Piperazine compounds as inhibitors of MMP or TNF

A compound of formula (I) wherein A is a sulfonyl or a carbonyl; R.sup.1 is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl; R.sup.2 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R.sup.3 is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substitued lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substitued amino; R.sup.4 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; R.sup.5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and R.sup.10 is a hydroxy or a protected hydroxy, and a pharmaceutically acceptable salt thereof. The compound of the present invention is useful as a medicament for prophylactic and therapeutic treatment of MMP- or TNF.alpha.-mediated diseases. ##STR1##

FIELD OF THE INVENTION
 The present invention relates to new compounds and pharmaceutically
 acceptable salts thereof.
 More particularly, it relates to new compounds and pharmaceutically
 acceptable salts thereof which are useful as inhibitors of matrix
 metalloproteinases (hereinafter to be referred to as MMP) or the
 production of tumor necrosis factor .alpha. (hereinafter to be referred to
 as TNF.alpha.), to pharmaceutical compositions comprising the same, to use
 of the same as medicaments, and to methods for using the same
 therapeutically in the treatment and/or the prevention of MMP- or
 TNF.alpha.-mediated diseases.
 BACKGROUND ART
 Some piperazine compounds to be useful as metalloproteinase inhibitors, or
 the like are known (WO 97/20824, etc.).
 DISCLOSURE OF THE INVENTION
 One object of the present invention is to provide new and useful compounds
 and pharmaceutically acceptable salts thereof, and to provide a process
 for preparing said new compound and salts thereof, which have
 pharmacological activities such as MMP- or TNF.alpha.-inhibitory activity
 and the like.
 Another object of the present invention is to provide a pharmaceutical
 composition comprising, as an active ingredient, said compound or a
 pharmaceutically acceptable salt thereof.
 A further object of the present invention is to provide use of said
 compounds and pharmaceutically acceptable salts thereof as medicaments for
 prophylactic and therapeutic treatment of MMP- or TNF.alpha.-mediated
 diseases.
 A still further object of the present invention is to provide a method for
 using the same for the treatment and/or the prevention of MMP- or
 TNF.alpha.-mediated diseases in mammals, especially humans.
 The compounds of the present invention have inhibitory activity on MMP or
 the production of TNF.alpha., and are useful for the treatment and/or
 prevention of diseases such as stroke, arthritis, cancer, tissue
 ulceration, decubitus ulcer, restenosis, periodontal disease,
 epidermolysis bullosa, scleritis, psoriasis and other diseases
 characterized by matrix metalloproteinase activity, as well as AIDS,
 sepsis, septic shock and other diseases caused by the production of
 TNF.alpha..
 There are a number of structurally related metalloproteases which effect
 the breakdown of structural proteins. Matrix-degrading metalloproteases,
 such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase
 (MMP-1, MMP-8, MMP-13), are involved in tissue matrix degradation and have
 been implicated in many pathological conditions involving abnormal
 connective tissue and basement membrane matrix metabolism, such as
 arthritis (e.g., osteoarthritis and rheumatoid arthritis), cerebral
 disease (e.g., stroke, etc.), tissue ulceration (e.g., corneal, epidermal
 and gastric ulcerations), abnormal wound healing, periodontal disease,
 bone disease (e.g., Paget's disease and osteoporosis), tumor metastasis or
 invasion and HIV-infection.
 A tumor necrosis factor is recognized to be involved in many infections and
 autoimmune diseases. Furthermore, it has been shown that TNF is the prime
 mediator of the inflammatory response seen in sepsis and septic shock.
