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WO1997047599A1 - Derives de succinamides utiles en tant qu'inhibiteurs du tnf et/ou des mmp - Google Patents

Derives de succinamides utiles en tant qu'inhibiteurs du tnf et/ou des mmp Download PDF

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Publication number
WO1997047599A1
WO1997047599A1 PCT/JP1997/002004 JP9702004W WO9747599A1 WO 1997047599 A1 WO1997047599 A1 WO 1997047599A1 JP 9702004 W JP9702004 W JP 9702004W WO 9747599 A1 WO9747599 A1 WO 9747599A1
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Prior art keywords
alkanoyl
group containing
alkoxycarbonyl
compound
membered
Prior art date
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PCT/JP1997/002004
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English (en)
Inventor
Masahiro Neya
Yasuharu Urano
Ichiro Shima
Keiji Hemmi
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Hemmi, Mitsue
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd., Hemmi, Mitsue filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP10501438A priority Critical patent/JP2000512290A/ja
Publication of WO1997047599A1 publication Critical patent/WO1997047599A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • C07D213/55—Acids; Esters
    • 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
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new compound andpharmaceutically acceptable salts thereof.
  • MMP matrix metalloprotemases
  • TNF ⁇ tumor necrosisfactor ⁇
  • One object of the present invention is to provide newand useful compounds and pharmaceutically acceptable saltsthereof which have pharmacological activities such as MMPor TNF ⁇ inhibitory activity and the like.
  • Another object of the present invention is to provide a pnarmaceutical composition
  • a pnarmaceutical composition comprising, as an activeingredient, said compound or a pharmaceutically acceptablesalt thereof.
  • a further object of the present invention is toprovide use of said compounds and pharmaceutically
  • a still further object of the present invention is toprovide a method for using the same for the treatmentan ⁇ /or the prevention of MMP or TNF ⁇ mediated diseases inmammals, especially humans.
  • the compounds of tne present invention have
  • inhibitory activity on MMP or the production of TNF ⁇ are useful in the treatment an ⁇ /or prevention of a diseasesucn as stroke, arthritis, cancer, tissue ulceration,decubitus ulcer, restenosis, periodontal disease,
  • TNF ⁇ TNF ⁇
  • Matrix-degradingmetalloprotease such as gelatmase (MMP-2, MMP-9),stromelysin (MMP-3) and collagenase (MMP-1), are involvedin tissue matrix degradation and have been implicated inmany pathological con ⁇ itions involving abnormal connectivetissue and basement membrane matrix matabolism, such asarthritis (e.g., osteoarthritis and rheumatoid arthritis),tissue ulceration (e.g., corneal, epidermal and gastriculceration), abnormal wound healing, periodonal disease,bone disease (e.g., Paget's disease and osteoporosis),tumor matastasis or invasion as well as HIV-infection.
  • MMP-2, MMP-9 gelatmase
  • MMP-3 stromelysin
  • MMP-1 collagenase
  • Tumor necrosis factor is recognized to be involved inmany infections and autoimune diseases. Furthermore, ithas been shown that TNF is the prime mediator of theinflammatory response seen in sepsis and septic shock.
  • R 1 is hydrogen or hydroxy-protective group
  • R 2 is hydrogen or acyl
  • R 3 is hydrogen cr lower alkyl, or
  • R 4 is heterocyclic(lower)alkyl
  • R 5 is lower alkoxy or lower alkylamino, or pharmaceutically acceptable salts thereof.
  • the compound (I) having the most potent activities can be represented by the following
  • R 1 , R 2 , R 3 , R 4 and R 5 are each as defined above, R ⁇ is hy ⁇ roxy-protective group,
  • Suitable pharmaceutically acceptable salts of theobject compound (I) may be a conventional non-toxic saltand include an aci ⁇ addition salt such as an organic acid salt (e.g. acetate, tri fluoroacetate, maleate, tartrate,fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.), an inorganic acid salt (e.g.
  • an organic acid salt e.g. acetate, tri fluoroacetate, maleate, tartrate,fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.
  • an inorganic acid salt e.g.
  • hydrcchloride hydrobromide, hydrio ⁇ ide, sulfate, nitrate,pnosphate, etc.
  • a salt with a base such as an aminoacid (e.g. arginine, aspartic acid, glutamic acid, etc.),an alkali metal salt (e.g. sodium salt, potassium salt,etc.), an alkaline earth metal salt (e.g. calcium salt,magnesium salt, etc.), an ammonium salt, an organic basesalt (e.g. trimethylamine salt, trietnylamme salt,pyridine salt, picoline salt, dicyclonexylamine salt,N,N -dibenzylethylenediamine salt, etc.), or the like.
  • an aminoacid e.g. arginine, aspartic acid, glutamic acid, etc.
  • an alkali metal salt e.g. sodium salt, potassium salt,etc.
  • an alkaline earth metal salt e.g. calcium salt
  • acceptable salts thereof may include a solvate [e.g.,enclosure compound (e.g., hydrate, etc.)].
  • Tie term "lower” is intended to mean 1 to 6 (or 2 to6 for lower alkenyl group), preferably 1 to 4 carbon atoms(or 2 to 4 carbon atoms for the same), and the term
  • “higher” is intended to mean more than 6, preferably 7 to12 carbon atoms, unless otherwise indicated.
