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WO1997031892A1 - Derives d'acide hydroxamique - Google Patents

Derives d'acide hydroxamique Download PDF

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Publication number
WO1997031892A1
WO1997031892A1 PCT/JP1997/000582 JP9700582W WO9731892A1 WO 1997031892 A1 WO1997031892 A1 WO 1997031892A1 JP 9700582 W JP9700582 W JP 9700582W WO 9731892 A1 WO9731892 A1 WO 9731892A1
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Prior art keywords
group
carbon atoms
compound
substituted
alkyl group
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PCT/JP1997/000582
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English (en)
Japanese (ja)
Inventor
Tomoyuki Shibata
Nobuyuki Ohkawa
Toshiyasu Takemoto
Susumu Sato
Kazuhiko Tamaki
Shinwa Kurihara
Kazuhiko Tanzawa
Tomowo Kobayashi
Shinichi Miura
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Sankyo Company, Limited
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Priority to AU18121/97A priority Critical patent/AU1812197A/en
Publication of WO1997031892A1 publication Critical patent/WO1997031892A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel yarn having excellent matrix metallobrotinase inhibitory activity.
  • the present invention relates to a hydroxamic acid derivative, an agent for inhibiting metastasis, invasion and growth of various cancer cells, and a therapeutic and prophylactic agent for osteoarthritis and rheumatoid arthritis, which contain the derivative as an active ingredient.
  • Matrix meta-oral proteinase is an enzyme that degrades the protein components that make up connective tissue.
  • Gelatinase which belongs to this group, degrades type IV collagen, a major component of the basement membrane. In the process of neovascularization and metastasis of cancer in cancer tissues, the expression of gelatinase is increased or activated. Therefore, it is said that gelatinase plays an important role in destroying the basement membrane of cells in normal tissues (Annua 1 Review of Cell Biology, vol. 9). , 541-573 (1993)).
  • N 2 described in WO 94-02447 (4-Hydroxyamino-12- (R) -isobutyl-3- (S) -hydroxysuccinyl) —L-t-one-isocyanate-N 1 -Methylamide is undergoing clinical trials in Europe and the United States as an anticancer agent (Proceedings of American As soci at ion for cancer Research, vol. 37, 633 (1996)).
  • the present inventors have conducted intensive studies on the synthesis of a derivative having excellent matrix metallobrotinase inhibitory activity and its pharmacological activity, and as a result, it has excellent enzyme inhibitory activity on matrix metallobulininase.
  • the present inventors have found novel derivatives useful as agents for inhibiting metastasis, invasion and proliferation of various cancer cells, and as therapeutic and preventive agents for osteoarthritis and rheumatoid arthritis, and completed the present invention.
  • the present invention relates to a novel hydroxamic acid derivative having excellent matrix meta-oral proteinase inhibitory activity, and an agent for inhibiting metastasis, invasion and growth of various cancer cells, and an osteoarthritis containing the derivative as an active ingredient. And a therapeutic and prophylactic agent for rheumatoid arthritis.
  • the compound of the present invention has the general formula (1)
  • R 1 is an alkyl group having 1 to 15 carbon atoms which may have a substituent
  • the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group or a halogeno group having 1 to 4 carbon atoms
  • the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group or a halogeno group having 1 to 4 carbon atoms
  • An aralkyloxy group having 7 to i4 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group) ,
  • alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is a halogeno group)
  • R 2 represents a hydrogen atom, a hydroxy group or an aliphatic acyloxy port having 1 to 4 carbon atoms
  • R 3 is an alkyl group having 1 to 6 carbon atoms which may have a substituent
  • R 4 is a hydrogen atom
  • An alkyl group having 1 to 4 carbon atoms which may have a substituent (the substituent is a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, C2-C5 alkoxyl-rubonyl group, C2-C5 alkyl-rubamyl group, C3-C9 dialkyl-rubamoyl group, or C2-C8 dialkylamino group
  • R 5 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • R e is a hydrogen atom
  • An aliphatic acyl group having 1 to 6 carbon atoms which may have a substituent (an amino group, a monoalkylamino group having 1 to 4 carbon atoms, a dialkylamino having 2 to 8 carbon atoms) Group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a monocyclic or condensed heterocyclyl group having 5 to 10 atoms or a carboxy group)
  • the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxycarbonylalkyl group having 3 to 9 carbon atoms, or a carboxy group having 2 to 5 carbon atoms.
  • R 1 is an optionally substituted alkyl group having 1 to 7 carbon atoms
  • R 2 is a hydrogen atom
  • R 4 is 2 to 5 carbon atoms
  • examples of the “alkyl group having 1 to 15 carbon atoms” of the “alkyl group having 1 to 15 carbon atoms which may have a substituent” for R 1 include, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 1-ethylbutyl, 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-ethylbuty
  • R 1 s s is an integer having 1 to 15 carbon atoms which may have a substituent.
  • the number of substitution is preferably 1 to 3, and more preferably 1.
  • the “alkoxy group having 1 to 6 carbon atoms” is For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2, 3-dimethylbutoxy group and the like, preferably those having 2 to 4 carbon atoms (especially ethoxy, isopropoxy and butoxy groups).
  • the substituent is an aryl group having 6 to 10 carbon atoms which may have a substituent (the substituent may be an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogeno group).
  • aryl groups such as phenyl and naphthyl; 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-bromophenyl, 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-diphenylpyruphenyl, 2,4-diphenylbiphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl 2,3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl.2,3,6-Tributylphenyl, 2,3,4-
  • Alkoxy substituted aryl groups such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl 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-triphenyl Fluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl,
  • a phenyl group which may have a substituent (the number of substituents is preferably 1 to 3, and more preferably 1).
  • phenyl Preferable are phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl (particularly 4-chlorophenyl), and the substituent "
  • a good aryloxy group having 6 to 10 carbon atoms is, for example, phenyloxy.
  • aryloxy groups such as naphthyloxy group; 2-methylphenyloxy, 3-methylphenyloxy, 4-methylphenyloxy, 2-ethylphenyloxy, 3-propylphenyloxy , 4-ethylphenyloxy, 2-butylphenyloxy, 3-pentylphenyloxy, 4-pentylphenyloxy, 3,5-dimethylphenyloxy, 2,5-dimethylphenyl Niloxy, 2,6-dimethylphenyloxy, 2,4-dimethylphenyloxy, 3,5-dibutylphenyloxy, 2,5-dipentylphenyloxy, 2,6-dibutyl biphenyloxy, 2,4-dipro Bilphenoxy, 2,3,6-trimethylphenyloxy, 2,3,4-trimethylphenyloxy, 3,4,5-trimethylphenyloxy, 2,5,6-trimethyl Limethylphenyloxy, 2,4,6-Trimethylphenyloxy, 2,3,6-Trimethylphenyloxy
  • a phenyloxy group substituted with a methoxy or chloro group more preferably a phenyloxy, 4-methylphenyloxy, 4-methoxyphenyloxy or 4-cyclophenyloxy group.
  • the substituent is an “aralkyloxy group having 7 to 14 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms, An alkoxy group or a halogeno group)] are benzyloxy, ⁇ -naphthylmethyloxy, / 3-naphthylmethyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 2,4 , 6-trimethylbenzyloxy, 3,4,5-trimethylbenzyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 3 , 4-dimethoxybenzyloxy, 2-chlorobenz
  • the substituent “alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is an octalogeno group)” J is methoxymethoxy, ethoxyethoxy, ethoxymethyl or the like.
  • Toxi isopropoxymethoxy, fluoromethoxime, (2,2,2-trifluoroethoxy) methoxy, trifluoromethoxime, chloromethoxime, promomethoxime, odomethoxime
  • Examples include toxic, methoxybutoxy and butoxybutoxy groups, preferably those having 3 to 6 carbon atoms.