 The object compounds of the present invention are novel and can be
 represented by the following formula (I):
 ##STR2##
 wherein
 A is a sulfonyl or a carbonyl;
 R.sup.1 is an optionally substituted aryl, an optionally substituted
 heterocyclic group, an optionally substituted lower alkyl or an optionally
 substituted lower alkenyl;
 R.sup.2 is a hydrogen, an optionally substituted lower alkyl, an optionally
 substituted aryl or an optionally substituted heterocyclic group;
 R.sup.3 is an optionally substituted lower alkyl, an optionally substituted
 lower alkoxy, an optionally substituted aryloxy, an optionally substituted
 lower alkenyl, an optionally substituted aryl, an optionally substituted
 heterocyclic group or an optionally substituted amino:
 R.sup.4 is a hydrogen, an optionally substituted lower alkyl, an optionally
 substituted aryl or an optionally substituted heterocyclic group;
 R.sup.5 is a hydrogen, an optionally substituted lower alkyl, an optionally
 substituted aryl or an optionally substituted heterocyclic group; and
 R.sup.10 is a hydroxy or a protected hydroxy, provided that when A--R.sup.3
 is methylsulfonyl, then R.sup.1 is an aryl substituted by a substituent
 selected from the group consisting of halogen, cyano, nitro, amino,
 acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy,
 lower alkyl, aryl and heterocyclic group, an optionally substituted
 heterocyclic group, an optionally substituted lower alkyl or an optionally
 substituted lower alkenyl, and the above-mentioned heterocyclic group is
 each selected from the group consisting of
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4
 nitrogen atoms,
 saturated 3- to 8-membered heteromonocyclic group containing 1 to 4
 nitrogen atoms,
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to
 5 nitrogen atoms,
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2
 oxygen atoms and 1 to 3 nitrogen atoms,
 saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen
 atoms and 1 to 3 nitrogen atoms,
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or
 2 oxygen atoms and 1 to 3 nitrogen atoms,
 unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2
 sulfur atoms and 1 to 3 nitrogen atoms,
 saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur
 atoms and 1 to 3 nitrogen atoms,
 unsaturated 3- to 8-membered heteromonocyclic group containing sulfur atom,
 unsaturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
 saturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or
 2 sulfur atoms and 1 to 3 nitrogen atoms and
 unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or
 2 oxygen atoms,
 and a pharmaceutically acceptable salt thereof.
 The object compounds of the present invention can be prepared by the
 following processes.
 ##STR3##
 ##STR4##
 ##STR5##
 ##STR6##
 In the above formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (X),
 (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) and
 (XXII), A, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined
 above, R.sup.10a is a protected hydroxy, X is a leaving group, R.sup.1a is
 a heterocyclic group having a substituent which is aryl substituted by
 acyloxy, R.sup.1b is a heterocyclic group having a substituent which is
 aryl substituted by hydroxy, R.sup.1c is a heterocyclic group having a
 substituent which is aryl substituted by cyanoalkyloxy, R.sup.1d is a
 heterocyclic group having a substituent which is aryl substituted by
 alkoxycarbonylalkyloxy, R.sup.3a is an alkyl substituted by halogen,
 R.sup.3b is a di(lower)alkylamino(lower)alkyl, an N-containing
 heterocyclic-(lower)-alkyl or an optionally substituted
 heterocyclic-thio(lower)alkyl, R.sup.3c is a protected carboxy(lower)alkyl
 or a protected carboxy(lower)alkylamino, R.sup.3d is a carboxy(lower)alkyl
 or a carboxy(lower)alkylamino, R.sup.3e is an N-containing
 heterocyclic-carbonyl(lower)alkyl, an optionally substituted
 amino-carbonyl(lower)alkyl or an optionally substituted
 amino-carbonyl(lower)alkylamino, R.sup.3f is a hydroxy(lower)alkyl, and
 R.sup.11 is a di(lower)alkylamino, an N-containing heterocyclic group or
 an optionally substituted heterocyclic-thiol. Heterocyclic group, aryl,
 acyl, alkyl, alkoxy, protected carboxy and halogen in the R.sup.1a,
 R.sup.1b, R.sup.1c, R.sup.1d, R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d,
 R.sup.3e, R.sup.3f and R.sup.11 are as defined below.
 The starting compounds (II), (VI), (XIV) and (XVI) can be prepared
 according to the following Preparations or by a conventional method.