  • Suitable "hydroxy-protective group” may include acommon one, for example, acyl as mentioned below,
  • ar(lower)alkyl such as mono- or di- or
  • triphenyl(lower)alkyl e.g. benzyl, benzhydryl, trityl,phenethyl, naphthylmethyl, etc.
  • trisubstituted silyl such as tri(lower)alkylsilyl (e.g.trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, diisopropylmethylsilyl, etc.),triarylsilyl (e.g. triphenylsilyl, etc.),
  • triar(lower)alkylsilyl e.g. tribenzylsilyl, etc.
  • tribenzylsilyl e.g. tribenzylsilyl, etc.
  • hydroxy-protective group thus definedmay be C 6 -C 10 aroyl, C 6 -C 10 ar(lower)alkyl and loweralkanoyl, and the most preferable one may be benzyl.
  • acyl may include an aliphatic acyl, anaromatic acyl, a heterocyclic acyl and an aliphatic acylsubstituted with aromatic or heterocyclic group(s) derivedfrom acids such as carboxylic, carbonic, carbamic,
  • heterocyclic group(s) may bethe same as those mentioned below.
  • the alipnatic acyl may include saturated or
  • unsaturated, acyclic or cyclic ones such as carbamoyl,oxamoyl, lower alkanoyl optionally substituted by halogen (e.g. chloro, fluoro, lodo, bromo, etc.) (e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl,
  • halogen e.g. chloro, fluoro, lodo, bromo, etc.
  • formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl
  • cyclonexanecarbonyl, etc. (C 3 -C 7 )cycloalkyl(lower)-alkanoyl (e.g. cyclohexylacetyl, etc.), amidmo, protectedcarboxycarbonyl such as lower alkoxalyl (e.g. methoxalyl,ethoxalyl, t-butoxalyl, etc.), mono- or di(lower)alkyl ⁇ amine(lower)alkanoyl (e.g. dimethylaminoacetyl, etc.);
  • lower alkoxalyl e.g. methoxalyl,ethoxalyl, t-butoxalyl, etc.
  • mono- or di(lower)alkyl ⁇ amine(lower)alkanoyl e.g. dimethylaminoacetyl, etc.
  • alkylcarbamoyl e.g. methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, t-butylcarbamoyl,
  • cycloheptylcarbamoyl, etc. N-lower alkyl-N-(C 3 -C 7 )-cycloalkylcarbamoyl (e.g. N-methyl-N-cyclopropylcarbamoyl,N-methyl-N-cyclonexylcarbamoyl, N-ethyl-N-cyclohexylcarbamoyl, N-propyl-N-cyclohexylcarbamoyl,etc.), di(C 3 -C 7 )cyclohexylcarbamoyl (e.g.
  • N-(lower)alkyl-N-[N,N-di(lower)alkylcarbamoyl] (lower)-alkylcarbamoyl [e.g. N-methyl-N-[1-dimethylcarbamoyl-2-methylbutyl]carbamoyl, N-methyl-N-[1-dimethylcarbamoyl-3-methylbutyl]carbamoyl, etc.], and the like.
  • the aromatic acyl may include C 6 -C 10 aroyl (e.g.
  • C 6 -C 10 arenesulfonyl e.g. benzenesulfonyl, tosyl, etc.
  • C 6 -C 10 arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • C 6 -C 10 aryloxalyl e.g.
  • the heterocyclic acyl may include heterocyclic-carbonyl such as furoyl, thenoyl, nicotmoyl,
  • oxolanecarbonyl optionally substituted byoxo (e.g. 2-oxo-5-oxolanecarbonyl, etc.),
  • morpholinocaroonyl pyrrolylcarbonyl, pyrazmyicarbonyl,thiomorpholinocarbonyl, pyridinecarbonyl optionallysubstituted by lower alkyl [e.g. 2-(or 3- or 4-)-pyridinecarbonyl, 6-methyl-2-pyndmecarbonyl, 2-methyl-5-pyridinecarbonyl, etc.], quinolmecarbonyl optionallysubstituted by hydroxy (e.g. 2-quinolmecarbonyl, 3-quinolinecarbonyl, 4-hydroxy-2-quinolmecarbonyl, etc.),lower alkyleneaminocarbonyl optionally substituted by oxo(e.g. aziridin-1-ylcarbonyl, azet ⁇ dm-1-ylcarbonyl,pyrrolidin-1-ylearbonyl, piperidin-1-ylcarbonyl,
  • oxo e.g. aziridin-1-ylcarbonyl, azet ⁇ dm
  • heterocyclic-carbamoyl such as pyridylcarbamoyl (e.g.
  • the aliphatic acyl substituted with aromatic group(s) may include (C 6 -C 10 )ar(lower)alkanoyl such as
  • phenyl(lower)alkanoyl e.g. phenylacetyl, phenylpropionyl,phenylhexanoyl, etc.
  • (C 6 -C 10 )ar(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl
  • phenoxy(lower)alkanoyl e.g. phenoxyformyl, phenoxyacetyl,phenoxypropionyl, etc.
  • ar(lower)alkoxalyl such asphenyl(lower)alkoxalyl (e.g. benzyloxalyl, etc.)
  • ar(lower)alkenoyl such as phenyl(lower)alkenoyl (e.g.
