculated: 460.1203 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   262 nm (ε 7,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:[α]D 20: +111° (c 0.41) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3391, 2941, 1684, 1466, 1400, 1333, 1269, 1205, 1137, 1115, 1062, 1020 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows:3.37 (3H, s), 3.79 (1H, dd, J=5.1, 6.4Hz), 4.17 (1H, ddd, J=1.6, 3.4, 4.6 Hz), 4.38 (1H,dd, J=3.5, 5.1 Hz), 4.48 (1H, dd, J=2.4, 6.4 Hz), 4.49 (1H, ddd, J=0.6, 2.7, 4.6 Hz),4.69 (1H, d, J=2.4 Hz), 5.32 (1H, dd, J=0.6, 3.4 Hz), 5.77 (1H, d, J=3.5 Hz), 5.90 (1H,d, J=8.1 Hz), 6.11 (1H, dd, J=1.6, 2.7 Hz), 7.75 (1H, d, J=8.1 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard substance. 13C nuclear magneticresonance spectrum is as follows:58.6 (q), 62.7 (d), 65.5 (d), 72.7 (d), 76.3 (d), 78.8 (d), 91.2 (d), 100.0 (d), 102.7 (d),114.8 (d), 140.7 (s), 141.9 (d), 152.1 (s), 165.4 (s), 167.0 (s), 173.9 (s) ppm. 11) HPLC analysis: Column: "Senshu Pak ODS-H-2151"6 x 150 mm (product of Senshu Scientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 18 minutes
    [0425] Compound A-500359H has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C16H19N3O12 4) Molecular weight: 445 5) Accurate mass, [M+H]+, as measured by high-resolution FAB spectrometry is asfollows: Found: 446.1025 Calculated: 446.1047 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   262 nm (ε 7,400) 7) Optical rotation: optical rotation measured in water exhibits the following value:[α]D 20: +115° (c 0.33) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3361, 2934, 1683, 1467, 1403, 1336, 1270, 1206, 1114, 1090, 1058, 1021 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows:4.13 (br. t, J=5.4 Hz), 4.15-4.19 (2H), 4.43 (1H, dd, J=2.5, 5.8Hz), 4.48 (1H, dd,J=2.9, 4.7 Hz), 4.72 (1H, d, J=2.5 Hz), 5.31 (1H, d, J=4.0 Hz), 5.80 (1H, d, J=4.0 Hz),5.89 (1H, d, J=8.3 Hz), 6.12 (1H, dd, J=1.4, 2.9 Hz), 7.75 (1H, d, J=8.3 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4ppm) as an internal standard substance. 13C nuclear magneticresonance spectrum is as follows:62.8 (d), 65.8 (d), 70.3 (d), 74.6 (d), 77.0 (d), 84.2 (d), 90.3 (d), 100.3 (d), 102.9 (d),113.9 (d), 141.2 (s), 141.9 (d), 152.2 (s), 165.9 (s), 167.0 (s), 174.2 (s) ppm. 11) HPLC analysis: Column: "Senshu Pak ODS-H-2151"6 x 150 mm (product of Senshu Scientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 8 minutes
    [0426] Into each of three 2 L Erlenmeyer flasks, each containing 500 ml of the seedculture medium having the composition described below were aseptically inoculated fourloopfuls of Strain SANK60196. These flasks were shaken on a rotary shaker at 23°C and210 rpm and thus, the initial seed culture was conducted for 3 days.
    [0427] The seed culture medium contains the following components in 1000 ml of tapwater. Glucose 20 g Soluble starch 10 g Pressed yeast 9 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g Antifoamer "CB442" 50 mg (product of NOF Corporation)
    [0428] After adjustment of pH to 7.4, sterilization was conducted at 121°C for 20minutes.
    [0429] The first seed culture thus obtained was inoculated at 3% into a 60 L tankcontaining 30 L of the same preculture medium, and the second seed culture was carriedout with aeration and agitation at 23°C for 24 hours.
    [0430] Cultivation was conducted as described below. Described specifically, the secondseed culture broth was inoculated at 3% (v/v) into two 600 L tanks, each containing 400L of the below-described cultivation medium and cultivation was then carried out withaeration and agitation at 23°C for 6 days.
    [0431] The medium for cultivation: containing the following components in 1000 ml oftap water. Glucose 20 g Soluble starch 10 gPressed yeast 9 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g Antifoamer "CB442" 50 mg (product of NOF Corporation)
    [0432] After adjustment to pH 7.4, 3 g of calcium carbonate was added and themixture was sterilized at 125°C for 20 minutes. Example 47: Purification of Compound A-500359E
    [0433] The cultured broth (810 L) obtained in Example 46 was filtered with the aid of"Celite 545" (product of Celite Corporation).
