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WO1998015525A1 - Acides hydroxamiques - Google Patents

Acides hydroxamiques Download PDF

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Publication number
WO1998015525A1
WO1998015525A1 PCT/JP1997/003542 JP9703542W WO9815525A1 WO 1998015525 A1 WO1998015525 A1 WO 1998015525A1 JP 9703542 W JP9703542 W JP 9703542W WO 9815525 A1 WO9815525 A1 WO 9815525A1
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WIPO (PCT)
Prior art keywords
group
amino
substituted
nmr
lower alkyl
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PCT/JP1997/003542
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English (en)
Japanese (ja)
Inventor
Fumio Samizo
Yumiko Kamikawa
Akira Sasaki
Yasuyuki Ueki
Hitoshi Hochigai
Kiyoko Kogita
Original Assignee
Sumitomo Pharmaceuticals Co., Ltd.
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Publication of WO1998015525A1 publication Critical patent/WO1998015525A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • 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
    • C07C323/50—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 carboxyl groups bound to the same carbon skeleton
    • C07C323/51—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—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 carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 hydroxamic acid derivative useful as a matrix meta-oral protease inhibitor and a matrix meta-oral protease inhibitor.
  • the matrix meta-oral proteases include collagenase (matrix meta-oral protease 1-1, MMP-1), gelatinase A (matrix meta-oral protease 1-2, MMP-2), and stromelysin (matrix meta-oral). Mouth Proteases 3, MMP-3), Gelatinase B (Matrix Meta-Mouth Proteinase 9, MMP-9), Collagenase 1-3 (Matrix Meta-Mouth Proteinase 13, MMP-1) 3) Currently 16 types are known.
  • Extracellular matrix is normally expressed at the level of synthesis and secretion of these matrix meta-oral proteases, or by endogenous extracellular inhibitors (e.g., TIMPs (Tissue Inhibitors of matrix metallo protease)). Tightly controlled. There are many reports on the relationship between elevated protease activity that occurs when this balance is disrupted and diseases that manifest as connective tissue destruction.
  • TIMPs tissue Inhibitors of matrix metallo protease
  • Collagenase 13 (matrix metalloprotease-13, MMP-13) is expressed on the synovium of patients with rheumatoid arthritis and on human chondrocytes developing osteoarthritis (J. Clin Invest., 97, 2011-2019 (1996); J. Rheumatol., 23, 509-595 (1996); J. Biol. Chem., 271, 23577-23581 (1996); J. Clin. Invest., 97, 761-768 (1996)).
  • ⁇ -13 has strong degrading activity on collagen type II and aggrecan, which are the major components of the extracellular matrix of the cartilage matrix, and has been linked to cartilage osteoarthritis and rheumatoid arthritis. (J. Biol. Chem., 271, 1544-1550 (1996); FEBS Lett "380, 17-20 (1996)).
  • the matrix meta-oral protease inhibitor can be used as a therapeutic or prophylactic agent for osteoarthritis, joint diseases such as rheumatoid arthritis, metastasis of cancer cells, gingivitis and the like.
  • matrix meta-oral proteases In addition to the above-mentioned extracellular matrix destruction, matrix meta-oral proteases also convert tumor necrosis factor from latent form to mature form (Nature, 370, 555-557 (1994)), serine proteinase. Of ⁇ 1-antitrypsin, an enzyme inhibitor (FEBS Lett., 279, 191-194 (1991)), activation by mutual interaction of matrix meta-oral proteases (Biochemistry, 29, 10261-10670 (1990); J. Biol. Chem., 267, 21712-21719 ( 1992)).
  • matrix metaoral protease inhibitors can be used as anti-inflammatory agents.
  • WO 95/35275 describes hydroxamic acid derivatives useful as matrix meta-oral protease inhibitors. However, it does not disclose the results of the inhibition test of this hydroxamic acid derivative and does not disclose which matrix metallobutase is inhibited. Disclosure of the invention
  • An object of the present invention is to provide a novel compound useful as a matrix meta-oral protease inhibitor, and a novel matrix meta-oral protease inhibitor.
  • the present inventors have conducted intensive studies on compounds having an inhibitory activity on matrix meta-oral protease, such as MMP-3 and MMP-13, and have found that hydroxamic acid derivatives have excellent inhibitory activity. Completed the invention.
  • R is an optionally substituted hydrocarbon cyclic group, an optionally substituted heterocyclic group, an optionally substituted hydrocarbon group, a vinyl group substituted with a hydrocarbon cyclic group, Represents a vinyl group or a modified amino group substituted with a heterocyclic group.
  • X is an alkylene group which may be substituted
  • Y represents an oxygen atom or a sulfur atom, or represents an imino group optionally substituted with a lower alkyl group.
  • M and n each independently represent an integer of 0 to 15, And the sum of m and n is an integer of 1-20. However, when n is 0, B is a carbonyl group or a sulfonyl group.