  • the alipnatic acyl substituted with heterocyclicgroup(s) may include heterocyclic(lower)alkanoyl such asthienyl(lower)alkanoyl, lmidazolyl(lower)alkanoyl (e.g. 4-lmidazolylacetyl, etc.), furyl(lower)alkanoyl,
  • tetrazolyl(lower)alkanoyl thiazolyl(lower)alkanoyl,thiadiazolyl(lower)alkanoyl, pyridyl(lower)alkanoyl [e.g.pyridin-3-ylacetyl, 3-(pyridin-3-yl)propionyl, etc.],lower alkyleneamino(lower)alkanoyl (e.g. 3-(piperidin-1-yl)propionyl, etc.), etc.;
  • heterocyclic(lower)alkylcarbamoyl such as
  • acyl groups may be further substituted with oneor more, preferably one to three suitable substituents such as carboxy, lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), halogen,(e.g. chlorine, bromine, iodine, fluorine), carbamoyl,mono- or di(lower)alkylcarbamoyl (e.g. methylcarbamoyi,etc.), amino, protected amino such as lower alkanoylamino(e.g.
  • ar(lower)alkyl e.g. benzyl, etc.
  • hydroxy, lower alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,t-butoxy, etc.
  • carboxy protected carboxy as mentionedbelow such as lower alkoxycarbonyl (e.g. methoxycarbonyl, etc.), carboxy(lower)alkyl (e.g. carboxymethyl,
  • carooxyethyl, etc. protecte ⁇ carboxy(lower)alkyl (e.g.t-butoxycarbonylmethyl, etc.), lower alkanoyloxy (e.g.acetoxy, etc.), lower alkoxycarbonyl (e.g.
  • acyl e.g. benzyloxycarbonyl, etc.
  • acyl e.g. benzyloxycarbonyl, etc.
  • Preferable acyl thus defined may be :
  • di(lower)alkylcarbamoyl e.g. dimethylcarDamoyl, etc.
  • - C 6 -C 10 aroyl e.g. benzoyl, etc.
  • arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • pyridinecarbonyl optionally substituted by lower alkyl [e.g. 2-(or 3- or 4-)pyridinecarbonyl, 3-methyl-2- pyridinecarbonyl, 4-methyl-3-pyndmecarbonyl, etc.]; qumolinecarbonyl optionally substituted by hydroxy (e.g. 2-quinolmecarbonyl, 3-quinolinecarbonyl,
  • pyridyl(lower)alkanoyl e.g. pyridin-3-ylacetyl
  • di(lower)alkylamino e.g. dimethylaminoacetyl, etc.); ana the like;
  • heterocyclic group may be saturated orunsaturated 3- to 8-membered (preferably 5- or ⁇ -membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s),or unsaturated 7- to 12-membered condensed (preferablybicyclic) heterocyclic group containing 1 to 4 nitrogenatom(s).
  • Another preferable acyl thus defined may be : (1) oxamoyl;
  • lower alkanoyl e.g. acetyl, propionyl, isobutyryl
  • halogen e.g. trifluoroacetyl, etc.
  • lower alkanesuifonyl e.g. mesyl, ethanesulfonyl, etc.
  • lower alkoxycarbonyl e.g. methoxycarbonyl
  • di(lower)alkylamino(lower)alkanoyl e.g.
  • lower alkylcarbamoyl e.g. methylcarbamoyl
  • di(lower)alkylcarbamoyl e.g. dimethylcarbamoyl, etc.
  • N-[(lower)alkylcarbamoyl(lower)alkyl]carbamoyl e.g.
  • C 6 -C 10 arenesulfonyl (e.g. benzenesulfonyl, etc.);
  • C 6 -C 10 arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • acyl such as C 6 -C 10
  • ar(lower)alkoxycarbonyl e.g. benzyloxycarbonyl, etc.
  • lower alkyl e.g. methyl, etc.
  • hydroxy and oxo said heterocyclic group being
  • - pyrrolylcarbonyl e.g. 2-pyrrolylcarbonyl, etc.
  • - pyridinecarbonyl ([e.g. 2-(or 3- or 4-)pyridine-carbonyl, etc.) optionally substituted by lower alkyl(e.g. 6-methyl-2-pyridinecarbonyl, 2-methyl-5-pyridinecarbonyl, etc.);
  • - pyrazinylcarbonyl e.g. pyrazin-2-ylcarbonyl, etc.
  • - pyrrolidinylcarbonyl e.g. pyrrolidm-1-ylcarbonyl,etc.
  • oxo e.g. 2-oxopyrrolidm-5-ylcarbonyl, etc.
  • - lmidazolizmylcarbonyl optionally substituted by thegroup consisting of oxo and C 6 -C 10 ar(lower)-alkoxycarbonyl (e.g. 2-oxo-4-imidazolizmecarbonyl, 1-benzyloxycarbonyl-2-oxo-4-imidazolidmecarbonyl, etc.); - quinolinecarbonyl (e.g. 2-quinolinecarbonyl, 3-quinolmecarbonyl, etc.) optionally substituted byhydroxy (e.g. 4-hydroxy-2-quinolmecarbonyl, etc.); - indolylcarbonyl; isoindolylcarbonyl;
  • oxolanecarbonyl optionally substituted by oxo (e.g. 2-oxo-5-oxolanecarbonyl, etc.); and the like;
  • pnenoxy(lower)alkanoyl e.g. phenoxyformyl, etc.