 Suitable pharmaceutically acceptable salts of the object compounds may be
 conventional non-toxic salts and include an acid addition salt such as an
 organic acid salt (e.g., acetate, trifluoroacetate, maleate, tartrate,
 fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate,
 etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide,
 hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base
 such as an amino acid (e.g., arginine, aspartic acid, glutamic acid,
 etc.), an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an
 alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an
 ammonium salt, an organic base salt (e.g., trimethylamine salt,
 triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
 N,N'-dibenzyl-ethylenediamine salt, etc.), or the like.
 The object compounds and pharmaceutically acceptable salts thereof may
 include solvates such as enclosure compounds (e.g., hydrate, etc.).
 Suitable examples and illustrations of the various definitions, which the
 present invention includes within its scope and which are shown in the
 above and subsequent descriptions of the present specification, are as
 follows.
 Suitable "aryl" in the term "optionally substituted aryl" and "optionally
 substituted aryloxy" includes an aryl having 6 to 10 carbon atoms, such as
 phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like, preferably
 phenyl, and may have one or more substituents. Examples of the
 substituents for substituted aryl are halogen, cyano, nitro, amino,
 acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy,
 lower alkyl, optionally substituted aryl, optionally substituted
 heterocyclic group and the like, preferably halogen, nitro and lower
 alkoxy (e.g., methoxy, etc.).
 Suitable "heterocyclic group" in the term "optionally substituted
 heterocyclic group" means saturated or unsaturated, 3- to 8-membered
 monocyclic or polycyclic heterocyclic group containing at least one hetero
 atom such as oxygen atom, sulfur atom, nitrogen atom and the like.
 More preferable heterocyclic groups are:
 unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl,
 imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl,
 pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl,
 etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl,
 2,5-dihydro-1,2,4-triazinyl, etc.), and the like;
 saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 to 4 nitrogen atoms, for example, azetidinyl,
 pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl,
 piperazinyl, and the like;
 unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered,
 heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl,
 isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,
 benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g.,
 tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, and the
 like;
 unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for
 example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl,
 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and the like;
 saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for
 example, morpholinyl, morpholino, and the like;
 unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered,
 heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen
 atoms, for example, benzoxazolyl, benzoxadiazolyl, and the like;
 unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for
 example, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g.,
 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
 1,2,3-thiadiazolyl, etc.), and the like;
 saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for
 example, thiazolidinyl, and the like;
 unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing sulfur atom, for example, thienyl, and the like;
 unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing oxygen atom, for example, furyl, and the like;
 saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic
 group containing oxygen atom, for example, oxolanyl, and the like;
 unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered,
 heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen
 atoms, for example, benzothiazolyl, benzothiadiazolyl, and the like;
 unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered,
 heterocyclic group containing 1 or 2 oxygen atoms, for example,
 benzodihydrofuranyl, benzodioxolenyl, and the like;
 The most preferable heterocyclic groups may be unsaturated 5- or 6-membered
 heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or
 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms,
 unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2
 oxygen atoms and 1 to 3 nitrogen atoms, saturated 5- or 6-membered
 heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen
 atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 or
 2 sulfur atoms and 1 to 3 nitrogen atoms, unsaturated 5- or 6-membered
 heteromonocyclic group containing a sulfur atom, and unsaturated 9- or
 10-membered heterobicyclic group containing 1 or 2 oxygen atoms.