  • (CH 2 ) m and (CH 2 ) n may be independently substituted with a substituent. ), Or
  • Formula:-(CH 2 ) p — Z-(CH 2 ) q- (where Z is a sulfinyl group, a sulfonyl group, a carbonyl group, one NL 1 — C ( NL 1 ) one NL 1- , one NL 2 —CO—NL 2 —, —O— CONL 2 —, —CON L 3 represents one or one of S 0 2 NL 3 — where L 1 is independently a hydrogen atom, a lower alkyl group, a lower alkanoyl group , An aryloyl group, a lower alkylsulfonyl group or an arylsulfonyl group, L 2 independently represents a hydrogen atom or a lower alkyl group, and L 3 represents a hydrogen atom or a lower alkyl group which may be substituted.
  • (CH 2 ) p and (CH 2 ) q may be independently substituted with a substituent.) represents a group represented by:
  • B represents a carbonyl group, a methylene group or a sulfonyl group.
  • R 1 represents a hydrogen atom or an optionally substituted lower alkyl group when B is a carbonyl group or a sulfonyl group, and a hydrogen atom or an optionally substituted lower alkyl group when B is a methylene group.
  • A represents a methylene group substituted with one or two lower alkyl groups which may be substituted.
  • R, R 1 and B are as defined above.
  • a 1 and X 1 are as follows.
  • a 1 represents a methylene group substituted with one or two lower alkyl groups which may be substituted.
  • X 1 is an alkylene group having 3 to 20 carbon atoms which may be substituted
  • M 1 and ⁇ 1 each independently represent an integer of 0 to 15 and the sum of m 1 and ⁇ 1 is an integer of 3 to 20.
  • CH 2 ml and (CH 2 ) nl may be independently substituted with a substituent, provided that when n 1 is 0, B is a carbonyl group or a sulfonyl group.
  • Z is as defined above.
  • P 1 represents an integer of 0 to 15
  • 1 represents an integer of 3 to 15
  • the sum of p 1 and q 1 is an integer of 3 to 20.
  • (CH 2 ) pl and (CH 2 ) ql may be independently substituted with a substituent.).
  • R 2 is an optionally substituted hydrocarbon cyclic group, an optionally substituted heterocyclic group, a vinyl group substituted with an optionally substituted hydrocarbon cyclic group, Represents a vinyl group or a modified amino group substituted with a heterocyclic group.
  • Z 1 represents one CONL 2 —, — S 0 2 NL 2 — or — 0— CONL 2 — (L 2 is as defined above).
  • i represents an integer of 1 to 7, and j represents 1, 2, 3, 5 or 6.
  • (CH 2 ) and (CH 2 ) "may be independently substituted with a substituent.
  • ⁇ represents a substituted methylene group represented by
  • X 1 is an alkylene group having 1 or 2 carbon atoms which may be substituted
  • hydrocarbon cyclic group examples include an aliphatic hydrocarbon cyclic group and an aromatic hydrocarbon cyclic group (aryl group).
  • Examples of the aliphatic hydrocarbon cyclic group include, for example, a saturated or unsaturated aliphatic hydrocarbon cyclic group having 5 to 8 carbon atoms. Specifically, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexyl Xenyl, cycloheptyl and the like.
  • Examples of aryl groups include aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl and naphthyl.
  • heterocyclic group examples include an aliphatic heterocyclic group and an aromatic heterocyclic group.
  • examples of the aliphatic heterocyclic group include a saturated or unsaturated monocyclic or bicyclic monocyclic or bicyclic ring having 1 to 4 nitrogen atoms, oxygen atoms, or 5 to 10 ring-containing atoms containing Z and sulfur atoms. And aliphatic heterocyclic groups.
  • a monocyclic 6-membered saturated heterocyclic ring containing one or two heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms such as piperidyl, piperazinyl, piberidinyl, and morpholinyl
  • heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms such as bicyclic 10-membered saturated heterocyclic groups including imidazoles, imidazolinyl, pipolinyl, and pyrazolinyl
  • aromatic heterocyclic group examples include monocyclic, bicyclic or tricyclic aromatic rings having 1 to 5 nitrogen atoms, oxygen atoms and / or sulfur atoms and having 5 to 14 ring atoms.
  • Group heterocyclic groups Specifically, a monocyclic 6-membered heterocyclic group containing one or two heteroatoms arbitrarily selected from the group of oxygen, nitrogen, and sulfur atoms such as pyridyl, pyridazinyl, and pyrazinyl; 5-membered monocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur such as imidazolyl, furyl, 2-oxo-1,3-dioxorenyl, phenyl, and pyrrolyl Heterocyclic group, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuryl and other oxygen atoms, nitrogen atoms, and sulfur containing two or more
  • a zero-membered heterocyclic group an oxygen atom such as anthraquinolyl, a nitrogen atom, a three-ring 12- to 14-membered heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from the group of sulfur atoms, and the like.
  • the substitution position of the vinyl group substituted by the hydrocarbon cyclic group and the vinyl group substituted by the heterocyclic group may be any position of the vinyl group, but preferably includes the 2-position of the vinyl group. Particularly preferred is the trans position at the 2-position of the vinyl group.
  • Examples of the substituent of the substituted hydrocarbon cyclic group and the substituted heterocyclic group include the following groups, and optionally selected 1 to 3 groups may be substituted.