  • heterocyclic(lower)alkanoyl said heterocyclic group
  • pyridyl(lower)alkanoyl e.g. pyridin-3-ylacetyl, 3- (pyri din-3-yl)propionyl, etc.
  • carboxy(lower)alkanoyl e.g. carboxyacetyl
  • alkoxycarbonyl(lower)alkanoyl e.g.
  • hydroxy(lower)alkanoyl e.g. hydroxyacetyl, 2,3- dihydroxypropionyl, 2,3,4,5,6-pentahydroxyhexanoyl, etc.
  • alkanoyloxy(lower)alkanoyl e.g. acetoxyacetyl, etc.); etc.;
  • lower alkoxy(lower)alkanoyl e.g. methoxyacetyl, etc.
  • lower alkoxy(lower)alkoxycarbonyl e.g. 2- methoxyethoxycarbonyl, etc.
  • amino(lower)alkoxycarbonyl e.g. 2-aminoethoxycarbonyl, etc.
  • ar(lower)alkoxycarbonylamino(lower)alkoxycarbonyl e.g. 2-(benzyloxycarbonylamino)ethoxycarbonyl, etc.
  • (29) protected hydroxy(lower)alkoxycarbonyl such as lower alkanoyloxy(lower)alkoxycarbonyl (e.g. 2- acetoxyethoxycarbonyl, etc.); etc.;
  • alkoxycarbonylamino and hydroxy e.g. 2-t- Dutoxycarbonylamino-3-hydroxyprop ⁇ onyl, etc.); etc.; (32) amino(lower)alkanoyl (e.g. aminoacetyl, etc.);
  • alkanoylamino(lower)alkanoyl e.g. acetamidoacetyl, etc.
  • lower alkoxycarbonylamino(lower)alkanoyl e.g. t-butoxycarbonylaminoacetyl, etc.
  • lower alkyl or lower alkyl moiety mayinclude, unless otherwise indicated, a straight or
  • branched one such as methyl, ethyl, propyl, isopropyl,butyl, lsooutyl, tert-outyl, pentyl, hexyl, and the like,in which the most preferred example may be methyl for R 3 .
  • Suitable "lower alkoxy" or lower alkoxy moiety mayinclude, unless otherwise indicated, a straight or
  • heterocyclic(lower)alkyl means lower alkylsubstituted by heterocyclic group as mentioned below, inwhich more preferable heterocyclic group may be saturatedor unsaturated 3- to 8-membered (preferably 5- or 6-membered) heteromonocyclic group containing 1 to 4
  • heterocyclic(lower)alkyl may be pyridyl(lower)alkyl, and the most preferable one may be 2-pyridylmethyl and
  • heterocyclic group as mentioned above mayinclude saturated or unsaturated, monocyclic or polycyclicheterocyclic group containing at least one hetero-atomsuch as oxygen, sulfur and nitrogen atom.
  • hetero-atom such as oxygen, sulfur and nitrogen atom.
  • Preferable heterocyclic group may be
  • nitrogen atom(s) for example, perhydroazepmyl (e.g.
  • quinolyl isoquinolyl, indazolyl, benzotriazolyl, etc.; saturated 7- to 12-membered (more preferably 9- to 10-membered) condensed (preferably bicyclic) heterocyclicgroup containing 1 to 4 nitrogen atom(s), for example, 7-azab ⁇ cyclo[2.2.1]heptyl,
  • oxazolyl isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxad ⁇ azolyl,1,3,4-oxad ⁇ azolyl, 1,2,5-oxad ⁇ azolyl, etc.), etc.;
  • morpholmyl e.g. morpholino, etc.
  • sydnonyl e.g. sydnonyl
  • thiazolyl isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazmyl, etc.;
  • Suitable "lower alkylamino” may include conventionalone such as methylamino, ethylamino, propylamino,
  • R 1 , R 2 , R 3 , R 4 and R 5 are asfollows :
  • R 1 is hydrogen
  • R 2 is hydrogen or acyl
  • R 3 is hydrogen or lower alkyl
  • R 4 is heterocyclic(lower)alkyl
  • heterocyclic group being saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) [e.g. 2-(or 4-)- pyridylmethyl, etc.], and
  • R 5 is lower alkoxy or lower alkylamino. Another preferable examples ofR 1 , R 2 , R 3 , R 4 and R 5 areas follows:
  • R 1 is hydrogen
  • R 2 is hydrogen; acyl such as oxamoyl; lower alkanoyl;
  • heterocyclic-carbonyl optionally substituted by thegroup consisting of acyl such as C 6 -C 10
  • heterocyclic-carbamoyl said heterocyclic group being unsaturated 3- to 8-membered (more preferably 5- or ⁇ -membered) heteromonocyclic group containing 1 to 4nitrogen atom(s),
  • heterocyclic(lower)alkanoyl said heterocyclic groupbeing
  • unsaturated 7- to 12-membered (more preferably 9-to 10-membered) condensed (preferably bicyclic)heterocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2oxygen atom(s), or
  • R 3 is hydrogen or lower alkyl, or the formula:
  • R 4 is neterocyclic(lower)alkyl
  • R 5 is lower alkoxy or lower alkylamino.
