WO2003018019A2 - Nouvelle utilisation de compose cyclique - Google Patents

Nouvelle utilisation de compose cyclique Download PDF

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Publication number
WO2003018019A2
WO2003018019A2 PCT/JP2002/008443 JP0208443W WO03018019A2 WO 2003018019 A2 WO2003018019 A2 WO 2003018019A2 JP 0208443 W JP0208443 W JP 0208443W WO 03018019 A2 WO03018019 A2 WO 03018019A2
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Prior art keywords
alkyl
phenyl
membered
alkoxy
optionally substituted
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PCT/JP2002/008443
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English (en)
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WO2003018019A3 (fr
Inventor
Takuma Oku
Yoshitaka Hirayama
Kaoru Yamagami
Yoshitaka Ohkubo
Hideaki Matsuoka
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Fujisawa Pharmaceutical Co., Ltd.
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Priority to AU2002313591A priority Critical patent/AU2002313591A1/en
Publication of WO2003018019A2 publication Critical patent/WO2003018019A2/fr
Publication of WO2003018019A3 publication Critical patent/WO2003018019A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to inflammatory respiratory disease treatment of a cop pound having MMP- Inhibiting activity.
  • inflammatory respiratory disease treatment of a compound having the following formulas (I-a) to (I-d) and pharmaceutically acceptable salts thereof which are useful as inhibitors of matrix metalloproteinases (hereinafter to be referred to as MMP) or the production of tumor necrosis factor ⁇ (hereinafter to be referred to as TNF ⁇ ) .
  • MMP matrix metalloproteinases
  • TNF ⁇ tumor necrosis factor ⁇
  • Inflammatory respiratory disease includes diseases or conditions such as chronic obstructive pulmonary disease (COPD) ; bronchial asthma; diseases associated with lung tissue injury and fibrosis, which occur from various causes, such as bronchitis, interstitial pneumonia, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) , etc.; rhinitis and sinusitis including allergic rhinitis and chronic sinusitis; and the like.
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma diseases associated with lung tissue injury and fibrosis, which occur from various causes, such as bronchitis, interstitial pneumonia, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) , etc.
  • ARDS acute respiratory distress syndrome
  • rhinitis and sinusitis including allergic rhinitis and chronic sinusitis; and the like.
  • One object of the present invention is to provide inflammatory respiratory disease treating agent comprising, as an active ingredient, the compounds of the following formulas (I-a) to (I-d) or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, the compounds of the following formulas (I-a) to (I-d) or a pharmaceutically acceptable salt thereof, useful for inflammatory respiratory disease treatment.
  • a further object of the present invention is to provide use of the compounds of the following formulas (I-a) to (I- d) or pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating inflammatory respiratory disease.
  • a still further object of the present invention is to provide a method for treating inflammatory respiratory disease comprising administering the compounds of the following formulas (I-a) to (I-d) or a pharmaceutically acceptable salt thereof to mammals, especially humans.
  • the compounds used in the present invention can be represented by the following formulas (I-a) to (I-d) : formula (I-a) :
  • a a is a sulfonyl or a carbonyl
  • R ⁇ a is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl;
  • R ⁇ a is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;
  • R ⁇ a i s an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substituted lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substituted amino:
  • R ⁇ a is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group
  • R 5a i s a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group
  • R ⁇ a is a hydroxy or a protected hydroxy, provided that when A a -R ⁇ a is methylsulfonyl, then R ⁇ a is an aryl substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl, and the above-mentioned heterocyclic group is each selected from the group consisting of unsatur
  • R ⁇ is lower alkyl, halogen, optionally substituted heterocyclic group or optionally substituted aryl, R ⁇ k is carboxy, protected carboxy or amidated carboxy, Ar b is optionally substituted aryl or optionally substituted heterocyclic group,
  • ⁇ !° is lower alkylene
  • xb is oxa or a single bond
  • Y-b is thia, sulfinyl or sulfonyl
  • ⁇ ° is methylene
  • vfi and n ⁇ are each an integer of 0 to 6
  • R is halogen, nitro, lower alkoxy, optionally substituted aryloxy, arylthio, aroyl, heterecyclic-oxy, optionally substituted aryl or optionally substituted heterocyclic group
  • R is hydrogen or halogen
  • R is hydrogen or lower alkyl
  • R and R are independently hydrogen, lower alkyl, or lower cycloalkyl, or R and R are combined together to form lower alkylene, which is optionally interrupted by oxygen, sulfur, sulfinyl, sulfonyl or optionally mono-substituted nitrogen
  • R is hydroxy or protected hydroxy
  • X c is aryl or heterocyclkic group
  • Y c is carbonyl or sulfonyl
  • Z c is lower alkylene, or a salt thereof.
  • R is halo, lower alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterecyclic group or optionally substituted lower alkynyl, R is carboxy, protected carboxy or amidated carboxy,
  • R is hydrogen or acyl, r is aryl or heterocyclic group, X d is thia, sulfinyl or sulfonyl, d and Z d are each lower alkylene, m ⁇ and n ⁇ are each an integer of 0 to 2, or a salt thereof.
  • the compounds of formula (I-d) can be prepared by a conventional manner, or by the following processes.
  • R ld , R 2d , R 3d , Ar d , X d , Y d , Z d , m d and n d are each as defined above, R l is halo, R-'-g is optionally substituted aryl or optionally substituted heterocyclic group,
  • R c is aryl, aryloxy or heterocyclic group having at least amino- or imino- moiety
  • R-'-g is aryl, aryloxy or heterocyclic group having at least acylamino- or acylimino-moiety
  • R 2 is protected hydroxycarbamoyl
  • R 3d is acyl
  • R 3 ⁇ is acyl having at least protected amino- or protected i ino- moiety
  • R 3 is acyl having at least amino- or imino-moiety
  • R ⁇ g is optionally substituted lower alkyl
  • R ⁇ and R 5d are each hydroxy, lower alkyl, or combined together to form lower alkylene
  • H ⁇ ⁇ 5o is optionally substituted lower alkynyl
  • R' d -CH0 is optionally substituted aldehyde.
  • the starting compounds used in the above processes can be prepared according to the following Preparations or by a conventional method.
  • Suitable salts of the object compounds (I-ad) to (I-fd) may be salts, and include a conventional non-toxic pharmaceutically acceptable acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a conventional non- toxic pharmaceutically acceptable salt with a base such as an amino acid (e.g.
  • a conventional non-toxic pharmaceutically acceptable acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulf
  • 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 e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc.
  • the object compounds and pharmaceutically acceptable salts thereof may include solvates such as enclosure compounds (e.g. hydrate, etc.).
  • lower is intended to mean up to 6 carbon atoms, preferably up to 4 carbon atoms, unless otherwise indicated.
  • Suitable "halo" includes fluoro, bromo, chloro and iodo.
  • Suitable "aryl” and aryl moiety in the term “optionally substituted aryl” may include an aryl having 6 to 10 carbon atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like, preferably phenyl and naphthyl, and the most preferably phenyl.
  • Suitable "aryloxy” in the term “optionally substituted aryloxy” may include an aryloxy having 6 to 10 carbon atoms, such as phenoxy, tolyloxy, xylyloxy, cumenyloxy, mesityloxy, naphthyloxy, and the like, preferably phenoxy.
  • Suitable "optionally substituted aryl” or “optionally substituted aryloxy” may include above-mentioned aryl or aryloxy respectively, where the aryl or aryloxy moiety is substituted by the group consisting of the following substituents:
  • lower alkoxy e.g. methoxy, ethoxy, propoxy, etc.
  • lower alkyl Cg-C 10 ) aryl (e.g. methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, etc.),
  • aryl e.g. methoxymethylphenyl, etc.
  • aryl e.g. methoxymethylphenyl, etc.
  • the most preferable one may be; phenyl, naphthyl (e.g. 2-naphthyl, etc.), methoxyphenyl (e.g. 4-methoxynaphthyl, etc.), ethoxyphenyl (e.g. 4-ethoxynaphthyl, etc.), methoxycarbonylaminophenyl (e.g. 3- methoxycarbonylaminophenyl, etc. ) , ethoxycarbonylaminophenyl (e.g.
  • trifluoromethylphenyl e.g. 4-trifluoromethylphenyl, etc.
  • cyanophenyl e.g. cyanophenyl, etc.
  • cyanomethylphenyl e.g. 4-cyanomethylphenyl, etc.
  • methoxymethylphenyl e.g. 4-methoxymethylphenyl, etc.
  • Preferable examples of the optionally substituted aryloxy thus defined may be C ⁇ -C, n aryloxy (e.g. phenoxy, etc.), lower alkoxy (C ⁇ -C, hopefully) aryloxy (e.g. methoxyphenoxy, etc.), lower alkyl (C ⁇ -C, n ) aryloxy (e.g. methylphenoxy, etc.), halo (C fi -C-, n ) aryloxy (e.g. chlorophenoxy, fluorophenyl, etc.), and the most preferable one may be phenoxy, methoxyphenoxy (e.g. 4-methoxyphenoxy, etc.), methylphenoxy (e.g. methylphenoxy, etc.), chlorophenoxy (e.g. 4-chlorophenoxy, etc.), fluorophenyl (e.g. 4-fluorophenyl, etc.), and the like.
  • aryloxy e.g. methoxyphenoxy, etc.
  • Suitable "lower alkoxy” may include a straight or branched alkyl having 1 to 6 carbon ' atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, preferably methoxy.
  • Suitable "lower alkoxycarbonylamino” may include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert- butoxycarbonylamino, pentyloxycarbonylamino, tert- pentyloxycarbonylamino, hexyloxycarbonoylamino, and the like, preferably methoxycarbonylamino and ethoxycarbonylamino.
  • Suitable "lower alkylaminocarbonylamino” may included methyla inocarbonylamino, ethylaminocarbonylamino, propylaminocarbonylamino, isopropylaminocarbonylamino, butylaminocarbonylamino, isobutylaminocarbonylamino, tert- butylaminocarbonylamino, pentylaminocarbonylamino, tert- pentylaminocarbonylamino, hexylaminocarbonoylamino, and the like, preferably methylaminocarbonylamino and ethylaminocarbonylamino .
  • Suitable "lower alkoxy (lower) alkanoylamino" methoxyacetylamino, ethoxyacetylamino, propoxyacetylamino, isopropoxyacetylamino, butoxypropanoylamino, isobutoxypropanoylamino, tert-butoxypropanoylamino, pentyloxypropanylamino, tert-pentyloxypropanylamino, hexyloxypropanylamino, and the like, preferably ethoxyacetylamino .
  • Suitable "aryloxy (lower) alkanoylamino” may include (C,-- C, n ) aryloxy (lower) alkanoylamino such as phenoxyacetylamino, phenoxypropanoylamino, naphthylacetylamino, naphthyloxypropanoylamino, and the like, preferably phenoxyacetylamino .
