WO1996016079A2 - Derives d'alpha-cetoamide utilises comme inhibiteurs de cathepsine l - Google Patents

Derives d'alpha-cetoamide utilises comme inhibiteurs de cathepsine l Download PDF

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WO1996016079A2
WO1996016079A2 PCT/JP1995/002389 JP9502389W WO9616079A2 WO 1996016079 A2 WO1996016079 A2 WO 1996016079A2 JP 9502389 W JP9502389 W JP 9502389W WO 9616079 A2 WO9616079 A2 WO 9616079A2
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group
substituted
heterocyclic group
compound
aromatic heterocyclic
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PCT/JP1995/002389
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English (en)
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WO1996016079A3 (fr
Inventor
Takashi Sohda
Yukio Fujisawa
Tsuneo Yasuma
Junji Mizoguchi
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Takeda Chemical Industries, Ltd
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Priority to AU39358/95A priority Critical patent/AU3935895A/en
Priority to CA002200964A priority patent/CA2200964A1/fr
Priority to EP95937173A priority patent/EP0793673A1/fr
Publication of WO1996016079A2 publication Critical patent/WO1996016079A2/fr
Publication of WO1996016079A3 publication Critical patent/WO1996016079A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to a cathepsin L inhibitor comprising an ⁇ r-ketoamide derivative or a salt thereof as an active ingredient, and use thereof.
  • Osteoporosis is a pathologic state or disease involving some symptom or risk due to quantitative bone reduction exceeding a certain degree.
  • Major symptoms are spinal kyphosis, fractures of dorsolumbar bones, vertebral centra, femoral necks, lower end of radius, ribs, upper end
  • bone resorption-suppressing agents such as estrogens and
  • cathepsin L a protease secreted by osteoclasts in the process of bone resorption
  • PCT Int. Appl. WO 94/00095 discloses a- ketoamide derivatives as calpain inhibitors
  • PCT Int. Appl. WO 92/12140 Japanese Publication of translations of International patent application No. 504547/1994 discloses 5 ⁇ -ketoamide derivatives as calpain, papain and cathepsin B inhibitors.
  • the present inventors sought to develop a more commonly applicable drug showing selective inhibition of cathepsin L and direct action on the bone to suppress bone resorption, and found that an ⁇ -ketoamide derivative shows potent cathepsin L inhibition and direct action on the bone 0 to excellently suppress bone resorption, and that it serves well as a prophylactic/therapeutic agent for bone disease.
  • the inventors made further investigations based on this finding, and developed the present invention.
  • a cathepsin L inhibitor comprising a compound of the formula (la) : ( la ) wherein Q represents a direct bond or 1 or 2 amino acid residues that may be substituted; R 1 represents a hydrogen atom or a hydrocarbon or heterocyclic group that may be substituted; R 4 represents an acyl group or a carboxyl group that may be esterified and R 5 and R 6 independently represent a hydrogen atom or a hydrocarbon or heterocyclic group that may be substituted or R 5 and R 6 may bind together to form a ring; or a salt thereof,
  • R -(N (I) wherein R 1 , R 2 and R 3 independently represent a hydrogen atom or a hydrocarbon or heterocyclic group that may be substituted; R 4 represents an acyl group or a carboxyl group that may be esterified and R 5 and R 6 independently represent a hydrogen atom or a hydrocarbon or heterocyclic group that may be substituted or R 5 and R 6 may bind together to form a ring; m and n independently represent 0 or 1; or a salt thereof,
  • a method for inhibiting a cathepsin L activity of a mammal which comprises administering to said mammal a pharmaceutically effective amount of a compound of the formula (la) in item (1),
  • R 4a is a group represented by the formula - COR a or -S ⁇ 2 R b wherein R a and R b are independently an optionally substituted aryl or aromatic heterocyclic group;
  • R 5a and R 6a independently represent a straight-chain or branched C ⁇ _ 6 alkyl group which may be substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group and m and n independently represent 0 or 1; provided that where R a is an optionally substituted aromatic heterocyclic group, R 5a and R 6a independently represent a straight-chain or branched C ⁇ - 6 alkyl group which is substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group; or
  • R 4b is represented by the formula -COR c wherein R c is a straight- chain or branched Ci- ⁇ alkyl group which is substituted with an optionally substituted aryl or aromatic heterocyclic group;
  • R 5b and R 6b independently represent a straight-chain or branched C ⁇ _ 6 alkyl group which is substituted with an optionally substituted aryl group or an esterified carboxyl group; and
  • m and n independently represent 0 or 1, or a salt thereof,
  • R 4a (N (II') wherein R 1 , R 2 and R 3 independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted;
  • R 4a is a group represented by the formula - COR a or -S ⁇ 2 R b wherein R a and R b are independently an optionally substituted aryl or aromatic heterocyclic group and R 5a and R 6a independently represent a straight-chain or branched C ⁇ - 6 alkyl group which may be substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group; provided that where R a is an optionally substituted aromatic heterocyclic group and R 5a and R 6a independently represent a straight- chain or branched C ⁇ - 6 alkyl group which is substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group; or a salt thereof, to an oxidation reaction,
  • R b (II'') wherein R 1 , R 2 and R 3 independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted;
  • R b is a group represented by the formula - COR c wherein R c is a straight-chain or branched C ⁇ _ 6 alkyl group which is substituted with an optionally substituted aryl or aromatic heterocyclic group and R 5b and R 6b independently represent a straight-chain or branched C ⁇ -6 alkyl group which is substituted with an optionally substituted aryl group or an esterified carboxyl group; or a salt thereof, to an oxidation reaction,
  • composition which comprises a compound of item (5) and (19) A composition which comprises a compound of item (15).
  • the ⁇ -ketoamide derivative for the present invention synthesized by oxidizing a corresponding optically active ⁇ -hydroxyamide derivative under easy DMSO oxidization conditions, is an optically active isomer with the S- configuration at ⁇ position.
  • the amino acid residue for the "1 or 2 amino acid residues that may be substituted," shown by Q is exemplified by o-amino acids, -amino acids and y-amino acids, which are represented by the respective formulas RCH(NH 2 )COOH, H 2 NCH 2 CHRC0 2 H and H 2 NCH 2 CH 2 CHRC0 2 H (R represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted), with preference given to ⁇ -amino acids.
  • RCH(NH 2 )COOH H 2 NCH 2 CHRC0 2 H and H 2 NCH 2 CH 2 CHRC0 2 H
  • R represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted
  • Q is a dipeptide residue resulting from the binding of 2 amino acids and the 2 amino acids may be of the same type or not, but the residue preferably consists of 2 ⁇ -amino acids.
  • the dipeptide residue consists of 2 amino acids of
  • hydrocarbon group that may be substituted shown by R
  • R is exemplified by the same hydrocarbon groups as those exemplifying the "hydrocarbon group that may be substituted," shown by R 1 , R 2 or R 3 below.
  • heterocyclic group that may be substituted shown by R
  • R 1 , R 2 or R 3 The "heterocyclic group that may be substituted,” shown by R, is exemplified by the same heterocyclic groups as those exemplifying the “heterocyclic group that may be substituted," shown by R 1 , R 2 or R 3 below.
  • R The substituent for the "hydrocarbon group or heterocyclic group that may be substituted," shown by R, is exemplified by the same substituents as those for the "hydrocarbon group or heterocyclic group that may be substituted," shown by R 1 , R 2 or R 3 below.
  • ⁇ -amino acid residue is exemplified by glycine and natural or non-natural L- or D- -r-amino acids.
  • amino acids include glycine, and a-L- amino acids or o-D-amino acids (e.g., ⁇ —L- or c-D-alanine, valine, leucine, isoleucine, serine, threonine, asparagine, gluta ine, aspartic acid, glutamic acid, lysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline), with preference given to glycine and ⁇ —L-alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan etc.
  • the "1 or 2 amino acid residues that may be substituted,” shown by Q, may have 1 to 3 substituents at any possible positions. Such substituents are exemplified by the same substituents for the "hydrocarbon group or heterocyclic group that may be substituted," shown by R 1 , R 2 or R 3 below.
  • Q is preferably a group represented by formula (Ia-Q):
  • R 2 and R 3 whether identical or not, independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted; m and n, whether identical or not, independently represent 0 or 1.
  • the "hydrocarbon group that may be substituted" shown by R 1 , R 2 or R 3 is exemplified by saturated or unsaturated aliphatic hydrocarbon chain groups, saturated or unsaturated alicyclic hydrocarbon groups and aryl groups.
  • saturated aliphatic hydrocarbon groups include straight or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (e.g., C ⁇ - ⁇ o alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.- pentyl, hexyl, isohexyl, heptyl and octyl), with preference given to straight or branched saturated aliphatic ' hydrocarbon groups having 1 to 6 carbon atoms.
  • C ⁇ - ⁇ o alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.
  • Such unsaturated aliphatic hydrocarbon groups include straight or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (e.g., C 2 _ ⁇ o alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl; C 2 - ⁇ o alkinyl groups such as ethynyl, 1- propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, 1- pentinyl, 2-pentinyl, 3-pentinyl, 4-
  • saturated alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g., C 3 - ⁇ 2 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl) , with preference given to saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms.
  • saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms e.g., C 3 - ⁇ 2 cycloalkyl groups such as cyclopropyl, cyclobutyl,
  • Such unsaturated alicyclic hydrocarbon groups include unsaturated alicyclic hydrocarbon groups having 5 to 12 carbon atoms (e.g., C 5 - 12 cycloalkenyl groups such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4- cycloheptadienyl, 2-cyclopenten-l-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3-cyclohexen-l-yl; C 5 - 12 ' cycloalkadienyl groups such as 2,4-cyclopentadien-l-yl, 2,4-cyclohexadien-l-yl and 2,5-cyclohexadien-l-yl)
  • the "hydrocarbon group that may be substituted,” shown by R 1 , R 2 or R 3 , may be a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms and substituted with one of the above saturated or unsaturated alicyclic hydrocarbon groups (e.g., C3- cycloalkyl-C ⁇ _ 8 alkyls or C5_ cycloalkenyl-C ⁇ -8 alkyls, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2- cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3- cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl) , or the like.
  • Aryl groups include monocyclic or condensed polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms.
  • aromatic hydrocarbon ring groups include phenyl, tolyl, xylyl, biphenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 9-phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl and acenaphthylenyl, with preference given to C ⁇ -io aryl such as phenyl, 1-naphthyl, 2-naphthyl etc.