    [0434] Upon subsequent purification, the active fraction was monitored by HPLCusing the following column and analytical conditions. Column: "YMC-Pak ODS-A A-312" 6 x 150 mm (product of YMC) Solvent: 0.04% aqueous trifluoroacetic acid containing 4% acetonitrile Flow rate: 1.0 ml/min Detection: UV 210 nm Retention time: 19.8 minutes
    [0435] The resulting filtrate (800 L) was charged on a column (160 L) packed with"Diaion HP-20P" (product of Mitsubishi Chemical). The column was washed with640 L of deionised water and the non-adsorbed fraction and washing fraction werethen combined (non-adsorbed·washing fraction). The adsorbed substance was elutedwith 348 L of 10% aqueous acetone.
    [0436] After concentration of the eluted fraction to 10 L, the residue was charged on acolumn (45 L) packed with "Diaion CHP-20P" (product of Mitsubishi Chemical).The column was then washed with 90 L of deionised water, 100 L of 10% aqueousmethanol and 100 L of 15% aqueous methanol. The adsorbed substance was elutedwith 100 L of 20% aqueous methanol.
    [0437] After concentration of the 20% aqueous methanol fraction to 5 L, theconcentrate was charged on a column (22 L) packed with "Toyopearl HW40F" (product of TOSOH Corporation). The column was developed with deionised waterand the eluate was collected by fractionation in portions of 5 L each. The activesubstance having a retention time of 19.8 minutes upon the above-described HPLCwas eluted in Fractions Nos. 3 to 6. These fractions were concentrated to 5.8 L andlyophilized to yield 55.8 g of a powder.
    [0438] The resulting powder was dissolved in 1.2 L of deionised water. A 200 mlportion of the resulting solution was charged on an HPLC column ("YMC-Pak ODS-1050-20-SR";100 x 500 mm; product of YMC) equilibrated with 0.04% aqueoustrifluoroacetic acid containing 4% acetonitrile. The column was developed at a flowrate of 200 ml/min with 0.04% aqueous trifluoroacetic acid containing 4%acetonitrile. The active substance had a retention time of 105 to 124 minutes. Thatoperation was repeated 6 times. The fractions thus obtained were combined,concentrated to 5 L by "Evapor" and then lyophilized, whereby 24.2 g of CompoundA-500359E was obtained as a pure product. Example 48: Purification of Compounds A-500359F and A-500359H
    [0439] Upon subsequent purification, the active fraction was monitored by HPLCusing the following column and analytical conditions. Column: "YMC-Pak ODS-A A-312" 6 x 150 mm (product of YMC) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 7.7 minutes (Compound A-500359H)16.6 minutes (Compound A-500359F)
    [0440] The non-adsorbed-washing fraction (1370 L) obtained in Example 47 wascharged on an activated charcoal column (65 L). After the column was washed with260 L of deionised water, the active substance was eluted with 270 L of 0.5N aqueousammonia containing 10% acetone. After concentration of the eluate to 40 L andadjustment of the concentrate to pH 2.4 with trifluoroacetic acid, it was charged on acolumn (45 L) packed with "Diaion CHP-20P" (product of Mitsubishi Chemical)equilibrated with 0.04% aqueous trifluoroacetic acid. The column was developedwith 0.04% aqueous trifluoroacetic acid to yield a fraction (Fraction H) eluted in 0 to47 L and another fraction (Fraction F) eluted in 47 to 91 L. Fraction H was concentrated to 1.5 L, while Fraction F was obtained as 287 g of a powder afterconcentration and lyophilization.
    [0441] The concentrate of Fraction H was diluted with deionised water to 3.2 L. A160 ml portion of it was charged on an HPLC column ("YMC-Pack ODS-1050-20-SR":100 x 500 mm; product of YMC) equilibrated with 0.04% aqueoustrifluoroacetic acid, followed by development at a flow rate of 200 ml/min. Ultravioletabsorption of the active fraction at 210 nm was detected and a peak eluted at aretention time of 67 to 72 minutes was collected by fractionation. This operation wasrepeated 20 times. The fractions thus obtained were concentrated by "Evapor"(product of Okawara Seisakujo) and lyophilized to yield 5.9 g of Compound A-500359Has a pure product.