  • Ri more preferably, Etokishe Bok carboxymethyl, I Sopurobokishe Bok alkoxy and (2, 2, 2-Torifuruoroe Bok carboxymethyl) a main Bok alkoxy group,
  • R 1 ⁇ an alkyl group having 1 to 15 carbon atoms which may have a substituent '' as a whole,
  • alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or methyl group Alkyl groups having 1 to 6 carbon atoms substituted with a good phenyl group, alkyl groups having 1 to 6 carbon atoms substituted with a cycloalkyl group having 4 to 6 carbon atoms, and alkoxy groups having 4 to 6 carbon atoms
  • examples of the “aliphatic acyloxy group having 1 to 6 carbon atoms” for R 2 include, for example, formyloxy, acetoxy, propionyloxy, petyriloxy, pentanoyloxy group and the like. Is an acetate group.
  • alkyl group having 1 to 6 carbon atoms of the “alkyl group having 1 to 6 carbon atoms which may have a substituent” for R 3 , for example, methyl, Ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 1-ethylbutyl, 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 group
  • examples of the “C 1 to C 4 alkoxy group” as a substituent in the “optionally substituted C 1 to C 6 alkyl group” for R 3 include, for example, , Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy groups, and is preferably a methoxy group.
  • examples of the “to 4 alkylthio groups” include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio, and tert-butyl. And preferably a methylthio and an ethylthio group, more preferably a methylthio group, '
  • substituents "aliphatic acyloxy group having 1 to 6 carbon atoms” include, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, and the like.
  • An ethoxy group, and the substituent, "an aryl group having 6 to 10 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, A hydroxy group, an aliphatic alkoxy group having 1 to 4 carbon atoms, an alkoxy group or a halogeno group having 1 to 4 carbon atoms)), for example, an aryl group such as a phenyl or naphthyl group; Tylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl Ny
  • Fluorophenyl 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-trichloromethylphenyl, 1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-Fluoro-1-naphthyl, 1-chloro- 2-naphthyl, 2-chloro-1-naphthyl, 3-bromo-1-naph
  • a furyl Preferable are a furyl, phenyl and benzofuranyl group, more preferably a furyl group, and the substituent "the cycloalkyl group having 3 to 8 carbon atoms" is , Cyclobutyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, preferably having 4 to 6 carbon atoms (especially cyclohexyl group),
  • an alkyl group having 1 to 6 carbon atoms which may have a substituent” for R 3 is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms, methylthio or ethylthio.
  • an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group and an alkyl group having 1 to 4 carbon atoms substituted with an acetyl group is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms, methylthio or ethylthio.
  • Isobrovir tert-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-1-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl and acetomethyl groups, most preferably tert-butyl.
  • Le, 1 Mechiruchio one 1 Mechiruechiru, is cyclohexylmethyl cyclohexylene and benzyl groups (especially tert- butyl and downy Njiru group)
  • examples of the “alkoxycarbonyl group having 2 to 5 carbon atoms” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl /
  • examples of the “alkyl group having 1 to 4 carbon atoms” of the “alkyl group having 1 to 4 carbon atoms which may have a substituent” for R 4 include methyl, Examples include ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and tert-butyl groups, preferably methyl, ethyl and propyl groups, and more preferably methyl and ethyl groups.
  • examples of the “C 1 to C 4 alkoxy group” which is a substituent in the “optionally substituted C 1 to C 4 alkyl group” include: Examples include methoxy, ethoxy, propoxy, isobroboxy, butoxy, isobutoxy, s-butoxy and tert-butoxy groups, and are preferably methoxy and ethoxy groups, and the substituents "1 to 1 carbon atoms"
  • examples of the "six aliphatic radicals” include, for example, acetate, propionyloxy, butyryloxy and pentanoyl radicals, preferably those having 2 to 3 carbon atoms (ie, Acetoxy and propionyloxy groups), and more preferably an acetoxy group, and the substituent “an alkoxycarbonyl group having 2 to 5 carbon atoms j” Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like.
  • alkyl C2-5 alkyl group examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamine, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl and tert-butylcarbamoyl groups.
  • Rucarbamoyl and ethylcarbamoyl groups are preferably a methylcarbamolyl group
  • the substituent “dialkyl-powered rubamoyl group having 3 to 9 carbon atoms” includes, for example, dimethylcarbamoyl, methyl (ethyl) Power rubamoyl, getylcarbamoyl, dipropyl power rubamoyl, methyl (propyl) power rubamoyl, diisoprovil power rubamoyl, dibutyl carbamoyl, diisobutyl carbamoyl, di (s-butyl) power rubamoyl, di (tert-butyl) power rubamoyl group, etc.
  • a dimethylcarbamoyl group and a dimethylcarbamoyl group, more preferably a dimethylcarbamoyl group, and the substituent “dialkylamino group having 2 to 8 carbon atoms” is dimethylamino.
  • an alkyl group having 1 to 4 carbon atoms which may have a substituent” for R 4 is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms or a hydroxy group.
  • alkyl groups having 1 to 4 carbon atoms substituted with hydroxy and hydroxy groups and alkyl groups having 1 to 4 carbon atoms substituted with dimethylamino and acetooxy groups (especially methyl, ethyl, hydroxyme Le, 2 - hydroxy E Chill, 3 - hydroxypropionic building, Ethoxycarbonylmethyl, acetoxymethyl, 2-acetoxitytyl, 3-acetooxypropyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, dimethylaminoethyl, 3-dimethylamino-2-hydroxypropyl and 3-dimethylamino-2-ace And more preferably an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or an alkyl group having 1 to 4 carbon atoms substituted with an acetyl group (especially, phenyl group).
  • the “alkyl group having 1 to 4 carbon atoms” for R 5 includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups And preferably a methyl group.
  • aliphatic Ashiru group having 1 to 6 carbon atoms in “optionally aliphatic Ashiru group which may having 1 to 6 carbon atoms have a substituent” for R e is, for example, And formyl, acetyl, propionyl, butyryl, isoptyryl, pentanoyl, and vivaloyl groups, preferably those having 2 to 3 carbon atoms (that is, acetyl and propionyl groups), and more preferably acetyl Group.
  • a monoalkylamino group having 1 to 4 carbon atoms which is a substituent of “an aliphatic acryl group having 1 to 6 carbon atoms which may have a substituent” for R 6
  • Examples thereof include a methylamino, ethylamino, propylamino, isobroviramino, butylamino, isobutylamino, s-butylamino and tert-butylamino group, preferably a methylamino group, and the substituent, "C2 having 2 carbon atoms" Or 8 dialkylamino groups '' , Dimethylamino, methyl (ethyl) amino, getylamino, methyl (propyl) amino, dibutylamino, diisopropylamino, diisopropylamino, dibutylamino, disobutylamino, di (s-butyl) amino, di (tert-butyl)
  • alkoxycarbonyl group having 2 to 5 carbon atoms is, for example, Toxoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobroboxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and tert-butoxycarbonyl groups, preferably ethoxycarbonyl group, Is "5 to 15 atoms Ring or heterocyclyl groups condensed (heteroatom nitrogen contained in the ring, oxygen or sulfur atom) as the "aforementioned alkyl" substituent a good number 1 to 6 carbon atoms which may have R 3
  • the same substituents as those described above as the substituent of the ⁇ group '' can be mentioned, and are preferably morpholino and pyrrolidino groups,
  • R 6 “optionally substituted aliphatic alkyl group having 1 to 6 carbon atoms” As a whole, preferred are acetyl, bropionyl, dimethylaminoacetyl, carboxyacetyl, and 3-carboxybutionyl group. And more preferably an acetyl and propionyl group (especially an acetyl group).