  • heterocyclic group in the term “optionally substituted heterocyclic group” means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like.
  • Preferable heterocyclic groups are following (HI) to (H14) : (HI) unsaturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 to
  • pyrrolyl e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2, 4-triazolyl,
  • nitrogen atoms e.g. azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl, piperazinyl, and the like
  • oxygen atoms e.g. furyl, and the like
  • H6 saturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 or 2 oxygen atoms
  • H10 saturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, morpholino, and the like);
  • Hll unsaturated condensed (preferably bicyclic) 7- to
  • (H12) unsaturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms e.g. thiazolyl, 1, 2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1, 2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 5-thiadiazolyl, 1,2,3- thiadiazolyl, etc.), and the like);
  • heterocyclic groups may have one or more substituents.
  • substituents for substituted heterocyclic group may be the same as those for "optionally substituted aryl" .
  • heterocyclic group thus defined may be:
  • HI unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyridyl, i idazolyl, pyrazolyl, pyrazinyl, etc.); (H2) saturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 to
  • H7 unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. oxazolyl, oxadiazolyl, etc.) which is optionally substituted by lower alkyl (e.g. methyloxadiazolyl, etc.);
  • (H8) unsaturated bicyclic 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms e.g. benzofuranyl, benzodihydrofuranyl, benzodioxolenyl, etc.
  • hydroxy (lower) alkyl or lower alkylcarbamoyl e.g. hydroxymethylbenzofuranyl, methylcarbamoylbenzofuranyl, etc.
  • (H14) unsaturated bicyclic 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms e.g. benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, etc.
  • lower alkyl and oxo e.g 3-methyl- 2-OXO-2, 3-dihydrobenzothiazolyl, etc.
  • H3 thienyl e.g. 2-thienyl, etc.
  • chlorothienyl e.g. 5-chloro-2-thienyl, etc.
  • (H5) furyl e.g. 2-furyl, etc.
  • Suitable "lower alkynyl” may include a straight or branched alkynyl having 2 to 6 carbon atoms, and exemplified by ethynyl, propynyl, butynyl, penynyl, hexynyl, and the like, and the most preferably ethynyl, hexynyl, and the like, and these "lower alkynyl” is optionally substituted by aforementioned aryl (e.g. phenyl, aminosulfonylphenyl, etc.).
  • aryl e.g. phenyl, aminosulfonylphenyl, etc.
  • Preferable examples of "optionally substituted lower alkynyl” thus defined may be lower alkynyl, C ⁇ -C, n aryl (lower) alkynyl, aminosulfonyl (C ⁇ -C, hopefully) aryl (lower) alkynyl, and the like, and the most preferable one may be hexynyl, phenylethynyl, aminosulfonylphenylethynyl (e.g. 4- (aminosulfonyl) phenylethynyl, etc.), and the like.
  • Suitable “lower alkyl” may include a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl and the like, and the most preferably methyl, ethyl, and the like.
  • Suitable "lower alkylthio” may include a straight or branched alkylthio having 1 to 6 carbon atoms, and exemplified by methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio and the like, and the most preferably methylthio, and the like.
  • Suitable "lower alkylsulfonyl” may include a straight or branched alkylsulfonyl having 1 to 6 carbon atoms, and exemplified by methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert- butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like, and the most preferably methylsulfonyl, and the like.
  • Suitable "lower alkenyl” may include a straight or branched alkenyl having 2 to 6 carbon atoms, and exemplified by ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl and the like and the most preferably ethenyl, and the like.
  • Suitable “lower alkanoylamino” may include a straight or branched one having 1 to 6 carbon atoms, and exemplified by formylamino, acetylamino, propionylamino, butylylamino, isobutylylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, and the like, and the most preferably acetylamino, and the like.
  • Suitable "lower alkylcarbamoyl (lower) alkenyl” may include a straight or branched alkenyl having 2 to 6 carbon atoms substituted by lower alkylcarbamoyl, and exemplified by methylcarbamoylvinyl, ethylcarbamoylvinyl, ethylcarbamoylpropenyl, methylcarbamoylbutenyl, methylcarbamoylpentenyl, and the like, and the most preferably methylcarbamoylvinyl, and the like.
  • Suitable "lower alkylcarbamoyl” may include a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarba oyl, and the like, and the most preferably ethylcarbamoyl .
  • Suitable "mono- or di (lower) alkyla inosulfonyl” may include aminosulfonyl substituted by lower alkyl such as methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, butylaminosulfonyl, pentylammosulfonyl, hexylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, dibutylaminosulfonyl, dipentylaminosulfonyl, dihexylaminosulfonyl, (methyl) (ethyl) aminosulfonyl, and the like, and the most preferably dimethylaminosulfonyl, and the like.
  • Suitable "aroyl” may include Cg-C o aroyl such as benzoyl, fluoren
  • Suitable "aryl (lower) alkanoyl” may include Cg-C Q aryl (lower) alkanoyl such as benzoyl, fluorenecarbonyl, phenylacetyl, phenylpropionyl, phenylbutylyl, phenylisobutylyl, phenylvaleryl, phenylisovaleryl, phenylpivaloyl, phenylhexanoyl, and the like, preferably phenyl (lower) alkanoyl, and the most preferably benzoyl, phenylacetyl, phenylpropionyl, and the like.
  • This "aryl (lower) alkanoyl” group is optionally substituted by a suitable substituent selected from the group as mentioned for "optionally substituted aryl".
  • aryl (lower) alkanoyl may be benzoyl, phenylacetyl or phenylpropionyl, each of the being substituted by the group consisting of;
  • halogen e.g. chloro, fluoro, etc.
  • chlorobenzoyl e.g. 2- or 3- or 4-chlorobenzoyl, etc.
  • dichlorobenzoyl e.g. 2,3- or 2,4- or 2,5- dichlorobenzoyl, etc.
  • fluorobenzoyl e.g. 2- fluorobenzoyl, etc.
  • methylbenzoyl e.g. 2-methylbenzoyl, etc.
  • hydroxybenzoyl e.g. 2-hydorxybenzoyl, etc.
  • trifluoromethybenzoyl e.g. 2- trifluoromethylbenzoyl, etc.
  • bis (trifluoromethy) benzoyl e.g. 2,4- bis (trifluoromethyl) benzoyl, etc.
  • nitrobenzoyl e.g. 2-nitrobenzoyl, etc.
  • trifluoromethoxybenzoyl e.g. 2- trifluoromethoxylbenzoyl, etc.
  • chloro methoxy benzoyl
  • Suitable "lower cycloalkylcarbamoyl” may include C3 ⁇ C cycloalkylcarbamonyl such as cyclopropylcarbamoyl, cyclobutyocarbamoyl, cyclopropylcarmamoyl, cyclobutylcarbamoyl, cyclopeantylcarba oyl, cyclohexylcarbamoyl, and the like, and the most preferably cyclohexylcarbamoyl, and the like.
  • Suitable "arylcarbamoyl” may include C -C Q arylcarbamonyl such as phenylcarbamoyl, tolylcarbamoyl, naphthylcarmamoyl, and the like, and the most preferably phenylcarbamoyl, and the like.
  • Suitable “lower alkanoyl” may include a straight or branched one having 1 to 6 carbon atoms, and exemplified by formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, and the like, and the most preferably acetyl, and the like.
  • Suitable "trihalo (lower) alkoxy” may include trihalogenated lower alkoxy such as trifluoromethoxy, trifluoroethoxy, and the like, and the most preferably trifluoromethoxy.
  • Suitable "trihalo (lower) alkyl” may include trihalogenated lower alkyl such as trifluoromethyl, trifluoroethyl, and the like, and the most preferably trifluoromethyl.
  • Suitable "aryl (lower) alkenoyl” may include Cg-C- [ _ Q aryl(C2 ⁇ Cg ) alkenyl such as phenylvinyl, phenylacryloyl, and the like, and the most prefabrably phenylacryloyl.
  • Suitable "amidated carboxy” can be referred to the ones as mentioned below.
  • amidated carboxy may include optionally substituted carbamoyl such as -carbamoyl, -N-hydroxycarbamoyl,
  • hydroxy- protective group may be the same as mentioned below (e.g. tetrahydropyranyl, etc.), -mono (or di) (lower) alkylcarbamoyl wherein the lower alkyl group may be the same as those mentioned above (e.g.
  • -lower alkyleneaminocarbonyl e.g. pyrrolidin-1- ylcarbonyl, hexahydro-lH-azepin-1-ylcarbonyl, etc.
  • said alkylene being optionally substituted bycarboxy or protected carboxy as mentioned above such as lower alkoxycarbonyl
  • Suitable "hydroxy-protective group” may include a conventional protective group, for example, substituted lower alkyl such as lower alkoxy (lower) alkyl (e.g. methoxymethyl) , lower alkoxy (lower) alkoxy (lower) alkyl (e.g. methoxyethoxymethyl) and substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl nitrobenzyl) ; acyl such as lower alkanoyl (e.g. acetyl, propionyl, pivaloyl) , aroyl (e.g. benzoyl, fluorenecarbonyl), lower alkoxycarbonyl (e.g.
  • Suitable "amino-protective group” may include a conventional protective group, for example, acyl such as lower alkanoyl (e.g. acetyl, propionyl, pivaloyl), aroyl (e.g. benzoyl, fluorenecarbonyl), lower alkoxycarbonyl (e.g.
  • aryl (lower) alkoxycarbonyl such as phenyl (or fluorenyl) (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, fluorenylmethoxyczrbonyl, etc.), substituted aryl (lower) alkoxycarbonyl (e.g.
  • benzyloxycarbonyl, bromobenzyloxycarbonyl) arenesulfonyl (e.g. benzenesulfonyl, tosyl) and alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl); tri (lower) alkylsilyl (e.g. trimethylsilyl) ; tetrahydropyranyl; and the like, preferably fluorenylmethoxycarbonyl.
  • alkanesulfonyl e.g. methanesulfonyl, ethanesulfonyl
  • tri (lower) alkylsilyl e.g. trimethylsilyl
  • tetrahydropyranyl tetrahydropyranyl
  • Suitable "hydroxycarbamoyl-protective group” may include a conventional protective group, for example, substituted lower alkyl such as lower alkoxy (lower) alkyl (e.g. methoxymethyl) , lower alkoxy (lower) alkoxy (lower) alkyl (e.g. methoxyethoxymethyl) and substituted or unsubstituted aryl (lower) alkyl (e.g. benzyl nitrobenzyl) ; acyl such as lower alkanoyl (e.g. acetyl, propionyl, pivaloyl), aroyl (e.g. benzoyl, fluorenecarbonyl), lower alkoxycarbonyl (e.g.