  • the "hydrocarbon group that may be substituted," shown 5 by R 1 , R 2 or R 3 , may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents include aryl groups that may be substituted, cycloalkyl or cycloalkenyl groups that may be substituted, heterocyclic groups that may be substituted, carboxyl groups that may be Q esterified, carbamoyl groups that may be substituted, amino groups that may be substituted, hydroxyl groups that may be substituted, thiol groups that may be substituted, halogens (e.g., fluorine, chlorine, bromine, iodine) and phosphono groups that may be substituted.
  • fluorine chlorine, bromine, iodine
  • aryl group that may be substituted is exemplified by C ⁇ - 14 aryl such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preference given to phenyl, 1-naphthyl and 2-naphthyl.
  • Said aryl may have 1 to 2 optionally chosen substituents at any possible Q positions, these substituents including hydroxy, alkoxy groups that may be substituted (e.g., C 1 - 3 alkoxys such as methoxy, ethoxy and propoxy), halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and alkyl groups that may be substituted (e.g., C 1 - 3 alkyls such as methyl, ethyl and propyl).
  • substituents including hydroxy, alkoxy groups that may be substituted (e.g., C 1 - 3 alkoxys such as methoxy, ethoxy and propoxy), halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and alkyl groups that may be substituted (e.g., C 1 - 3 alkyls such as methyl, ethyl and propyl).
  • alkoxy groups and alkyl groups may have 1 or 2 optionally chosen substituents at any possible positions, these substituents including phosphono groups that may be substituted (e.g., dimethoxyphosphoryl, di- ethoxyphosphoryl) .
  • cycloalkyl group that may be substituted is exemplified by C 3 - 7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the kinds and number of substituents for the cycloalkyl group that may be substituted are the same as those of the substituents for the above-described aryl group that may be 0 substituted.
  • cycloalkenyl group that may be substituted is exemplified by C 3 - 6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • the kinds and number of substituents for the c cycloalkenyl group that may be substituted are the same as those of the substituents for the above-described aryl group that may be substituted.
  • heterocyclic group that may be substituted is exemplified by aromatic heterocyclic groups having at least Q 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), with preference given to aromatic heterocyclic groups.
  • the aromatic heterocyclic 5 group is exemplified by 5- to 7-membered aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, 5- to 6-membered aromatic heterocyclic groups containing 2 to 4 atoms of nitrogen and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 atoms of Q nitrogen and 1 atom of sulfur or oxygen.
  • aromatic heterocyclic groups may have condensed with a 6-membered ring containing 2 or fewer atoms of nitrogen, a benzene ring or a 5-membered ring containing 1 atom of sulfur.
  • aromatic heterocyclic groups include aromatic 5 monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
  • the non- aromatic heterocyclic group is exemplified by 5- to 7- membered non-aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, and 4- to 7-membered non- aromatic heterocyclic groups containing 1 atom of nitrogen and 3 or fewer atoms selected from nitrogen, oxygen and sulfur.
  • Such non-aromatic heterocyclic groups include oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperizyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
  • the substituent for said heterocyclic group that may be substituted is exemplified by alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl).
  • the carboxyl groups that may be esterified include - COOH, (lower(C ⁇ - 6 )alkoxy)carbonyls (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyloxycarbonyl) and (C ⁇ -io aryloxy)carbonyls (e.g., phenoxycarbonyl, 1- naphthoxycarbonyl) , (C 7 - 13 aralkyloxy)carbonyls (e
  • the substituent for said carbamoyl group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl) and C 7 - 13 aralkyl groups (e.g., benzyl, phenethyl); 1 or 2 of these substituents, whether identical or not, may be present.
  • the substituent for said amino group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 -.
  • lower alkyls e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl
  • cycloalkyl groups e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • C 6 - 10 aryl groups e.g., phenyl, 1-naphthyl, 2-naphthyl
  • C 7 -. 13 aralkyl groups e.g., benzyl, phenethyl
  • the substituent for said hydroxyl group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl) and C 7 - 13 aralkyl groups (e.g., benzyl, phenethyl).
  • lower (Ci- ⁇ ) alkyls e.g., methyl, eth
  • the substituent for said thiol group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g.. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups (e.g., phenyl, 1-naphthyl, 2-naphthyl) and C 7 - 13 aralkyl groups (e.g., benzyl, phenethyl).
  • lower (Ci- ⁇ ) alkyls e.g.. methyl, e
  • the substituent for said phosphono group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- 0 butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), lower (C ⁇ _ 6 ) alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.- butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy) .
  • lower (Ci- ⁇ ) alkyls e.g., methyl, ethyl, propyl, isopropyl, butyl
  • Said phosphons groups include phosphoryl, 5 dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl and tetramethylenedioxyphosphoryl.
  • the substituent may be an aliphatic hydrocarbon group that may be substituted.
  • Such aliphatic hydrocarbon groups include the same saturated or unsaturated (preferably saturated) aliphatic hydrocarbon groups as those exemplifying the "hydrocarbon group that may be substituted," shown by R 1 , R 2 or R 3 above, with preference given to alkyl groups (e.g., C 1 - 3 alkyls such as methyl, ethyl and propyl).
  • the aliphatic hydrocarbon group may have 1 or 2 optionally chosen substituents at any 0 possible positions, these substituents including phosphono groups that may be substituted (e.g., phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl) .
  • heterocyclic group that may be substituted shown by R 1 , R 2 or R 3 , is exemplified by aromatic 5 heterocyclic groups having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring- constituting atom (ring atom), and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), with preference given to aromatic heterocyclic groups.
  • aromatic heterocyclic groups are exemplified by 5- to 7-membered heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, 5- to 6-membered heterocyclic groups containing 2 to 4 atoms of nitrogen and 5- or 6- membered aromatic heterocyclic groups containing 1 or 2 0 atoms of nitrogen and 1 atom of sulfur or oxygen.
  • These aromatic heterocyclic groups may have condensed with a 6- membered ring containing 2 or fewer atoms of nitrogen, a benzene ring or a 5-membered ring containing 1 atom of sulfur.
  • aromatic heterocyclic groups include aromatic 5 monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, Q 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 2-, 3- or 4- pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-pyrazinyl, triazinyl) and aromatic condensed heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[
  • non-aromatic heterocyclic groups are exemplified by 5- to 7-membered non-aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, and 4- to 7-membered non-aromatic heterocyclic groups containing 1 atom of nitrogen and 3 or fewer atoms selected from nitrogen, oxygen and sulfur (e.g., oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, 0 thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, ho opiperidyl, pyrrolinyl, imidazolidinyl) .
  • nitrogen, oxygen and sulfur e.g., oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidiny
  • non-aromatic heterocyclic groups may condense with a benzene ring, a 6-membered ring containing 2 or fewer atoms of nitrogen, or a 5-membered c ring containing 1 atom of sulfur.
  • condensed non-aromatic heterocyclic groups include chro anyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl.
  • the "heterocyclic group that may be substituted," Q shown by R 1 , R 2 or R 3 , may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents include aryl groups that may be substituted, cycloalkyl or cycloalkenyl groups that may be substituted, heterocyclic groups that may be substituted, carboxyl groups that may be 5 esterified, carbamoyl groups that may be substituted, amino groups that may be substituted, hydroxyl groups that may be substituted, thiol groups that may be substituted, halogens (e.g., fluorine, chlorine, bromine, iodine), phosphono groups that may be substituted, and aliphatic hydrocarbon 0 groups that may be substituted.
  • fluorine chlorine, bromine, iodine
  • phosphono groups that may be substituted
  • aliphatic hydrocarbon 0 groups that may be substituted.
  • the "hydrocarbon group that may be substituted,” shown by R 1 , R 2 or R 3 above, is exemplified by alkyl groups, preferably C ⁇ - ⁇ o alkyls, with greater preference given to linear or branched lower alkyls having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl, 4-methylpentyl, 1,1- dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2- ethylbutyl).
  • Preferable substituents for the "hydrocarbon group that may be substituted" are aryls that may be substituted (preferably phenyl etc.) and heterocyclic
  • Rl is preferably an alkyl group substituted with an optionally substituted aryl or heterocyclic group.
  • R 1 is an alkyl group substituted with an aryl or heterocyclic group.
  • Said alkyl substituted with an aryl is exemplified by groups resulting from binding of a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl) and a lower alkyl having 1 to 6 carbon atoms (preferably C 1 - 4 alkyl) (e.g., benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1- phenylpropyl, ⁇ -naphthylmethyl, ⁇ -naphthylethyl, ⁇ - naphthylmethyl, /?-naphthylethyl) .
  • Said alkyl substituted with a heterocyclic group is exemplified by groups resulting from binding of an aromatic heterocyclic group and a lower alkyl having 1 to 6 carbon atoms (preferably C 1 - 4 alkyl group) .
  • aromatic heterocyclic groups include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-oxazolyl, 4-o
  • Rl is more preferably a straight-chain or branched C ⁇ _ 6 alkyl group which is substituted with phenyl.
  • R2 and R3 are independently a straight-chain or branched C ⁇ _ 6 alkyl.
  • R 1 is preferably indol-3-ylmethyl, benzyl, methyl, isopropyl, 1-naphthylmethyl, or the like.
  • R2 and R 3 are preferably sec.-butyl, benzyl, isobutyl, isopropyl, or the like.
  • R 1 be indol-3-ylmethyl, benzyl, methyl, isopropyl or 1-naphthylmethyl and R 2 be sec.-butyl, benzyl, isobutyl or isopropyl.
  • R 1 be indol-3-ylmethyl, benzyl, methyl, isopropyl or 1-naphthylmethyl
  • R 2 be sec.-butyl, benzyl, isobutyl or isopropyl
  • R 3 be sec.-butyl, benzyl, isobutyl or isopropyl.
  • the "acyl group" shown by R 4 is exemplified by acyl groups derived from carbamic acids that may be substituted, thiocarbamic acids that may be substituted, carboxylic acids that may be substituted, sulfinic acids that may be substituted, sulfonic acids that may be substituted, etc., specifically those represented by the respective general formulas -CONHR 7 , -CSNHR 8 , -COR 9 , - SOR 10 , -SO 2 R 11 (R 7 , R 8 , R 9 , R 10 and R 11 , whether identical or not, independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted) etc.
  • hydrocarbon group that may be substituted shown by R 7 , R 8 , R 9 , R 10 or R 11 , is exemplified by the same hydrocarbon groups as those exemplifying the "hydrocarbon group that may be substituted," shown by R 1 , R 2 or R 3 above.