    [0442] A 277 g portion of Fraction F in powder form was dissolved in 50 L ofdeionised water and the resulting solution was adjusted to pH 2.2 with trifluoroaceticacid. The solution was charged again on a column (45 L) packed with "Diaion CHP-20P"(product of Mitsubishi Chemical) equilibrated with 0.04% aqueoustrifluoroacetic acid. After washing the column with 97 L of 0.04% aqueoustrifluoroacetic acid, the active substance was eluted with 120 L of deionised water.The deionised water eluted fraction was concentrated and lyophilized, whereby 75.6 gof Fraction F was obtained as a lyophilized powder.
    [0443] The resulting lyophilized powder of Fraction F was dissolved in 4 L of water.A 150 ml portion of the solution was charged on an HPLC column ("YMC-Pak ODS-1050-20-SR",100 x 500 mm; product of YMC) equilibrated with a mixture of 0.5%acetonitrile and 0.04% aqueous trifluoroacetic acid, followed by development with thesame solvent system at a flow rate of 200 ml/min. The absorption of the activefraction at the ultraviolet portion of 210 nm was detected and a peak eluted at aretention time of 88 to 97 minutes was collected by fractionation. This operation wasrepeated 27 times. The fractions thus obtained were concentrated and lyophilized,whereby 19.2 g of Compound A-500359F was obtained as a pure product. Example 49: Preparation process of each of Compound A-500359F and the amidederivative of compound A-500359F (chemical conversion of Compound A-500359Eby aqueous ammonia)
    [0444] Compound A-500359E (75 mg) obtained in Example 44 was dissolved in 2 mlof 0.5N aqueous ammonia. The resulting solution was allowed to stand at roomtemperature for 2 hours. After completion of the reaction, the reaction mixture waslyophilized to yield 78 mg of a powder.
    [0445] The resulting powder was dissolved in 1 ml of 0.04% aqueous TFA. A 100 µlportion of the resulting solution was charged on an HPLC column ("Capcellpak UG120Å", 20ø x 250 mm; product of Shiseido) equilibrated with 0.04% aqueoustrifluoroacetic acid, followed by elution with 0.04% aqueous trifluoroacetic acid at aflow rate of 10 ml/min. The ultraviolet absorption of the active fraction at 210 nmwas detected and peaks eluted at a retention time of 21 to 22 minutes and at aretention time of 31 to 33 minutes were collected by fractionation, the process beingcarried out 10 times.
    [0446] The fractions eluted at a retention time of 21 to 22 minutes were concentratedby a rotary evaporator and lyophilized, whereby 14 mg of the amide derivative ofcompound A-500359F was obtained in pure form.
    [0447] The fractions eluted at a retention time of 31 to 33 minutes were concentratedby a rotary evaporator and lyophilized, whereby 50 mg of Compound A-500359F wasobtained in pure form.
    [0448] The amide derivative of compound A-500359F has the following physico-chemicalproperties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C17H22N4O11 4) Molecular weight: 458 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 459.1328 Calculated: 459.1364 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   258 nm (ε 7,500) 7) Optical rotation: optical rotation measured in water exhibits the following value: [α]D 25: +119° (c 0.87) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3339, 2943, 1686, 1598, 1495, 1402, 1337, 1272, 1205, 1136, 1115, 1060, 1019 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with thesignal of water as 4.75 ppm. 1H nuclear magnetic resonance spectrum is as follows:3.30 (3H, s) 3.67 (1H, dd, J=5.0, 6.8 Hz), 4.17 (1H, ddd, J=1.8, 2.9, 4.4 Hz), 4.35 (1H,dd, J=3.2, 5.0 Hz), 4.43 (1H, dd, J=2.3, 6.8 Hz), 4.45 (1H, dd, J=2.4, 4.4 Hz), 4.66(1H, d, J=2.3 Hz), 5.35 (1H, d, J=2.9 Hz), 5.71 (1H, d, J=3.2 Hz), 5.85 (1H, d, J=8.1Hz), 5.97 (1H, dd, J=1.8, 2.4 Hz), 7.71 (1H, d, J=8.1 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard substance. 13C nuclear magneticresonance spectrum is as follows:58.6 (q), 62.7 (d), 65.3 (d), 72.6 (d), 75.7 (d), 78.7 (d), 82.3 (d), 91.3 (d), 99.8 (d),102.7 (d), 110.8 (d), 141.9 (d), 142.3 (s), 152.1 (s), 166.0 (s), 167.0 (s) ppm. 11) HPLC analysis: Column: "Senshu Pack ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.5 ml/min Detection: UV 210 nm Retention time: 11 minutes
    [0449] Compound A-500359E (4.4 mg) obtained in Example 44 was dissolved in 0.5ml of distilled water. After the dropwise addition of 0.5 ml of 0.02N aqueous sodiumhydroxide, 1 ml of 0.1N aqueous sodium hydroxide was added dropwise. Theresulting mixture was allowed to stand at room temperature for 50 minutes. Thereaction mixture was neutralized with 1N hydrochloric acid and then charged on 2 mlof an activated charcoal column. The column was washed with 8 ml of distilled waterand the reaction substance was then eluted with 8 ml of 0.5N aqueous ammoniacontaining 10% acetone.