 These heterocyclic groups may have one or more substituents. Examples of
 the substituents for substituted heterocyclic group are halogen, cyano,
 nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower
 alkoxy, aryloxy, lower alkyl, aryl, optionally substituted heterocyclic
 group, haloaryl, hydroxyaryl, lower alkoxyary, lower alkylaryl, nitroaryl,
 biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl,
 cyanoaryl, cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower
 alkanoyloxy(lower)alkylaryl, di(lower)-alkylaminosulfonylaryl,
 hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower
 alkoxycarbonyl(lower)alkoxyaryl, lower alkoxysulfonyloxyaryl, aryl
 substituted by halogen and hydroxy, aryl substituted by halogen and
 alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower
 alkyl-heterocyclic group and aryl-heterocyclic group and the like,
 preferably halogen; phenyl; halophenyl; hydroxyphenyl; lower alkoxyphenyl;
 lower alkylphenyl; nitrophenyl; biphenylyl; phenoxyphenyl;
 trihalo(lower)alkylphenyl; cyano(lower)alkoxyphenyl; cyanophenyl;
 cyano(lower)alkylphenyl; lower alkanoyloxyphenyl; lower
 alkanoyloxy(lower)alkylphenyl; di(lower)alkylaminosulfonylphenyl;
 hydroxy(lower)alkylphenyl; lower alkoxycarbonylphenyl; lower
 alkoxycarbonyl(lower)alkoxyphenyl; lower alkoxysulfonyloxyphenyl; phenyl
 substituted by halogen and hydroxy, phenyl substituted by halogen and
 lower alkanoyloxy; phenyl substituted by halogen and lower alkoxy;
 heterocyclic group selected from the group consisting of unsaturated 9- or
 10-membered heterobicyclic group containing 1 or 2 oxygen atoms,
 unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4
 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group
 containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms and unsaturated
 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and
 1 to 3 nitrogen atoms; and a lower alkyl- or (phenyl-)heterocyclic group,
 said heterocyclic group being unsaturated 5- or 6-membered
 heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen
 atoms.
 Suitable "lower alkyl" in the term "optionally substituted lower alkyl" is
 a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified
 by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,
 hexyl and the like, preferably methyl and propyl, which may have one or
 more substituents. Examples of the substituents for substituted alkyl are
 halogen, cyano, nitro, acylamino, carbamoyl, hydroxy, lower alkoxy,
 optionally substituted aryloxy, optionally substituted aryl, heterocyclic
 group, heterocyclic-carbonyl, lower alkylcarbamoyl, carboxy, protected
 carboxy, di(lower)alkylamino, lower alkylamino, protected amino,
 arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower
 alkylsulfonylamino, di(lower)alkylaminosulfonylamino,
 heterocyclic-sulfonylamino, heterocyclic-thio, lower
 alkylheterocyclic-thio and the like, preferably halogen for R.sup.1, and
 halogen, carbamoyl, heterocyclic group, heterocyclic-carbonyl, lower
 alkylcarbamoyl, carboxy, protected carboxy, di(lower)alkylamino, lower
 alkylamino, protected amino, arylcarbonylamino,
 heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino,
 di(lower)alkylaminosulfonylamino, heterocyclic-sulfonylamino,
 heterocyclic-thio and lower alkylheterocyclic-thio for R.sup.3.
 Suitable "lower alkenyl" in the term "optionally substituted lower alkenyl"
 is a straight or branched alkenyl having 2 to 6 carbon atoms, and
 exemplified by ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
 1-pentenyl, 2-pentenyl and the like, preferably ethenyl, which may have
 one or more substituents. Examples of the substituents for substituted
 alkyl are halogen, cyano, nitro, acylamino, lower alkylamino, carbamoyl,
 hydroxy, lower alkoxy, optionally substituted aryloxy, optionally
 substituted aryl, heterocyclic group, heterocyclic-carbonyl and the like,
 preferably aryl (e.g., phenyl, etc.) for R.sup.1, and heterocyclic group
 (e.g., pyridyl, etc.) for R.sup.3.
 Suitable "lower alkoxy" in the term "optionally substituted alkoxy" is a
 straight or branched alkenyl having 1 to 6 carbon atoms, and exemplified
 by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,
 pentyloxy, tert-pentyloxy, hexyloxy and the like, preferably methoxy,
 which may have one or more substituents. Examples of the substituents for
 substituted alkoxy are halogen, cyano, nitro, acylamino, lower alkylamino,
 carbamoyl, hydroxy, lower alkoxy, optionally substituted aryloxy,
 optionally substituted aryl, heterocyclic group, heterocyclic-carbonyl and
 the like, preferably aryl (e.g., fluorenyl, etc.).