  • the "hydrocarbon group that may be substituted for,” shown by R 7 , R 8 , R 9 , R 10 or R 11 , may have 1 to 3 optionally chosen substituents at any possible positions, these substituents being exemplified by the same substituents as those defined for the "hydrocarbon group that may be substituted," shown by R 1 , R 2 or R 3 above.
  • the "heterocyclic group that may be substituted,” shown by R 7 , R 8 , R 9 , R 10 or R 11 , is exemplified by the same heterocyclic groups as those for the "heterocyclic group that may be substituted," shown by R 1 , R 2 or R 3 above.
  • the "heterocyclic group that may be substituted,” shown by R 7 , R 8 , R 9 , R 10 or R 11 may have 1 to 3 optionally chosen substituents at any possible positions, these substituents being exemplified by the same substituents as those defined for the "heterocyclic group that may be substituted," shown by R 1 , R 2 or R 3 above.
  • acyl group shown by R 4 is exemplified by aliphatic acyl groups such as alkanoyl groups (e.g., (lower C 1 - 6 alkyl)carbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl), alkenoyl groups (e.g., (lower C 2 - ⁇ alkenyl)carbonyl groups such as acryloyl, methacryloyl, crotonoyl and isocrotonoyl) , cycloalkanecarbonyl groups (e.g., (C 3 _ 6 cycloalkyl)carbonyl groups such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl) , (C 3 -7 cycloalkan
  • acyl groups for R 4 those represented by the formula -COR 9 or -SO 2 R 11 are preferable.
  • the groups of the formula -COR 9 are preferably represented by the formula -CORa (Ra is an optionally substituted aryl or aromatic heterocyclic group) or the formula -CORc (Re is a straight-chain or branched C ⁇ -6 alkyl group which is substituted with an optionally Q substituted aryl or aromatic heterocyclic group) .
  • the "optionally substituted aryl group" shown by Ra is exemplified by C ⁇ -io aryl such as phenyl, 1-naphthyl, 2- naphthyl.
  • the "optionally substituted aromatic heterocyclic 5 group" shown by Ra is exemplified by quinolyl, isoquinolyl, furyl, thienyl, indolyl, isoindolyl, pyrazinyl and pyridyl, with preference given to quinolyl, isoquinolyl.
  • the "optionally substituted aryl or aromatic heterocyclic group" shown by Ra may have one or more optionally chosen substituents at any possible position, these substituents being exemplified by C 1 - 3 alkyls (e.g. methyl, ethyl, propyl), hydroxy, C 1 - 3 alkoxys (e.g. methoxy, ethoxy, propoxy) and halogens (e.g. fluorine, chlorine, bromine).
  • C 1 - 3 alkyls e.g. methyl, ethyl, propyl
  • hydroxy e.g. methoxy, ethoxy, propoxy
  • halogens e.g. fluorine, chlorine, bromine
  • the "straight-chain or branched C 1 - 6 alkyl group" shown by Re includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl.
  • the "straight-chain or branched C ⁇ - 6 alkyl group” 5 shown by Re has one or more (preferably one or two) substituents such as an optionally substituted aryl or aromatic heterocyclic group. Said optionally substituted aryl or aromatic heterocyclic group is exemplified by the same "optionally substituted aryl or aromatic heterocyclic Q group" as defined in Ra.
  • Re is more preferably a straight-chain or branched Ci- 4 alkyl group which has one or two optionally substituted aryl (preferably phenyl) groups.
  • the group of the formula -S0 2 RH is preferably 5 represented by the formula -S0 2 Rb (Rb is an optionally substituted aryl or aromatic heterocyclic group) .
  • Rb is an optionally substituted aryl or aromatic heterocyclic group
  • the "optionally substituted aryl or aromatic heterocyclic group” shown by Rb is exemplified by the same "optionally substituted aryl or aromatic heterocyclic 0 group" as defined in Ra.
  • Rb is more preferably an optionally substituted aryl group.
  • aryl group that may be substituted shown by R b , is exemplified by C ⁇ -i aryl group such as phenyl, 1- 5 naphthyl and 2-naphthyl. Said aryl group may have 1 or 2 optionally chosen substituents at any possible positions, these substituents including alkyl groups (e.g., C 1 -3 alkyls such as methyl, ethyl and propyl).
  • alkyl groups e.g., C 1 -3 alkyls such as methyl, ethyl and propyl.
  • R 12 represents a hydrogen atom, a C ⁇ -6 alkyl, a C 2 - 6 alkenyl, a C ⁇ -io aralkyl, or the like).
  • groups resulting from binding of a carboxyl group and an alkyl group having 1 to 6 carbon atoms include C ⁇ _6 alkoxycarbonyls (e.g., methoxycarbonyl, ethoxycarbonyl, 0 propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec.-butoxycarbonyl, tert.- butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl) ;
  • groups resulting from binding of a carboxyl group and an alkenyl group having 2 to 6 carbon atoms include C2-6 5 alkenyloxycarbonyls (e.g., allyloxycarbonyl, crotyloxycarbonyl, 2-
  • the "hydrocarbon group that may be substituted" shown by R 5 or R 6 is exemplified by saturated or unsaturated aliphatic chain hydrocarbon groups, saturated or unsaturated 5 alicyclic hydrocarbon groups and aryl groups.
  • saturated aliphatic hydrocarbon groups include straight or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (e.g., C ⁇ _ ⁇ o alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- 0 butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.- pentyl, hexyl, isohexyl, heptyl and octyl), with preference given to straight or branched saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms.
  • C ⁇ _ ⁇ o alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- 0 butyl, tert.-butyl, pentyl, isopentyl, neopentyl, ter
  • Such unsaturated aliphatic hydrocarbon groups include 5 straight or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (e.g., C2-10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl; C2- 1 0 alkynyl groups such as ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pent
  • saturated alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g., C 3 - 12 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl) , with preference given to saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms.
  • saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms e.g., C 3 - 12 cycloalkyl group such as cyclopropyl, cyclobutyl, cycl
  • Such unsaturated alicyclic hydrocarbon groups include unsaturated alicyclic hydrocarbon groups having 5 to 12 carbon atoms (e.g., Cs- ⁇ 2 cycloalkenyl groups such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4- cycloheptadienyl, 2-cyclopenten-l-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3-cyclohexen-l-yl; C 5 - 12 cycloalkadienyl groups such as 2,4-cyclopentadien-l-yl, 2,4-cyclohexadien-l-yl and 2,5-cyclohexadien-l-yl) .
  • the "hydrocarbon group that may be substituted,” shown by R 5 or R 6 may be a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms and substituted with one of the above saturated or unsaturated alicyclic hydrocarbon groups (e.g., C3-7 cycloalkyl-C ⁇ - 8 alkyls or Cs- 7 cycloalkenyl-Ci-e alkyls, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl) , or the like.
  • saturated or unsaturated alicyclic hydrocarbon groups e.g.
  • Aryl groups include monocyclic or condensed polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms.
  • aromatic hydrocarbon ring groups include 0 phenyl, tolyl, xylyl, biphenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 9-phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl and acenaphthylenyl, with preference given to C ⁇ -io aryl such as phenyl, 1-naphthyl and 2-naphthyl.
  • the "hydrocarbon group that may be substituted,” shown 5 by R 5 or R 6 may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents include aryl groups that may be substituted, cycloalkyl or cycloalkenyl groups that may be substituted, heterocyclic groups that may be substituted, carboxyl groups that may be esterified, Q carbamoyl groups that may be substituted, amino groups that may be substituted, hydroxyl groups that may be substituted, thiol groups that may be substituted for, halogens (e.g., fluorine, chlorine, bromine, iodine) and phosphono groups that may be substituted.
  • halogens e.g., fluorine, chlorine, bromine, iodine
  • aryl group that may be substituted is exemplified by C 6 - 14 aryl such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, with preference given to phenyl, 1-naphthyl and 2-naphthyl.
  • Said aryl may have 1 to 2 optionally chosen substituents at any possible 0 positions, these substituents including hydroxy, alkoxy groups that may be substituted (e.g., C 1 - 3 alkoxys such as methoxy, ethoxy and propoxy), halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and alkyl groups that may be substituted (e.g., C 1 - 3 alkyls such as methyl, ethyl 5 and propyl). These alkoxy groups and alkyl groups may each have 1 to 2 optionally chosen substituents at any possible positions, these substituents including phosphono groups that may be substituted (e.g., dimethoxyphosphoryl, diethoxyphosphoryl) .
  • substituents including hydroxy, alkoxy groups that may be substituted (e.g., C 1 - 3 alkoxys such as methoxy, ethoxy and propoxy), halogen atoms (
  • cycloalkyl group that may be substituted is exemplified by C 3 - 7 cycloalkyl groups such as cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the kinds and number of substituents for the cycloalkyl group that may be substituted are the same as those of the substituents for the above-described aryl group that may be substituted.
  • cycloalkenyl group that may be substituted is exemplified by C3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • the kinds and number of substituents for the cycloalkenyl group that may be substituted are the same as those of the substituents for the above-described aryl group that may be substituted.
  • heterocyclic group that may be substituted is exemplified by aromatic heterocyclic groups having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), with preference given to aromatic heterocyclic groups.
  • the aromatic heterocyclic group is exemplified by 5- to 7-membered aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, 5- to 6-membered aromatic heterocyclic groups containing 2 to 4 atoms of nitrogen and 5- or 6-membered aromatic heterocyclic groups containing 1 to 2 atoms of nitrogen and 1 atom of sulfur or oxygen.
  • aromatic heterocyclic groups may be condensed with a 6-membered ring containing 2 or fewer atoms of nitrogen, a benzene ring or a 5-membered ring containing 1 atom of sulfur.
  • aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl.
  • pyrazolyl 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic condensed heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, lH-benzotriazolyl,
  • the non-aromatic heterocyclic group is exemplified by 5- to 7-membered non- aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, and 4- to 7-membered non-aromatic heterocyclic groups containing 1 atom of nitrogen and 3 or fewer atoms selected from nitrogen, oxygen and sulfur.
  • Such non-aromatic heterocyclic groups include oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperizyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl.
  • the substituent for said heterocyclic group that may be substituted is exemplified by alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl).