    [0450] After concentration of the eluate to 700 µl, the concentrate was charged on anHPLC column ("Senshu Pak ODS-H-4251"; 10 x 250 mm; product of SenshuScientific) equilibrated with 0.04% aqueous trifluoroacetic acid, followed by elutionat a flow rate of 4 ml/min. The ultraviolet absorption of the active substance at 210nm was detected and a peak eluted at a retention time of 25 to 30 minutes wascollected by fractionation. This operation was repeated three times. The fractionsthus obtained were concentrated in a rotary evaporator and lyophilized, whereby 2.6mg of Compound A-500359F was obtained in pure form. Example 51: Cultivation of Streptomyces griseus Strain SANK60196 (FERM BP-5420)
    [0451] One loopful of strain SANK60196 was sterilised before being inoculated intoa 500 ml Erlenmeyer flask (seed flask) containing 100 ml of a medium having thecomposition described below. Seed culture was conducted for 3 days by shaking theflask in a rotary shaker at 23°C and 210 rpm.
    [0452] Seed culture medium containing the following components in 1000 ml of tapwater. Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g "Antifoamer CB442" 50 mg
    [0453] After adjustment to pH 7.4, sterilization was conducted at 121°C for 30 minutes.
    [0454] Cultivation was conducted as described below. Described specifically, theseed culture was inoculated at 3% (V/V) into each often 500 ml Erlenmeyer flasks,each containing 100 ml of a sterilized medium having the composition describedbelow. Cultivation was conducted for 11 days by shaking the flasks in a rotary shakerat 23°C and 210 rpm.
    [0455] Cultivation medium: containing the following components in 1000 ml of tapwater. Glucose 50 gMeat extract 4 g Polypeptone 3 g Skimmed milk 10 g Corn steep liquor 10 g Sodium chloride 5 g "Antifoamer CB442" 50 mg
    [0456] After adjustment to pH 7.4, sterilization was conducted at 125°C for 30 minutes. Example 52: Purification of Compound A-500359J
    [0457] Upon subsequent purification, the active fraction was monitored by HPLCusing the following column and analytical conditions.
    [0458] Column: "Pegasil ODS", 6 x 150 mm (product of Senshu Scientific Co.,Ltd.) Solvent: 0.04% aqueous trifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 260 nm Retention time: 5.57 minutes The cultured broth obtained in Example 51 was filtered with the aid of "Celite 545"added at 5% (W/V). The filtrate (1 L) thus obtained was charged on a column (200ml) of "Diaion HP-20". The column was then washed with distilled water (500 ml).After adjustment of the pH of 1.5 L of non-adsorbed washing fraction to 9 with 6Nsodium hydroxide, the fraction was charged on a column (100 ml) of "Dowex SBR-P(OH-)". The column was washed with distilled water (300 ml) and the adsorbedsubstance was eluted with 300 ml of 1N aqueous hydrochloric acid.After adjustment of pH after elution to 7 with sodium hydroxide, the eluate wascharged on an active charcoal column (50 ml). The column was washed with distilledwater (100 ml) and the active substance was diluted with 60% aqueous acetone (200ml). Concentration and lyophilization of the eluate yielded 558 mg of a powder.The powder was dissolved in 5 ml of distilled water and 500 µl portions of theresulting solution were charged on an HPLC column ("Senshu Pack Pegasil ODS";20 x 250 mm; product of Senshu Scientific) equilibrated with 0.05% aqueoustrifluoroacetic acid. They were developed at a flow rate of 10.0 ml/min. Theultraviolet absorption of the active substance at 260 nm was detected and a peak eluted at a retention time of 11.1 minutes was collected by fractionation, the processbeing carried out 10 times. The resulting fractions were concentrated by a rotaryevaporator and then lyophilized, whereby 16.2 mg of Substance A-500359J wasobtained in pure form.