  • substituted lower alkyl such as lower alkoxy (lower) alkyl (e.g. methoxymethyl)
  • lower alkoxy (lower) alkoxy (lower) alkyl e.g. methoxyethoxy
  • Suitable "arylcarbamoyl” may include C -C Q arylcarbamoyl, such as phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, cumenylcarbamoyl, mesitylcarbamoyl, naphthylcarbamoyl, and the like, preferably phenylcarbamoyl, and the like.
  • Suitable "arylsulfonyl” may include Cg-C- j _g arylsulfonyl, such as phenylsulfonyl, tolylsulfonyl, xylylsulfonyl, cumenylsulfonyl, mesitylsulfonyl, naphthylsulfonyl, and the like, preferably phenylsulfonyl, and the like.
  • Suitable "aryl (lower) alkylsulfonyl” may include Cg-C g aryl (lower) alkylsulfonyl, such as benzylsulfonyl, tolylethylsulfonyl, xylylmethylsulfonyl, cu enylpropylsulfonyl, mesitylbutylsulfonyl, naphthylmethylsulfonyl, and the like, preferably benzylsulfonyl, and the like.
  • Suitable “amino (lower) alkanoyl” may include a straight or branched one having 1 to 6 carbon atoms, and exemplified by aminoformyl, aminoacetyl, aminopropionyl, aminobutylyl, aminoisobutylyl, aminovaleryl, aminoisovaleryl, aminopivaloyl, aminohexanoyl, and the like, and the most preferably aminoacetyl, and the like.
  • Suitable "arylaroyl” may include C -C Q aroyl substituted by C -C Q aryl l such as phenylbenzoyl, phenylfluorenecarbonyl, and the like, and the most preferably phenylbenzoyl, and the like.
  • acyl and acyl moiety includes acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by aromatic or heterocyclic group (s) derived from carboxylic, carbonic, sulfonic and carbamic acids .
  • the aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, 3-methylbutyryl, hexanoyl,
  • alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, 3-methylbutyryl, hexanoyl,
  • alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), mono- or di (lower) alkylaminosulfonyl (e.g.
  • C -C o arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • Cg-C Q ar (lower) alkylcarbamoyl e.g. benzylcarbamoyl, etc.
  • alkoxycarbonyl such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.)
  • alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.
  • alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, 3-methylcrotonoyl, etc.), lower cycloalkanecarbonyl such as lower cycloalkanecarbonyl (e.g. cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), lower cycloalkylcarbamoyl (e.g.
  • lower cycloalkenecarbonyl e.g. cyclobutenecarbonyl, cyclopentenecarbonyl, cyclohexenecarbonyl, etc.
  • aryloxycarbonyl e.g. phenoxycarbonyl, etc.
  • the aromatic acyl may include C -C Q aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, etc.) optionally substituted by the group consisting of halo (e.g. chloro, fluoro, etc.), lower alkyl (e.g. methyl, etc.), lower alkanoyl (e.g. acetyl, etc.) hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.) nitro, trihalo (lower) alkoxy (e.g. trifluoromethoxy, etc.), Cg-C ] _ Q aryl (e.g.
  • phenyl, etc. Cg-C Q aryloxy (e.g. phenoxy, etc.) and trihalo (lower) alkyl (e.g. trifluoromethyl, etc.)
  • N- (C -C Q ) arylcarbamoyl e.g. N-phenylcarbamoyl, N-tolylcarbamoyl, N- naphthylcarbamoyl, etc.
  • C -C Q aryl Cg-C ⁇ g) aroyl (e.g. phenylbenzoyl, etc.), and the like.
  • the heterocyclic acyl may include heterocyclic-carbonyl, heterocyclic-carbamoyl, heterocyclic-sulfonyl, etc, wherein the heterocyclic group being selected from the above- mentioed groups (Hi) to (H14), preferably
  • (HI) unsaturated 3- to 8-membered, preferably 5- or 6- membered, heteromonocyclic group containing 1 to 4 nitrogen atoms e.g. pyridyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, etc.
  • lower alkyl e.g. methyl, etc.
  • lower alkanoyl e.g. acetyl, etc.
  • lower alkoxy e.g. methoxy, etc.
  • H4 unsaturated condensed preferably bicyclic 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms (e.g. indolyl, quinolyl, etc.),
  • pyridylcarbonyl e.g 2- or 3- 4-pyridylcarbonyl, etc.
  • lower alkylpyridylcarbonyl e.g. 3-methyl-2- pyridylcarbonyl, etc.
  • pyridylsulfonyl e.g. 3- pyridylsulfonyl, etc.
  • imidazolylcarbonyl optionally substituted by lower alkyl (e.g. l-methyl-2- imidzolylcarbonyl, etc.)
  • pyrazolylcarbonyl e.g. 4- pyrazolylcarbonyl, etc.
  • pyrimidinylcarbonyl optionally substituted by lower alkyl (e.g. 4-methyl-
  • 5-pyrimidinyl, etc. furylcarbonyl (e.g. 2- furylcarbonyl, etc.), thienylcarbonyl (e.g. 2- or 3- thenoyl, etc.), thienylsulfonyl (e.g. 2- thienylsulfonyl, etc.) indolylcarbonyl (e.g. 2- indolylcarbonyl, etc.), pyrazinylcarbonyl (e.g. 2- pyrazinylcarbonyl, etc.), quinolinecarbonyl (e.g. 3- or 8-quinolinecarbonyl, etc.), isoquinolylcarbonyl (e.g.
  • pyrrolidinecarbonyl e.g. 1-pyrrolidinecarbonyl, etc.
  • pyrrolidinesulfonyl e.g. 1- pyrrolidinesulfonyl, etc.
  • piperidinecarbonyl e.g. 1- or 4-piperidinecarbonyl
  • lower alkanoyl e.g. l-acetyl-4- piperidinecarbonyl, etc.
  • piperidinesulfonyl e.g. 1-piperidinesulfonyl, etc.
  • lower alkoxy e.g.
  • the aliphatic acyl substituted by aromatic group (s) may include Cg-C g aralkanoyl such as phenyl (lower) alkanoyl (e.g.
  • Cg-C Q aryl (lower) cycloalkylcarbonyl e.g. phenylcycloporopylcarbonyl, etc.
  • Cg-C- j _o aryl (lower) alkenoyl e.g. phenylacryloyl, etc.
  • alkenoyl e.g. phenylacryloyl, etc.
  • the aliphatic acyl substituted by heterocyclic group (s) may include heterocyclic (lower) alkanoyl (e.g. thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, etc.), heterocyclic (lower) alkenoyl
  • heterocycliccarbamoyl optionally substituted by lower alkyl (e.g. methylisoxazolylcarbamoyl, etc. ), heterocyclic (lower) alkylcarbamoyl (e.g. thienylethylcarbamoyl, etc.), and the like.
  • acyl groups may be further substituted by one or more suitable substituents as those for "optionally substituted aryl” .
  • suitable substituents as those for “optionally substituted aryl” .
  • Preferable examples of the acyl thus defined may be: (Aid) lower alkylsufonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) optionally substituted by Cg-C g aryl (e.g. benzylsulfonyl, etc. ) , (A2d) lower alkoxycarbonyl (e.g.
  • Cg-C Q aryl or thienyl e.g. benzylcarbamoyl, 1-phenyletylcarbamoyl, 2-thienylethylcarbamoyl, etc.
  • lower alkanoyl e.g. acetyl, etc.
  • (preferable examples may be benzoyl, naphthoyl, benzoyl substituted by lower alkoxy (e.g. 2- or 3- or 4-methoxybenzoyl, 2-ethoxybenzoyl, 2-propoxybenzoyl, 2,3- or 2,4- or 2, 5-methoxybenzoyl, 2,3,4- trimethoxybenzoyl, etc.), benzoyl substituted by halogen (e.g. 2- or 3- or 4- chlorobenzoyl, 2,3- or 2,4- or 2,5- dichlorobenzoyl, 2-fluorobenzoyl, etc.), benzoyl substituted by lower alkyl (e.g.
  • 2- methylbenzoyl, etc. benzoyl substituted by hydroxy (e.g. 2-hydroxybenzoyl, etc.), benzoyl substituted by phenoxy (e.g. 2- phenoxybenzoyl, etc.), benzoyl substituted by phenyl (e.g. 2-phenylbenzoyl, etc.), benzoyl substituted by trihalo (lower) alkyl (e.g. 2-trifluoromethylbenzoyl, 2,4- bis (trifluoromethyl) benzoyl, etc.), benzoyl substituted by nitro (e.g. 2-nitorobenzoyl, etc.), benzoyl substituted by lower alkanoyl (e.g. 2-acetylbenzoyl, etc.), benzoyl substituted by trihalo (lower) alkyloxy (e.g.
  • (Hi) unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms e.g. imidazolyl, pyrazolyl, pyridyl and its N- oxide, pyrimidyl, pyrazinyl, etc.
  • (H2) saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms e.g. pyrrolidinyl, piperidinyl, piperidino, etc.
  • 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms e.g. indolyl, quinolyl, isoquinolyl, etc.
  • heterocyclic acyl may be imidazolylcarbonyl (e.g. 2- imidazolylcarbonyl, etc.) optionally substituted by lower alkyl (e.g. 1- methyl-2-imidazolylcarbonyl, etc.) , pyrazolylcarbonyl (e.g. 4- pyrazolylcarbonyl, etc. ) , pyridylcarbonyl (e.g. 2- or 3- or 4- pyridylcarbonyl, etc.) optionally substituted by lower alkyl (e.g.
  • pyridylsulfonyl e.g. 3-pyridylsulfonyl, etc.
  • pyrimidinylcarbonyl e.g. 5- 5 pyrimidinylcarbonyl, etc.
  • lower alkyl e.g. 4- methyl-5-pyrimidinylcarbonyl, etc.
  • pyrazinylcarbonyl e.g. 2- pyrazinylcarbonyl, etc.
  • pyrrolidinylcarbonyl e.g. 1- pyrrolidinylcarbonyl, etc.
  • pyrrolidinylsulfonyl e.g. 1- pyrrolidinylsulfonyl, etc.
  • piperidinylcarbonyl e.g. 1- or 4-
  • piperidinylcarbonyl, etc. optionally substituted by lower alkanoyl (e.g. 1- acetyl-4-piperidinylcarbonyl, etc.) , piperidinylsulfonyl (e.g. 1- piperidinylsulfonyl, etc.) optionally
  • lower alkoxy e.g. 4- methoxy-1-piperidinylsulfonyl, etc.
  • thienylcarbonoyl e.g. 2- or 3- thienylcarbonyl, etc.
  • thienylsulfonyl e.g. 2-thienylsulfonyl, etc.
  • indolylcarbonyl e.g. 2-indolylcarbonyl, etc.
  • quinolylcarbonyl e.g. 3- or 8- quinolylcarbonyl, etc.