  • lower alkyl group carboxyl group, lower alkoxycarbonyl group, one CO-NHOH, amino group, lower alkyl-substituted amino group (one or two lower alkyl groups may be substituted), tri-lower alkyl ammonium group, Rubamoyl group, lower alkyl substitution rubamoyl group, guanidinocarbonyl group, lower alkanoylamino group, lower alkylsulfonylamino group, lower alkoxycarbonylamino group, arylsulfonylamino group, amino lower alkyl group, Lower alkyl group, lower alkanoylamino lower alkyl group, lower alkylsulfonylamino lower alkyl group, lower alkoxycarbonylamino lower alkyl group, arylsulfonylamino lower alkyl group, lower alkylamino lower alkyl group, guanidino Group, substitution group Nidino group (Examples of
  • Groups carboxyl group, lower alkoxycarbonyl group, amino group, amino lower alkyl group, cyano lower alkyl group, lower alkoxycarbonylamino lower alkyl group, guanidino lower alkyl group, nitro group, cyano group, amidino group, lower alkyl group Kill group, hydroxyl group, oxo group, lower alkoxy group, halogen atom, lower alkylamino lower alkyl group, lower alkanoylamino group.
  • More preferred groups include, for example, the following groups.
  • a commonly used protecting group for example, “Protective Groups in Organic Synthes is, TW Greene, PGM Wuts, A Wiley-Interscience Publication, New York; “Basic and Experimental Peptide Synthesis” Nobuo Izumiya et al., Described in Maruzen), etc.
  • Specific modifying groups include, for example, benzyloxycarbonyl group, t-butyloxycarbonyl group Urethane-type modifying group such as a group, amide-type modifying group such as acetyl, cyclic imid-type modifying group such as phthaloyl, aryl-type modifying group such as aryl, benzyl-type modifying group such as benzyl, t-butyldimethylsilyl group
  • alkylene group include a linear or branched alkylene group having 1 to 20 carbon atoms, and specifically, methylene, ethylene, and trimethylene.
  • Tetramethylene styrene pentamethylene, to Kisamechiren, nonamethylene, 3 Mechirunonamechi Ren, decamethylene, Undekamechiren, dodecamethylene, eicosapentaenoic methylene, and the like.
  • the lower alkyl group includes, for example, a linear or branched alkyl group having 1 to 7 carbon atoms, specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2 — Methylpropyl, pentyl, hexyl, heptyl and the like.
  • Examples of the substituted lower alkyl group, the substituted alkanoyl group and the substituted alkylsulfonyl group in R 1, and the substituted lower alkyl group in L 3 include the following groups.
  • Groups may be substituted. Groups: carboxyl group, lower alkoxycarbonyl group, mono-CO—NHOH, amino group, lower alkyl-substituted amino group (one or two lower alkyl groups may be substituted), tri-lower alkylammonio group, carbamoyl Group, lower alkyl-substituted carbamoyl group, guanidinocarbonyl group, lower alkanoylamino group, lower alkylsulfonylamino group, lower alkoxycarbonylamino group, guanidino group, Substituted guanidino group (this substituent includes, for example, a lower alkyl group, a lower alkanoyl group, a lower alkylsulfonyl
  • Examples of the substituent in the substituted lower alkyl group in A in Formula 1 or A 1 in Formula 2 include the following groups, and one to three groups selected arbitrarily may be substituted.
  • a group represented by The group represented by one NH—A—CO— in Formula 1 or one NH—A 1 —CO— in Formula 2 includes, for example, a residue of an ⁇ -amino acid.
  • alanine, valine, norparin, leucine, isoleucine, norleucine, serine, threonine, aspartic acid asparagine, glutamic acid, glutamine, homoglutamic acid, homoglutamine, lysine, hydroxylysine, orditin, arginine, Histidine, homohistidine, fenylalanine, homophenylalanine, tyrosine, tributofan, cystine, methionine, methionine sulfoxide, methionine sulfone, homocitrulline, citrulline, / 3-methyldaltaminate, / 3-— Residues such as methyl homoglutamic acid, 0-carboxymethylthreonine, S
  • NH—A—CO— in Formula 1 or one NH—A 1 —CO— in Formula 2 preferably, aspartic acid, glutamic acid, homodaltamic acid, ordinine, lysine, arginine, Examples include homocitrulline and citrulline residues.
  • Preferred examples of the group represented by A in Formula 1 or A 1 in Formula 2 include, for example,
  • Examples of the substituent of the substituted hydrocarbon cyclic group and the substituted heterocyclic group in R 2 include the substituents of the above-mentioned substituted hydrocarbon cyclic group and the substituted heterocyclic group, and the following are particularly preferred. .
  • Lower alkanoyl groups include, for example, linear or branched C 1-7 Examples thereof include a lucanyl group, and specific examples include an acetyl, propionyl, butanol, 2-methylpropanol, hexanoyl, and heptanyl group.
  • arylo group examples include an arylcarbonyl group having 7 to 11 carbon atoms, and specific examples include benzoyl and naphthylcarbonyl.
  • alkoxy group examples include straight-chain or branched-chain alkoxy groups having 1 to 7 carbon atoms. Specific examples include methoxy, ethoxy, propoxy, butoxy, 2-methylpropoxy, hexyloxy, and heptyloxy groups. And the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • salts of the hydroxamic acid derivatives of Formula 1 include acid addition salts and base addition salts.
  • acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, citrate, oxalate, acetate, and formate.