    [0459] The compound A-500359J has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water, slightly soluble in methanol, insoluble in normalhexane and chloroform 3) Molecular formula: C16H21N3O13 4) Molecular weight: 463 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry isas follows: Found: 462.0996 Calculated: 462.1006 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   194 (ε 8800), 262 (ε 10000) nm 7) Optical rotation: optical rotation measured in water exhibits the following value:   [α]D 28; +83° (c 0.1, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3372, 2931, 1684, 1467, 1407, 1273, 1204, 1107, 1058 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (3.53 ppm) as an internal standard substance. 1H nuclear magneticresonance spectrum is as follows:3.75 (1H, t, J=3.4 Hz), 3.83 (1H, ddd, J=1.4, 1.9, 3.4 Hz), 4.02 (1H, ddd, J=1.4, 1.7,3.4 Hz), 4.05 (1H, dd, J=5.3, 5.6 Hz), 4.11 (1H, t, J=5.6 Hz), 4.13 (1H, dd, J=3.1, 5.6Hz), 4.30 (1H, d, J=5.3 Hz), 4.33 (1H, d, J=1.7 Hz), 4.90 (1H, d, J=1.9 Hz), 5.50 (1H,d, J=3.1 Hz), 5.7 (1H,d, J=8.2 Hz), 7.6 (1H, d, J=8.2 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with1,4-dioxane (67.4 ppm) as an internal standard substance. 13C nuclear magneticresonance spectrum is as follows: 64.4 (d), 68.8 (d), 68.9 (d), 69.7 (d), 71.4 (d), 73.0 (d), 75.4 (d), 82.8 (d), 90.7 (d),99.2 (d), 101.7 (d), 141.6 (d), 151.0 (s), 165.9 (s), 171.9 (s), 172.6 (s) ppm. 11) HPLC analysis: Column: "Senshu Pak ODS-H-2151", 6 x 150 mm (product of SenshuScientific Co., Ltd.) Solvent: 0.05% aqueous trifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 260 nm Retention time: 5.57 minutes
    [0460] One loopful of strain SANK60196 was sterilised prior to inoculation in a 500ml Erlenmeyer flask (seed flask) containing 100 ml of a medium having thecomposition described below. Preculture was conducted for 3 days by shaking theflask in a rotary shaker at 23°C and 210 rpm.
    [0461] Medium for preculture: containing the following components in 1000 ml oftap water. Maltose 30 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g "Antifoamer CB442" 50 mg
    [0462] After adjustment to pH 7.4, sterilization was conducted at 121°C for 30minutes.
    [0463] Cultivation was conducted as described below. Described specifically, thepreculture broth was inoculated at 3% (V/V) into each of ten 500 ml Erlenmeyerflasks, each containing 100 ml of a sterilized medium having the compositiondescribed below. Cultivation was conducted by shaking the flasks in a rotary shakerat 23°C and 210 rpm. Six hours after initiation of the cultivation, filter-sterilized S-(2-aminoethyl)-L-cysteinehydrochloride and L-allylglycine were added to give afinal concentration of 10 mM. Cultivation was then continued for 7 days.
    [0464] Cultivation medium: containing the following components in 1000 ml of tap water. Maltose 30 g Yeast extract (product of Difco Laboratories) 5 g Meat extract 5 g Polypeptone 5 g Sodium chloride 5 g Calcium carbonate 3 g "Antifoamer CB442" 50 mg
    [0465] After adjustment to pH 7.4, sterilization was conducted at 125°C for 30minutes. Example 54: Purification of Substance A-500359M-3
    [0466] The cultured broth (1 L) obtained in Example 53 was centrifuged at 3000 rpmfor 20 minutes and the resulting supernatant was purified.
    [0467] Upon subsequent purification, the active fraction was monitored by HPLCusing the following column and analytical conditions. Column: "Pegasil ODS" 6 x 150 mm (product of Senshu Scientific) Solvent: 7.2% acetonitrile - 0.05% aqueous trifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 260 nm Retention time: 10.1 minutes
    [0468] After adjustment of the supernatant to pH 3 with trifluoroacetic acid, theresulting solution (1 L) was charged on a "Diaion HP-20" column (200 ml)equilibrated with 0.05% aqueous trifluorocetic acid. The column was washed with0.05% aqueous trifluoroacetic acid (500 ml), followed by elution with distilled water(500 ml). The distilled water eluate (500 ml) thus obtained was concentrated andlyophilized to yield 230 mg of a crude powdery product.