  • isoquinolylcarbonyl e.g. 1- isoquinolylcarbonyl, etc.
  • furylcarbonyl e.g. 2-furylcarbonyl, etc.
  • benzothienylcarbonyl e.g. 2- benzothienylcarbonyl, etc.
  • morpholinylcarbonyl e.g. 4- morpholinylcarbonyl, etc.
  • morpholinylsulfonyl e.g. 4- morpholinylsulfonyl, etc.
  • lower cycloalkylcarbamoyl e.g.
  • arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • the aryl group is optionally substituted by the group consisting of halogen, lower alkyl and lower alkoxy (e.g. mono- or dicholophenylcarbamoyl, methylphenylcarbamoyl, methoxyphenylcarbamoyl, etc.),
  • C -C Q arylsulfonyl e.g. phenylsulfonyl, etc.
  • lower alkoxy e.g. methoxyphenylsulfonyl, etc.
  • heterocycliccarbamoyl wherein the heterocyclic group is (H7) unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. isoxazolyl, etc.) optionally substituted by lower alkyl (e.g 5- methylisoxazolyl, etc.),
  • lower cycloalkylcarbonyl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • phenyl e.g. 1-phenyl- 1-cyclopropylcarbonyl, etc.
  • (Al8d) lower cycloalkenecarbonyl e.g. cyclohexenecarbonyl, etc.
  • more preferable one may be (Aid) lower alkylsufonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) optionally substituted by Cg-C Q aryl (e.g. benzylsulfonyl, etc. ) , (A2d) lower alkoxycarbonyl (e.g.
  • (A5d) mono- or di (lower) alkylaminosulfonyl e.g. ethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, N-methyl-N- ethylaminosulfonyl, etc.
  • lower alkoxy e.g. N-
  • Cg-C Q arylcarbonyl substituted by Cg-C 10 aryloxy e.g. 2-phenoxybenzoyl, etc.
  • _ Q arylcarbonyl substituted by C -C ⁇ Q aryl e.g. 2- phenylbenzoyl, etc.
  • Cg-C o arylcarbonyl substituted by trihalo (lower) alkyl e.g. 2- trifluoromethylbenzoyl, 2,4- bis (trifluoromethyl) benzoyl, etc.
  • Cg-C Q arylcarbonyl substituted by nitro e.g.
  • imidazolylcarbonyl e.g. 2-imidazolylparbonyl, etc.
  • lower alkyl e.g. l-methyl-2-imidazolylcarbonyl, etc.
  • pyrazolylcarbonyl e.g. 4-pyrazolylcarbonyl, etc.
  • pyridylcarbonyl e.g. 2- or 3- or 4- pyridylcarbonyl, etc.
  • pyridylsulfonyl e.g.
  • 3-pyridylsulfonyl, etc. pyrimidinylcarbonyl (e.g. 5- pyrimidinylcarbonyl, etc.) optionally substituted by lower alkyl (e.g. 4-methyl ⁇ 5- pyrimidinylcarbonyl, etc.), pyrazinylcarbonyl (e.g. 2-pyrazinylcarbonyl, etc.), pyrrolidinylcarbonyl (e.g. 1- pyrrolidinylcarbonyl, etc. ) , pyrrolidinylsulfonyl (e.g. 1- pyrrolidinylsulfonyl, etc.), piperidinylcarbonyl (e.g.
  • 1- or 4-piperidinylcarbonyl, etc.) optionally substituted by lower alkanoyl e.g. l-acetyl-4-piperidinylcarbonyl, etc.
  • piperidinylsulfonyl e.g. 1-piperidinylsulfonyl, etc.
  • lower alkoxy e.g. 4-methoxy-l-piperidinylsulfonyl, etc.
  • thienylcarbonoyl e.g. 2- or 3-thienylcarbonyl, etc.
  • thienylsulfonyl e.g.
  • 2-thienylsulfonyl, etc. indolylcarbonyl (e.g. 2-indolylcarbonyl, etc.), quinolylcarbonyl (e.g. 3- or 8- quinolylcarbonyl, etc.), isoquinolylcarbonyl (e.g. 1-isoquinolylcarbonyl, etc.), furylcarbonyl (e.g. 2-furylcarbonyl, etc.), benzothienylcarbonyl (e.g. 2- benzothienylcarbonyl, etc.), morpholinylcarbonyl (e.g. 4-morpholinylcarbonyl, etc.), morpholinylsulfonyl (e.g.
  • aryl group is optionally substituted by the group consisting of halogen, lower alkyl and lower alkoxy (e.g. mono- or dicholophenylcarbamoyl, methylphenylcarba oyl, methoxyphenylcarbamoyl, etc. ) ,
  • C -C- j _ Q arylsulfonyl e.g. phenylsulfonyl, etc.
  • lower alkoxy e.g. methoxyphenylsulfonyl, etc.
  • lower cycloalkylcarbonyl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • Cg-C g aryl e.g.
  • alkenoyl e.g. 3-methylcrotonoyl, etc.
  • alkenoyl e.g. 3-methylcrotonoyl, etc.
  • alkenoyl optionally substituted by Cg-C g aryl (e.g. phenylacryloyl, etc.)
  • Al5d pyridyl (lower) alkenoyl (e.g. pyridylacryloyl, etc. )
  • lower alkanoyl e.g. acetyl, propionyl, isobutyryl, isovaleryl, pivaloyl, hexanoyl, 3,3- dimethylbutyryl, 2-ethylbutyryl, etc.
  • phenoxycarbonyl, etc. ) (A18d) lower cycloalkenecarbonyl (e.g. cyclohexenecarbonyl, etc. ) , and the like, and the most preferable one may be (Aid) methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, (A2d) methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, 2- methoxyethoxycarbonyl,
  • Suitable “lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene, and the like, preferably ethylene, trimethylene, and the like.
  • Suitable “protected carboxy” includes esterified carboxy wherein “esterified carboxy” is as defined below.
  • ester moiety of the esterified carboxy are lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) and the like, which may have at least one suitable substituent.
  • lower alkyl ester e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.
  • substituted lower alkyl ester examples include lower alkanoyloxy (lower) alkyl ester [e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1- (or 2-) acetoxyethyl ester, 1- (or 2- or 3-) acetoxypropyl ester, l-(or 2- or 3- or 4-)- acetoxybutyl ester, 1- (or 2-) propionyloxyethyl ester, 1- (or 2- or 3-) propionyloxypropyl ester, l-(or 2-)- butyryloxyethyl ester, l-(or 2-) isobutyryloxyethyl ester, 1- (or 2-) pivaloyloxyethyl ester, l-(or 2-) hexanoyloxyethyl
  • X is thia, sulfinyl or sulfonyl, preferably sulfonyl, and R is hydrogen or acyl.
  • R is carboxy, protected carboxy, hydroxycarbamoyl or protected hydroxycarbamoyl,
  • R is hydrogen, lower alkylsufonyl or lower alkoxycarbonyl
  • Ar is phenyl or unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms
  • ⁇ d is sulfonyl
  • ⁇ d and Z d are each C, -C-, alkylene
  • m d is an integer of 0, .and n d is an integer of 1, or ;pharmaceutically acceptable salts thereof, and more preferred compounds of fromula (i- -d) are:
  • R1 is halo; phenyl optionally substituted by the group consisting of lower alkoxy, lower alkoxycarbonylamino, lower alkylaminocarbonylamino, lower alkoxy (lower) alkanoylamino and phenoxy (lower) - alkanoylamino; or furyl; R 2 is carboxy, protected carboxy, hydroxycarbamoyl or protected hydroxycarbamoyl,
  • R is hydrogen, lower alkylsufonyl or lower alkoxycarbonyl, or pharmaceutically acceptable salts thereof.
  • R l is halo; lower alkoxy; aryl optionally substituted by the group consisting of lower alkoxy, lower ' alkoxycarbonylamino, lower alkylaminocarbonylamino, lower alkoxy (lower) alkanoylamino, C,-C, n aryloxy (lower) alkanoylamino, halo, lower alkyl, lower alkylthio, heterocyclic group, said heterocyclic group being unsaturated 3- to 8- membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, or saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms which is optionally substituted by oxo, lower alkenyl, amino, lower alkanoylamino, hydroxy, lower alkylsulfonyl, C fi ⁇ C 10 aryloxy, C.--C.
  • aryl lower alkylcarbamoyl (lower) alkenyl and lower alkylcarbamoyl; aryloxy optionally substituted by the group consisting of lower alkoxy, lower alkoxycarbonylamino, lower alkylaminocarbonylamino, lower alkoxy (lower) alkanoylamino, C fi -C, - aryloxy (lower) alkanoylamino, halo, lower alkyl, lower alkylthio, heterocyclic group, said heterocyclic group being unsaturated 3- to 8- membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, or saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms which is optionally substituted by oxo, lower alkenyl, amino, lower alkanoylamino, hydroxy, lower alkylsulfonyl,
  • R is carboxy, protected carboxy, hydroxycarbamoyl or protected hydroxycarbamoyl
  • R is hydrogen, lower alkylsufonyl, lower alkoxycarbonyl, Cg-C- j _g ar (lower) alkoxycarbonyl
  • Y and Z d are each C, -C-, alkylene, m is an integer of 0, and n d is an integer of 1, or pharmacyeutically acceptable salts thereof; or
  • R 3d is hydrogen, lower alkylsufonyl, lower alkoxycarbonyl, Cg-C Q ar (lower) alkoxycarbonyl, 9-fluorenylmethoxycarbonyl, mono- or di (lower) alkylaminosulfonyl, N- (lower) alkylcarbamoyl, Cg-C Q aroyl, heterocyclic acyl, and Ar is phenyl or thienyl, or pharmaceutically acceptable salts thereof; or
  • R is halo; lower alkoxy, C fi -C, - aryl optionally substituted by the group consisting of lower alkoxy, lower alkoxycarbonylamino, lower alkylaminocarbonylamino, lower alkoxy (lower) alkanoylamino, C.--C, - aryloxy (lower) alkanoylamino, halo, lower alkyl, lower alkylthio, oxazolyl, lower alkenyl, amino and lower alkanoylamino; or furyl;
  • R 2d is carboxy, protected carboxy, hydroxycarbamoyl or protected hydroxycarbamoyl
  • R 3d is hydrogen, lower alkylsufonyl, lower alkoxycarbonyl, C -C g ar (lower) alkoxycarbonyl, 9-fluorenylmethoxycarbonyl, mono- or di (lower) alkylaminosulfonyl, N- (lower) alkylcarbamoyl, Cg-C Q aroyl, pyridylcarbonyl, pyrazinylcarbonyl, or thienylcarbonyl, or pharmaceutically acceptable salts thereof; or
  • R Id is lower alkoxy; C ⁇ -C, - aryloxy optionally substituted by the group consisting of lower alkoxy, lower alkoxycarbonylamino, lower alkylaminocarbonylamino, lower alkoxy (lower) alkanoylamino, C ⁇ -C,tician aryloxy (lower) alkanoylamino, halo, lower alkyl, lower alkylthio, oxazolyl, lower alkenyl, amino and lower alkanoylamino; (preferably lower alkoxy or C.--C, - aryloxy), R is carboxy, protected carboxy, hydroxycarbamoyl or protected hydroxycarbamoyl, R is hydrogen, lower alkylsufonyl, lower alkoxycarbonyl, Cg-C Q ar (lower) alkoxycarbonyl, 9-fluorenylmethoxycarbonyl, mono- or di (lower) alkylaminosulfon
  • R is halo, lower alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterecyclic group or optionally substituted lower alkynyl
  • R is carboxy, protected carboxy or amidated carboxy selected from N-hydroxycarbamoyl and N- (protected hydroxy) carbamoyl
  • R is hydrogen or acyl
  • Ar is aryl or heterocyclic group
  • X d is thia, sulfinyl or sulfonyl
  • Y d and Z are each lower alkylene
  • m and n d are each an integer of 0 to 2
  • a salt thereof wherein the above-mentioned optional substituents for aryl, aryloxy, heterocyclic group and lower alkynyl in R are each selected from the group consisting of: (SI) lower alkoxy (e.g.