  • Such carboxyls that may be esterified include -COOH, (lower C ⁇ _ 6 alkoxyJcarbonyls (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyloxycarbonyl) and (C ⁇ -io aryloxy)carbonyls (e.g., phenoxycarbonyl, 1- naphthoxycarbonyl) , (C 7 -. 13 aralkyloxy)carbonyls (e.g., benzyloxycarbonyl), (e.g., with preference given to the carboxyl group, methoxycarbonyl and ethoxycarbonyl.
  • the substituent for said carbamoyl group that may be substituted is exemplified by lower (C ⁇ _ 6 ) alkyls that may Q be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups that may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups c that may be substituted (e.g., phenyl, 1-naphthyl, 2- naphthyl) and C 7 - 13 aralkyl groups that may be substituted (e.g., benzyl, phenethyl);
  • the substituent for said lower (C 1 - 6 ) alkyl that may be substituted and C3-6 Q cycloalkyl group that may be substituted is exemplified by carboxyl groups that may be esterified, aromatic heterocyclic groups (e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl), amino groups, hydroxyl groups and phenyl groups.
  • aromatic heterocyclic groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl
  • amino groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl
  • the 5 substituent for said aryl group that may be substituted and aralkyl group that may be substituted is exemplified by halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and carboxyl groups that may be esterified.
  • 2 substituents on the nitrogen atom may cooperate with the Q nitrogen atom to form a cyclic amino group, such cyclic amino groups including 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl.
  • the substituent for said amino group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls that may 5 be substituted for (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups that may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C 6 - 1 0 aryl groups that may be substituted (e.g., phenyl, 1-naphthyl, 2- naphthyl) and C 7 - 13 aralkyl groups that may be substituted (e.g., benzyl, phenethyl); 1 or 2 of
  • the substituent for said lower (Ci- ⁇ ) alkyl that may be substituted and C3-6 cycloalkyl group that may be substituted is exemplified by carboxyl groups that may be esterified, aromatic heterocyclic groups (e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl), amino groups, hydroxyl groups and phenyl groups.
  • aromatic heterocyclic groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl
  • amino groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl
  • amino groups
  • the substituent for said aryl group that may be substituted and 5 aralkyl group that may be substituted is exemplified by halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and carboxyl groups that may be esterified.
  • 2 substituents on the nitrogen atom may cooperate with the nitrogen atom to form a cyclic amino group, such cyclic Q amino groups including 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl.
  • the substituent for said hydroxyl group that may be substituted is exemplified by lower (C ⁇ _ ⁇ ) alkyls that may be substituted (e.g., methyl, ethyl, propyl, isopropyl, 5 butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups that may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups that may be substituted (e.g., phenyl, 1-naphthyl, 2- Q naphthyl) and C 7 .- 13 aralkyl groups that may be substituted (e.g. , benzyl, phenethyl) .
  • the substituent for said thiol group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls that may be substituted (e.g., methyl, ethyl, propyl, isopropyl, 5 butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups that may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups that may be substituted for (e.g., phenyl, 1-naphthyl, 2- naphthyl) and C7- 13 aralkyl groups that may be substituted (e.g., benzyl, phenethyl).
  • the substituent for said phosphono group that may be substituted is exemplified by lower (Ci- ⁇ ) alkyls (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, 0 isohexyl), lower (C ⁇ _ 6 ) alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, tert.- butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy) .
  • lower (C ⁇ _ 6 ) alkoxys e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, is
  • Said phosphono groups include phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, 5 dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl and tetramethylenedioxyphosphoryl.
  • the substituent may be an aliphatic hydrocarbon group that may be substituted.
  • Said aliphatic hydrocarbon group is exemplified by the same saturated or unsaturated (preferably saturated) aliphatic hydrocarbon groups as those exemplifying the "hydrocarbon group that may be substituted," shown by R 5 or R 6 above, with preference given to alkyl groups (e.g., C 1 -. 3 alkyls such as methyl, ethyl and propyl).
  • the aliphatic hydrocarbon group may have 1 or 2 optionally chosen substituents at any possible positions, these substituents including phosphono groups Q that may be substituted (e.g., phosphoryl, dimethoxyphos ⁇ phoryl, diethoxyphosphoryl).
  • substituents including phosphono groups Q that may be substituted (e.g., phosphoryl, dimethoxyphos ⁇ phoryl, diethoxyphosphoryl).
  • heterocyclic group that may be substituted is exemplified by aromatic heterocyclic groups having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), with preference given to aromatic heterocyclic groups.
  • aromatic heterocyclic groups are exemplified by 5- to 7-membered heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, 5- to 6-membered heterocyclic groups containing 2 to 4 atoms of nitrogen and 5- or 6- membered aromatic heterocyclic groups containing 1 or 2 atoms of nitrogen and 1 atom of sulfur or oxygen.
  • These aromatic heterocyclic groups may have condensed with a 6- membered ring containing 2 or fewer atoms of nitrogen, a benzene ring or a 5-membered ring containing 1 atom of sulfur.
  • aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 2-, 3- or 4- pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-pyrazinyl, triazinyl) and aromatic condensed heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b]
  • Such non-aromatic heterocyclic groups are exemplified by 5- to 7-membered non-aromatic heterocyclic groups containing 1 atom of sulfur, nitrogen or oxygen, and 4 - to 7-membered non-aromatic heterocyclic groups containing 1 atom of nitrogen and 3 or fewer atoms selected from nitrogen, oxygen and sulfur (e.g., oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperizyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl, imidazolidinyl) .
  • nitrogen, oxygen and sulfur e.g., oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl
  • non-aromatic heterocyclic groups may be condensed with a benzene ring, a 6-membered ring containing 2 or fewer atoms of nitrogen, or a 5-membered ring containing 1 atom of sulfur.
  • condensed non-aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl.
  • the "heterocyclic group that may be substituted,” shown by R 5 or R 6 may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents include aryl groups that may be substituted, cycloalkyl or cycloalkenyl groups that may be substituted, heterocyclic groups that may be substituted, carboxyl groups that may be esterified, carbamoyl groups that may be substituted, amino groups that may be substituted, hydroxyl groups that may be substituted, thiol groups that may be substituted, halogens (e.g., fluorine, chlorine, bromine, iodine), phosphono groups that may be substituted, and aliphatic hydrocarbon groups that may be substituted.
  • fluorine chlorine, bromine, iodine
  • phosphono groups that may be substituted
  • aliphatic hydrocarbon groups that may be substituted.
  • R 5 and R 6 in cooperation with the adjoining nitrogen atom, may bind together to form a heterocyclic ring that may contain 1 more hetero atom (e.g., oxygen, nitrogen, sulfur), such heterocyclic groups including 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and 0 1-homopiperazinyl.
  • heterocyclic groups may each have 1 or 2 substituents at any possible positions, these substituents including alkyls (e.g., C 1 - 3 alkyls), carboxyl groups and hydroxyl groups.
  • hydrocarbon group that may be substituted shown 5 by R 5 or R 6 above, is exemplified by alkyl groups, preferably C ⁇ - 10 alkyls, with greater preference given to straight or branched lower alkyls having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, ⁇ neopentyl, tert.-pentyl, hexyl, isohexyl, 4-methylpentyl,
  • alkyl groups preferably C ⁇ - 10 alkyls, with greater preference given to straight or branched lower alkyls having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-but
  • substituents for the "hydrocarbon group that may be substituted" are aryls that may be substituted (preferably phenyl etc.), heterocyclic 5 groups that may be substituted and carboxyl groups that may be esterified.
  • the "hydrocarbon group that may be substituted," shown by R 5 and R 6 is an alkyl group substituted with an aryl or heterocyclic group.
  • Said alkyl Q substituted with an aryl is exemplified by groups resulting from binding of a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl) and a lower alkyl having 1 to 6 carbon atoms (preferably C 1 - 4 alkyl) (e.g., benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, ⁇ — naphthylmethyl, a-naphthylethyl, /3-naphthylmethyl, ⁇ - naphthylethyl) .
  • Said alkyl substituted with a heterocyclic group is exemplified by groups resulting from binding of an aromatic heterocyclic group and a lower alkyl having 1 to 6 carbon atoms (preferably C 1 - 4 alkyl group).
  • aromatic heterocyclic groups include 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4- pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4- thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-o
  • R 5 and R 6 it is preferable that one be a hydrogen atom, and the other be sec.-butyl, benzyl, isobutyl or isopropyl, with preference given to benzyl.
  • one of R 5 and R 6 is a hydrogen atom
  • the other is exemplified by a group represented by formula (Ia-aa):
  • Rd represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted; R « represents a carboxyl group that may be esterified or a carbamoyl group that may be substituted.
  • R d represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted; R « represents a carboxyl group that may be esterified or a carbamoyl group that may be substituted.
  • R d represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted
  • R « represents a carboxyl group that may be esterified or a carbamoyl group that may be substituted.
  • the "hydrocarbon group that may be substituted,” shown by Rd, may have 1 to 3 optionally chosen substituents at any possible positions, these substituents being exemplified by the same substituents as those for the "hydrocarbon group that may be substituted," shown by R 1 , R 2 or R 3 above.
  • the "heterocyclic group that may be substituted,” shown by Rd is exemplified by the same heterocyclic groups exemplifying the "heterocyclic group that may be substituted,” shown by R 1 , R 2 or R 3 above.
  • heterocyclic group that may be substituted may have 1 to 3 optionally chosen substituents at any possible positions, these substituents being exemplified by the same substituents as those for the "heterocyclic group that may be substituted," shown by R 1 , ⁇ R 2 or R 3 above.
  • the "hydrocarbon group that may be substituted for,” shown by Rd, is exemplified by alkyl groups, preferably Ci-io alkyl, with greater preference given to linear or branched lower alkyls having 1 to 6 carbon atoms (e.g., 5 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.- pentyl, hexyl, isohexyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl) .
  • Preferable substituents for the "hydrocarbon group that may Q be substituted" are aryls that may be substituted
  • the "carboxyl group that may be esterified" shown by Re is exemplified by 5 carboxy, (lower C ⁇ _ ⁇ alkoxy)carbonyls (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl.
  • aryloxycarbonyls e.g., phenoxycarbonyl, 1-naphthoxycarbonyl
  • C 7 - 13 aralkyloxycarbonyls e.g. ,benzyloxycarbonyl
  • the substituent for the "carbamoyl group that may be substituted," shown by Re, is exemplified by lower (Ci- ⁇ ) alkyls that may be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 - 6 cycloalkyl groups that may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C ⁇ -io aryl groups that may be substituted (e.g., phenyl, 1-naphthyl, 2-naphthyl) and C 7 .- 13 aralkyl groups that may be substituted (e.g., phenyl, 1-
  • the substituent for said lower (C 1 -6) alkyl that may be substituted and C 3 - 6 cycloalkyl group that may be substituted is exemplified by carboxyl groups that may be esterified, aromatic heterocyclic groups (e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl), amino groups, hydroxyl groups and phenyl groups.