  • organic salts such as propionate, benzoate, trifluoroacetate, fumarate, maleate, tartrate, aspartate, glutamate, methanesulfonate and benzenesulfonate.
  • base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.
  • organic base salts such as organic salts.
  • the hydroxamic acid derivative of Formula 1 or a pharmaceutically acceptable salt thereof also includes a solvate such as a hydrate thereof.
  • the hydroxamic acid derivative of the formula 1 can be produced, for example, according to the following production method.
  • R 3 represents a protecting group for an amino group
  • R 4 represents benzyl, t-butyl, t-butyldimethylsilyl, trimethylsilyl, trityl, tetrahydroviranyl or benzhydryl.
  • Q represents a hydroxyl group, a chlorine atom, a bromine atom or an iodine atom.
  • Examples of the protecting group for the amino group represented by R 3 include commonly used protecting groups, and are preferably t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzoyloxycarbonyl, p- Those which can be easily deprotected by hydrogenolysis or hydrolysis, such as methoxybenzyloxycarbonyl and 91-fluorenylmethyloxycarbonyl.
  • the condensation reaction between the compound of the formula 3 and the compound of the formula 4 can be performed according to a method known in peptide chemistry (“Nobuo Izumiya et al., Maruzen et al.”, “Basics and Experiment of Peptide Synthesis”).
  • C-terminal activation method (acid halide method, acid azide method, mixed acid anhydride method, active ester method, symmetric acid anhydride, etc.), method using coupling reagent (N, N'-dicyclo) A method using hexylcarpoimide (DCC) or the like; an N-terminal activation method (an isocyanate method, a phosphazo method, a phosphite method, etc.).
  • a compound of the formula 3 and a compound of the formula 4 can be prepared by mixing N- (dimethylaminoethyl) -N'-ethylcarbohydrate in N, N-dimethylformamide (DMF).
  • Imid hydrochloride WSC hydrochloride
  • 1-hydroxybenzoto A method of condensation at 0 ° C. to room temperature in the presence of riazol (HOB t) is exemplified.
  • the compound subjected to the condensation reaction is then subjected to deprotection of the protecting group for the amino group represented by R 3 according to a conventional method, whereby a compound of formula 5 can be obtained.
  • R 3 When t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or the like is used as R 3 Can be deprotected by hydrogenolysis or hydrolysis.
  • a hydrogenation catalyst for example, a palladium catalyst
  • an acid such as acetic acid or hydrochloric acid is added in an inert organic solvent (for example, methanol or ethanol).
  • the hydrolysis reaction is performed, for example, in the presence of an acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, or hydrobromic acid, in a solvent-free or aqueous organic solvent at room temperature.
  • an acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, or hydrobromic acid, in a solvent-free or aqueous organic solvent at room temperature.
  • the condensation reaction between the compound of the formula 5 and the compound of the formula 6 can be carried out as follows.
  • the compound of the formula 6 it is preferable to react with the compound of the formula 5 using a compound in which Q represents a chlorine atom, a bromine atom or an iodine atom.
  • the reaction between the compound of the formula 5 and the compound of the formula 6 can be carried out under the same conditions as ordinary nucleophilic substitution reactions.
  • the compound of formula 5 and the compound of formula 6 can be reacted in DMF in the presence of potassium carbonate at room temperature.
  • a compound of the formula 5 and a compound of the formula 6 can be reacted in DMF in the presence of triethylamine at room temperature.
  • a compound obtained by condensation reaction, followed by a protective group for a hydroxyl group represented by R 4 By accordance connection deprotected conventional method, to give a compound of formula 1.
  • deprotection can be achieved by hydrogenolysis, hydrolysis or treatment with a Lewis acid in a non-aqueous solution.
  • Specific reaction conditions include the same conditions as described above, and those using boron dibromide, boron trichloride, and trimethylsilane iodide in an aprotic solvent such as methylene chloride.
  • the protecting group for the amino group represented by R 3 it is preferable to select a protecting group having different deprotection conditions from the protecting group for the hydroxyl group represented by R 4 .
  • the compound of the formula 6 can be produced as follows depending on the type of the group represented by X.
  • the compound of formula 6 can be prepared according to a conventional method, or, if necessary, by increasing the carbon by, for example, a Wittig reaction or a Horner-Emmons reaction, and further reducing the double bond to extend the alkylene group. Can be manufactured.
  • the compound of formula 6 forms an ether bond, a thioether bond or an imino group by a nucleophilic substitution reaction according to a conventional method, and further converts a thioether into an acid, if necessary. Can be manufactured. Alternatively, an imino group can be formed by a reductive amination reaction.
  • the compound of the formula 6 can be produced by condensing the corresponding amine and acid in the same manner as described above. it can.
  • Q 1 represents a protected hydroxyl group, a protected hydroxymethyl group or a protected mercapto group.
  • the compound of formula 6 can be prepared as described above, for example, according to Synthesis, 1988, 456. That is, the compound of the formula 8 is produced by reacting the compound of the formula 7 with benzoylisothiocyanate, followed by debenzoylation and subsequent treatment with methyl iodide. By subjecting the compound of formula 8 to a compound of formula 9 by nucleophilic substitution reaction, a compound of formula 10 is obtained.Deprotection and, if necessary, oxidation or Z and halogenation are carried out. Compounds of formula 11 can be prepared.