  • halo e.g. chloro, fluoro, etc.
  • lower alkyl e.g. methyl, ethyl, propyl, isopropyl, t-butyl, etc.
  • lower alkylthio e.g. methylthio, etc.
  • (S9) heterocyclic group selected from: unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, which is optionally substituted by lower alkyl (e.g. oxazolyl, oxadiazolyl, methyloxadiazolyl, etc.] and saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, which is optionally substituted by oxo (e.g. thiazolidinyl, isothiazolidinyl, 1,1- dioxoisothiazolidinyl, etc.
  • lower alkyl e.g. oxazolyl, oxadiazolyl, methyloxadiazolyl, etc.
  • saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms which is optionally substituted by oxo (e
  • pyrrolyl e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1, 2, 4-triazolyl, 1H- 1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H- tetrazolyl, etc.), dihydrotriazinyl (e.g.
  • thiazolyl 1, 2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1, 2, 3-thiadiazolyl, etc.); (H13) saturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, and
  • acyl for R- ⁇ d i s each selected from (Aid) lower alkylsufonyl optionally substituted by aryl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, etc.), (A2d) lower alkoxycarbonyl optionally substituted by lower alkoxy (e.g.
  • halo e.g. chloro, fluoro, etc.
  • lower alkyl e.g. methyl, ethyl, propyl, isopropyl, t-butyl, etc.
  • S13 hydroxy (e.g. hydroxy, etc.)
  • aryloxy e.g. phenoxy, etc.
  • aryl optionally substituted by halogen (e.g. phenyl, chlorophenyl, etc.),
  • lower alkanoyl e.g. acetyl, etc.
  • (Ad7) may be benzoyl, naphthoyl, benzoyl substituted by lower alkoxy (e.g. 2- or 3- or 4-methoxybenzoyl, 2-ethoxybenzoyl, 2-propoxybenzoyl, 2,3- or 2,4- or 2, 5-methoxybenzoyl, 2,3,4- trimethoxybenzoyl, etc.), benzoyl substituted by halogen (e.g.
  • heterocyclic-carbonyl or heterocyclic- sulfonyl wherein the heterocyclic group being selected from: (Hi) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, etc.); (H2) saturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.
  • heterocyclic-carbonyl or heterocyclic-sulfonyl may be imidazolylcarbonyl (e.g. 2-imidazolylcarbonyl, 25 etc.) optionally substituted by lower alkyl
  • pyrazolylcarbonyl e.g. 4-pyrazolylcarbonyl, etc.
  • pyridylcarbonyl e.g. 2- or 3- or 4- pyridylcarbonyl, etc.
  • lower alkyl e.g. 3-methyl-2- pyridylcarbonyl, etc.
  • pyridylsulfonyl e.g. 3-pyridylsulfonyl, etc.
  • pyrimidinylcarbonyl e.g. 5-pyrimidinylcarbonyl, etc.
  • lower alkyl e.g.
  • pyrazinylcarbonyl e.g. 2-pyrazinylcarbonyl, etc.
  • pyrrolidinylcarbonyl e.g. 1- pyrrolidinylcarbonyl, etc.
  • pyrrolidinylsulfonyl e.g. 1- pyrrolidinylsulfonyl, etc.
  • piperidinylcarbonyl e.g. 1- or 4- piperidinylcarbonyl, etc.
  • optionally substituted by lower alkanoyl e.g. 1-acetyl- 4-piperidinylcarbonyl, etc.
  • piperidinylsulfonyl e.g. 1- piperidinylsulfonyl, etc.
  • piperidinylsulfonyl e.g. 1- piperidinylsulfonyl, etc.
  • lower alkoxy e.g. 4-methoxy- 1-piperidinylsulfonyl, etc.
  • thienylcarbonoyl e.g. 2- or 3- thienylcarbonyl, etc.
  • thienylsulfonyl e.g.
  • 2-thienylsulfonyl, etc. indolylcarbonyl (e.g. 2-indolylcarbonyl, etc.), quinolylcarbonyl (e.g. 3- or 8- quinolylcarbonyl, etc.), isoquinolylcarbonyl (e.g. 1-isoquinolylcarbonyl, etc.), furylcarbonyl (e.g. 2-furylcarbonyl, etc.), benzothienylcarbonyl (e.g. 2- benzothienylcarbonyl, etc.), morpholinylcarbonyl (e.g. 4- morpholinylcarbonyl, etc.), morpholinylsulfonyl (e.g.
  • arylcarbamoyl wherein the aryl group is optionally substituted by the group consisting of halogen, lower alkyl and lower alkoxy (e.g. phenylcarbamoyl, mono- or dicholophenylcarbamoyl, methylphenylcarbamoyl, methoxyphenylcarbamoyl, etc. ) , (Alld) Cg-C-
  • heterocycliccarbamoyl wherein the heterocyclic group is (H7) unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, optionally substituted by lower alkyl (e.g. isoxazolyl, 5-methylisoxazolyl, etc.), (A13d) lower cycloalkylcarbonyl optionally substituted by aryl (e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-phenyl-l- cyclopropylcarbonyl, etc.
  • aryl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-phenyl-l- cyclopropylcarbonyl, etc.
  • aryl e.g. 3-methylcrotonoyl, phenylacryloyl, etc.
  • heterocyclic (lower) alkenoyl wherein the heterocyclic group is unsaturated 3- to 8- membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyridylacryloyl, etc.
  • lower alkanoyl optionally substituted by the group consisting of aryl, hydroxy, lower cycloalkyl, amino, lower alkoxycarbonylamino, lower alkoxy, lower alkoxy (lower) alkoxy, aryloxy, and heterocyclic group consisting of unsaturated 3- to 8-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and unsaturated 3- to 8-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.
  • aryloxycarbonyl e.g. phenoxycarbonyl, etc.
  • lower cycloalkenecarbonyl e.g. cyclohexenecarbonyl, etc.
  • -(CH 2 is one of the following formulas:
  • R ⁇ d and x are each as defined in above [1] , is an integer of 0 to 1, and nid°- is an integer of 1 or 2.
  • lower alkoxy e.g. methoxy, ethoxy, etc.
  • lower alkylaminocarbonylamino e.g. methylaminocarbonylamino, ethylaminocarbonylamino, etc.
  • lower alkoxy (lower) alkanoylamino e.g. ethoxyacetylamino, etc.
  • halo e.g. chloro, fluoro, etc.
  • S7 lower alkyl e.g. methyl, ethyl, propyl, isopropyl, etc.
  • S8 lower alkylthio e.g. methylthio, etc.
  • S9 heterocyclic group selected from: unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, which is optionally substituted by lower alkyl (e.g.
  • oxazolyl methyloxadiazolyl, etc.
  • lower alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl , etc .
  • lower alkoxy (lower) alkyl e.g. methoxymethyl, etc.
  • (H8) unsaturated bicyclic 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms e.g. benzofuranyl, etc.
  • (H14) unsaturated bicyclic 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms e.g. benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, etc.
  • these heterocyclic group being optionally substituted by the group consisting of halogen, hydroxy (lower) alkyl, lower alkylcarbamoyl, lower alkyl and oxo;
  • lower alkylsufonyl optionally substituted by Cg-C o ar yl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, etc.),
  • lower alkoxycarbonyl optionally substituted by lower alkoxy (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, methoxyethoxycarbonyl, etc.),
  • Cg-C Q aroyl substituted by the group consisting of lower alkoxy and halogen e.g. 2-methoxy-4-chlorobenzoyl, etc.
  • 35 alkoxy e.g. imidazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyridylsulfonyl, pyrimidylcarbonyl, pyrazinylcarbonyl, methylimidazolylcarbonyl, 5 methylpyridylcarbonyl, methylpyrimidinylcarbonyl, 4- methoxy-1-piperidinylsulfonyl, etc. ) ; (H2) saturated 5- or 6-membered,
  • heteromonocyclic group containing 1 to 4 nitrogen atoms optionally substituted by lower alkanoyl or lower alkoxy e.g. pyrrolidinylcarbonyl,
  • (H5) unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms e.g. furylcarbony, etc.
  • (H9) unsaturated bicyclic 9- or 10- membered, heterocyclic group containing 1 or 2 sulfur atoms e.g. benzothienylcarbonyl, etc.
  • 5 (HlO) saturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinylcarbonyl, 10 morpholinylsulfonyl, etc.
  • heterocyclic acyl may be imidazolylcarbonyl (e.g. 2- imidazolylcarbonyl, etc.) optionally substituted by lower alkyl (e.g. 1- 15 methyl-2-imidazolylcarbonyl, etc.), pyrazolylcarbonyl (e.g. 4- pyrazolylcarbonyl, etc.), pyridylcarbonyl (e.g. 2- or 3- or 4- pyridylcarbonyl, etc.) optionally 20 . substituted by lower alkyl (e.g. 3- methyl-2-pyridylcarbonyl, etc. ) , pyridylsulfonyl (e.g.
  • piperidinylcarbonyl, etc. optionally 35 substituted by lower alkanoyl (e.g. 1- acetyl-4-piperidinylcarbonyl, etc. ) , piperidinylsulfonyl (e.g. 1- piperidinylsulfonyl, etc.) optionally substituted by lower alkoxy (e.g. 4- methoxy-1-piperidinylsulfonyl, etc.), thienylcarbonyl (e.g. 2- or 3- thienylcarbonyl, etc.), thienylsulfonyl (e.g.