  • examples of the “alkyl group having 1 to 4 carbon atoms” which is a substituent of the “optionally substituted rubamoyl group” of R 6 include methyl, ethyl, n —Propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups, preferably methyl and ethyl groups, and the substituent “alkoxycarbonylalkyl having 3 to 9 carbon atoms” Examples of the group include methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonylpropyl, butoxycarbonylbutyl, and the like.
  • the benzyl group include carboxymethyl, 2-carboxyethyl, 3-carboxybutyl pill, 2-carboxy-1-methylethyl, 4-carboxybutyl, 3-carboxy-1-methylpropyl, and 3-carboxy-2-methylpropyl.
  • carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and 4-carboxybutyl groups are examples of the substituent is a carboxyalkyl group having 2 to 5 carbon atoms.
  • the benzyl group include carboxymethyl, 2-carboxyethyl, 3-carboxybutyl pill, 2-carboxy-1-methylethyl, 4-carboxybutyl, 3-carboxy-1-methylpropyl, and 3-carboxy-2-methylpropyl.
  • R 1 is preferably a non-substituted alkyl group having 4 to 10 carbon atoms, or a carbon atom having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms.
  • alkyl group having 1 to 6 carbon atoms a cycloalkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 4 to 6 carbon atoms, which may be substituted with one methyl, methoxy, Substituted alkyl group having 1 to 6 carbon atoms and 4 to 4 carbon atoms -it,
  • alkyl group having 1 to 6 carbon atoms substituted with 6 alkoxyalkoxy groups more preferably octyl, 7-methyloctyl, nonyl, 8-methylnonyl, phenylpropyl, 4-methylphenyl Propyl, 4-methoxyphenylphenyl, 4-cyclophenylphenyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl and 4-butoxybutyl, more preferably Is a nonyl, 7-methyloctyl and 4-cyclophenylphenylpropyl group.
  • R 2 as a whole is preferably a hydrogen atom, a hydroxy or an acetyl group, and more preferably a hydrogen atom or a hydroxy group.
  • R 3 as a whole is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with one methylthio or ethylthio group.
  • R 4 as a whole is preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms substituted with one hydroxy group.
  • 1 to 4 carbon atoms substituted with 1 dimethylcarbamoyl group 1 to 4 carbon atoms substituted with 1 dimethylcarbamoyl group, and 1 carbon atom substituted with 1 dimethylamino group
  • R 5 is a hydrogen atom.
  • R 6 is a hydrogen atom and an unsubstituted aliphatic acyl group having 2 to 3 carbon atoms, a dialkylamino group having 1 to 2 carbon atoms or 1 Aliphatic carbonyl group having 2 to 3 carbon atoms, more preferably a hydrogen atom, acetyl and propionyl group, most preferably a hydrogen atom and acetyl group .
  • preferred are those represented by the formula (1):
  • R 1 is an unsubstituted alkyl group having 4 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted by an alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or Or an alkyl group having 1 to 6 carbon atoms substituted by a phenyl group which may be substituted by a chloro group, or an alkyl group having 1 to 6 carbon atoms substituted by a cycloalkyl group having 4 to 6 carbon atoms A compound having 1 to 6 carbon atoms, which is substituted by a group or an alkoxyalkoxy group having 4 to 6 carbon atoms,
  • R 1 is octyl, 7-methyloctyl, nonyl, 8-methylnonyl, Phenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-chlorophenylpropyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl Or a compound that is a 4_butoxybutyl group,
  • R 2 is a hydrogen atom, a hydroxy or acetyl group
  • R 2 force a compound which is a hydrogen atom or a hydroxy group
  • R 3 is an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a methylthio or ethylthio group, or a cycloalkyl group having 4 to 6 carbon atoms.
  • a substituted or unsubstituted phenyl-substituted phenyl group-substituted alkyl group having 1 to 4 carbon atoms, a hydroxy-substituted alkyl group having 1 to 4 carbon atoms, or an acetoxy group A compound which is a substituted alkyl group having 1 to 4 carbon atoms,
  • R 3 force A compound that is an isobrovir, tert-butyl, 1-methylbrovir, 2-methylbutyl, 1-methylthio-11-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl or acetyloxymethyl group,
  • R 3 compound which is tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group, 10) a compound that is an R 3 tert-butyl or benzyl group;
  • R 4 is a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, or a carbon number substituted with an ethoxycarbonyl group 1 to 4 alkyl groups, 1 to 4 carbon atoms substituted with an acetyloxy group, 1 to 4 carbon atoms substituted with a methylcarbamoyl group, and carbon substituted with a dimethylcarbamoyl group
  • R 4 force A compound which is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or an acetoxy group,
  • R 5 force A compound that is a hydrogen atom
  • R 6 force Hydrogen atom or unsubstituted aliphatic carbon group having 2 to 3 carbon atoms, carbon atom substituted by dialkylamino group having 2 to 4 carbon atoms or carboxy group A compound that is 2 to 3 aliphatic acyl groups,
  • R 6 is a hydrogen atom, acetyl or propionyl group
  • R 6 force A compound which is a hydrogen atom or an acetyl group
  • R 1 is an unsubstituted alkyl group having 4 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or chloro.
  • R 2 force, a hydrogen atom, a hydroxy or acetyl group
  • R 3 is substituted with an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a methylthio or ethylthio group, or a cycloalkyl group having 4 to 6 carbon atoms Substituted with methyl or ethyl, unsubstituted phenyl-substituted alkyl group having 1 to 4 carbon atoms, hydroxy-substituted alkyl group having 1 to 4 carbon atoms or substituted with acetyl group Alkyl group having 1 to 4 carbon atoms,
  • R 4 a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, and an ethoxycarbonyl group Alkyl group having 1 to 4 carbon atoms, alkyl group having 1 to 4 carbon atoms substituted with acetooxy group, alkyl group having 1 to 4 carbon atoms substituted with methylcarbamoyl group, substituted with dimethylcarbamoyl group An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group, an alkyl group having 1 to 4 carbon atoms or a dimethylamino group substituted with a dimethylamino group and a hydroxy group, and An alkyl group having 1 to 4 carbon atoms, which is substituted with an acetoxy group;
  • R 5 force 5 hydrogen atom
  • R 6 is a hydrogen atom or an unsubstituted aliphatic C2 to C3 aliphatic acyl group, a C2 to C3 aliphatic C2 to C4 dialkylamino group or a carboxy group A compound that is
  • R 2 is a hydrogen atom or a hydroxy group
  • R 3 is tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group,
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R 6 is a hydrogen atom or an acetyl group
  • R 1 is a nonyl or 3- (4-monophenyl) propyl group
  • R 2 is a hydrogen atom or a hydroxy group
  • R 3 is a tert-butyl or benzyl group
  • R 4 is a hydrogen atom
  • R 5 is a hydrogen atom
  • a compound wherein R e is a hydrogen atom or an acetyl group Can be given.
  • the compound (1) of the present invention has a carboxy group, it can be converted into a salt.
  • Such salts are preferably alkali metal salts such as sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt, Metal salts such as copper salts, 2'-sokel salts, and cobalt salts; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N —Methylglucamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N '—dibenzylethylenediamine salt, chlorobrocaine salt, pro-forcein salt, diethanolamine salt, N-benzyldiene Tilamine salt, biradine salt, tetramethylammonium Salts and amine salts such as organic salt
  • Such salts preferably include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates, and the like.
  • Inorganic acid salts such as phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; benzenesulfonates; and salts such as P-toluenesulfonate.