  • R, p, L 2 , q, B, Q and Q 1 are as defined above.
  • Q 2 represents an oxygen atom or 1 NL 2 — (L 2 is as defined above).
  • the compound of formula 6 can be prepared as described above, for example, according to Angew. Chem. Int. Ed., 26, 894 (1997). That is, the compound of the formula 12 is reacted with triphosgene to form a compound with the formula 13, and the compound of the formula 14 is further reacted with the compound of the formula 14, further deprotected and, if necessary, The compound of Formula 16 can be produced by oxidation or halogenation.
  • the compound of the formula 6 can be produced, for example, by reacting a corresponding aldehyde with a Grignard reagent and then oxidizing a generated hydroxyl group according to a conventional method.
  • the compound of the formula 3 can be synthesized by a known method or a method similar to the method of the compound of the above formula 6, and the like.
  • the compound of the formula 3 is reacted with the compound of the formula 4 and further reacted with the compound of the formula 6, but the order is changed. Or a compound of the formula 3 in which the carboxy group is protected, followed by removing the protecting group of the carboxy group, and then reacting the compound of the formula 4 it can.
  • the hydroxamic acid derivative of the formula 1 has a functional group that changes under the above reaction conditions and the like, it is preferable to protect these functional groups.
  • the protecting group a generally known protecting group can be used.
  • the hydroxamic acid derivative of the formula 1 can be converted into a pharmaceutically acceptable salt according to a conventional method.
  • the hydroxamic acid derivative of Formula 1 or a pharmaceutically acceptable salt thereof is formulated according to a compatible formulation, and is orally or parenterally (injectable (intravenous, intramuscular, subcutaneous, intraarticular) , Transdermal, ophthalmic, suppository, nasal, etc.).
  • the preparation When administered orally, the preparation may be in the form of, for example, tablets, capsules, pills, granules, powders, liquids, syrups and the like.
  • the preparation When administered parenterally, the preparation can be in the form of an aqueous or oily injection, an ointment, a cream, a lotion, a patch, an aerosol, or the like.
  • These preparations can be prepared according to a conventional method.
  • pharmaceuticals such as a hydroxamic acid derivative of Formula 1 or a pharmaceutically acceptable salt thereof, such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, coating agents, etc. It can be formulated using known adjuvants usually used in the field of formulation technology.
  • the dosage and frequency of administration of the hydroxamic acid derivative of Formula 1 or a pharmaceutically acceptable salt thereof will vary depending on the patient's condition, weight, age, administration method and dosage form. Per dose, 1 to 100 mg, preferably 5 to 30 mg can be administered once or in several divided doses.
  • Examples of specific compounds of the present invention include the following compounds. CONHOH
  • a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ether-hexane to give (4R) -5-[(benzyloxy) amino] _4 — [(t-butoxycarbonyl). 2) g of benzyl] -5-oxopentanoate were obtained.
  • (4R) -5- (hydroxyamino) _5-oxo-141-[(6-phenylhexanoyl) amino] pentanoic acid 400 mg
  • 415 mg of sodium salt of (4R) -5- (hydroxyamino) -l5-oxo-l 4-[(6-phenylhexanoyl) amino] pentanoic acid was obtained.
  • Benzyl butanoate of Example 1 was used as the starting material (3 R) —4- (benzyloxyamino) 14-oxo 13-[(10-phenyldecanoyl) amino]. Prepared by methods analogous to those described in Section 2.
  • J H-NMR ⁇ (DMSO-d 6 ) 10.57 (s, 1H), 8.8 l (s, 1H), 7.91 (d, 1H, J 8.25 Hz), 7.25 (m , 2H), 7.11-7.
  • N — ⁇ (1R) —11-[(benzyloxyamino) carbonyl] pentyl ⁇ -11-phenyldecanamide (1 g) )
  • N — ⁇ (1 R) -11-[(hydroxyamino) carbonyl] pentyl ⁇ -11-phenyldecanamide 727 mg of N — ⁇ (1 R) -11-[(hydroxyamino) carbonyl] pentyl ⁇ -11-phenyldecanamide.
  • N — ⁇ (1R) -1-[(benzyloxyamino) carbonyl] pentyl ⁇ -10-phenyldecanamide used as a starting material was prepared according to the method described in Section 2 of Example 1. Prepared by a similar method.
  • N — ⁇ (1R) —11-[(benzyloxyamino) carbonyl] butyl ⁇ 1-10-phenyldecanamide (1 g)
  • N — ⁇ (1R) -1-[(hydroxyamino) carbonyl] butyl ⁇ -11-phenyldecanamide 767 mg of N — ⁇ (1R) -1-[(hydroxyamino) carbonyl] butyl ⁇ -11-phenyldecanamide.
  • N-[((1R) -111-benzyl-2- (benzyloxyamino) -12-oxoethyl]-10-phenyldecanamide used as a starting material was prepared according to the method described in Example 1, section 2 Prepared by a similar method.
  • N — ⁇ (1R) —1-[(benzyloxyamino) carbonyl] -13-phenylpropyl ⁇ —10-phenyl 722 mg of N — ⁇ (1R) 111 [(hydroxyamino) carbonyl] —3-phenylpropyl ⁇ —10-phenyldecanamid was obtained from nildecanamide (1 g).