 Suitable "optionally substituted amino" includes a group of the formula:
 ##STR7##
 wherein R.sup.8 and R.sup.9 are the same or different and each is hydrogen,
 lower alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,
 carbamoyl(lower)alkyl, hydroxy(lower)alkyl, aryl or cyclo(lower)alkyl.
 Suitable "protected hydroxy" includes hydroxy protected by a conventional
 protective group, for example, substituted lower alkoxy such as lower
 alkoxy(lower)alkoxy (e.g., methoxymethoxy), lower
 alkoxy(lower)alkoxy(lower)alkoxy (e.g., methoxyethoxymethoxy) and
 substituted or unsubstituted aryl(lower)alkoxy (e.g., benzyloxy,
 nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g., acetoxy,
 propionyloxy, pivaloyloxy), aroyloxy (e.g., benzoyloxy,
 fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g., methoxycarbonyloxy,
 ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy,
 butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy,
 pentyloxycarbonyloxy, hexyloxycarbonyloxy), substituted or unsubstituted
 aryl(lower)alkoxycarbonyloxy (e.g., benzyloxycarbonyloxy,
 bromobenzyloxycarbonyloxy), arenesulfonyloxy (e.g., benzenesulfonyloxy,
 tosyloxy) and alkanesulfonyloxy (e.g., methanesulfonyloxy,
 ethanesulfonyloxy); tri(lower)alkylsilyloxy (e.g., trimethylsilyloxy);
 tetrahydropyranyloxy; and the like.
 The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4
 carbon atoms, unless otherwise indicated.
 Suitable "halogen" includes fluorine, bromine, chlorine and iodine.
 Suitable acyl moiety of "acylamino" includes acyl such as aliphatic acyl,
 aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by
 aromatic or heterocyclic group(s) derived from carboxylic, carbonic,
 sulfonic and carbamic acids.
 The aliphatic acyl includes saturated or unsaturated, acyclic or cyclic
 ones, for example, alkanoyl such as lower alkanoyl (e.g., formyl, acetyl,
 propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl,
 etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g., mesyl,
 ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
 isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl,
 N-alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.),
 alkoxycarbonyl such as lower alkoxycarbonyl (e.g., methoxycarbonyl,
 ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
 etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.,
 vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl
 (e.g., acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such
 as cyclo(lower)-alkanecarbonyl (e.g., cyclopropanecarbonyl,
 cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
 The aromatic acyl may include C.sub.6 -C.sub.10 aroyl (e.g., benzoyl,
 toluoyl, xyloyl, etc.), N-(C.sub.6 -C.sub.10)arylcarbamoyl (e.g.,
 N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C.sub.6
 -C.sub.10 arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.), and the
 like.
 The heterocyclic acyl may include heterocyclic-carbonyl (e.g., furoyl,
 thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl,
 thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
 The aliphatic acyl substituted by aromatic group(s) may include aralkanoyl
 such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl,
 phenylhexanoyl, etc.), aralkoxycarbonyl such as
 phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl,
 phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as
 phenoxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and
 the like.
 The aliphatic acyl substituted by heterocyclic group(s) may include
 heterocyclic-alkanoyl such as heterocyclic-(lower)alkanoyl (e.g.,
 thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl,
 thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl,
 thiadiazolylpropionyl, etc.), and the like.
 These acyl groups may be further substituted by one or more suitable
 substituents such as nitro and the like, and preferable acyl having such
 substituent(s) may be nitroaralkoxycarbonyl (e.g., nitrobenzyloxycarbonyl,
 etc.) and the like.