  • aromatic heterocyclic groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl
  • amino groups e.g., furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, imidazolyl
  • the substituent for said aryl group that may be substituted and aralkyl group that may be substituted is exemplified by halogen atoms (e.g., fluorine, chlorine, bromine, iodine) and carboxyl groups that may be esterified.
  • 2 substituents on the nitrogen atom may cooperate with the nitrogen atom to form a cyclic amino group, such cyclic amino groups including 1- azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1- piperazinyl.
  • i) m be 1 and n be 1, ii) m be 1 and n be 0, or iii) m be 0 and n be 0.
  • the salt of the compound of general formula (la), (I), (I') or (I") is preferably a physiologically acceptable salt, exemplified by salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids.
  • Preferable salts with 0 inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt.
  • Preferable salts with organic bases include ammonium salts and salts with trimethylamine, triethylamine, pyridine, 5 picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.
  • Preferable salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable salts with organic ⁇ acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p- toluenesulfonic acid.
  • Preferable salts with basic amino acids include salts with arginine, lysine and ornithine.
  • Preferable salts with acidic amino acids include salts with aspartic acid and glutamic acid.
  • the starting compound used in each of the reactions for synthesizing the below-described desired compounds has an amino group, carboxyl group or hydroxyl group as a substituent, these 5 substituents may have a protective group in common use in peptide chemistry etc.; the desired compound can be obtained by removing, as appropriate, the protective group after completion of the reaction.
  • Amino-protecting groups include, for example, formyl, C ⁇ - 6 alkylcarbonyl groups (e.g., acetyl, ethylcarbonyl) , phenylcarbonyl group, C ⁇ _ 6 alkyl-oxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl group, C7- 1 0 aralkyl-carbonyl group (e.g., benzylcarbonyl) , trityl group, phthaloyl group and N,N-dimethylaminomethylene group, which are optionally substituted.
  • C ⁇ - 6 alkylcarbonyl groups e.g., acetyl, ethylcarbonyl
  • phenylcarbonyl group e.g., C ⁇ _ 6 alkyl-oxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl)
  • substituents which these groups optionally have include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C 1 - 6 alkyl-carbonyl groups (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents being 1 to 3.
  • carboxyl-protecting groups include C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl) , phenyl, trityl and silyl, which are optionally substituted.
  • substituents which these groups optionally have include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, Ci- ⁇ alkyl ⁇ carbonyl groups (e.g., acetyl, ethylcarbonyl, butylcarbonyl) and nitro groups, the number of substituents being 1 to 3.
  • hydroxyl-protecting groups include C ⁇ _ 6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl) , phenyl, C 7 - 10 aralkyl groups (e.g., benzyl), formyl, C 1 -6 alkyl-carbonyl groups (e.g., acetyl, ethylcarbonyl), phenyloxycarbonyl, benzoyl, C7- 10 aralkyl- carbonyl groups (e.g., benzylcarbonyl), pyranyl, furanyl and silyl, which are optionally substituted.
  • C ⁇ _ 6 alkyl groups e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.-butyl
  • phenyl C 7 - 10 a
  • substituents which these groups optionally have include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), C 1 - 6 alkyl groups (e.g., methyl, ethyl, n-propyl), phenyl, C 7 - 10 aralkyl groups (e.g., benzyl) and nitro groups, the number of substituents being 1 to 4.
  • halogen atoms e.g., fluorine, chlorine, bromine, iodine
  • C 1 - 6 alkyl groups e.g., methyl, ethyl, n-propyl
  • phenyl C 7 - 10 aralkyl groups
  • nitro groups the number of substituents being 1 to 4.
  • Protecting groups can be removed by commonly known methods or modifications thereof, including treatments with acids, bases, reducing agents, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyld
  • Compound (la) can be produced by subjecting to an oxidation reaction described in detail below a compound represented by general formula (Ila):
  • Q represents a direct bond or 1 or 2 amino acid residues that may be substituted;
  • R 1 represents a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted;
  • R 4 represents a carboxyl group that may be esterified or an acyl group;
  • R 5 and R 6 whether identical or not, independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted;
  • R 5 and R 6 may bind together to form a ring.
  • Compound (I) can be produced by subjecting to an oxidation reaction described in detail below a compound represented by general formula (II):
  • R 1 , R 2 and R 3 whether identical or not, independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group that may be substituted for;
  • R 4 represents a carboxyl group that may be esterified or an acyl group;
  • R 5 and R 6 whether identical or not, independently represent a hydrogen atom or a hydrocarbon group or heterocyclic group which may be substituted for;
  • R 5 and R 6 may bind together to form a ring;
  • m and n whether identical or not, independently represent 0 or 1.
  • Compound (I') and (I") can be produced by the same manner as mentioned above in production of compounds (I) and (la).
  • This oxidation is carried out by a known oxidizing reaction.
  • Such reactions include chromic acid oxidations such as Jones' oxidation, using chromium oxide-sulfuric acid-pyridine, Collins oxidation, using chromium oxide- pyridine complex, oxidation with pyridinium chlorochromate (PCC) and oxidation with pyridinium dichromate (PDC); oxidation with activated DMSO, described in detail for method B below; and oxidation with oxoammonium salt.
  • PCC pyridinium chlorochromate
  • PDC oxidation with pyridinium dichromate
  • this oxidation is advantageously carried out by activated dimethyl sulfoxide (DMSO) oxidation.
  • DMSO dimethyl sulfoxide
  • Activated DMSO oxidation is carried out in a solvent in the presence of both DMSO and an electrophilic reagent.
  • This solvent is exemplified by ethers such as ethyl ether, isopropyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, N,N-dimethylformamide (DMF) , pyridine and dimethyl sulfoxide, chosen as appropriate according to the kind of electrophilic reagent.
  • ethers such as ethyl ether, isopropyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as chloroform and dichloromethane, N,N-dimethylformamide (DMF) , pyridine and dimethyl sulfoxide, chosen as appropriate according to the kind of electrophilic reagent.
  • Methods of activated DMSO oxidation include the dicyclohexylcarbodiimide (DCC) method, the acetic anhydride method, the phosphorus pentoxide method, the chlorine method, the sulfur trioxide-pyridine method, the ketenimine-enamine method and the mercury (II) acetate method, named according to the electrophilic reagent used.
  • DCC dicyclohexylcarbodiimide
  • acetic anhydride method the phosphorus pentoxide method
  • the chlorine method the sulfur trioxide-pyridine method
  • the ketenimine-enamine method the mercury (II) acetate method
  • This oxidation is advantageously carried out by a modification of the dicyclohexylcarbodiimide (DCC) method, in which oxidation is achieved using the pyridine salt of trifluoroacetic acid as a catalyst and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HC1) as a DMSO activator reagent.
  • DCC dicyclohexylcarbodiimide
  • WSCD-HC1 l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • This reaction can also be carried out with dimethyl sulfoxide as a solvent.
  • the amount of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD-HC1) used is 1 to 10 mol, preferably 2 to 5 mol per mol of compound (II).
  • the amount of the pyridine salt of trifluoroacetic acid used is 0.1 to 2 mol per mol of compound (II).
  • Reaction temperature is -70 to 80°C, preferably -20 to 40 ⁇ C, reaction time being 0.5 to 10 hours.
  • Ketoamide derivatives (la) and (I) thus obtained may be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redissolution and chromatography.
  • Compound (II) for the present invention can, for example, be produced as follows: Method B
  • Preferable derivatives of compound (IV) reactive at the amino group thereof include Schiff's base type imino or enamine form tautomeric isomers resulting from reaction of compound (IV) and a carbonyl compound such as aldehyde or ketone; silyl derivatives resulting from reaction of compound (IV) and a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide or bis(trimethylsilyl)urea; and derivatives resulting from reaction of compound (IV) and phosphorus trichloride or phosgene.
  • Preferable salts of compound (IV) and its reactive derivatives are exemplified by the same acid adduct salts as specified for compound (I) above.
  • Preferable derivatives of compound (III) reactive at the carboxyl group thereof include acid halides, acid anhydrides, activated amides and activated esters.
  • Other preferable reactive derivatives include acid chlorides; acid azides; mixed acid anhydrides such as those with a substituted phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid, or with dialkylphosphorous acid, sulfurous acid, thiosulfuric acid or sulfuric acid, or with a sulfonic acid such as methanesulfonic acid, or with an aliphatic carboxylic acid, such as acetic acid, propionic acid, butyric acid, isobutyropivalic acid, pentanoic acid, isopentanoic acid or trichloroacetic acid, or with an aromatic carboxylic acid such as benzoic acid; symmetric acid anhydrides; activated amides with imi
  • reactive derivatives can be optionally chosen according to the kind of compound (III) used.
  • Preferable salts of reactive derivatives of compound (III) include salts with bases, exemplified by alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, and organic base salts such as trimethylamine salt, triethylamine salt, 5 pyridine salt, picoline salt, dicyclohexylamine salt and N,N-dibenzylethylenediamine salt.
  • This reaction is normally carried out in an ordinary solvent such as water, an alcohol such as methanol or ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene ⁇ chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide or pyridine, but can be carried out in any other organic solvent, as long as it does not interfere with the reaction.
  • an ordinary solvent such as water, an alcohol such as methanol or ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene ⁇ chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide or pyridine, but can be carried out in any other organic solvent, as long as it does not interfere with the reaction.
  • These ordinary solvents may be used in mixture with water.
  • This reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal hydrogen carbonate tri(lower)alkylamine, pyridine, N- (lower)-alkylmorpholine or N,N-di(lower)alkylbenzylamine.
  • an inorganic or organic base such as alkali metal hydrogen carbonate tri(lower)alkylamine, pyridine, N- (lower)-alkylmorpholine or N,N-di(lower)alkylbenzylamine.
  • reaction temperature is not subject to limitation, this reaction is normally carried out under cooling to heating conditions.
  • L represents a carboxy-protecting 30 group; the other symbols have the same definitions as those given above.