  • N-[(1R) -12- (benzyloxyamino) -11-methyl-2-oxoethyl] _10-phenyldecanamide used as a starting material was prepared according to the method described in the second section of Example 1. Prepared by a similar method.
  • N- ⁇ (1R) -5- (benzyloxycarbonyl) amino-11-((benzyloxyamino) carbonyl] pentyl ⁇ -10-phenyldecanamide (1 g) to N- ⁇ (1R) —5-amino-1-[(hydroxyamino) carbonyl] pentyl ⁇ 103-mg of 10-phenyldecanamide trifluoroacetate Obtained.
  • Example 1 N- ⁇ (1R) -5- (benzyloxycarbonyl) amino-1-[(benzyloxyamino) carbonyl] pentyl ⁇ —10-phenyldecanamide used as a starting material was prepared in Example 1. It was prepared by a method similar to that described in section 2 of
  • N- ⁇ (1R) -1-[(t-butoxyamino) carbonyl] 3- (methylthio) propyl ⁇ -10-phenyldecanamide (1.0 g, 2.22 mmo 1)
  • a reagent prepared from acetic acid (TFA) (19 ml), water (0.5 ml), and ethanedithiol (0.5 ml) was added under ice-water cooling, stirred for 2 hours, and then stirred at room temperature for 4 hours. did.
  • N — ⁇ (1R, 2R) —2-benzyloxy 11-[(benzyloxyamino) carbonyl] propyl ⁇ —10-phen N- ⁇ (1R, 2R) -12-hydroxy-11-[(hydroxyamino) carbonyl] propyl ⁇ -11-phenyldecanamide was obtained from nildecanamide (lg) in an amount of 51.0 mg.
  • Benzyl-1-5-oxopentanoate (1.47 g) to (4R) -4-[ ⁇ 11-[(t-butoxycarbonyl) amino] ⁇ decanoyl ⁇ amino] 15- (hydroxyamino) —Oxopentanoic acid was obtained quantitatively.
  • Benzyl 2-aminopropanoate (33.9 g) and 9-decenoic acid (32.2 g) are dissolved in dichloromethane (400 ml), and under ice-cooling, WSC HC1 (36.3 g) is added for 4 hours. Stirred. After adding 1N-hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate.
  • Bromide-4-cyanobenzylphosphonium (5.5 g) was dried at 85 ° C under reduced pressure for 1 hour, suspended in THF (50 ml), and sodium hydride (60%, 0.5%). 48 g) and stirred at room temperature for 1 hour. 2-[(9-oxononanoyl) amino] benzyl (33.3 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into 1N-hydrochloric acid under ice-cooling, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate.
  • N— [2- (Hydroxyamino) -1-methyl-12-oxoethyl] —10— (4-cyanophenyl) -19-decenamide (200 mg) was dissolved in methanol (5 ml) and dissolved in methanol (5 ml). % Palladium Z-carbon (20 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 7 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by thin-layer chromatography (stationary phase: silica gel, silica gel 60, 0.5 mm thick, mobile phase: ethyl acetate acetone 5Z 1). As a result, there were obtained 172 mg of N— [2- (hydroxyamino) -1-1-methyl-2-oxoethyl] —10— (4-cyanophenyl) decanamide.
  • N- [2- (hydroxyami-]-methyl-2-oxohexyl] -10- (3-cyanophenyl) -19-decenamide 200 mg
  • N- [2- (hydroxyamino) -1-methyl-2-oxoethyl] -10-[(3-aminomethyl) phenyl] decanamid acetate 192 mg
  • N— [2- (hydroxyamino) -1-methyl-12-oxoethyl] -10- (2-cyanophenyl) -19-decenamide 200 mg was converted to N — [2- (Hydroxyamino) -11-methyl-12-oxoethyl] -10- (2-cyanophenyl) decanamide was obtained quantitatively.
  • N- [2- (hydroxyamino) -1-methyl-12-oxoethyl] -10- (2-cyanophenyl) -19-decenamide 200 mg was converted to N — [2 -— (Hydroxyamino) -1-1-methyl-1-oxo-ethyl] -10— [2- (aminomethyl) phenyl] decanamide (138 mg) was obtained.
  • Ether was added to separate two layers, and the aqueous layer was added with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure.
  • the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • Example 102 The compound (200 mg) described in Example 102 was dissolved in ethanol (2.5 ml), and p-toluenesulfonylhydrazine (118 mg, 0.64 mmol) and trimethoxyborane (68.8 mg) were dissolved. , 0.66 mmol) and heated to reflux for 5 hours. During this time, a 1 N aqueous solution of sodium hydroxide (0.8 ml) was added in seven portions. After cooling to room temperature, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate.