  • 2-thienylsulfonyl, etc. indolylcarbonyl (e.g. 2-indolylcarbonyl, etc.), quinolylcarbonyl (e.g. 3- or 8- quinolylcarbonyl, etc. ) , isoquinolylcarbonyl (e.g. 1- isoquinolylcarbonyl, etc.), furylcarbonyl (e.g. 2-furylcarbonyl, etc.), benzothienylcarbonyl (e.g. 2- benzothienylcarbonyl, etc. ) , morpholinylcarbonyl (e.g. 4- morpholinylcarbonyl, etc. ) , morpholinylsulfonyl (e.g. 4- morpholinylsulfonyl, etc.), etc.),
  • lower cycloalkylcarbamoyl e.g. cyclopropylcarbamoyl, cyclohexylcarbamoyl, etc.
  • AlOd Cg-C o arylcarbamoyl, halo (Cg-C g) ⁇ arylcarbamoyl, lower alkyl (C -C Q ) - arylcarbamoyl, lower alkoxy(Cg-C ⁇ ) - arylcarbamoyl (e.g. phenylcarbamoyl, mono- or dicholophenylcarbamoyl, methylphenylcarbamoyl, methoxyphenylcarbamoyl, etc.),
  • Cg-C Q arylsulfonyl e.g. phenylsulfonyl, etc.
  • lower alkoxy e.g. methoxyphenylsulfonyl, etc.
  • heterocycliccarbamoyl wherein the heterocyclic group is (H7) unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms optionally substituted by lower alkyl (e.g. isoxazolyl, 5-methylisoxazolyl, etc.),
  • Al3d lower cycloalkylcarbonyl (e.g.
  • phenoxycarbonyl, etc. and (A18d) lower cycloalkenecarbonyl (e.g. cyclohexenecarbonyl, etc.), and Ar d is C-.-C n aryl or (H3) unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms .
  • phenyl or naphthyl selected from (SaO) phenyl or naphthyl (e.g. phenyl, naphthyl, etc. ) ,
  • halophenyl e. g. chlorophenyl, fluorophenyl, etc.
  • lower alkylphenyl e. g. methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, etc.
  • thienyl optionally substituted by halogen (e.g. 2-thienyl, 5-chloro-2-thienyl, etc. ) , (H4) quinolyl (e.g. 6-quinolyl, etc.), (H5) furyl (e.g. 2-furyl, etc.),
  • halogen e.g. 2-thienyl, 5-chloro-2-thienyl, etc.
  • quinolyl e.g. 6-quinolyl, etc.
  • furyl e.g. 2-furyl, etc.
  • H14 dihydrobenzothiazolyl substituted by lower alkyl and oxo (e.g 3-methyl-2-oxo- 2, 3-dihydrobenzothiazolyl, etc.); or -lower alkynyl, phenyl (lower) alkynyl or aminosulfonyphenyl (lower) alkynyl; (e.g. 2- hexynyl, 2-phenylethynyl, 2-(4- aminosulfonylphenyl) ethynyl, etc.
  • R is carboxy or N-hydroxycarbamoyl
  • R is acyl selected from the group consisting of; (Aid) lower alkylsufonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) optionally substituted by phenyl (e.g. benzylsulfonyl, etc.), (A2d) lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t- butoxycarbonyl, etc.) optionally substituted by lower alkoxy (e.g. methoxyethoxycarbonyl, etc. ) , (A3d) phenyl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc) ,
  • (A4d) fluorenylmethoxycarbonyl e.g. 9- fluorenylmethoxycarbonyl, etc.
  • (A5d) mono- or di (lower) alkylaminosulfonyl e.g. ethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, N-methyl-N- ethylaminosulfonyl, etc.
  • lower alkoxy e.g. N- (methoxyethyl) aminosulfonyl, N-methyl-N- (methoxyethyl) aminosulfonyl, etc.
  • (A6d) mono- or di (lower) alkylcarbamoyl e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, t- butylcarbamoyl, dimethylcarbamoyl, etc.
  • phenyl or thienyl e.g. benzylcarbamoyl, 1- phenylethylcarbamoyl, 2- thienylethylcarbamoyl, etc.
  • benzoyl, naphthoyl, benzoyl substituted by lower alkoxy e.g. 2- or 3- or 4- methoxybenzoyl, 2-ethoxybenzoyl, 2- propoxybenzoyl, 2,3- or 2,4- or 2,5- dimethoxybenzoyl, 2,3,4-trimethoxybenzoyl, etc.
  • benzoyl substituted by halogen e.g. 2- or 3- or 4-chlorobenzoyl, 2,3- or 2,4- or 2, 5-dichlorobenzoyl, 2-fluorobenzoyl, etc.
  • benzoyl substituted by lower alkyl e.g.
  • 2- methylbenzoyl, etc. benzoyl substituted by hydroxy (e.g. 2-hydroxybenzoyl, etc.), benzoyl substituted by phenoxy (e.g. 2- phenoxybenzoyl, etc.), benzoyl substituted by phenyl (e.g. 2-phenylbenzoyl, etc.), benzoyl substituted by trihalo (lower) alkyl (e.g. 2-trifluoromethylbenzoyl, 2,4- bis (trifluoromethyl) benzoyl, etc.), benzoyl substituted by nitro (e.g. 2-nitorobenzoyl, etc.), benzoyl substituted by lower alkanoyl (e.g.
  • 2-acetylbenzoyl, etc. benzoyl substituted by trihalo (lower) alkyloxy (e.g. 2-trifluoromethyloxybenzoyl, etc.), benzoyl substituted by lower alkoxy and halogen (e.g.
  • (Hal) imidazolylcarbonyl e.g. 2- imidazolylcarbonyl, etc. optionally substituted by lower alkyl (e.g. 1- methyl-2-imidazolylcarbonyl, etc. ) , pyrazolylcarbonyl (e.g. 4- pyrazolylcarbonyl, etc.), pyridylcarbonyl (e.g. 2- or 3- or 4- pyridylcarbonyl, etc.) optionally substituted by lower alkyl (e.g. 3- methyl-2-pyridylcarbonyl, etc.), pyridylsulfonyl (e.g. 3- pyridylsulfonyl, etc.
  • lower alkyl e.g. 1- methyl-2-imidazolylcarbonyl, etc.
  • pyrazolylcarbonyl e.g. 4- pyrazolylcarbonyl, etc.
  • pyridylcarbonyl e.g
  • pyrimidinylcarbonyl e.g. 5- pyrimidinylcarbonyl, etc.
  • pyrazinylcarbonyl e.g. 2- pyrazinylcarbonyl, etc.
  • pyrrolidinylcarbonyl e.g. 1- pyrrolidinylcarbonyl, etc.
  • pyrrolidinylsulfonyl e.g. 1- pyrrolidinylsulfonyl, etc.
  • piperidinylcarbonyl e.g. 1- or 4-
  • piperidinylcarbonyl, etc. optionally substituted by lower alkanoyl (e.g. l-acetyl-4- piperidinylcarbonyl, etc. ) , piperidinylsulfonyl (e.g. 1-
  • thienylcarbonyl, etc. 25 thienylcarbonyl, etc.
  • thienylsulfonyl e.g. 2- thienylsulfonyl, etc.
  • Ha4 indolylcarbonyl e.g. 2- indolylcarbonyl, etc.
  • quinolylcarbonyl e.g. 3- or 8- quinolylcarbonyl, etc.
  • isoquinolylcarbonyl e.g. 1- isoquinolylcarbonyl, etc.
  • furylcarbonyl e.g. 2-furylcarbonyl
  • phenylsulfonyl e.g. phenylsulfonyl, etc.
  • lower alkoxy e.g. methoxyphenylsulfonyl, etc.
  • isoxazolylcarbamoyl lower alkylisoxazolylcarbamoyl (e.g. methylisoxazolylcarbamoyl, etc.)
  • lower cycloalkylcarbonyl e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • phenyl e.g. phenylsulfonyl, etc.
  • Rl d , R3d a nd X are each as defined in above [5] .
  • (Sa8) lower alkylthiophenyl e.g. 4- methylthiophenyl, etc.
  • (Sa9) oxazolylphenyl e.g. 2- (or 5- ) oxazolylphenyl, etc.
  • lower alkyloxadiazolylphenyl e.g. 5-methyl- 1, 2, 4-oxadiazol-3-ylphenyl, etc.
  • 1,1- dioxoisothiazolidinylphenyl e.g. 1,1- dioxoisothiazolidin-2-ylphenyl, etc.
  • (SalO) lower alkenylphenyl e . g. 4-vinylphenyl, etc.
  • lower alkylsufonyl phenyl (lower) alkylsufonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, etc.), 10 (A2d) lower alkoxycarbonyl, lower alkoxy (lower) alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, 2-methoxyethoxycarbonyl, etc.), 15 (A3d) phenyl (lower) alkoxycarbonyl (e.g.
  • (lower) alkoxy (lower) alkylaminosulfonyl e.g. dimethylaminosulfonyl, 25 diethylaminosulfonyl, N-(2- methoxyethyl) aminosulfonyl, N-methyl- N- (2-methoxyethyl) aminosulfonyl, etc.
  • (A6d) mono- or di (lower) alkylcarbamoyl, phenyl (lower) alkylcarbamoyl, 30 thienyl (lower) alkylcarbamoyl e.g.
  • lower alkylbenzoyl e.g. 2- methylbenzoyl, etc.
  • hydroxybenzoyl e.g. 2-hydroxybenzoyl, etc.
  • phenoxybenzoyl e.g. 2-phenoxybenzoyl, etc.
  • phenylbenzoyl e.g. 2-
  • phenylbenzoyl, etc. mono- or bis (trihalo (lower) alkyl) benzoyl (e.g. 2-trifluoromethylbenzoyl, 2,4- bis (trifluoromethyl) benzoyl, etc. ) , nitrobenzoyl (e.g. 2-nitorobenzoyl,
  • lower alkanoylbenzoyl e.g. 2- acetylbenzoyl, etc.
  • trihalo (lower) alkyloxybenzoyl e.g. 2- trifluoromethyloxybenzoyl, etc.
  • halogen e.g. 2-methoxy-4- chlorobenzoyl, etc.
  • benzoyl substituted by lower alkoxy and hydroxy e.g. 3-methoxy-2- hydroxybenzoyl, etc.
  • heterocyclic-carbonyl or heterocyclic- sulfonyl selected from: (Hal) imidazolylcarbonyl, lower alkylimidazolylcarbonyl, pyrazolylcarbonyl,
  • phenylcarbamoyl halophenylcarbamoyl, lower alkylphenylcarbamoyl, lower alkoxyphenylcarbamoyl, (e.g. phenylcarbamoyl, 2-, 3- or 4- 15 chlorophenylcarbamoyl, 2,3- or 2,5- dicholophenylcarbamoyl, 2- methylphenylcarbamoyl, 2- methoxyphenylcarbamoyl, etc.), (Alld) phenylsulfonyl, lower 20 alkoxyphenylsulfonyl (e.g.