    [0469] The crude powdery product was dissolved in 2 ml of distilled water and a 500µl portion of the resulting solution was charged on an HPLC column ("Pegasil ODS",trade name; 20 x 250 mm; product of Senshu Scientific) equilibrated with 0.05%aqueous trifluoroacetic acid containing 7% acetonitrile.
    [0470] The column was developed with the same solvent at a flow rate of 10.0 ml/minand the ultraviolet absorption at 210 nm was monitored. resulting in elution of the activesubstance at a retention time of 28.0 minutes. This operation was repeated four times andthe eluates were combined, concentrated and lyophilized, whereby 11.1 mg of SubstanceA-500359M-3 was obtained in pure form.
    [0471] The compound A-500359M-3 has the following physico-chemical properties: 1) Appearance of the substance: white powder 2) Solubility: soluble in water and methanol, insoluble in normal hexane and chloroform 3) Molecular formula: C22H28N4O13 4) Molecular weight: 556 (as measured by FAB mass spectrometry) 5) Accurate mass, [M+H]+, as measured by high-resolution FAB mass spectrometry is asfollows: Found: 557.1754 Calculated: 557.1731 6) Ultraviolet absorption spectrum: ultraviolet absorption spectrum measured in waterexhibits the following maximum absorption:   236 nm (ε 10,000) 7) Optical rotation: optical rotation measured in water exhibits the following value:   [α]D 26: +92° (c 0.1, H2O) 8) Infrared absorption spectrum: Infrared absorption spectrum as measured by thepotassium bromide (KBr) disk method exhibits the following absorption maxima:3407, 2938, 1684, 1524, 1465, 1399, 1385, 1335, 1268, 1205, 1139, 1118, 1095, 1063,1021 cm-1. 9) 1H nuclear magnetic resonance spectrum was measured in deuterium oxide with 1,4-dioxane(3.53 ppm) as an internal standard substance. 'H nuclear magnetic resonancespectrum is as follows:2.44 (1H, ddd, J=4.3, 7.3, 13.3 Hz), 2.52 (1H, ddd, J=4.3, 7.5, 13.3 Hz), 3.27 (3H, s),3.66 (1H, t, J=5.5 Hz), 4.17 (1H, ddd, J=1.1, 2.5, 3.1 Hz), 4.32 (1H, dd, J=3.7, 5.5 Hz),4.33 (1H, t, J=4.3 Hz), 4.45 (1H, m), 4.46 (1H, m), 4.73 (1H overlapped with HDO), 5.07(1H, d, J=10.2 Hz), 5.36 (1H, d, J=3.1 Hz), 5.51 (1H, d, J=17.1 Hz), 5.58 (1H, d, J=8.1Hz), 5.73 (1H, m), 5.74 (1H, d,J=3.7 Hz), 5.95 (1H, dd, J=1.1, 1.9Hz), 7.72 (1H, d,J=8.1 Hz) ppm. 10) 13C nuclear magnetic resonance spectrum was measured in deuterium oxide with 1,4-dioxane(67.4 ppm) as an internal standard substance. 13C nuclear magnetic resonancespectrum is as follows:37.1 (t), 55.4 (d), 58.6 (q), 62.6 (d), 65.3 (d), 72.6 (d), 75.7 (d), 78.9 (d). 82.4(d), 90.6 (d).99.8(d), 102.6 (d), 109.9 (d), 119.0 (t), 134.0 (d), 141.7 (d), 142.2 (s), 152.0 (s), 162.3(s), 166.8 (s), 173.6 (s), 177.6 (s) ppm. 11) HPLC analysis: Column: "Pegasil ODS" 6 x 150 mm (product of Senshu Scientific Co.. Ltd.) Solvent: 7.2% acetonitrile - 0.05% aqueous trifluoroacetic acid Flow rate: 1.0 ml/min Detection: UV 260 nm Retention time: 10.1 minutes
    [0472] The minimum inhibitory concentration of the compounds of the invention againstMycobacterium smegmatis Strain SANK 75075 was determined in accordance with theprocess described below. The concentration of the compound to be tested was set at fourstages by four-fold dilution starting from 1000 µg/ml (1000 µg/ml, 250 µg/ml, 62 µg/mland 15 µg/ml). A 1 ml portion of the diluted sample of each stage was poured into a Petridish ("Terumo Petri dish", 90 x 20 mm). A nutrient agar medium (9 ml, product of EikenChemical) containing 5% glycerol was added and they were mixed to prepare a platemedium. A test microorganism Mycobacterium smegmatis SANK 75075 was preculturedovernight at 37°C on a trypto-soy broth (T.S.B) medium (product of Eiken Chemical)containing 5% glycerol. On the testing day, the microorganism solution was diluted 100-foldwith T.S.B. and one loopful of the diluted culture was streaked onto the platemedium. After cultivation at 37°C for 18 hours, the minimum concentration (MIC) of thetest substance inhibiting the growth of the microorganism was determined. The resultsare shown in Table 6. Antibacterial activities against Mycobacterium smegmatis SANK 75075 Exemp. Compound No. Minimum inhibitory concentration (µg/ml) 1 6.2 7 6.2 8 1.5 9 3.1 10 6.2 11 6.2 16 6.2 17 6.2 18 3.1 50 3.1 51 1.5 52 3.1 53 1.5 135 1.5 282 6.2 548 6.2 891 6.2 1091 6.2 Capuramycin 12.5