  • the object compound (I) or a salt thereof can be
  • Suitable reactive derivative at the amino group ofthe compound (III) may include Schiff's base type imino orits tautomerie enamme type isomer formed by the reactionof the compound (III) with a carbonyl compound such asaldehyde, ketone or the like; a silyl derivative formed bythe reaction of the compound (III) with a silyl compoundsuch as bis(trimethylsilyl)acetamide,
  • Suitable salts of the compound (III) and its reactivederivative can be referred to the acid addition salts asexemplified for the compound (I).
  • Suitable reactive derivative at the carboxy group ofthe compound (II) may include an acid halide, an acidanhydride, an activated amide, an activated ester, and thelike.
  • Suitable examples of the reactive derivatives maybe an acid chloride; an acid azide; a mixed acid anhydridewith acid such as substituted phosphoric acid [e.g.
  • halogenated phosphoric acid, etc. dialkylphosphorousacid, sulfurous acid, thiosulfuric acid, sulfuric acid,sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyricacid, isobutyric acid, pivalic acid, pentanoic acid,isopentanoic acid, 2-ethylbutyric acid, tri chloroaceticaci ⁇ , etc.] or aromatic carboxylic acid [e.g. benzoicacid, etc.]; a symmetrical acid anhydride; an activatedamide with imidazole, 4-subst ⁇ tuted imidazole,
  • dimethylpyrazole triazole or tetrazole
  • an activatedester e.g. cyanomethyl ester, methoxymethyl ester,
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamme,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccimmide,
  • N-hydroxyphthalimide 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivatives can optionallybe selected from them according to the kind of the
  • Suitable salts of the compound (II) and its reactivederivative may be the same as those for the compound (I).
  • the reaction is usually carried out in a conventionalsolvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventionalsolvent such as water, alcohol [e.g. methanol, ethanol,etc.], acetone, dioxane, acetonitrile, chloroform,
  • a conventionalcondensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;
  • N-cyclohexyl-N'-(4-d ⁇ ethylaminocyclohexyl)carbodiimide N,N'-diethylcarbodiimide, N,N'-dnsopropylcarbodiimide;1-ethyl-3-(3-d ⁇ methylaminopropyl)carbodiimide (WSCD);
  • ethyl polyphosphate ethyl polyphosphate
  • isopropyl polyphosphhte phosphorus oxychloride (phosphoryl chloride)
  • thionyl chloride oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.];tripnenylphosphine; 2-ethyl-7-hydroxybenz ⁇ soxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide
  • the reaction may also be carried out in the presenceof an inorganic or organic base such as an alkali metalbicarbonate, tri (lower)alkylamine (e.g. triethylamme,etc.), pyridine, N-(lower)alkylmorpholme,
  • an inorganic or organic base such as an alkali metalbicarbonate, tri (lower)alkylamine (e.g. triethylamme,etc.), pyridine, N-(lower)alkylmorpholme,
  • N,N-di(lower)alkylbenzylamine N,N-diiospropyl-N-ethylamine, or the like.
  • reaction temperature is not critical, and thereaction is usually carried out under cooling to warming.
  • the object compound (I-b) or a salt thereof can beprepared by subjecting the compound (I-a) or a saltthereof to a removal reaction of the phthalimido moiety.
  • Suitable salts of the compound (I-a) and (I-b) can bereferred to the ones as exemplified for the compound (I).
  • This reaction can be carried out by a conventionalmethod which can convert the phthalimido moiety to aminomoiety such as reacting with lower alkylamine (e.g.
  • arylhydrazme or its salt e.g. phenylhydrazme
  • hydrochloride, etc. reducing with a suitable reducingagent (e.g. sodium borohydride, etc.), reacting with a combination of sodium sulfide or its hydrate (e.g. sodiumsulfide monohydride, etc.) and 1,3-dicyclohexylcarbodnmide (DCC), and the like.
  • a suitable reducingagent e.g. sodium borohydride, etc.
  • DCC 1,3-dicyclohexylcarbodnmide
  • This reaction is usually carried out in a
  • reaction temperature is not critical and thereaction is usually carried out under from cooling toheating.
  • the object compound (i-c) or a salt thereof can beprepared by alkylatmg the amino group of a compound (i-b)or a salt thereof.
  • Suitable salts of the compounds (i-b) and (i-c) canbe referred to the ones as exemplified for the compound(I).
  • Suitable alkylating agent used in this reaction mayinclude a conventional one which is capable of alkylatmgamino group to alkylamino group such as dialkyl sulfate(e.g. dimethyl sulfate, diethyl sulfate, etc.), alkylsulfonate (e.g. methyl sulfonate, etc.), alkyl halide (e.g. methyl iodide, ethyl iodide, propyl bromide, etc.),diazoalkanes (e.g. diazomethane, diazoethane, etc.), a combination of formaldehyde and a suitable reducingagent (e.g.
  • dialkyl sulfate e.g. dimethyl sulfate, diethyl sulfate, etc.
  • alkylsulfonate e.g. methyl sulfonate, etc.
  • This reaction is preferably carried out in thepresence of an inorganic or organic base such as thosegiven m the explanation of the Process 1. Furtner, this reaction is usually carried out in a conventional solvent which does not adversely influencethe reaction such as water, acetone, dichloromethane,methanol, ethanol, propanol, pyridine,
  • N,N-dimethylformamide or a mixture thereof.
  • Tne reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.