  • the compound (1) of the present invention absorbs moisture when left in the air. In some cases, water may be collected and adsorbed water may be formed, or may be hydrated. Such a hydrate is also included in the present invention. Furthermore, the compound (1) of the present invention has an asymmetric carbon atom in the molecule, and there are stereoisomers each of which is in the R or S configuration. Any of the mixtures are included in the present invention.
  • examples of the compound having a suitable configuration include those of the following formula (wherein, R 1 , R 2 , R 3 , R 4 , R s and R s are Same meaning as above).
  • Me represents a methyl group
  • Et represents an ethyl group
  • Pr represents a bromo group
  • ⁇ Pr represents an isopropyl group
  • Bu represents a butyl group
  • ⁇ Bu represents isobutyl group.
  • Bu represents a t-butyl group
  • Bn represents a benzyl group
  • Ac represents an acetyl group
  • ct represents an octyl group
  • Non represents a nonyl group
  • HX represents cyclo.
  • Ph represents a hexyl group
  • Ph represents a phenyl group
  • Mor represents a morpholino group
  • T hi represents a chelyl group.
  • Non H tBu CH 2 0Me HH preferred ones are 8, 9, 10, 10, 11, 12, 13, 16, 17, 17, 20, 21, 28, 29, 66, 67, 70, 7 1, 74, 75, 102, 107, 108, 109, 110, 167, 168, 171, 1 72, 1 75, 1 76, 30 1, 302, 305, 306, 307, 308 and 313, and more preferably,
  • the hydroxamic acid derivative of the present invention can be produced by the method described in the following! (3)
  • R ′, R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as described above, and R 6a is an optionally substituted C 2-5 aliphatic acyl group.
  • the substituent may be an amino group which may be protected, an alkylamino group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, or an alkoxycarbonyl group having 2 to 5 carbon atoms.
  • R 7 represents a “silyl-type” protecting group (preferably a tert-butyldimethylsilyl group) or a benzyl-type protecting group (preferably a benzyl group), and R 8 represents the same group as R 7.
  • R 13 , R 14 and R 15 are the same or different and represent an alkyl group having 1 to 4 carbon atoms
  • R 16 represents an aliphatic or aromatic acyl group
  • R 17 represents an alkyl group
  • R ie represents a fat aliphatic or aromatic Ashiru radical
  • n represents 1 to 4 integers
  • t B u represents a t-Bed butyl group
  • i P r is Indicates an isopropyl group
  • TBS represents a t one heptyl dimethyl silyl group
  • T s is. Below showing the p- toluenesulfonyl group, will be described for each step.
  • the condensation is carried out by a conventional method, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method.
  • compound (2) is reacted with hydrazine in an inert solvent (eg, dimethylformamide) at around room temperature, and then the produced acid hydrazide is reacted with a nitrite compound to convert the compound to an azide compound. After that, it is performed by treating with an amine compound (3).
  • an inert solvent eg, dimethylformamide
  • nitrite compound to be used examples include an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite.
  • the reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and N-methylvilolid. And pyrrolidones such as don.
  • the two steps of the present method are usually performed in one reaction solution, and the reaction temperature is ⁇ 50 to 0 ° C. in the first stage, and 110 ° C. to 10 ° C. in the second stage.
  • the time required for the reaction is 5 minutes to 1 hour in the first stage and 10 hours to 5 days in the second stage.
  • the active ester method is carried out by reacting the compound (2) with an active esterifying agent to produce an active ester, and then reacting it with the amine compound (3).
  • Both reactions are preferably carried out in an inert solvent and the solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, ethers and tetrahydrofuran. Examples thereof include amides such as ethers, dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile.
  • active esterifying agent examples include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene and the like. Shi-
  • N-hydroxy compounds such as 2,3-dicarboximide and disulfide compounds such as dipyridyl disulfide.
  • the active esterification reaction is carried out by dicyclohexylcarbodiimide or triphenylphosphine. It is suitably carried out in the presence of a condensing agent such as
  • an organic amine such as triethylamine, N-methylmorpholine, or dimethylaminopyridine may be used as the base catalyst.
  • the reaction temperature is between 110 ° C. and 100 ° C. for the active esterification reaction, and is around room temperature for the reaction of the active ester compound with the amine (3). 30 minutes to 80 hours.
  • the mixed acid anhydride method is carried out by producing a mixed acid anhydride of the compound (2) and reacting the mixed acid anhydride with an amine.
  • the reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, ethers (preferably tetrahydrofuran)) in a mixed acid dehydrating agent such as chlorocarbonic acid.
  • a mixed acid dehydrating agent such as chlorocarbonic acid.
  • Ethyl, lower alkanol halides such as pivaloyl chloride or lower (C, -C 4) alkyl halides such as isobutyl chlorocarbonate or lower alkyls or diarylcyanos such as getylcyanophosphate, diphenylcyanophosphate. This can be achieved by reacting compound (2) with phosphoric acid or the like.
  • the reaction is preferably carried out in the presence of an organic amine such as triethylamine, N-methylmorpholine, dimethylaminoviridine, pyridine, and the reaction temperature is 120 to 50, and the time required for the reaction is 30. Minutes to 20 hours.
  • the reaction of the mixed anhydride with the amine (3) is preferably carried out in an inert solvent (for example, the amides or ethers described above) in the presence of the organic amine!
  • the reaction is performed at a temperature of 0 to 80 ° C., and the time required for the reaction is 1 hour to 24 hours.
  • This reaction is also performed in the presence of compound (2), compound (3) and a mixed acid anhydride-forming agent.
  • the compound (2) and the amine (3) can be obtained by diluting the compound (2) in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, ⁇ -methyl-2-chloro-pyridinyl-m-zidotriethylamine. It is done by reacting directly. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil Column chromatography using a simple carrier; Sephadex LH-20 (Pharmacia), Amber-Light XAD-11 (Rohm and Haas), Diaion HP-20 ( Synthesis such as partition column chromatography using a carrier such as Mitsubishi Kasei Co., Ltd.
  • a conventional method for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil Column chromatography using a simple carrier; Sephadex LH-20 (Pharmacia), Amber-Light XAD-11 (Rohm and Haas), Diaion HP-20 ( Synthesis such as partition column chromatography using a carrier such as Mitsubishi Kasei Co.
  • This step is a step of condensing compound (5) and compound (3) in an inert solvent to produce compound (6).
  • This step can be performed in the same manner as in the first step.
  • This step is a step of producing compound (8) by condensing compound (2) and compound (7) in an inert solvent. This step can be performed in the same manner as in the first step.
  • This step is performed when R 7 is a silyl-type protecting group.
  • the acid used is an organic acid such as acetic acid, methanesulfonic acid, para-toluenesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, or an inorganic acid such as hydrochloric acid, and preferably trifluoroacetic acid.
  • the solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform.
  • Ethers such as tyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane and diethylene glycol dimethyl ether; And organic solvents and mixed solvents thereof.
  • Methylene chloride is preferred.
  • the reaction temperature and the reaction time are not particularly limited, but are usually 0 to 100 (preferably 10 ° C. to 30 ° C.) and 1 to 72 hours (preferably 1 to 24 hours). Time) Implemented.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Add an organic solvent that is immiscible with water and wash with water etc.
  • the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • This step is a step of condensing compound (5) and compound (7) in an inert solvent to produce compound (10).
  • This step can be performed in the same manner as in the first step.
  • this step in an inert solvent, with an acid to remove the isopropylidene group and the protective group represented by R 7 of the compound (10) is a step for preparing a compound (9).
  • This step is performed when R 7 is a silyl-type protecting group.
  • This step can be performed in the same manner as in the fourth step.
  • acetic acid is used as the acid
  • a mixed solution of tetrahydrofuran and water is used as the solvent.
  • This step is a step of removing the isopropylidene group of compound (10) using an acid in an inert solvent to produce compound (6a).