    [0473] The minimum inhibitory concentration of the invention compound of the formula(Ia) against Mycobacterium avium Strain NIHJ1605 was determined. Describedspecifically, Tween 80 (0.1%) was added to Middleblook 7H9 broth. After autoclavesterilization, Middleblook ADC enrichment was added (20%). Into each of micro-testtubes was poured a 0.8 ml portion of the resulting mixture. To each of the test tubes wasadded a 0.1 ml portion of each of the compounds of the invention diluted two-fold (whichwill hereinafter be abbreviated as "medicament-containing medium"). On the side, acolony obtained by preculturing Mycobacterium avium NIHJ1605 on a Tween egg medium for 10 to 14 days was charged in a test tubecontaining Tween 80 and glass beads. After sufficient mixing, Middleblook 7H9broth was added to form a uniform microorganism solution. The microorganismsolution was adjusted to OD625nm = 0.10 (viable cell count: about 1 x 108 CFU/ml),followed by 100-fold dilution. A 0.1 ml portion of the resulting microorganismsolution was inoculated into the above-described medicament-containing medium(final viable cell count: about 1 x 105 CFU/ml), followed by aerobic culture at 37°Cfor 6 days. The minimum medicament amount at which no colony having a diameterof 1 mm or greater was recognized on the bottom of the test tube was determined asMIC (µg/ml). The results are shown in Table 7. Antibacterial activities against Mycobacterium avium NIHJ 1605 Exemp. compound Minimum inhibitory concentration No. (µg/ml) 539 0.25 571 1 594 1 Capuramycin 8 (2) Disk Assay
    [0474] So-called disk assay was conducted using 40 µg of a test substance per paperdisk of 8 mm. Compound A-500359M-2 (Exemp. compound No. 396) exhibited aninhibitory zone of 14 mm in diameter against Bacillus subtilis PCI 219, that of 30 mmin diameter against Mycobacterium smegmatis SANK 75075 and that of 25 mm indiameter against Klebsiella pneumoniae PCI 602.
    [0475] So-called Disk assay ("Experimental Agricultural Chemistry", ed, byAgricultural Chemistry Class/Agriculture Dept./Tokyo Univ., 3rd edition, Volume II,published by Asakura Shoten in 1978) was conducted using 40 µg of a test substanceper paper disk of 8 mm. Compound A-500359E exhibited an inhibitory circle of 12mm in diameter against Mycobacterium smegmatis SANK 75075, the amide derivative of compound A-500359F exhibited an inhibitory circle of 12 mm indiameter and Compound A-500359M-3 also exhibited an inhibitory circle of 12 mmin diameter. Preparation Example 1
    [0476] Capsules A-500359A or C 100 mg Lactose 100 mg Corn starch 148.8 mg Magnesium stearate 1.2 mg Total amount 350 mg
    [0477] A capsule was obtained by mixing powders in accordance with the above-describedformulation, sieving the resulting mixture through a 60-mesh sieve, andthen charging the resulting powder in a gelatin capsule. Preparation Example 2
    [0478] Capsules were each obtained by mixing 100 mg of Compound A-500359E,Compound A-500359F, the amide derivative of compound A-500359F, CompoundA-500359H, Compound A-500359J or Compound A-500359M-3, 100 mg of lactoserespectively, 148.8 mg of corn starch and 1.2 mg of magnesium stearate (totally, 350mg) in the powdery form, sieving the resulting mixture through a 60-mesh sieve andcharging the powder in a gelatin capsule. Toxicity Test
    [0479] The invention compound A-500359A exhibited no toxicity whenintravenously administered to a mouse in an amount of 500 mg/kg.