  • Example 102 To the compound of Example 102 (0.2 g ) was added water (11 ml), acetone (55 ml), IN-sodium hydroxide aqueous solution (7. Oml) and sodium hydrosulfite (92.3 mg). Was added and the mixture was heated under reflux for 0.5 hour. The solvent was distilled off under reduced pressure, and 1N monohydrochloric acid and ether were added to separate two layers. The aqueous layer was neutralized by adding sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • DL-alanyl hydroxamic acid (0.36 g) is suspended in acetonitrile (7.5 ml), diisopropylethylamine (1.2 ml) is added, and trimethylsilyl chloride (1. 0 ml) was added dropwise. After stirring at room temperature for 2.5 hours, the above-mentioned acid chloride solution of acetonitrile was added dropwise under ice-cooling. After stirring at room temperature for 1 hour, ethyl acetate and a 5% aqueous solution of potassium hydrogen sulfate were added to separate two layers, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, and a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • the drying agent was filtered off, and the crystals obtained by concentration under reduced pressure were added with ether and collected by filtration to obtain 768 mg of the desired product.
  • the drying agent was filtered off, and the residue obtained by concentration under reduced pressure was purified by HPLC (column: YMC-ODS (SH-363-5) 3 cm ⁇ 25 cm; solvent: (solution A) 0.1% TFA / H 20 (Solution B) 0.1% TF AZCH 3 CN; Gradient: (B%: 0 ⁇ 20% (30 min) ⁇ 40% (150 min); Flow rate: 7 m 1 min; Detection: UV 220 nm Yield 49.7 mg (26.3%).
  • the desiccant was filtered off and concentrated under reduced pressure. ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the desired product as an oil. Yield 2.61 g (89.4%).
  • the organic layer was washed sequentially with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • the drying agent was filtered off, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (silica gel 25 g; solvent: chloroform-form-methanol (100: 1 ⁇ 50: 1 ⁇ 20: 1). )). Yield 238 mg (90.8%).
  • N-Benzyl N '— (3-phenylpropyl) thiopurea (31.4 g) was dissolved in a mixed solvent of methanol (50 ml) and THF (100 ml), and potassium carbonate (34.3 g) was dissolved. Was added and the mixture was heated under reflux for 2 hours. The potassium carbonate was removed by filtration, the solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • N- (3_phenylpropyl) thioperia (19.2 g) was dissolved in acetone (250 ml), and potassium carbonate (17.8 g) was added. After methyl iodide (1.0 g) was added dropwise thereto under cooling with ice water, the mixture was heated to room temperature, stirred for 3 hours, and allowed to stand at room temperature for 2 days. The potassium carbonate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and hexane to give a solution of 3- (3- 15.1 g of ⁇ [imino (methylsulfanyl) methyl] amino ⁇ propyl) benzene was obtained.
  • 18.5 g of the obtained crude product and sodium hydrogencarbonate (6.89 g) were added to methylene chloride (50 ml) and water (100 ml). Under ice-cooling, benzyloxycarbonyl chloride (8.39 g) was added thereto, followed by heating to room temperature and stirring for 15 hours. Water is added and the mixture is extracted with black hole form.
  • the organic layer is washed with 1N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous Dried over magnesium sulfate.
  • the mixture was made weakly acidic with 1 N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous solution of potassium hydrogen sulfate and brine, and dried over anhydrous magnesium sulfate.
  • Cinnamyl bromide (19.7 g) was dissolved in toluene (100 ml), ethylene glycol monobenzyl ether (15.2 g) was added, and toluene (180 ml) was added and dissolved. .
  • a 50% aqueous solution of sodium hydroxide (200 ml) and tetra-n-butylammonium hydrogen sulfate (3.4 g) were added, and the mixture was stirred at room temperature for 1 hour.
  • the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and water.
  • This crude product was dissolved in methanol (20 ml), 10% -PdC (wet) (0.25 g) was added, and the mixture was stirred for 3 hours under a hydrogen atmosphere.
  • the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure.
  • the residue was dissolved in methanol (20 ml), and 10% —PdZC (wet) (0.25 g) was added. For 7 hours.
  • the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 1.5 g of ethyl 6- (3-phenylpropoxy) hexanoate.
  • (2RS) Methyl 2- (5-hexenoylamino) propanoate (43.6 g) was dissolved in methanol (100 ml), and a 5 N aqueous solution of sodium hydroxide (88 ml) was added under ice cooling. And stirred at room temperature for 3 hours. Water was added, the mixture was washed with ether, 1N-hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (20.2 g) of (2RS) -2- (5-hexenoylamino) propanoic acid.
  • 0-Benzylhydroxyamine hydrochloride (1.1) was added, N-methylmorpholine (0.76 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the desiccant is removed by filtration, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 120 g, mobile phase: pore-form methanol). As a result, 2.55 g of t-butyl 9- (2-phenylethylamino) nonanoate was obtained.
  • T-butyl 9- (2-phenylethyl-N-benzyloxycarbonylamino) nonanoate (2.34 g) was dissolved in trifluoroacetic acid (5 ml) under ice cooling, and the temperature was gradually raised to room temperature. Stirred for minutes. The mixture was concentrated under reduced pressure to obtain 2.24 g of 9- (2-phenylethyl-N-benzyloxycarbonylamino) nonanoic acid. This was used for the next reaction without further purification.
  • Example 1 From t-butyl 2- (4- (4- (5-phenylpentyl-N-benzyloxycarbonylamino) butanoylamino) propanoate (914 mg) in a manner similar to that described in section (C) of 54, — ⁇ 4— (5-Phenylpentyl-N-benzyloxycarbonylamino) butanoylamino ⁇ 81 mg of propanoic acid was obtained.