  • the object compound (I-e) or a salt thereof can beprepared by acylatmg the compound (I-d) or a salt
  • Suitable acylatmg agent used in this reaction may be a conventional acylatmg agent which is capable ofintroducing the acyl group as mentioned before such ascarboxylic acid, carbonic acid, sulfonic acid and theirreactive derivative, for example, an acid halide, an acidanhydride, an activated amide, an activated ester, and thelike.
  • reactive derivative mayinclude acid chloride, acid bromide, a mixed acid
  • anhydride with an acid such as substituted phosphoric acid(e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphori c acid, dibenzylphosphoric acid,
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphori c acid, dibenzylphosphoric acid
  • halogenated phosphoric acid etc.
  • dialkylphosphorousacid sulfurous acid, thiosulfuric acid, sulfuric acid,alkyl carbonate (e.g. methyl carbonate, ethyl carbonate,propyl carbonate, etc.), aliphatic carboxylic acid (e.g.pivalic acid, pentanoic acid, isopentanoic acid,
  • heterocyclic compound containing imino function such asimidazole, 4-subst ⁇ tuted imidazole, dimethylpyrazole,triazole and tetrazole, an activated ester (e.g.
  • thioester p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyridyl ester, piperidinyl ester,8-qumolyl thioester, or an ester with a N-hydroxy
  • This reaction can be carried out m the presence ofan organic or inorganic base such as alkali metal (e.g.lithium, sodium, potassium, etc.), alkaline earth metal(e.g. calcium, etc.), alkali metal hydride (e.g. sodiumhydri ⁇ e, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodiumhydroxide, potassium hydroxide, etc.), alkali metalcarbonate (e.g.
  • alkali metal e.g.lithium, sodium, potassium, etc.
  • alkali metal hydride e.g. sodiumhydri ⁇ e, etc.
  • alkaline earth metal hydride
  • alkali metal bicarbonate e.g. sodium bicarbonate,potassium bicarbonate, etc.
  • alkali metal alkoxide e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • alkali metal alkanoic acid e.g. sodiumacetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picolme, 4-d ⁇ methylaminopyridine, etc.
  • qumolme and the like.
  • a condensingagent such as a carbodiimide compound [e.g.
  • a ketenimine compound e.g. N,N'-carbonylbis(2-methylimidazole), pentamethyieneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimme, etc.
  • an olefinic or acetylenic ether compounds e.g.
  • triphenylphosphme and carbon tetrachloride triphenylphosphme and carbon tetrachloride, disulfide ordiazenedicarboxylate (e.g. diehyl diazenedicarboxylate,etc.), a phosphorus compound (e.g.
  • ethyl polyphosphate isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.
  • thionyl chloride oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate
  • a reagent referred to a so-called "Vilsmeierreagent" formed by the reaction of an amide compound suchas N,N-di(lower)alkylformamide (e.g. dimethylformamide,etc.), N-methylformamide or the like, with a halogencompound such as thionyl chloride, phosphoryl chloride,phosgene or the like.
  • the reaction is usually carried out m a conventionalsolvent which does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.methanol, ethanol, etc.), tetrahydrofuran, pyridine,N,N-dimethylformamide, etc., or a mixture thereof.
  • a conventionalsolvent which does not adversely influence the reaction
  • alcohol e.g.methanol, ethanol, etc.
  • tetrahydrofuran pyridine,N,N-dimethylformamide, etc., or a mixture thereof.
  • the reaction temperature is not critical and thereaction is usually carried out under from cooling toheating.
  • the object compound (i-g) or a salt thereof can beprepared by subjecting the compound (i-f) or a saltthereof to a removal reaction of the hydroxy-protectivegroup.
  • Suitable salts of the compounds (i-f) and (i-g) canbe referred to the ones as exemplified for the compound (I).
  • Suitable base may include an alkalimetal hydroxide (e.g. sodium hydroxide, potassium
  • alkaline earth metal hydroxide e.g.magnesium hydroxide, calcium hydroxide, etc.
  • alkalimetal hydride e.g. sodium hydride, potassium hydride,etc.
  • alkaline earth metal hydride e.g. calcium hydride,etc.
  • alkali metal alkoxide e.g. sodium methoxide,sodium etnoxide, potassium t-butoxide, etc.
  • an alkalimetal carbonate e.g. sodium carbonate, potassium
  • Suitable acid may include an organic acid (e.g.
  • cation trapping agent e.g.phenol, anisole, etc.
  • the hydrolysis can be carried out inthe presence of tri(lower)alkylammonium fluoride (e.g.tributylammonium fluoride, etc.).
  • This reaction is usually carried out in aconventional solvent which does not adversely influencethe reaction sucn as water, diehloromethane, alcohol (e.g.methanol, etnanol, etc.), tetrahydrofuran, dioxane,acetone, etc., or a mixture thereof.
  • a liquid base oracid can be also used as the solvent.
  • the reaction temperature is not critical and thereaction is usually carried out under from cooling toheating.
  • Tne reduction method applicable for this removalreaction may include, for example, reduction by using acombination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride,
  • chromous acetate, etc. an organic or inorganic acid(e.g. acetic acid, propionic acid, hydrochloric acid,sulfuric acid, etc.); and conventional catalytic reductionin the presence of a conventional metallic catalyst suchas palladium catalysts (e.g. spongy palladium, palladiumblack, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.),nickel catalysts (e.g. reduced nickel, nickel oxide, Raneynickel, etc.), platinum catalysts (e.g. platinum plate,spongy platinum, platinum black, colloidal platinum,platinum oxide, platinum wire, etc.), and the like.