  • the carboxy-protecting group for L is exemplified by protecting groups in common use in the field of peptide synthesis, such as ester derivatives. 35
  • compound (V), its derivative reactive at the carboxyl group thereof, or a salt thereof is reacted with compound (VI), its derivative reactive at the amino group thereof, or a salt thereof to yield compound (VII), which is then subjected to a deprotecting reaction to remove the carboxy-protecting group to yield compound (III).
  • the reaction of compound (V), its derivative reactive at the carboxyl group thereof, or a salt thereof and compound (VI), its derivative reactive at the amino group thereof, or a salt thereof is carried out in the same manner as method B.
  • the deprotecting reaction of compound (VII) to remove its carboxy-protecting group can be achieved by any common method of carboxy-protecting group removing reaction, such as deprotection by hydrolysis, reduction or Lewis acid.
  • carboxy-protecting group is an ester, it can be 5 removed by hydrolysis or Lewis acid, preferably in the presence of a base or acid.
  • Preferable bases include inorganic bases such as alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium ⁇ hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal acetates (e.g., sodium 5 acetate, potassium acetate), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate), alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate), and organic bases such as trialkylamines (e.g., trimethylamine, Q triethylamine) , picoline, N-methylpyrrolidine, N- methylmorpholine
  • Hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or mixture thereof.
  • Preferable acids include organic acids (e.g., formic acid, acetic acid) and inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid). This hydrolysis is normally carried out in an organic solvent, water or a mixture thereof.
  • Reaction temperature not subject to limitation, is chosen as appropriate, according to the kind of carboxy-protecting group and method of deprotection.
  • a Lewis acid is achieved by reacting compound (VII) or a salt thereof with a Lewis acid such as a boron trihalide (e.g., boron trichloride, boron trifluoride) , a titanium tetrahalide (e.g., titanium ⁇ tetrachloride, titanium tetrabromide) , an aluminum halide (e.g., aluminum chloride, aluminum bromide) or a trihaloacetic acid (e.g., trichloroacetic acid, trifluoroacetic acid).
  • a Lewis acid such as a boron trihalide (e.g., boron trichloride, boron trifluoride) , a titanium tetrahalide (e.g., titanium ⁇ tetrachloride, titanium tetrabromide) , an aluminum halide (e.g., aluminum chloride, aluminum bromide) or a trihaloacetic
  • This deprotecting reaction is preferably carried out in the presence of a cation 5 capturing agent (e.g., anisole, phenol) and normally carried out in a solvent which does not interfere with the reaction, such as a nitroalkane (e.g., nitromethane, nitroethane) , an alkylene halide (e.g., methylene chloride, ethylene chloride), diethyl ether or carbon disulfide.
  • a nitroalkane e.g., nitromethane, nitroethane
  • an alkylene halide e.g., methylene chloride, ethylene chloride
  • diethyl ether e.g., diethyl ether or carbon disulfide.
  • Deprotection by reduction is preferably applied to removing the protecting groups such as esters of haloalkyls (e.g., 2-iodoethyl, 2,2,2-trichloroethyl) and esters of aralkyls (e.g., benzyl).
  • protecting groups such as esters of haloalkyls (e.g., 2-iodoethyl, 2,2,2-trichloroethyl) and esters of aralkyls (e.g., benzyl).
  • Methods of reduction for this 5 deprotecting reaction include reduction with a combination of a metal (e.g., zinc, zinc amalgam) or a chromium compound salt (e.g., primary chromium chloride, primary chromium acetate) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid), and Q ordinary catalytic reduction in the presence of an ordinary metal catalyst (e.g., palladium-carbon, Raney nickel).
  • a metal e.g., zinc, zinc amalgam
  • a chromium compound salt e.g., primary chromium chloride, primary chromium acetate
  • organic or inorganic acid e.g., acetic acid, propionic acid, hydrochloric acid
  • Q ordinary catalytic reduction in the presence of an ordinary metal catalyst (e.g., palladium-carbon, Raney nickel).
  • reaction temperature is not subject to limitation, this reaction is normally carried out under cooling, room temperature
  • compound (XI) or a salt thereof is reacted with compound (VIII) or a salt thereof to yield Q * compound (XII), which is then subjected to a deprotecting reaction to remove its carboxy-protecting group to yield compound (III-2).
  • the reaction of compounds (VIII) and (XI) is carried out in an appropriate solvent.
  • This solvent is exemplified by aromatic hydrocarbons such as 5 benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixtures thereof.
  • aromatic hydrocarbons such as 5 benzene, toluene and xylene
  • ethers such as dioxane, tetrahydrofuran and dimethoxyethane
  • alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile
  • pyridine N,
  • the reaction of compounds (VIII) and (XI) is carried out in the presence of an appropriate base, exemplified by alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N,N-dimethylaniline, sodium hydride and potassium hydride.
  • an appropriate base exemplified by alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N,N-dimethylaniline, sodium hydride and potassium hydride.
  • the amount of these bases used is preferably about 1 to 5 mol per mol of compound (VIII).
  • the reaction is normally carried out at -20 to 150°C, preferably about -10 to 100°C.
  • Compound (XII) thus obtained is subjected to a deprotecting reaction to yield compound (III
  • compound (XIII) or a salt thereof is reacted with compound (XI) or a salt thereof to yield compound (III-2).
  • This sulfonylation is normally carried out under what is called Schotten Baumann's conditions, in which amino acid derivative (XIII), prepared as a sodium salt in an aqueous solution, is reacted with compound (XI) and then acidified.
  • compound (VIII) or a salt thereof is reacted with compound (XVI) to yield compound (XVII), which is then subjected to a deprotecting reaction to remove its carboxy-protecting group to yield compound (III-5).
  • the reaction of compound (VIII) or a salt thereof and compound (XVI) is carried out in an appropriate solvent.
  • This solvent is exemplified by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixtures thereof.
  • the amount of compound (XVI) used is preferably 0 about 1 to 5 mol per mol of compound (VIII).
  • compound (VIII) or a salt thereof is reacted with compound (XVIII) to yield compound (XIX), which is then subjected to a deprotecting reaction to remove its carboxy-protecting group to yield compound (III- 6).
  • This reaction is carried out in the same manner as 0 method I.
  • M represents an amino-protecting group; the other symbols have the same definitions as those shown above.
  • the amino-protecting group for M is exemplified by protecting groups in common use in the field of peptide synthesis, such as oxycarbonyl derivatives, with preference given to benzyloxycarbonyl.
  • compound (XX), its derivative reactive at the carboxyl group thereof, or a salt thereof is reacted with compound (XXI), its derivative reactive at the amino group thereof, or a salt thereof to yield compound (XXII), which is then subjected to a deprotecting reaction to remove its carboxyl-protecting group to yield compound (XXIII).
  • the reaction of compound (XX), its derivative reactive at the carboxyl group thereof, or a salt thereof and compound (XXI), its derivative reactive at the amino group thereof, or a salt thereof is carried out in the same manner as method B.
  • the carboxyl-protecting group-removing reaction of compound (XXII) can be carried out by the method described for method C above.
  • the benzyloxycarbonyl group is removed by catalytic reduction in the presence of a commonly used metal catalyst (e.g., palladium-carbon, Raney 5 nickel).
  • a commonly used metal catalyst e.g., palladium-carbon, Raney 5 nickel.
  • Reaction temperature is not subject to limitation; the reaction is normally carried out under cooling, room temperature or heating conditions.
  • Compound (XXV) is then acylated in the same manner as the reaction of compounds (VIII) and (IX) in method D or the reaction of Q compounds (XIII) and (XIV) in method G, sulfonylated in the same manner as the reaction of compounds (VIII) and (XI) in method E, oxycarbonylated in the same manner as the reaction of compounds (VIII) and (XV) in method H, carbamoylated in the same manner as the reaction of 5 compounds (VIII) and (XVI) in method I, and then thiocarbamoylated in the same manner as the reaction of compounds (VIII) and (XVIII) in method J, to yield compound (II).
  • the compound of general Q formula (I), (la), (I') or (I") can be administered orally or non-orally, as formulated at an effective dose with a physiologically acceptable carrier, in the form of solid preparations such as tablets, capsules, granules and powders, or liquid preparations such as syrups and 5 injectable preparations.
  • a physiologically acceptable carrier in the form of solid preparations such as tablets, capsules, granules and powders, or liquid preparations such as syrups and 5 injectable preparations.
  • Pharmaceutically acceptable carriers are various organic or inorganic carrier substances in common use as pharmaceutical materials, including excipients, lubricants, binders and disintegrating agents for solid preparations, and solvents, dissolution aids, suspending agents, isotonizing agents, buffers and soothing agents for liquid preparations.
  • Other pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweetening agents may be used as necessary.
  • Preferable excipients include lactose, sucrose, D- mannitol, starch, crystalline cellulose and light silicic anhydride.
  • Preferable lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferable binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyvinylpyrrolidone.
  • Preferable disintegrating agents include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, cross carmelose sodium and carboxymethyl starch sodium.
  • Preferable solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil.
  • Preferable dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
  • Preferable suspending agents include surfactants such as stearyltriethanola ine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkoniu chloride, benzethonium chloride and monostearic glycerol; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxy ethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • Preferable isotonizing agents include sodium chloride, glycerol and D-mannitol.
  • Preferable buffers include buffer solutions of phosphates, acetates, carbonates and citrates.
  • Preferable soothing agents include benzyl alcohol.
  • Preferable preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable antioxidants include sulfites and ascorbic 0 acid.
  • the compound represented by general formula (I), (la), (I 1 ) or (I") or a salt thereof can be orally or non-orally used by inhalation, rectal injection or local administration. It can be used as a pharmaceutical 5 composition or preparation (e.g., powders, granules, tablets, pills, capsules, injectable preparations, syrups, emulsions, elixirs, suspensions, solutions), which may contain one or more inventive compounds with pharmaceutically acceptable carriers (e.g., adjutants, ⁇ excipients, shaping agents and/or diluents).
  • pharmaceutically acceptable carriers e.g., adjutants, ⁇ excipients, shaping agents and/or diluents.
  • compositions can be prepared as pharmaceutical preparations by ordinary methods.
  • non-oral includes subcutaneous injection, intravenous injection, intramuscular injection, 5 intraperitoneal injection and drip infusion.
  • injectable preparations e.g., aqueous or oily suspensions for aseptic injection, can be prepared by methods known in relevant fields, using an appropriate dispersing agent or wetting agent and a suspending agent.
  • the aseptic injectable ⁇ preparation thus obtained may be an aseptically injectable solution or suspension in a diluent or solvent which permits non-toxic non-oral administration, such as an aqueous solution.