  • Example 1 56 From t-butyl 2- (4- (4- (5-phenylpentyl-N-benzyloxycarbonylamino) butanoylamino) propanoate (914 mg) in a manner similar to that described in section (C) of 54, — ⁇ 4— (5-Phenylpentyl-N-benzyloxycarbonylamino) butanoylamino ⁇ 81 mg of propanoic acid was obtained.
  • Example 1 56 From t-butyl 2- (4- (4-
  • N-t-butoxycarbonylaniline (734 mg) and ethyl 9-iodononanoate (1.186 g) were dissolved in dry tetrahydrofuran (8 ml), and the mixture was dissolved in ice-cooled 60% sodium hydride (152 m2). g ) was added. Further, dry N, N-dimethylformamide (8 ml) was added, and the mixture was reacted at the same temperature overnight. After diluting the reaction solution with getyl ether, ice water was added to stop the reaction. Add more ethyl acetate and extract Liquid. The organic layer was washed with water (4 times), washed with brine, and dried over anhydrous magnesium sulfate.
  • the desiccant is removed by filtration, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (stationary phase: silica gel 60, 70-230 mesh, 70 g, mobile phase: hexane / ethyl acetate) ) To give 1.30 g of ethyl (N-t-butoxycarbonyl-N-phenylamino) nonanoate.

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Abstract

L'invention concerne des dérivés d'acide hydroxamiques représentés par la formule générale R-X-B-N(R1)-A-CO-NHOH, et utiles comme inhibiteurs de la métalloprotéase matricielle. Dans ladite formule, R est un groupe hydrocarbure cyclique éventuellement substitué ou similaire; X représente alkylène éventuellement substitué ou similaire; B représente carbonyle ou similaire; R1 représente hydrogène ou alkyle inférieur éventuellement substitué dans le cas où B représente carbonyle ou sulfonyle, et R1 représente hydrogène, alkyle inférieur éventuellement substitué, alcanoyle inférieur éventuellement substitué ou similaire dans le cas où B représente méthylène; et A représente méthylène substitué par un ou deux groupes alkyle inférieur éventuellement substitués.
PCT/JP1997/003542 1996-10-07 1997-10-02 Acides hydroxamiques WO1998015525A1 (fr)

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US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
JP2006519772A (ja) * 2003-01-08 2006-08-31 カイロン コーポレイション 抗菌剤
WO2010014943A3 (fr) * 2008-08-01 2011-01-13 Bioxiness Pharmaceutics, Inc. Analogues de méthionine, et procédés d'utilisation de ceux-ci
WO2011033009A1 (fr) 2009-09-17 2011-03-24 Galderma Research & Development Composés de n-[2-hydroxycarbamoyl-2-(pipérazinyl)éthyl]benzamide, leur préparation et utilisation à titre d'inhibiteurs de tace
WO2011033010A1 (fr) 2009-09-17 2011-03-24 Galderma Research & Development Composés de 4-alcoxy-n-(2-hydroxycarbamoyl-2-pipéridinyléthyl)benzamide en tant qu'inhibiteurs de tace sélectifs destinés au traitement de maladies inflammatoires
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US6455522B1 (en) * 1998-02-11 2002-09-24 Bristol-Myers Squibb Pharma Company Cyclic sulfonamide derivatives as metalloproteinase inhibitors
US6426402B1 (en) 1998-12-10 2002-07-30 Syntex (U.S.A.) Llc Peptidic procollagen C-proteinase inhibitors
US6951918B2 (en) 1998-12-10 2005-10-04 Syntex (U.S.A.) Llc Peptidic procollagen C-proteinase inhibitors
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6376665B1 (en) 1999-04-02 2002-04-23 Du Pont Pharm Co Amide derivatives as inhibitors of matrix metalloproteinases, TNF-α, and aggrecanase
WO2000059874A1 (fr) * 1999-04-02 2000-10-12 Du Pont Pharmaceuticals Company Nouveaux derives d'amides faisant office d'inhibiteurs de metalloproteases matricielles, de tnf-alpha, et de l'aggrecanase
US6689771B2 (en) 1999-04-02 2004-02-10 Bristol-Myers Squibb Pharma Company Amide derivatives as inhibitors of matrix metalloproteinases, TNF-α, and aggrecanase
JP2004509941A (ja) * 2000-09-29 2004-04-02 プロリフィクス　リミテッド Ｈｄａｃインヒビターとしてのアミド結合を含むカルバミン酸化合物
WO2002030873A1 (fr) * 2000-10-10 2002-04-18 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur des mmp
US6800638B2 (en) 2000-12-23 2004-10-05 Hoffman-La Roche Inc. Tetrahydropyridine derivatives, their preparation and their use as cell proliferation inhibitors
KR100836545B1 (ko) * 2000-12-23 2008-06-10 에프. 호프만-라 로슈 아게 테트라히드로피리딘 유도체, 이의 제조 방법 및 세포증식억제제로서의 그의 용도
RU2276140C2 (ru) * 2000-12-23 2006-05-10 Ф.Хоффманн-Ля Рош Аг Производные тетрагидропиридина и фармацевтическая композиция на их основе
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US6838466B2 (en) 2001-12-20 2005-01-04 Schering Corporation Compounds for the treatment of inflammatory disorders
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