  • a conventional metallic catalyst suchas palladium catalysts (e.g. spongy palladium, palladiumblack, palladium oxide, palladium on carbon, palladiumhydroxide on carbon, colloidal
  • anacid e.g. formic acid, etc.
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.
  • Suitable palladium compound used in this reaction maybe palladium on carbon, palladium hydroxide on carbon,palladium chloride, a palladium-ligand complex such astetrakis(triphenylphosphme)palladium(0),
  • This reaction can preferable be carried out in thepresence of a scavenger of allyl group generated in situ, such as amine (e.g. morpholme, N-methylaniline, etc.), anactivated methylene compound (e.g. dimedone,
  • a scavenger of allyl group generated in situ such as amine (e.g. morpholme, N-methylaniline, etc.), anactivated methylene compound (e.g. dimedone,
  • a cyanohydrin compound e.g. ⁇ -tetrahydropyranyloxybenzyl-cyanide, etc.
  • lower alkanoic acid or a salt thereof e.g. formic acid, acetic acid, ammonium formate, sodiumacetate, etc.
  • N-hydroxysuccinimide and the like.
  • This reaction can be carried out in the presence of abase such as lower alkylamine (e.g. butylamine,
  • reaction can preferably be carried out in the presence of the corresponding ligand (e.g.
  • triphenylphosphme triphenyl phosphite
  • This reaction is usually carried out in a
  • the reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.
  • the reaction can be selected according to the kind ofhydroxy-protective group to be eliminated.
  • the compound (I-i) or a salt thereof can be preparedby reacting the compound (I-h) or a salt thereof with thecompound (IV) or its reactive derivative at the aminogroup, or a salt thereof.
  • Suitable salts of the compounds (I-g) and (I-h) maybe the same as those for the compound (I).
  • Suitable salts of the compound (IV) may be the sameacid addition salts as exemplified for the compound (I).
  • Suitable reactive derivative of the compound (IV) canbe referred to the ones as exemplified for the compound(III).
  • the reaction is usually carried out in a conventionalsolvent which does not adversely influence the reaction such as water, acetone, dioxane, dimethylformamide,diehloromethane, chloroform, pyridine, etc., or a mixturethereof.
  • a conventionalsolvent which does not adversely influence the reaction such as water, acetone, dioxane, dimethylformamide,diehloromethane, chloroform, pyridine, etc., or a mixturethereof.
  • reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.
  • the compound (I-k) or a salt thereof can be preparedby subjecting the compound (I-j) or a salt thereof to aremoval reaction of the carboxy-protective group on
  • Suitable salts of the compounds (I-k) and (I-j) maybe the same as those for the compound (I).
  • the reaction is usually carried out in substantiallythe same manner as those for the process 5, and thereforetne reagents to be used and tne reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5.
  • tne reaction condition e.g.solvent, reaction temperature, etc.
  • the compound (I-m) or a salt thereof can be preparedby subjecting the compound (I-l) or a salt thereof to aremoval reaction of the amino-protective group on
  • Suitable salts of the compounds (1-l) and (I-m) maybe the same as those for the compound (I).
  • the reaction is usually carried out in substantiallythe same manner as those for the Process 5, and thereforethe reagents to be used and the reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5.
  • the reaction condition e.g.solvent, reaction temperature, etc.
  • the compound (I-o) or a salt thereof can be preparedby subjecting the compound (I-n) or a salt thereof to aremoval reaction of the hydroxy-protective group on
  • Suitable salts of the compounds (I-n) and (I-o) maybe the same as those for the compound (I).
  • the reaction is usually carried out in substantiallythe same manner as those for the Process 5, and thereforethe reagents to be used and the reaction condition (e.g.solvent, reaction temperature, etc.) can be referred tothose of the Process 5.
  • the reaction condition e.g.solvent, reaction temperature, etc.
  • the compound (I-q) or a salt thereof can be preparedby reacting the compound (I-p) or a salt thereof withlower alkylamine.
  • Suitable salts of the compounds (I-p) and (I-q) maybe the same as those for the compound (I).
  • the reaction is usually carried out in a conventionalsolvent which does not adversely influence the reaction such as water, acetone, diehloromethane, alcohol (e.g.
  • N,N-dimethylformamide, etc. or a mixture thereof.
  • the reaction temperature is not critical and thereaction is usually carried out under from cooling towarming.
  • the compounds obtained by the above processes can beisolated and purified by a conventional method such aspulverization, recrystallization, column chromatography,reprecipitation, or the like.
  • the object compound (I) can be transformed into itssalt in a conventional manner.
  • the compound (I) and the othercompounds may include one or more stereoisomers due toasymmetric carbon atoms, and all of such isomers andmixture thereof are included withm the scope of thisinvention.
  • Collagenases initiate the degradation of collagen invertebrates and in addition to their normal function inthe metabolism of connective tissue and wound healing, ithas been implicated in a number of pathological conditions such as joint destruction in rheumatoid arthritis,
  • osteoporosis proriasis, chronic active heatitis
  • the peptide compound (I) and a pharmaceutically acceptable salt thereof of the presentinvention can be used in a form of pharmaceutical
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solution,suspension, emulsion, sublmgual tablet, suppositories,ointment, and the like. If desired, there may be includedin these preparations, auxiliary substances, stabilizingagents, wetting or emulsifying agents, buffers and othercommonly used additives.