  • This step is performed when R 7 is a benzyl-type protecting group.
  • This step can be performed in the same manner as in the sixth step.
  • This step is a step of producing a compound (9) by removing the t-butyl group of the compound (4) using an acid in an inert solvent.
  • This step can be performed in the same manner as in the fourth step.
  • This step can be performed in the same manner as in the first step. 6?
  • R 8 is a silyl-type protecting group, the ability to carry out in the same manner as in the fourth step.
  • hydrochloric acid is used as the acid
  • a mixed solvent of dioxane and water is used as the solvent.
  • R 8 is a benzyl-type protecting group
  • a method of removing by contacting with a reducing agent in a solvent is generally suitable.
  • the solvent used is not particularly limited as long as it does not take part in the reaction, but includes alcohols such as methanol, ethanol and isopropanol, ethers such as getyl ether, tetrahydrofuran and dioxane, toluene, benzene, Aromatic hydrocarbons such as xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, dimethylacetamide, Amides such as N-methyl-2-virolidone and hexamethyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and a mixed solvent thereof are more preferable, and alcohol is more preferable, and alcohol is more preferable, and alcohol
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, palladium Aluminum monoxide, rhodium aluminum monoxide, triphenylphosphine-rhodium chloride, and palladium-barium sulfate are used, preferably palladium-aluminum oxide.
  • the pressure is not particularly limited, but it is usually 1 to 10 atm.
  • the reaction temperature and reaction time vary depending on the starting material, solvent and type of catalyst, but are usually 0. C to 100 (preferably 20 to 5 CTC), 5 minutes to 48 hours (preferably 30 minutes to 10 hours).
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.For example, after removing the reduction catalyst by filtration, the solvent is distilled off if necessary, and the mixture is mixed with water such as ethyl acetate. An organic solvent containing no target compound is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be.
  • Suitable solvents used are ethers such as getyl ether and tetrahydrofuran; hydrocarbons such as methylene chloride and chloroform; and amides such as dimethylformamide.
  • organic amines such as pyridine, dimethylaminopyridine, N-methylmorpholine, and triethylamine are suitable.
  • the reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting material, solvent, base and the like used.
  • ethers such as Jethyl ether and tetrahydrofuran
  • hydrocarbons such as methylene chloride and chloroform
  • amides such as dimethylformamide
  • Suitable bases used are organic amines such as pyridine, dimethylamino pyridine, N-methylmorpholine and triethylamine.
  • the reaction temperature is usually from 0 to room temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting material, solvent, base and the like used.
  • R e when R 6a is a carbamoyl group R 6a when R 6a is a carbamoyl group.
  • NCO R 6 represents the portion of Rea excluding the carbonyl group
  • the solvent to be used aromatic hydrocarbons such as benzene and toluene are preferable, and pyridine and triethylamine are used as bases.
  • the reaction temperature is usually from room temperature to 60, and the reaction time is from 30 minutes to 3 days.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • a water-immiscible organic solvent such as that described above is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • This step is a step of producing a compound (14) by removing the t-butyl group of the compound (13) using an acid in an inert solvent.
  • This step can be performed in the same manner as in the fourth step.
  • This step can be performed in the same manner as in the eighth step.
  • This step is a step of removing the protecting group represented by R 8 of compound (15) in an inert solvent to produce the target compound (lb) of the present invention.
  • This step can be performed in the same manner as in the ninth step.
  • a step for preparing the object compound (1 a) of the present invention in an inert solvent in the presence of a base to remove the coercive Mamorumoto represented by R ea compound (lb), a step for preparing the object compound (1 a) of the present invention.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, carbon dioxide Alkali metal carbonates such as lime and lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or ammonia water, ammonia such as concentrated ammonia-methanol , But are preferably sodium carbonate and potassium carbonate.
  • the solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction.
  • organic solvents such as alcohols and mixed solvents of water and the above-mentioned organic solvents, and more preferred are alcohols (particularly methanol).
  • reaction temperature and reaction time vary depending on the starting material, the solvent, the base used, and the like, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at 0 to 150 ° C (preferably at 20 to 150 ° C). Performed at 30 ° 0 for 1 to 24 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then ethyl acetate is added.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • This step is a step of removing the isopropylidene group of compound (6) using an acid in an inert solvent to produce compound (11).
  • the compound (1 1) by reacting Arukokishiamin R a 0 NH 2, is a step for preparing Compound (1-6).
  • This step can be performed in the same manner as in the eighth step.
  • the compound (1 1 a) by reacting an alkoxyamine R beta ONH 2, is a step for preparing a compound (16 a).
  • This step can be performed in the same manner as in the eighth step.
  • R 2 is a benzyl-type protecting group.
  • This step is a step for producing the target compound (lc) of the present invention by removing the protecting group represented by R 8 of the compound (16) in an inert solvent.
  • This step can be performed in the same manner as in the ninth step.
  • compound (6) is reacted with R 6a X (described above) in an inert solvent to produce compound (17).
  • This step can be performed in the same manner as in the tenth step.
  • This step is a step of producing compound (18) by removing the isopropylidene group of compound (17) using an acid in an inert solvent.
  • This step can be performed in the same manner as in the sixth step.
  • the compound (1 8) is reacted with Arukokishiami emissions R 8 0 NH z, it is a step for preparing Compound (1-9).
  • This step can be performed in the same manner as in the eighth step.
  • This step is a step of removing the protecting group represented by Ra of compound (19) in an inert solvent to produce the target compound (Id) of the present invention.
  • This step can be performed in the same manner as in the ninth step.
  • This step can be performed in the same manner as in the fourteenth step.
  • compound (20) is produced by reacting compound (19) with R 9 X in an inert solvent.
  • This step can be performed in the same manner as in the tenth step.
  • compound (16a) is reacted with R 9 X in an inert solvent to produce compound (47).
  • This step can be performed in the same manner as in the tenth step.
  • this step in an inert solvent, to remove the protecting group represented by R e of the compound (20), it is a step for preparing the objective compound of the present invention (le).
  • This step can be performed in the same manner as in the ninth step.
  • this step in an inert solvent, to remove the protecting group represented by R 8 and R 7 of the compound (47), is a step for preparing the objective compound of the present invention (I f).
  • This step can be performed in the same manner as in the ninth step.
  • This step is a step of reacting compound (21) with compound (21a) using a base in an inert solvent to produce compound (22).
  • ethers such as tetrahydrofuran and getyl ether are preferable, and as the base to be used, n-butyllithium is preferable.
  • the reaction is usually performed at 178 ° C, and the reaction time is 10 minutes to 5 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Add water-immiscible organic solvent and wash with water
  • the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • This step is a step of reacting compound (22) with t-butyl bromoacetate in an inert solvent to produce compound (23).
  • a combination of lithium diisopropylamide (LDA) and an ether such as tetrahydrofuran and getyl ether, or a mixture of dibutylboron triflate-triethylamine and methylene chloride, and methylform Combinations of such halogenated hydrocarbons are preferred.
  • the reaction temperature, when using the LDA is usually one 7 8 gradually warmed to room temperature from a ⁇ 8 e C in the case of using dibutyl boron tri frame Bok.
  • Anti The reaction time varies from 30 minutes to 1 day depending on the reagents and raw materials.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Add an organic solvent that is immiscible with clean water and wash with water etc.
  • the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • This step is a step of producing compound (2) by hydrolyzing compound (23) in an inert solvent using a base.
  • a mixed solvent of tetrahydrofuran and water is preferable, and as a base to be used, an alkali metal hydroxide such as lithium hydroxide is preferable, and the reaction is carried out by adding hydrogen peroxide. Can be performed efficiently.
  • the reaction temperature is usually from 0 to 5 CTC, and the reaction time is usually from 30 minutes to 5 hours, varying depending on a raw material and a reagent.