    [0480] The results described above show that the compounds of the inventionrepresented by the formulae (I), (XI), (XII), (XIII), (XIV), (XV) and (XVI)respectively, various derivatives of the compound represented by the formula (Ia), andpharmacologically acceptable salts thereof exhibit excellent antibacterial activitiesagainst various bacteria including Mycobacteria so that they are useful in theprevention or treatment of infectious diseases caused by such bacteria. Streptomyces griseus SANK60196 (FERM BP-5420) is useful as a bacterium producing thecompound represented by the formula (I), (XI), (XII), (XIV), (XV) or (XVI). Thecompounds of the invention represented by the formulae (I), (XI), (XIII), (XIV), (XV)or (XVI) are also useful as a starting material for the synthesis of a derivative for thepreparation of a prevention or treatment of various infectious diseases by organicchemical or microbiological conversion.
    权利要求:
    Claims (12)
    [1]
    A compound A-500359E of formula (XI) or a salt thereof.
    [2]
    A compound A-500359F of formula (XII) or a salt thereof.
    [3]
    An amide derivative of compound A-500359F of formula (XIII) or a saltthereof.
    [4]
    A compound A-500359H of formula (XIV) or a salt thereof.
    [5]
    A compound A-500359J of formula (XV) or a salt thereof.
    [6]
    A compound A-500359M-3 of formula (XVI) or a salt thereof.
    [7]
    A process for preparing a compound according to any one of claims 1, 2, 4 or5 by a cultivation procedure which comprises i) cultivating a strain of micro-organismof the genus Streptomyces and ii) isolating the compound from the cultivationproducts.
    [8]
    A process according to claim 7 wherein the strain of micro-organism isStreptomyces griseus (SANK 60196; FERM BP-5420).
    [9]
    A pharmaceutical composition comprising an effective amount of apharmacologically active compound together with a carrier or diluent therefor,wherein said pharmacologically active compound is a compound according to any oneof claims 1 to 6 or a pharmaceutically acceptable salt thereof.
    [10]
    The use of a compound according to any one of claims 1 to 6 or apharmaceutically acceptable salt thereof in the manufacture of a medicament for thetreatment or prevention of a bacterial infection.
    [11]
    A compound according to any one of claims 1 to 6 or a pharmaceuticallyacceptable salt thereof for use as a medicament.
    [12]
    A compound according to any one of claims 1 to 6 or a pharmaceuticallyacceptable salt thereof for use in the treatment or prevention of a bacterial infection.
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    同族专利:
    公开号 | 公开日
    WO2000002892A1|2000-01-20|
    ES2248654T3|2006-03-16|
    HK1053127A1|2003-10-10|
    AT304548T|2005-09-15|
    AU751470B2|2002-08-15|
    HK1053063A1|2003-10-10|
    IL187551A|2009-12-24|
    IL140731D0|2002-02-10|
    AU4650599A|2000-02-01|
    US6844173B2|2005-01-18|
    KR100622889B1|2006-09-12|
    KR100729196B1|2007-06-19|
    KR20060011919A|2006-02-03|
    NO20010105L|2001-03-08|
    US20030069204A1|2003-04-10|
    NO322083B1|2006-08-14|
    HU0103711A3|2003-11-28|
    KR20010083101A|2001-08-31|
    US6472384B1|2002-10-29|
    BR9911965A|2001-05-29|
    PT1095947E|2007-06-20|
    DK1095947T3|2007-07-16|
    ES2284260T3|2007-11-01|
    ID27955A|2001-05-03|
    ZA200100200B|2002-06-26|
    EP1319666B1|2005-09-14|
    DE69927306T2|2006-07-06|
    NZ509233A|2003-05-30|
    PL200426B1|2009-01-30|
    IL187551D0|2008-03-20|
    EP1319406A1|2003-06-18|
    HK1053127B|2005-12-30|
    CN1317008A|2001-10-10|
    DK1319666T3|2005-12-05|
    AT356825T|2007-04-15|
    DE69935513T2|2007-11-29|
    PL345403A1|2001-12-17|
    CA2337225C|2009-05-26|
    RU2209210C2|2003-07-27|
    DE69927306D1|2005-10-20|
    IL140731A|2008-06-05|
    EP1095947B1|2007-03-14|
    HU0103711A2|2002-02-28|
    CN1181087C|2004-12-22|
    CA2337225A1|2000-01-20|
    DE69935513D1|2007-04-26|
    EP1095947A1|2001-05-02|
    EP1095947A4|2002-01-16|
    TR200100059T2|2001-05-21|
    NO20010105D0|2001-01-08|
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    EP99929772A|EP1095947B1|1998-07-09|1999-07-09|Novel antibacterial compounds|
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