  • a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of ahuman being, m the case of intramuscular administration, a daily dose of 0.05 - 100 mg of the same per kg weight ofa human being, in case of oral administration, a dailydose of 0.1 - 100 mg of the same per kg weight of a humanbeing is generally given for the treatment of collagenase-mediated diseases.
  • the pharmacological test data of a representative compound of the compound (I) are shown inthe following. Inhibitory activity of collagenase 1. Test method
  • Human collagenase was prepared from the culturemedium of human skin fibroblast stimulated by
  • test Compound Compound A The compound of Example 12-4; 3. Test Result
  • L-4-Pyridylalanine ethyl ester dihydrochloride (24.3 g) was dissolved in H 2 O and the pH was adjusted to 8-9 by theaddition of sodium hydrogen carbonate. The solution wassaturated with sodium chloride and was extracted with
  • L-4-Pyridylalanine ethyl ester 14.79 g was dissolvedinto a solution of 20% methylamme in methanol (60 ml), andthe mixture was stirred for 4 hours at room temperature. Thesolution was evaporated to give L-4-pyridylalanine
  • N-phenoxycarbonylglycme methyl ester (1.37 g) as a whitecrystal.
  • N-[(2R,3R)-3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalaninemethylamide (413 mg) and N,N-dnsopropyl-N-ethylamine (142mg) in DMF (8 ml) was added N,N-dimethylcarbamoyl chloride(105 mg) at 0°C. The mixture was stirred at room temperatureovernight. The solution was evaporated. The precipitate wascollected by filtration and was washed with water and ethylacetate.
  • N-[(2R,3?)-3-Ammomethyl-4-(N-benzyloxyamino)-2-isoputylsuccinyl]-L-4-pyridylalanine methylamide (1.73 g) wasdissolved in water (15 ml) and the pH was adjusted to 8-9 bythe addition of sodium hydrogen carbonate. The precipitate was collected by filtration to give N-[(2R,3R)-[3-aminomethyl-4-(N-benzyloxyamino)-2-isobutylsuccinyl]-L-4-pyridylalanine metnylamide (1.02 g).
  • MeCN:H 2 O:TFA 20:80:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.
  • MeCN:H 2 O:TFA 30:70:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.
  • MeCN:H 2 O:TFA 30:70:0.05, 260 nm, flow rate 1.0 ml/min., at R.T.

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Abstract

L'invention se rapporte à un composé représenté par la formule générale (I) dans laquelle R1 est hydrogène ou un groupe hydroxy-protecteur, R2 est hydrogène ou acyle, R3 est hydrogène ou alkyle inférieur ou bien le sous-ensemble de la formule (I) représenté par la formule (II) est équivalent à la formule (III), R4 est alkyle (inférieur) hétérocyclique et R5 est alcoxy inférieur ou alkylamino inférieur. L'invention se rapporte également à un sel pharmaceutiquement acceptable dudit composé qui s'avère utile en tant que médicament.
PCT/JP1997/002004 1996-06-14 1997-06-11 Derives de succinamides utiles en tant qu'inhibiteurs du tnf et/ou des mmp WO1997047599A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003826A2 (fr) * 1997-07-18 1999-01-28 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinases
EP1283823A1 (fr) * 2000-05-24 2003-02-19 Smithkline Beecham Corporation Inhibiteurs des mmp-2/mmp-9
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
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024449A1 (fr) * 1992-06-03 1993-12-09 Celltech Limited Derives de peptidyle et leur utilisation comme inhibiteurs de metalloproteinases
WO1995019965A1 (fr) * 1994-01-21 1995-07-27 Glycomed Incorporated Inhibiteurs synthetiques de metalloproteases matricielles et utilisations correspondantes
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
JPH0853403A (ja) * 1994-06-20 1996-02-27 Fujisawa Pharmaceut Co Ltd 新規な化合物とその製造法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024449A1 (fr) * 1992-06-03 1993-12-09 Celltech Limited Derives de peptidyle et leur utilisation comme inhibiteurs de metalloproteinases
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1995019965A1 (fr) * 1994-01-21 1995-07-27 Glycomed Incorporated Inhibiteurs synthetiques de metalloproteases matricielles et utilisations correspondantes
JPH0853403A (ja) * 1994-06-20 1996-02-27 Fujisawa Pharmaceut Co Ltd 新規な化合物とその製造法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 096, no. 006 28 June 1996 (1996-06-28) *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003826A2 (fr) * 1997-07-18 1999-01-28 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinases
WO1999003826A3 (fr) * 1997-07-18 1999-04-01 British Biotech Pharm Inhibiteurs de metalloproteinases
US6271262B1 (en) 1997-07-18 2001-08-07 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US6358987B1 (en) 1997-07-18 2002-03-19 British Biotech Pharmaceuticals Limited Metalloproteinase 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
EP1283823A1 (fr) * 2000-05-24 2003-02-19 Smithkline Beecham Corporation Inhibiteurs des mmp-2/mmp-9
EP1283823A4 (fr) * 2000-05-24 2005-07-27 Smithkline Beecham Corp Inhibiteurs des mmp-2/mmp-9
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl

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