  • Acceptable vehicles or solvents include water, Ringer's solution and isotonic saline.
  • any non- volatile oil or fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or acids, and natural, synthetic or semi-synthetic mono- or di- or tri- glycerides.
  • Suppositories for rectal administration may be produced as a mixture of the drug and an appropriate non- irritative shaping agent, such as cacao butter or polyethylene glycol, which is solid at normal temperatures and liquid at intestinal temperatures and melts and 0 releases the drug in the rectum.
  • an appropriate non- irritative shaping agent such as cacao butter or polyethylene glycol
  • Solid dosage forms for oral administration include the above-mentioned forms such as powders, granules, tablets, pills and capsules.
  • the active ingredient compound may be mixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride.
  • Such dosage forms may contain Q additional additives as usual, including inert diluents, lubricants such as magnesium stearate, preservatives such as paraben and sorbic acid, antioxidants such as ascorbic acid, c-tocopherol and cysteine, disintegrating agents, binders, thickening agents, buffers, sweeteners, flavoring 5 agents and perfumes. Tablets and pills may be produced with enteric coating.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, which may contain inert diluents, such as water, in common ⁇ use in relevant fields.
  • the dose for a particular patient is determined according to age, body weight, general health status, sex, dietary status, administration time, method of administration, excretion rate, drug combination, severity 5 of the illness being treated and other factors. Since the compound represented by general formula (I), (la), (I') or (I") or a salt thereof possesses potent cathepsin L inhibitory activity, it excellently suppresses bone resorption, and can be safely used at low toxicity.
  • the compounds (la), (I), (I 1 ) or (I") of the present invention can therefore be advantageously used to prevent or treat osteoporosis in mammals (e.g., mice, rats, rabbits, dogs, cats, bovines, swines, humans).
  • the compound (la), (I), (I') or (I") of the present invention or a salt thereof is used as a prophylactic/therapeutic agent for osteoporosis
  • its daily dose for an adult (50 kg) is normally about 1 to 500 mg, preferably about 10 to 500 mg for oral administration, and about 1 to 300 mg, preferably about 5 to 100 mg for non-oral administration.
  • a 1 / /l sample previously diluted to 10 "2 M with dimethyl sulfoxide (DMSO), and 25 ⁇ l of 20 ⁇ M Z-Phe-Arg-NHMec (enzyme substrate solution) were added, followed by incubation at 30°C for 10 minutes, after which 100 ⁇ l of a reaction stopper (100 mM sodium monochloroacetate, 30 mM sodium acetate, pH 4.3) was added.
  • a reaction stopper 100 mM sodium monochloroacetate, 30 mM sodium acetate, pH 4.3
  • Bone resorption was measured by the method of Raisz [Journal of Clinical Investigation, £4, 103-116 (1965)]. Specifically, one Sprague-Dawley rat at 18 days of gestation was given 50 Ci of 5 Ca (calcium isotope, in CaCl 2 solution) by subcutaneous injection. On the following day, the animal was laparotomized and fetal rats aseptically removed. Both forearm bones (radius and ulna) were cut from the body of each fetus under an anatomical microscope, and connective tissue and cartilage were removed to the maximum possible extent, to prepare bone culture samples.
  • Each bone fragment was pre-cultured at 37°C for 24 hours in 0.6 ml of a medium (Fitton-Jackson modification, GIBCO Laboratories, the United States) prepared by adding bovine serum albumin (final concentration 2 mg/ml), after which it was transferred to the same medium as above but containing each compound (final concentration 10 M) and cultured for two more days, 45 Ca radioactivity in the medium and 5 Ca radioactivity in the bone were then measured; the percent ratio of 45 Ca released from the bone to the medium was calculated using the following equation:
  • Optical rotation was determined at 20 to 25 ⁇ C.
  • the room temperature ranged from about 15°C to about 25°C.
  • N-Benzyloxycarbonyl-L-isoleucyl-(2R,3S)-3-amino-2- hydroxy-4-phenylbutyric acid benzylamide (5.0 g) was dissolved in a mixed solvent of dimethyl sulfoxide (DMSO) (20 ml) and toluene (60 ml).
  • DMSO dimethyl sulfoxide
  • WSCD*HC1 l-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride
  • pyridinium trifluoroacetate 1.6 g
  • Example 2 5 The same procedure as in Example 1 was followed to yield N-[ (3S)-3-dibenzylacetylamino-2-oxo-4-phenylbutyryl]-
  • Example 2 The same procedure as in Example 1 was followed to yield a colorless crystal of N-(l-naphthalenesulfonyl)-L- isoleucyl-(3S)-3-amino-2-oxo-4-phenylbutyric acid benzylamide.
  • Example 2 The same procedure as in Example 1 was followed to yield a light yellow solid of N-benzyloxycarbonyl-L- isoleucyl-(3S)-3-amino-2-oxo-4-phehylbutyric acid p- diethylphosphonomethylphenylamide.
  • Example 2 The same procedure as in Example 1 was followed to yield a white solid of N-benzyloxycarbonyl-L-isoleucyl- (3S)-3-amino-2-oxo-4-phenylbutyric acid isobutylamide.
  • Example 2 The same procedure as in Example 1 was followed to yield a white crystal of N-(quinoline-2-carbonyl)-L- isoleucyl-(3S)-3-amino-2-oxo-4-phenylbutyric acid benzylamide. Melting point: 181-182°C
  • Example 2 The same procedure as in Example 1 was followed to yield a white solid of N-(p-diethylphosphonomethyl- cinnamoyl)-L-isoleucyl-(3S)-3-amino-2-oxo-4-phenylbutyric acid benzylamide. Melting point: 207-209 ⁇ C
  • Example 2 The same procedure as in Example 1 was followed to yield a colorless crystal of N-(l-naphthalenesulfonyl)-L- phenylalanyl-(3S)-3-amino-2-oxo-4-phenylbutyric acid benzylamide.
  • Example 2 The same procedure as in Example 1 was followed to yield a colorless crystal of N-(l-naphthalenesulfonyl)-L- isoleucyl-(3S)-3-amino-2-oxo-4-phenylbutyric acid 4- pyridylmethylamide. Melting point: 162-163°C
  • N-benzyloxycarbonyl-L-isoleucyl-(2R,3S)-3-amino-2- hydroxy-4-phenylbutyric acid benzylamide (4.7 g) and 5% Pd- C (2.5 g) were added to a mixed solvent of tetrahydrofuran (THF) (20 ml) and methanol (20 ml), followed by stirring at room temperature for 1 hour in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (DMF) (30 ml).
  • THF tetrahydrofuran
  • methanol methanol
  • Reference Example 16 The same procedure as in Reference Example 6 was followed to yield a white solid of N-benzyloxycarbonyl-L- isoleucyl-(2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid 2- pyridylmethylamide.
  • a cathepsin L inhibitor comprising inventive compound (I) or (la) or a salt thereof as an active ingredient can, for example, be produced with the following formulations:
  • Components (1), (2) and (3) and a half portion of component (4) are mixed and granulated. To these granules, the remaining portion of component (4) is added, and the whole mixture is packed in a gelatin capsule.
  • Components (1), (2) and (3), a two-third portion of component (4) and a half portion of component (5) are mixed and granulated.
  • the remaining portions of components (4) and (5) are added, and the whole mixture is tableted by compressive tableting.
  • Components (1), (2) and (3) and a half portion of component (4) are mixed and granulated. To these granules, the remaining portion of component (4) is added, and the whole 0 mixture is packed in a gelatin capsule.
  • Components (1), (2) and (3), a two-third portion of component 4 and a half portion of component (5) are mixed and granulated. To these granules, the remaining portions of components (4) and (5) are added, and the whole mixture is tableted by compressive tableting. 6. Injectable preparation
  • the compound represented by general formula (I), (la), (I 1 ) or (I") or a salt thereof possesses potent cathepsin L inhibitory activity, it excellently suppresses bone resorption, and it can therefore be advantageously used to prevent or treat osteoporosis in mammals.

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Abstract

Inhibiteur de cathepsine L qui comporte un composé de formule générale (Ia) dans laquelle Q représente une liaison directe ou 1 ou 2 restes d'acides aminé qui peuvent être substitutés; R1 représente un atome d'hydrogène ou un groupe hydrocarbure ou un groupe hétérocyclique qui peut être substitué; R4 représente un groupe acyle ou un groupe carboxyle qui peut être estérifié et R5 et R6 représentent indépendamment un atome d'hydrogène ou un groupe hydrocarbure ou un groupe hétérocyclique qui peut être substitué ou R5 et R6 peuvent se lier pour former un cycle; ou sel dudit inhibiteur, qui présente une forte activité de suppression de la résorption osseuse et est utile pour prévenir ou traiter l'ostéoporose.