  • the desired compound of this reaction according to a conventional method, collected from the reaction mixture, for example, the reaction mixture was appropriately neutralized, and, after removing by ⁇ if insoluble materials exist, acetic E 1 A water-immiscible organic solvent, such as toluene, is added, the organic layer containing the target compound is separated after washing with water or the like, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • acetic E 1 A water-immiscible organic solvent, such as toluene, is added, the organic layer containing the target compound is separated after washing with water or the like, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be.
  • Step 28 Alkylation
  • a known compound (24) is reacted with an arylhalide R′′X (X represents a halogen atom, preferably bromine or chlorine) using a base in an inert solvent to give a compound.
  • R′′X represents a halogen atom, preferably bromine or chlorine
  • ethers such as tetrahydrofuran and getyl ether are preferable.
  • disilazides such as lithium hexamethyldisilazide and potassium hexamethyldisilazide, and lithium disoproviramide are preferable, and disilazides are more preferable.
  • the reaction temperature is usually raised gradually from 18 C to room temperature.
  • the reaction time varies depending on the reagents and raw materials, and is 1 to 20 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be.
  • This step is a step of producing a compound (26) by reducing the double bond of the compound (25) in an inert solvent.
  • the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • the solvent include alcohols such as methanol, ethanol, and isopropanol; ethers such as dimethyl ether, tetrahydrofuran, and dioxane; Aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, Dimethylacetamide, N-methyl-2-viroli Amides such as methacrylic acid and hexane methyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and a mixed solvent thereof are more preferable. Alcohols (particularly methanol) ), Esters (especially ethyl acetate).
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, palladium aluminum monoxide Rhodium aluminum monoxide, triphenylphosphine-rhodium chloride and palladium barium monosulfate are used, preferably palladium carbon.
  • the pressure is not particularly limited, but it is usually 1 to 10 atm.
  • reaction temperature and reaction time vary depending on the type of the starting material, the solvent and the catalyst, but are usually 0 ° C to 10 CTC (preferably 20 to 50 ° C), 5 minutes to 48 hours. (Preferably 30 minutes to 10 hours).
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the solvent is distilled off if necessary, and the mixture is mixed with water such as ethyl acetate.
  • An organic solvent containing no target compound is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be.
  • This step is a step of producing a compound (27) by hydrolyzing the compound (26) using a base in an inert solvent.
  • Alkali metal hydroxides such as potassium hydroxide and sodium hydroxide are suitable as the base used, and a mixed solvent of ethers and water such as dioxane and tetrahydrofuran is used as the solvent. It is.
  • the reaction temperature is usually 60 to 100 ° C, and the reaction time varies depending on the raw material, base, etc. But usually 5 hours to 1 day.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method. Thereafter, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • This step is a step of producing a compound (5) by simultaneously protecting the hydroxyl group and the carboxylic acid of the compound (27) by removing the generated water by azeotropic distillation in an inert solvent using an acid catalyst. It is.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, but preferably includes aromatic hydrocarbons such as benzene and toluene.
  • the acid catalyst to be used is not particularly limited as long as it is usually used as an acid, but is preferably an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or pyridium-P-toluenesulfonate. Or an inorganic acid such as hydrochloric acid.
  • the reaction temperature varies depending on the acid catalyst used, the starting compound, etc., but is usually from 80 to 100, and the reaction time is mainly determined by the reaction temperature, the starting compound, and the type of solvent used. It usually varies from 30 minutes to 10 hours, depending on the situation.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble substances are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separating and purifying an organic compound, for example, the method described in the first step described above. be able to.
  • ethers such as tetrahydrofuran and getyl ether are preferable.
  • the reaction temperature is -78 to 0 C, and the reaction time varies depending on the raw materials, but is usually 10 minutes to 10 hours.
  • the reaction can be carried out efficiently by using a copper salt such as copper iodide.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble substances are present, they are removed by permeation. Add an organic solvent that is immiscible with water and wash with water, etc.
  • the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • This step is a step of producing compound (34) by reacting compound (28) with methoxymethylamine in an inert solvent.
  • This step is performed when R 17 is hydrogen, and is performed according to the active ester method and the condensation method described in the first step.
  • the step is a step of reducing compound (28) in an inert solvent to produce compound (29).
  • a mixed solvent of tetrahydrofuran and ethyl alcohol is preferable.
  • the reducing agent to be used lithium borohydride or a combination of sodium borohydride and lithium chloride is suitable.
  • the reaction temperature is usually 0 to 40 ° C, and the reaction time is usually 10 hours to 3 days.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method, for example, to reduce residual
  • a water-immiscible organic solvent such as ethyl acetate, washing with water, etc., and containing the target compound
  • the organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • This step is a step of oxidizing compound (29) in an inert solvent to produce compound (30).
  • This step can be performed by a method called Moffatt oxidation or Swern oxidation.
  • the reaction temperature is usually 10 to 50 ° C, and the reaction time is usually 30 minutes to 5 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the remaining oxidizing agent is decomposed and neutralized as appropriate, and if insolubles are present, they are removed by filtration.
  • an organic solvent immiscible with water such as ethyl acetate, is added, washed with water, etc., the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off. .
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be carried out by a method that has been used for separation and purification of organic compounds, for example, the method described in the first step.
  • Step 36 Alkylation In this step, in an inert solvent, Compound (3 0) the alkylating agent R 4 M g X a are reacted in a step of producing the compound (3 1).
  • This step can be performed in the same manner as in the 32nd step.
  • This step is a step of producing a compound (32) by alkylating the compound (34) in an inert solvent.
  • This step can be performed in the same manner as in the 32nd step.
  • This step is a step of reacting compound (30) with a cyanating agent in an inert solvent to produce compound (35).
  • a mixed solvent of a halogenated hydrocarbon such as methylene chloride and water is suitable.
  • an alkali metal cyanide such as sodium cyanide or potassium cyanide and hydrochloric acid are used.
  • the reaction temperature is usually from 0 to 40 ° C, and the reaction time is usually from 5 hours to 1 day, varying depending on a raw material, a reagent and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • Step 38 Hydrolysis This step is a step of hydrolyzing compound (35) under acidic conditions to produce compound (36).
  • R 12 is a group that can be removed by an acid such as a tert-butoxycarbonyl group.
  • Water is preferred as the solvent used.
  • the acid to be used is not particularly limited as long as it is usually used, but hydrochloric acid is preferred.
  • the reaction temperature is usually from 60 to 100 ° C, and the reaction time is usually from 5 to 24 hours, depending on the starting materials, reagents and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method, and can be obtained, for example, by filtering off the crystals generated by concentrating the reaction mixture.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • This step is a step of hydrolyzing compound (36) using a base in an inert solvent to produce compound (37).
  • R ′ 2 is an acid-stable group such as a benzyloxycarbonyl group.
  • This step can be performed in the same manner as in the 26th step.
  • This step is a step of producing a compound (40) by hydrolyzing the compound (39) using a base in an inert solvent.
  • This step can be performed in the same manner as in the thirtieth step.
  • This step is a step of producing compound (41) by condensing compound (40) and a desired amine in an inert solvent.
  • This step can be performed in the same manner as in the first step.
  • a mixed acid anhydride is synthesized from compound (42) in an inert solvent and then reacted with diazomethane to produce compound (43).
  • the reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, and ethers (preferably, ethyl ether)) in a mixed acid anhydride agent such as chloro.
  • Ethyl carbonate, lower (C,-) alkyl halides such as isobutyl chlorocarbonate, lower alkanol halides such as vivacyl chloride, or lower alkyls or phenyls such as getylcyanophosphate, diphenylcyanophosphate. This is achieved by reacting compound (42) with lucyanophosphoric acid or the like.