  • lower alkanoyl e.g. acetyl, propionyl, isobutyryl, isovaleryl, 5 pivaloyl, hexanoyl, 3,3- dimethylbutyryl, 2-ethylbutyryl, etc.
  • acyl selected from the group consisting of; (Aid) methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, (A2d) methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, methoxyethoxycarbonyl, (A3d) benzyloxycarbonyl, (A4d) fluorenylmethoxycarbonyl, (A5d) dimethylaminosulfonyl, diethylammosulfonyl,
  • R 3d is acyl selected from the group consisting of;
  • lower alkylsufonyl e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, etc.
  • phenyl (lower) alkylsufonyl e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, etc.
  • (lower) alkoxy (lower) alkylaminosulfonyl e.g. dimethylaminosulfonyl, diethylammosulfonyl, N- (2-methoxyethyl) aminosulfonyl, N-methyl-N- (2-methoxyethyl) aminosulfonyl, etc.
  • 2-phenoxybenzoyl, etc. phenylbenzoyl (e.g. 2-phenylbenzoyl, etc. ) , mono- or bis (trihalo (lower) alkyl) benzoyl (e.g. 2- trifluoromethylbenzoyl, 2,4- bis (trifluoromethyl) enzoyl, etc.), nitrobenzoyl (e.g. 2-nitorobenzoyl, etc.), lower alkanoylbenzoyl (e.g. 2-acetylbenzoyl, etc.), trihalo (lower) alkyloxybenzoyl (e.g.
  • lower alkanoyl e.g. acetyl, propionyl, isobutyryl, isovaleryl, pivaloyl, hexanoyl, 3, 3-dimethylbutyryl, 2-ethylbutyryl, etc.
  • 3-phenylpropionyl 2-amino-2- phenylacetyl, 2-t-butoxycarbonylamino-2- phenylacetyl, 2-hydroxy-2-phenylacetyl, 2- hydroxy-3-phenylpropionyl, 2-methoxy-2- pheylacetyl, cyclopropylacetyl, cyclopentylacetyl, aminoacetyl, t- butoxycarbonylaminoacetyl, 3-aminopropionyl, 3-t-butoxycarbonylaminopropionyl, 2- aminoisovaleryl, 2-t- butoxycarbonylaminoisovarelyl, 2- aminopivaloyl, 2-t- butoxycarbonylaminopivaloyl, methoxyacetyl, (2-methoxyethoxy) acetyl, phenoxyacetyl, 2- pyridylacetyl, 3-thienylacetyl, etc.).
  • R is -optionally substituted phenyl or naphthyl selected from: (Sal) 4-methoxyphenyl, 4-ethoxyphenyl,
  • R is acyl selected from the group consisting of; (Aid) methylsulfonyl, ethylsulfonyl, propylsulfonyl, benzylsulfonyl, (A5d) dimethylaminosulfonyl, diethylaminosulfonyl, N- (2-methoxyethyl) aminosulfonyl, N-methyl-N- (2- methoxyethyl) aminosulfonyl, (A7d) benzoyl, 2-naphthoyl, 2- or 3- or 4- methoxybenzoyl, 2-ethoxybenzoyl, 2- propoxybenzoyl, 2,3- or 2,4- or 2,5- dimethoxybenzoyl, 2,
  • 3-pyridylsulfonyl 4-methyl-5- pyrimidinylcarbonyl, 2-pyrazinylcarbonyl, 1- pyrrolidinylcarbonyl, 1-pyrrolidinylsulfonyl, 1- or 4-piperidinylcarbonyl, l-acetyl-4- piperidinylcarbonyl, 1-piperidinylsulfonyl, 4- methoxy-1-piperidinylsulfonyl, 2- or 3- thienylcarbonyl, 2-thienylsulfonyl, 2- indolylcarbonyl, 3- or 8-quinolylcarbonyl, 1- isoquinolylcarbonyl, 2-furylcarbonyl, 2- benzothienylcarbonyl, 4-morpholinylcarbonyl,
  • R is - (C,-C, mecanic) aryloxy optionally substituted by the group consisting of lower alkoxy, lower alkyl and halo (e.g. methoxyphenoxy, methylphenoxy, chlorophenoxy, fluorophenyl, etc.);
  • R 2d is carboxy or N-hydroxycarbamoyl
  • R 3d is -acyl selected from the group consisting of:
  • lower alkylsufonyl e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.
  • (A6d) mono- or di (lower) alkylcarbamoyl e.g. propylcarbamoyl, isopropylcarbamoyl, t-butylcarbamoyl, etc.
  • nitrogen atoms e.g. pyridylcarbonyl, pyrazinylcarbonyl, etc.
  • H2 saturated 5- or 6-membered, heteromonocyclic group containing 5 1 to 4 nitrogen atoms e.g. piperidinylcarbonyl, etc.
  • H3 unsaturated 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms e.g. 2- or
  • heterocyclic acyl may be pyridylcarbonyl (e.g. 2- or 3- or 4-pyridylcarbonyl,
  • pyrazinylcarbonyl e.g. 2- pyrazinylcarbonyl, etc.
  • piperidinylcarbonyl e.g. 1- piperidinylcarbonyl, etc.
  • thienylcarbonyl e.g. 2- or 3-
  • thienylcarbonyl, etc. 25 thienylcarbonyl, etc.
  • thienylsulfonyl e.g. 2- thienylsulfonyl, etc.
  • morpholinylsulfonyl e.g. 1- morpholinylsulfonyl, etc.
  • lower cycloalkylcarbamoyl e.g. cyclohexylcarbamoyl, etc.
  • lower cycloalkylcarbonyl e.g. cyclopropylcarbonyl, etc.
  • Al6d lower alkanoyl
  • Ar d is phenyl
  • Rld, R3d and xd are each as defined in above
  • R is - (C fi -C. n ) aryloxy (e.g. phenoxy, etc.) optionally substituted by the group consisting of lower alkoxy, lower alkyl and halo (e.g. methoxyphenoxy, methylphenoxy, chlorophenoxy, fluorophenyl, etc.),
  • R 3d is -acyl selected from the group consisting of:
  • lower alkylsufonyl e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.
  • heterocyclic-carbonyl or heterocyclic- 5 sulfonyl wherein the heterocyclic group being selected from; (Hi) unsaturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. 10 pyridylcarbonyl, pyrazinylcarbonyl, etc. ) , (H2) saturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. 15 piperidinylcarbonyl, etc.),
  • heterocyclic acyl may be pyridylcarbonyl (e.g. 2- or 3- or 4-pyridylcarbonyl, etc.) pyrazinylcarbonyl (e.g. 2- 30 pyrazinylcarbonyl, etc.), piperidinylcarbonyl (e.g. 1- piperidinylcarbonyl, etc. ) , thienylcarbonyl (e.g. 2- or 3- thienylcarbonyl, etc.), 35 thienylsulfonyl (e.g. 2- thienylsulfonyl, etc.), morpholinylsulfonyl (e.g. 1- morpholinylsulfonyl, etc.), (A9d) lower cycloalkylcarbamoyl (e.g. cyclohexylcarbamoyl, etc.),
  • R 1 d is -phenoxy, lower alkoxyphenoxy, lower alkylphenoxy or halophenoxy (e.g. 4- methoxyphenoxy, 4-ethoxyphenoxy, 4- methylphenoxy, 4-chlorophenoxy, 4-fluorophenyl, etc. ) ;
  • R is -acyl selected from the group consisting of: (Aid) lower alkylsufonyl (e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.),
  • alkylcarbamoyl e.g. propylcarbamoyl, isopropylcarbamoyl, t- butylcarbamoyl, etc.
  • benzoyl e.g. benzoyl, etc.
  • benzoyl substituted by lower alkoxy e.g. 2- methoxybenzoyl, etc.
  • heterocyclic-carbonyl or heterocyclic- sulfonyl selected from; (Hi) pyridylcarbonyl, pyrazinylcarbonyl (e.g. 2-pyridylcarbonyl, 2- pyrazinylcarbonyl, etc. ) , (H2) piperidinylcarbonyl (e.g. 1- piperidinylcarbonyl, etc.),
  • lower cycloalkylcarbamoyl e.g. cyclohexylcarbamoyl, etc.
  • Al3d lower cycloalkylcarbonyl (e.g. cyclopropylcarbonyl, etc.)
  • Al ⁇ d lower alkanoyl, lower alkanoyl substituted by phenyl and hydroxy (e.g. isovaleryl, 2-hydroxy-2-phenylacetyl, etc. ) .
  • R 1 d is -phenoxy, 4-methoxyphenoxy, 4-ethoxyphenoxy, 4- methylphenoxy, 4-chlorophenoxy, 4-fluorophenyl
  • R 3d is -acyl selected from the group consisting of:
  • heterocyclic-carbonyl or heterocyclic- sulfonyl selected from; (HI) 2-pyridylcarbonyl, 2- pyrazinylcarbonyl, (H2) 1-piperidinylcarbonyl,
  • (A16d) isovaleryl, 2-hydroxy-2-phenylacetyl .
  • the compound (I-bd) or a salt thereof can be prepared by acylating the compound (I-ad) or its reactive derivative at the amino group, or a salt thereof.
  • Suitable salts of the compounds (I-ad) and (I-bd) may be the same as those for the compound (I-d) .
  • Suitable acylating agent used in this reaction may be a conventional acylating agent which is capable of introducing the acyl group as mentioned before, such as carboxylic acid, carbonic acid, sulfonic acid and their reactive derivative, for example, an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • reactive derivative may include acid chloride, acid bromide, a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.
  • dialkylphosphoric acid phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid 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, 2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g.
  • benzoic acid etc.
  • a symmetrical acid anhydride an activated acid amide with a heterocyclic compound containing imino function such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, an activated ester (e.g.
  • p-nitrophenyl ester 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy-2- (IH) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, l-hydroxy-6- chlorobenzotriazole, etc.), isocyanic acid or a salt thereof (e.g. sodium isocyanate, etc.), lower alkylisocyanate (e.g
  • This reaction can be carried out in the presence of an 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. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.
  • alkali metal e.g. lithium, sodium potassium, etc.
  • alkaline earth metal e.g. calcium, etc.
  • alkali metal hydride e.g. sodium hydride, etc.
  • alkaline earth metal hydride e.g. calcium hydride, etc.
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.
  • quinoline and the like.
  • the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound [e.g. N, N' -dicyclohexylcarbodiimide, N-cyclohexyl-N' - (4-diethylaminocyclohexyl) carbodiimide, N,N' -diethylcarbodiimide, N,N' -diisopropylcarbodiimide, N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide, etc. ] a ketenimine compound (e.g.