PCT/JP1995/002389 1994-11-24 1995-11-24 Derives d'alpha-cetoamide utilises comme inhibiteurs de cathepsine l WO1996016079A2 (fr)

Priority Applications (3)

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AU39358/95A AU3935895A (en) 1994-11-24 1995-11-24 Alpha-ketoamide derivatives as cathepsin l inhibitor
CA002200964A CA2200964A1 (fr) 1994-11-24 1995-11-24 Derives d'alpha-cetoamide utilises comme inhibiteurs de cathepsine l
EP95937173A EP0793673A1 (fr) 1994-11-24 1995-11-24 Derives d'alpha-cetoamide utilises comme inhibiteurs de cathepsine l

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JP29013294 1994-11-24
JP6/290132 1994-11-24

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5912352A (en) * 1996-05-31 1999-06-15 Novartis Finance Corporation Intermediates for the preparation of peptide analogues
WO2003013518A1 (fr) * 2001-08-03 2003-02-20 Smithkline Beecham Corporation Derives d'alpha-cetoamide utilises en tant qu'inhibiteurs de la cathepsine k
WO2003062192A1 (fr) * 2002-01-17 2003-07-31 Smithkline Beecham Corporation Derives de cetoamides a substitution cycloalkyle, utiles comme inhibiteurs de cathepsine k
WO2003086385A1 (fr) * 2002-04-10 2003-10-23 Smithkline Beecham Corporation Derives de 1-(oxoaminoacetyl) pentylcarbamate utilises en tant qu'inhibiteurs de la cathepsine dans le traitement de la perte osseuse
US6703368B2 (en) * 1997-10-07 2004-03-09 Cephalon, Inc. Peptide-containing α-ketoamide cysteine and serine protease inhibitors
US6703513B1 (en) * 2000-06-02 2004-03-09 K-Quay Enterprises Llc Production and use of derivatized homoserine lactones
US6774212B2 (en) * 1999-12-03 2004-08-10 Bristol-Myers Squibb Pharma Company Alpha-ketoamide inhibitors of hepatitis C virus NS3 protease
US7022738B2 (en) 2002-07-22 2006-04-04 Senju Pharmaceutical Co., Ltd. α-ketoamide derivative and use thereof
WO2010070615A1 (fr) * 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
EP2289888A3 (fr) * 2000-06-30 2011-07-13 Seikagaku Corporation Amides d'acide expoxy-carboxylique, azides et amino-alcools et procédés de préparation d'alpha-ceto amides à l'aide de ces derniers
WO2013127981A1 (fr) 2012-03-01 2013-09-06 Veterinärmedizinische Universität Wien Inhibiteurs de protéases pour le traitement des infections par trichomonas gallinae
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
EP2994143A4 (fr) * 2013-05-08 2017-02-01 Board of Regents, The University of Texas System Inhibiteurs de stat6
WO2018098208A1 (fr) * 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Inhibiteurs de désoxyuridine triphosphatase liés à un cycle azote
US10544105B2 (en) 2015-07-08 2020-01-28 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US10562860B2 (en) 2015-07-08 2020-02-18 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10577321B2 (en) 2015-07-08 2020-03-03 University Of Southern California Deoxyuridine triphosphatase inhibitors
US10858344B2 (en) 2016-11-23 2020-12-08 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10889563B2 (en) 2013-01-07 2021-01-12 University Of Southern California Deoxyuridine triphosphatase inhibitors
US11014924B2 (en) 2016-11-23 2021-05-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11198677B2 (en) 2015-07-08 2021-12-14 University Of Southern California Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
US11247984B2 (en) 2017-01-05 2022-02-15 Cv6 Therapeutics (Ni) Limited Uracil containing compounds
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0468339A2 (fr) * 1990-07-27 1992-01-29 Nippon Kayaku Kabushiki Kaisha Dérivés d'amide-alpha-céto ayant une activité inhibante de protéases
WO1992011850A2 (fr) * 1990-12-28 1992-07-23 Cortex Pharmaceuticals, Inc. Utilisation d'inhibiteurs de la calpaine dans l'inhibition et le traitement de la neurodegenerescence
WO1992012140A1 (fr) * 1990-12-28 1992-07-23 Georgia Tech Research Corporation Cetoamides, cetoacides et cetoesters peptidiques
WO1994000095A2 (fr) * 1992-06-24 1994-01-06 Cortex Pharmaceuticals, Inc. Emploi d'inhibiteurs de calpaine dans l'inhibition et le traitement d'etats medicaux associes a une activite de calpaine accrue
WO1994008941A1 (fr) * 1992-10-16 1994-04-28 Corvas International, Inc. Ceto-amide d'arginine comme inhibiteurs enzymatiques
EP0603769A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'alpha-aminocétones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0468339A2 (fr) * 1990-07-27 1992-01-29 Nippon Kayaku Kabushiki Kaisha Dérivés d'amide-alpha-céto ayant une activité inhibante de protéases
WO1992011850A2 (fr) * 1990-12-28 1992-07-23 Cortex Pharmaceuticals, Inc. Utilisation d'inhibiteurs de la calpaine dans l'inhibition et le traitement de la neurodegenerescence
WO1992012140A1 (fr) * 1990-12-28 1992-07-23 Georgia Tech Research Corporation Cetoamides, cetoacides et cetoesters peptidiques
WO1994000095A2 (fr) * 1992-06-24 1994-01-06 Cortex Pharmaceuticals, Inc. Emploi d'inhibiteurs de calpaine dans l'inhibition et le traitement d'etats medicaux associes a une activite de calpaine accrue
WO1994008941A1 (fr) * 1992-10-16 1994-04-28 Corvas International, Inc. Ceto-amide d'arginine comme inhibiteurs enzymatiques
EP0603769A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'alpha-aminocétones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ARTHRITIS & RHEUMATISM, vol. 37, no. 2, 1 February 1994, pages 236-247, XP000566128 ESSER, R.E. ET AL.: "Cysteine proteinase inhibitors decrease articular cartilage and bone destruction in chronic inflammatory arthritis" *
J. MED. CHEM., vol. 36, 1993, pages 3472-3480, XP000565670 LI, Z. ET AL.: "Peptide alpha-keto ester, alpha-keto amide, and alpha-keto acid inhibitors of calpains and other csyteine proteases" *

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US5912352A (en) * 1996-05-31 1999-06-15 Novartis Finance Corporation Intermediates for the preparation of peptide analogues
US6703368B2 (en) * 1997-10-07 2004-03-09 Cephalon, Inc. Peptide-containing α-ketoamide cysteine and serine protease inhibitors
US6774212B2 (en) * 1999-12-03 2004-08-10 Bristol-Myers Squibb Pharma Company Alpha-ketoamide inhibitors of hepatitis C virus NS3 protease
US6703513B1 (en) * 2000-06-02 2004-03-09 K-Quay Enterprises Llc Production and use of derivatized homoserine lactones
US7560572B2 (en) 2000-06-02 2009-07-14 K-Quay Enterprises, Llc Production and use of derivatized homoserine lactones
EP2289888A3 (fr) * 2000-06-30 2011-07-13 Seikagaku Corporation Amides d'acide expoxy-carboxylique, azides et amino-alcools et procédés de préparation d'alpha-ceto amides à l'aide de ces derniers
US8163943B2 (en) 2000-06-30 2012-04-24 Seikagaku Kogyo Kabushiki Kaisha Epoxycarboxamide compound, azide compound, and amino alcohol compound, and process for preparing α-keto amide compound using them
WO2003013518A1 (fr) * 2001-08-03 2003-02-20 Smithkline Beecham Corporation Derives d'alpha-cetoamide utilises en tant qu'inhibiteurs de la cathepsine k
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
WO2003062192A1 (fr) * 2002-01-17 2003-07-31 Smithkline Beecham Corporation Derives de cetoamides a substitution cycloalkyle, utiles comme inhibiteurs de cathepsine k
US7402606B2 (en) 2002-04-10 2008-07-22 Smithkline Beecham Corporation Derivatives of 1-(oxoaminoacetyl) pentylcarbamate as cathepsin K inhibitors for the treatment of bone loss
WO2003086385A1 (fr) * 2002-04-10 2003-10-23 Smithkline Beecham Corporation Derives de 1-(oxoaminoacetyl) pentylcarbamate utilises en tant qu'inhibiteurs de la cathepsine dans le traitement de la perte osseuse
US7022738B2 (en) 2002-07-22 2006-04-04 Senju Pharmaceutical Co., Ltd. α-ketoamide derivative and use thereof
AU2009329066B2 (en) * 2008-12-19 2012-05-24 Medivir Uk Ltd Cysteine protease inhibitors
EA019277B1 (ru) * 2008-12-19 2014-02-28 МЕДИВИР ЮКей ЛТД. Ингибиторы цистеинпротеазы
US8853281B2 (en) 2008-12-19 2014-10-07 Medivir Uk Ltd Cysteine protease inhibitors
WO2010070615A1 (fr) * 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
US8541363B2 (en) 2010-01-22 2013-09-24 St George's Hosptial Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
US8637453B2 (en) 2010-01-22 2014-01-28 St George's Hospital Medical School Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use
WO2013127981A1 (fr) 2012-03-01 2013-09-06 Veterinärmedizinische Universität Wien Inhibiteurs de protéases pour le traitement des infections par trichomonas gallinae
US10889563B2 (en) 2013-01-07 2021-01-12 University Of Southern California Deoxyuridine triphosphatase inhibitors
EP2994143A4 (fr) * 2013-05-08 2017-02-01 Board of Regents, The University of Texas System Inhibiteurs de stat6
US9765099B2 (en) 2013-05-08 2017-09-19 Board Of Regents, The University Of Texas System STAT6 inhibitors
US10385080B2 (en) 2013-05-08 2019-08-20 Board Of Regents, The University Of Texas System STAT6 inhibitors
US11104649B2 (en) 2015-07-08 2021-08-31 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11198677B2 (en) 2015-07-08 2021-12-14 University Of Southern California Deoxyuridine triphosphatase inhibitors containing amino sulfonyl linkage
US10570098B2 (en) 2015-07-08 2020-02-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10577321B2 (en) 2015-07-08 2020-03-03 University Of Southern California Deoxyuridine triphosphatase inhibitors
US12098133B2 (en) 2015-07-08 2024-09-24 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11584723B2 (en) 2015-07-08 2023-02-21 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US10544105B2 (en) 2015-07-08 2020-01-28 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US11479531B2 (en) 2015-07-08 2022-10-25 University Of Southern California Deoxyuridine triphosphatase inhibitors
US10562860B2 (en) 2015-07-08 2020-02-18 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11124485B2 (en) 2015-07-08 2021-09-21 Cv6 Therapeutics (Ni) Limited Deoxyuridine triphosphatase inhibitors containing cyclopropano linkage
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds
US11377439B2 (en) 2016-06-21 2022-07-05 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
US11267803B2 (en) 2016-06-21 2022-03-08 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11866422B2 (en) 2016-06-21 2024-01-09 Orion Ophthalmology LLC Carbocyclic prolinamide derivatives
US11174271B2 (en) 2016-11-23 2021-11-16 Cv6 Therapeutics (Ni) Limited 6-membered uracil isosteres
US11168059B2 (en) 2016-11-23 2021-11-09 Cv6 Therapeutics (Ni) Limited Amino sulfonyl compounds
WO2018098208A1 (fr) * 2016-11-23 2018-05-31 Cv6 Therapeutics (Ni) Limited Inhibiteurs de désoxyuridine triphosphatase liés à un cycle azote
US11014924B2 (en) 2016-11-23 2021-05-25 Cv6 Therapeutics (Ni) Limited Hydantoin containing deoxyuridine triphosphatase inhibitors
US11518746B2 (en) 2016-11-23 2022-12-06 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
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US10829457B2 (en) 2016-11-23 2020-11-10 Cv6 Therapeutics (Ni) Limited Nitrogen ring linked deoxyuridine triphosphatase inhibitors
US11247984B2 (en) 2017-01-05 2022-02-15 Cv6 Therapeutics (Ni) Limited Uracil containing compounds

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CA2200964A1 (fr) 1996-05-30
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EP0793673A1 (fr) 1997-09-10

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