  • the reaction is preferably performed in the presence of an organic amine such as triethylamine, N-methylmorpholine, dimethylaminoviridine, pyridine, and the reaction temperature is 120 ° C to 0 ° C, and the time required for the reaction is Is from 30 minutes to 1 hour.
  • the reaction between the mixed acid anhydride and diazomethane is preferably performed in an inert solvent (for example, the above-mentioned ethers) at a reaction temperature of 0 ° C. to 50 ° C., and the time required for the reaction is 1 to 10 hours. It is.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, when insolubles are present, they are removed by filtration and then the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • a solvent using a desired alcohol or acid, or an ether such as dioxane or tetrahydrofuran is preferable.
  • Suitable catalysts are copper salts such as cupric acetate, cupric chloride and copper oxide.
  • the reaction temperature is usually from 20 to 100 ° C., and the reaction time is usually from 10 minutes to 3 hours, depending on raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • Step 46 Reduction In this step, compound (44) is reduced in an inert solvent to produce compound (45).
  • This step is performed when R 18 is an acyl group.
  • This step can be performed in the same manner as in the thirty-fourth step.
  • R 18 is an alkyl group
  • R 18 is not removed, and a compound corresponding to compound (53) can be obtained.
  • compound (39) is reduced in an inert solvent to produce compound (46).
  • This step can be performed in the same manner as in the thirty-fourth step.
  • This step is a step of producing compound (33) by reacting compound (32) with alkylating agent R 4 MgX 8 in an inert solvent.
  • This step can be performed in the same manner as in the thirty-second step.
  • This step is a step of producing a compound (48) by reacting the compound (34) with an aryl Grignard reagent in an inert solvent.
  • This step can be performed in the same manner as in the thirty-seventh step.
  • This step is a step of producing compound (49) from compound (48) in an inert solvent.
  • This step can be carried out by a method called hydroboration-hydrogen peroxide oxidation method.
  • ethers such as getyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene are preferable.
  • borating reagent to be used 9-borabicyclo [3,3,1] nonane, borane-dimethylthioether complex and the like are suitable.
  • the reaction temperature for volatilization is usually 10 to 50 ° C, and the reaction time is usually 1 to 10 hours.
  • Subsequent oxidation is performed by using hydrogen peroxide in water in the presence of sodium hydroxide.
  • the reaction temperature is usually 0 to 40 ° C, and the reaction time is usually 10 minutes to 5 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the remaining oxidizing agent is decomposed, the reaction mixture is appropriately neutralized, and if there is an insoluble substance, the compound is renatured.
  • an organic solvent that is immiscible with water such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, etc., and evaporate the solvent Obtained by:
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • This step is a step of reacting compound (49) with a reducing agent in an inert solvent to produce compound (50).
  • alcohols such as methanol and ethanol are suitable.
  • sodium borohydride is preferable.
  • the reaction temperature is usually 0 ° C to 40 ° C, and the reaction time varies depending on the raw material and the reducing agent, but is usually 1 hour to 1 hour.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the remaining reducing agent is decomposed, the reaction mixture is appropriately neutralized, and if an insoluble substance is present, the reaction is performed.
  • an organic solvent that is immiscible with water such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, etc., and evaporate the solvent Obtained by:
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • the method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.
  • compound (51) is reacted with t-butyldimethylsilyl halide in an inert solvent using a base to produce compound (52).
  • halogenated hydrocarbons such as methylene chloride and black form
  • ethers such as getyl ether and tetrahydrofuran
  • amides such as dimethylformamide are preferable.
  • Suitable bases used are organic amines such as triethylamine, 4,4-dimethylaminopyridine and imidazole.
  • the reaction temperature is usually 0 to 40 ° C, and the reaction time is 30 minutes to 5 hours, depending on the raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method, ⁇
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • a water-immiscible organic solvent such as ethyl acetate is added, and the target compound is washed with water or the like. It is obtained by separating the organic layer containing, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • Compound (5 1) by reacting Ashiruharai de R 1 6 X or R 1 6 OR 1 6, is a step for preparing a compound (5 3).
  • This step can be performed in the same manner as in the tenth step.
  • This step is a step of reacting compound (51) with p-toluenesulfonyl halide (or anhydride) in an inert solvent to produce compound (54).
  • halogenated hydrocarbons such as methylene chloride and black form
  • ethers such as getyl ether and tetrahydrofuran
  • amides such as dimethylformamide are preferable. is there.
  • organic amines such as triethylamine, 4,4-dimethylaminopyridin and imidazole are preferable.
  • the reaction temperature is usually 0 to 40 ° C, and the reaction time is 30 minutes to 24 hours, depending on the raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • halogenated hydrocarbons such as methylene chloride and black form
  • ethers such as getyl ether and tetrahydrofuran
  • amides such as dimethylformamide are preferable. .
  • Suitable bases to be used are organic amines such as triethylamine and 4,4-dimethylaminopyridin.
  • the reaction temperature is usually from 20 to 100, and the reaction time is from 30 minutes to 24 hours, depending on raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • Such an organic solvent immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • ethers such as getyl ether and tetrahydrofuran are preferable.
  • Suitable bases used are alkali metal hydrides such as sodium hydride and potassium hydride, and alkyllithiums such as n-butyllithium.
  • the reaction temperature is usually 20 to 60 ° C, and the reaction time is 30 minutes to 24 hours, depending on the raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble substances are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above.
  • a conventional method for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above.
  • the hydroxyl group of compound (54) is protected immediately before Steps 55 and 56, and the hydroxyl group is deprotected immediately after Steps 55 and 56.
  • the desired compounds (55) and (56) As the protecting group for the hydroxyl group, a tetrahydrobiranyl group and a methoxymethyl group are suitable, and protection and deprotection are performed by a conventional method.
  • This step is a step of reacting compound (51) with an oxidizing agent in an inert solvent to produce compound (57).
  • Amides such as dimethylformamide are suitable as the solvent to be used, and pyridinum chromatochromate and pyridinium dichromate are suitable as the oxidizing agent to be used.
  • the reaction can be performed efficiently by using molecular sieve 4A.
  • the reaction temperature is usually 10 to 40 ° C, and the reaction time varies depending on the raw materials and the like. o minutes to 5 hours.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the remaining oxidizing agent is decomposed, the reaction mixture is appropriately neutralized, and, if insoluble matters are present, filtration is performed.
  • an organic solvent that is immiscible with water such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, and distill off the solvent.
  • the obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or
  • This step is a step of producing a compound (58) by reacting the compound (57) with an alcohol in an inert solvent.
  • This step is performed according to the active ester method or the condensation method of the first step. (Step 59) Reduction
  • This step is a step of producing a compound (59) by reacting the compound (58) with a reducing agent in an inert solvent.
  • This step can be performed in the same manner as in the 51st step.
  • halogenated hydrocarbons such as methylene chloride and chloroform are preferred; ethers such as dimethyl ether and tetrahydrofuran; and amides such as dimethylformamide are suitable.
  • the reaction temperature is usually 20 to 100 ° C, and the time varies depending on the raw materials and the like, but is usually 1 hour to 3 days.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration.
  • An organic solvent that is immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • the compound (60) is produced by reducing the ketone of the compound (57) according to the 59th step, and then condensing it with an amine according to the active ester method or the condensation method of the 1st step. You can also.
  • compound (30) is reacted with arylmagnesium halide (preferably, promide or chloride) using a base in an inert solvent to produce compound (61). is there.
  • arylmagnesium halide preferably, promide or chloride
  • This step can be performed according to step 36.
  • compound (61) is reacted with t-butyldimethylsilyl halide in an inert solvent to produce compound (62).