  • an olefinic or acetylenic ether compounds e.g. ethoxyacetylene, ⁇ -chlorovinylethyl ether
  • a sulfonic acid ester of N-hydroxybenzotriazole derivative e.g. l-(4- chlorobenzen
  • ethyl polyphosphate isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, a reagent (referred to a so-called "Vilsmeier reagent") formed by the reaction of an amide compound such as N, N-di (lower) alkylformamide (e.g. dimethylformamide, etc.), N-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like, and the like.
  • a reagent referred to a so-called "Vilsmeier reagent” formed by the reaction of an amide compound such as N, N-di (lower) alkylformamide (e.g. dimethyl
  • the reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, chloroform, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, acetone, dichloromethane, chloroform, alcohol (e.g. methanol, ethanol, etc.), tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixture thereof.
  • the reaction temperature is not critical and the reaction can be carried out under from cooling to heating.
  • the compound (I-dd) or a salt thereof can be prepared by reacting the compound (I-cd) or a salt thereof with the compound (II-d) .
  • Suitable salts of the compound (I-cd) and (I-dd) may be the same as those exemplified for the compound (I-d) .
  • the reaction can be carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2- dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not ⁇ adversely affect the reaction.
  • a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2- dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not ⁇ adversely affect the reaction.
  • This reaction can be carried out in the presence o'f an 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. sodium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.
  • alkali metal e.g. lithium, sodium, potassium, etc.
  • alkaline earth metal e.g. calcium, etc.
  • alkali metal hydride e.g. sodium hydride, etc.
  • alkaline earth metal hydride e.g. calcium
  • alkali metal alkanoic acid e.g. sodium acetate, etc.
  • trialkylamine e.g. triethylamine, etc.
  • pyridine compound e.g. pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.
  • quinoline lithium diisopropylamide
  • alkali metal halide e.g. sodium iodide, potassium iodide, etc.
  • alkali metal thiocyanate e.g.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • di (lower) alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholinoethylcarbodiimide;
  • a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholinoethylcarbodiimide;
  • N,N' -diethylcarbodiimide N,N' -diisopropylcarbodiimide
  • 1-alkoxy-l-chloroethylene 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride) ; phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate
  • the reaction temperature is not critical, and the reaction can be carried out under from warming to heating.
  • the object compound (I-fd) or a salt thereof can be prepared by subjecting a compound (I-ed) or a salt thereof to a removal reaction of the hydroxycarbamoyl-protective group.
  • Suitable salts of the compounds (I-ed) and (I-fd) can be referred to the ones as exemplified for the compound (I- d).
  • This reaction is carried out in accordance with a conventional method such as solvolysis including hydrolysis, reduction or the like.
  • the solvolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, lithium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1, 5-diazabicyclo [4.3.0] - non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec-7-ene, or the like.
  • Suitable acid may include and organic acid [e.g.
  • the removal reaction using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like, is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
  • the reaction can be carried out in a solvent such as water, an alcohol [e.g.
  • methanol, ethanol, etc. methylene chloride, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, N,N-dimethylformamide, a mixture thereof or any Other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent .
  • the reaction temperature is not critical and the reaction can be carried out under cooling to heating.
  • the reduction method applicable for the removal reaction may include chemical reduction and catalytic reduction. Suitable reducing agents to be used in chemical reduction may include a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p- toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc. ] .
  • metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p- toluenesulf
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like, and these catalysts may be used in a combination with ammonium formate (e.g. a combination of palladium on carbon and ammonium formate, etc. ) .
  • platinum catalysts
  • the reduction can be carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above- mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction can be carried out under cooling to heating.
  • the compound (I-ad) or a salt thereof can be prepared by subjecting the compound (I-bd) or a salt thereof to a removal reaction of the acyl group.
  • reaction of this process can be carried out in a manner similar to that of Process 3.
  • the compound (I-d) or a salt thereof can be prepared by amidating the compound (Ill-d) or its reactive derivative at the carboxy group, or a salt thereof.
  • Suitable salts of the compound (Ill-d) may be the same as those for the compound (I-d) .
  • Suitable reactive derivative at the carboxy group may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride which acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g.
  • methanesulfonic acid, etc. aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (I-b) to be used.
  • the reaction can be carried out in a conventional solvent such as water, alcohol [e.g.
  • the reaction when the starting compound is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N' -dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholinoethylcarbodiimide; N-cyclohexyl-N ' - (4-diethylaminocyclohexyl) carbodiimide; N,N' -diethylcarbodiimide, N,N' -diisopropylcarbodiimide; l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSCD) its hydrochloricde; N,N' -carbonylbis (2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxy
  • the amidation reaction applicable to this process may include a conventional amidation reaction which can convert a carboxy group to an amidated carboxy group as mentioned above, for example, reaction with an optionally protected hydroxylamine (e.g. hydroxylamine, tetrahydropyranyloxyamme, etc.), and the like.
  • the reaction may also be carried out in the presence of an inorganic or organic base as mentioned above such as an alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N,N-di (lower) alkylbenzylamine, alkali metal hydroxide, or the like.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to warming.
  • the compound (I-hd) or a salt thereof can be prepared by subjecting the compound (I-gd) or a salt thereof to a removal reaction of the amino- or imino-protective group on
  • Suitable salts of the compounds (I-gd) and (I-hd) may be the same as those for the compound (I-d) .
  • the compound (I-jd) or a salt thereof can be prepared by acylating the compound (I-id) or a salt thereof.
  • Suitable salts of the compounds (I-id) and (I-jd) may be the same as those for the compound (I-d) .
  • the reaction of this process can be carried out in a manner similar to that of Process 1.
  • the compound (I-kd) or a salt thereof can be prepared by reacting the compound (I-cd) or a salt thereof with the compound (IV) .
  • Suitable salts of the compound (I-kd) may be the same as those for the compound (I-d) .
  • This reaction can preferably be carried out in the presence of palladium compound (e.g. palladium acetate,- . etc.), triphenylphosphine, copper compound' (e.g. copper iodide, etc.), and aforementioned base (e.g. triethylamine, etc. ) .
  • palladium compound e.g. palladium acetate,- . etc.
  • triphenylphosphine e.g. copper iodide, etc.
  • copper compound' e.g. copper iodide, etc.
  • aforementioned base e.g. triethylamine, etc.
  • the reaction can be carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compound (I-ld) or a salt thereof can be prepared by reacting the compound (I-ad) or a salt thereof with the compound (V) .
  • Suitable salts of the compound (I-ld) may be the same as those for the compound (I-d) .
  • This reaction can preferably be carried out in the presence of aforementioned chemical reducing agent (e.g. cyanoborohydride, triacetoxyborohydride, etc.), and aforementioned acid (e.g. acetic acid etc.).
  • aforementioned chemical reducing agent e.g. cyanoborohydride, triacetoxyborohydride, etc.
  • aforementioned acid e.g. acetic acid etc.
  • the reaction can be carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the compounds obtained above can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation and the like.
  • the object compounds can be transformed into their salts or solvates in a conventional manner.
  • the object compounds may include one or more stereoisomers or optical isomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention.
  • the compounds having the formulas (I-a) to (I-d) and pharmaceutically acceptable salts thereof are useful as inhibitors of MMP and/or the production of TNF ⁇ , and therefore they are useful for treating inflammatory respiratory disease, for example, chronic obstructive pulmonary disease (COPD) ; bronchial asthma; diseases associated with lung tissue injury and fibrosis, which occur from various causes, such as bronchitis, interstitial pneumonia, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) , etc.; rhinitis and sinusitis including allergic rhinitis and chronic sinusitis; and the like.
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma diseases associated with lung tissue injury and fibrosis, which occur from various causes, such as bronchitis, interstitial pneumonia, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) , etc.
  • ARDS acute respiratory distress syndrome
  • rhinitis and sinusitis including allergic rhinitis and
  • the compounds and pharmaceutically acceptable salts thereof of the present invention can be used in the form of a pharmaceutical preparation containing, as an active ingredient, one of said compounds in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • the pharmaceutical preparations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, sublingual tablets, suppositories, ointments, and the like. If desired, there may be included, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifying agents, buffers and other commonly used additives.
  • a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of a human being in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the active ingredient per kg weight of a human being, and in the case of intramuscular administration, a daily dose of 0.05 - 100 mg of the same per kg weight of a human being, or in the case of oral administration, a daily dose of 0.1 - 100 mg of the same per kg weight of a human being, is generally given for the treatment of MMP or TNFD ⁇ -mediated diseases.
  • LPS lipopolysaccharide
  • Test Method Mice were anesthetized and injected LPS solution intratracheally. After 24 hours, mice were sacrificed and bronchoalveolar lavage (BAL) was repeated three times via a tracheal cannula. The BAL fluid was freeze-thawed and sonicated to lyse cells including erythrocytes . Hemoglobin content in the cell lysate was assayed by measuring optical density at 406 nm as a lung injury marker. Bovine hemoglobin was used to construct a standard curve. The Test Compound (32 mg/kg) or the vehicle was given perorally four times, 24, 16 and 1 hour before plus 7 hours after the LPS injection. Test Compound:
  • reaction mixture was concentrated in vacuo and hydrogen chloride was azeotropically removed with toluene to give tert-butyl 2- [7- (5- (4- (5-oxazolyl) phenyl) -2-thienyl) -1,1- dioxoperhydro-1, 4-thiazepin-7-yl] acetate hydrochloride (4.2 g) as an oil.
  • N- (N-t-butoxycarbonyl-N- (2- methoxyethyl) aminosulfonyloxy) succinimide 200 mg
  • dichloromethane 2 ml
  • trifluoroacetic acid 2 ml
  • the solution was evaporated in vacuo to give N- (2-methoxyethylaminosulfonyloxy) succinimide as a colorless amorphous powder (149 mg) .

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Abstract

La présente invention concerne un agent comprenant un composé de formule (I-a) et analogue, ou un sel de celui-ci, l'utilisation d'un composé de formule (I-a) et analogue, ou un sel de celui-ci pour la fabrication d'un médicament, ou un procédé comportant l'administration d'un composé de formule (I-a) et analogue, ou un sel de celui-ci, pour le traitement de maladie respiratoire inflammatoire, dans laquelle formule: Aa est un groupe sulfonyle ou carbonyle; R1a est un aryle éventuellement substitué; R2a est hydrogène; R3a est un alkyle inférieur éventuellement substitué; R4a est hydrogène, un alkyle inférieur éventuellement substitué, un aryle éventuellement substitué ou un groupe hétérocyclique éventuellement substitué; R5a est hydrogène; et R6a est un hydroxyle ou un hydroxyle protégé.
PCT/JP2002/008443 2001-08-24 2002-08-21 Nouvelle utilisation de compose cyclique WO2003018019A2 (fr)

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