  • This step can be performed in the same manner as in the 52nd step.
  • This step is a step of producing a compound (63) by reacting the compound (62) with an oxidizing agent in an inert solvent.
  • This step is performed by oxidizing with sodium periodate after the dihydroxylation reaction.
  • the dihydroxylation reaction and sodium periodate oxidation can be performed simultaneously.
  • ethers such as ethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene are preferable.
  • the dihydroxylating reagent to be used a combination of osmium tetroxide or smear oxide and a co-oxidant such as N-methylmorpholine N-oxide is preferable.
  • the reaction temperature for boration is usually 0 to 5 crc, and the reaction time is usually 1 to 10 hours.
  • the subsequent oxidation takes place in a mixed solvent of water and alcohols such as methanol.
  • the reaction is carried out by using sodium periodate.
  • the reaction temperature is usually 0 to 40 ° C, and the reaction time is usually 10 minutes to 3 hours.
  • the remaining oxidizing agent is decomposed, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an organic solvent immiscible with water, such as ethyl acetate, is added.
  • the organic layer containing the target compound is separated after washing with, for example, and dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • This step is a step of producing a compound (64) by reacting the compound (63) with ethyl ethylphosphonoacetate in an inert solvent in the presence of a base.
  • the solvent used in the Wittig reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • it is dimethyl ether, disopropyl ether, or tetraethyl ether. These are ethers such as lahydrofuran.
  • the reaction temperature is usually 0 to 4 (TC), and the reaction time is usually 30 minutes to 20 hours, depending on the raw materials and the like.
  • the target compound of this reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble substances are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of organic compounds, for example, the method described in the first step described above. Can be.
  • This step is a step of producing a compound (65) by reacting the compound (64) with a reducing agent in an inert solvent. This step can be performed in the same manner as in the 29th step.
  • compound (65) is reacted with compound (65) in an inert solvent to produce compound (66).
  • This step can be performed in the same manner as in the forty-seventh step.
  • This step is a step of reacting compound (66) with a deprotecting agent in an inert solvent to produce compound (67).
  • Compound (3) and compound (7) are compound (33), compound (31), compound (32a), compound (38), compound (39), compound (41), compound (45), compound (46), compound (50), compound (51), compound (52), compound (53), compound (55), compound (56), compound (59), compound (60), and compound (67) the protective group represented by the R 12, by conventional method carried out, obtained by divided.
  • the present invention relates to a novel hydroxamic acid derivative having an excellent matrix metalloproteinase inhibitory activity, and an agent for suppressing metastasis, invasion and growth of various cancer cells, and an osteoarthritis and rheumatism containing the derivative as an active ingredient.
  • a therapeutic agent and a preventive agent for rheumatoid arthritis are provided.
  • the dosage form of the compound (1) of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories.
  • preparations may contain excipients (eg, lactose, sucrose, dextrose, saccharides such as mannitol, sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, starch such as carboxymethyl starch).
  • excipients eg, lactose, sucrose, dextrose, saccharides such as mannitol, sorbitol; corn starch, potato starch, ⁇ -starch, dextrin, starch such as carboxymethyl starch.
  • Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked carboxymethylcellulose sodium; arabia gum; dextran Organic excipients such as pullulan: and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; Sulfuric acid Inorganic excipients such as sulfates such as sodium chloride, etc.), lubricants (for example, metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica) Waxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL le
  • Stabilizers paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; and sorbic acid
  • flavoring agents for example, commonly used sweeteners, sour agents, flavors, etc.
  • the dosage varies depending on the symptoms, age, administration method, etc.
  • the lower limit is 1 mg (preferably 10 mg) and the upper limit is 10 OO mg
  • the lower limit is preferably 0.5 mg (preferably 5 mg) and the upper limit is 500 mg (preferably 25 mg).
  • Omg is preferably administered once or several times daily depending on the symptoms.
  • N 1 one Benjiruokishi N 4 - [1 - (S ) one t one-butyl - 2- (R) - arsenide Dorokishi 3- (N- methylcarbamoyl) propyl] one 2-(S) over human Dorokishi one 3— (R) -nonylsuccinamide
  • N 1 one Benjiruokishi N 4 one [1 one (S) - t-butyl-2- (R), 4- dihydric Dorokishibuchiru] one 2 - (S) over human Dorokishi one 3 - (R) - Noel Sukushinami de
  • the target compound (340 mg, 74.0%) was obtained as a white compound from (R) -nonylsuccinamide (550 mg) in the same manner as in Example 2-c).

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Abstract

Cette invention concerne des composés correspondant à la formule générale (1) où R1 représente alkyle C¿1-15? éventuellement substitué; R2 représente H, hydroxy ou acyloxy C1-4; R?3¿ représente alkyle C¿1-6? éventuellement substitué; R?4¿ représente H, alcoxycarbonyle C¿2-5? ou alkyle C1-4 éventuellement substitué; R?5¿ représente H ou alkyle C¿1-4?; et R?6¿ représente H, acyle C¿2-5? éventuellement substitué ou carbamoyle éventuellement substitué. Ces composés possède une excellente activité inhibitrice de métaprotéinases matricielles, et peuvent être utilisés en qualité d'inhibiteurs de métastase cancéreuse, entre autres.
PCT/JP1997/000582 1996-03-01 1997-02-27 Derives d'acide hydroxamique WO1997031892A1 (fr)

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WO1998055449A1 (fr) * 1997-06-06 1998-12-10 The University Of Queensland Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires
WO2001047901A1 (fr) * 1999-12-23 2001-07-05 Pfizer Limited Acides ox(adi)azolyl-hydroxamiques utilises comme inhibiteurs de la procollagene c-proteinase
US6448278B2 (en) 1999-12-23 2002-09-10 Pfizer Inc. Procollagen C-proteinase inhibitors
WO2014067861A1 (fr) * 2012-10-29 2014-05-08 F. Hoffmann-La Roche Ag Dérivés d'oxazolidinone 3,4-disubstituée et leur utilisation comme inhibiteurs des canaux potassiques activés par le calcium

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WO1996033165A1 (fr) * 1995-04-18 1996-10-24 British Biotech Pharmaceuticals Limited Derives de succinamide et leur utilisation en tant qu'inhibiteurs de la metalloproteinase

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WO1994025434A1 (fr) * 1993-04-27 1994-11-10 Celltech Limited Derives peptidiques inhibiteurs de metalloproteinases
WO1995019961A1 (fr) * 1994-01-22 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1996033166A1 (fr) * 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Acides hydrodynamiques et carboxyliques inhibiteurs des metalloproteases
WO1996033165A1 (fr) * 1995-04-18 1996-10-24 British Biotech Pharmaceuticals Limited Derives de succinamide et leur utilisation en tant qu'inhibiteurs de la metalloproteinase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055449A1 (fr) * 1997-06-06 1998-12-10 The University Of Queensland Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires
WO2001047901A1 (fr) * 1999-12-23 2001-07-05 Pfizer Limited Acides ox(adi)azolyl-hydroxamiques utilises comme inhibiteurs de la procollagene c-proteinase
US6448278B2 (en) 1999-12-23 2002-09-10 Pfizer Inc. Procollagen C-proteinase inhibitors
US6897306B2 (en) 1999-12-23 2005-05-24 Pfizer Products, Inc. 3-heterocyclylpropanohydroxamic acids
WO2014067861A1 (fr) * 2012-10-29 2014-05-08 F. Hoffmann-La Roche Ag Dérivés d'oxazolidinone 3,4-disubstituée et leur utilisation comme inhibiteurs des canaux potassiques activés par le calcium
US9611232B2 (en) 2012-10-29 2017-04-04 Hoffmann-La Roche Inc. Oxazolidinone and imidazolidinone compounds

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