 Suitable "lower alkyl" and lower alkyl moiety of "lower alkylamino", "lower
 alkylaryl", "trihaloalkylaryl", "cyano(lower)alkylaryl", "lower
 alkanoyloxy(lower)alkylaryl", "lower alkylsulfonyloxyaryl",
 "di(lower)alkylaminosulfonylaryl", "hydroxy(lower)alkylaryl", "lower
 alkyl-heterocyclic group", "lower alkylcarbamoyl", "di(lower)alkylamino",
 "lower alkylsulfonylamino", "di(lower)alkylaminosulfonylamino", "lower
 alkylheterocyclic-thio", "carboxy(lower)alkyl", "lower
 alkoxycarbonyl(lower)alkyl", "carbamoyl(lower)alkyl" and
 "hydroxy(lower)-alkyl" are the same as lower alkyl defined above with
 regard to "optionally substituted lower alkyl".
 Suitable "lower alkoxy" and lower alkoxy moiety of "lower alkoxyaryl",
 "cyano(lower)alkoxyaryl", "lower alkoxycarbonylaryl", "lower
 alkoxycarbonyl(lower)alkoxyaryl" and "lower alkoxycarbonyl(lower)alkyl"
 are the same as alkoxy defined above with regard to "optionally
 substituted alkoxy".
 Suitable "aryl" and aryl moiety of "aryloxy", "haloaryl", "hydroxyaryl",
 "lower alkoxyaryl", "lower alkylaryl", "nitroaryl", "aryloxyaryl",
 "trihaloalkylaryl", "cyano(lower)alkoxyaryl", "cyanoaryl",
 "cyano(lower)alkylaryl", "lower alkanoyloxyaryl", "lower
 alkanoyloxy(lower)alkylaryl", "di(lower)alkylaminosulfonylaryl",
 "hydroxy(lower)alkylaryl", "lower alkoxycarbonylaryl", "lower
 alkoxycarbonyl(lower)alkoxyaryl", "lower alkylsulfonyloxyaryl", "aryl
 substituted by halogen and hydroxy", "aryl substituted by halogen and
 alkanoyloxy", "aryl substituted by halogen and lower alkoxy",
 "aryl-heterocyclic group" and "arylcarbonylamino" are the same as aryl
 defined above with regard to "optionally substituted aryl".
 Suitable "heterocyclic group" of the substituent and heterocyclic group
 moiety of "heterocyclic-carbonyl", "lower alkyl-heterocyclic group",
 "aryl-heterocyclic group", "heterocyclic-carbonylamino",
 "heterocyclic-sulfonylamino", "heterocyclic-thio", "lower
 alkylheterocyclic-thio", "heterocyclic-(lower)alkyl" and
 "heterocyclic-thio" are the same as heterocyclic group defined above with
 regard to "optionally substituted heterocyclic group".
 Suitable halo moiety of "haloaryl" and "trihaloalkylaryl" is halogen
 defined above.
 Suitable alkanoyl moiety of "lower alkanoyloxyaryl", "lower
 alkanoyloxy(lower)alkyl", "alkanoyloxy" and "lower alkanoylamino" is a
 straight or branched alkanoyl having 1 to 10, preferably 1 to 6, carbon
 atoms. Such group includes, for example, formyl, acetyl, propionyl,
 isopropionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl and the
 like, preferably acetyl.
 Suitable "protected carboxy" includes esterified carboxy wherein
 "esterified carboxy" is as defined below.
 Suitable examples of the ester moiety of the esterified carboxy are lower
 alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl
 ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl
 ester, etc.) and the like, which may have at least one suitable
 substituent. Examples of the substituted lower alkyl ester are lower
 alkanoyloxy(lower)alkyl ester [e.g., acetoxymethyl ester,
 propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,
 pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)-acetoxyethyl
 ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or
 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or
 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or
 2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or
 2-)hexanoyloxyethyl ester, isobutyryloxymethylester,
 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethylester, 1-(or
 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)-alkyl ester
 (e.g., 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester
 (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower
 alkoxycarbonyloxy(lower)alkyl ester [e.g., methoxycarbonyloxymethyl ester,
 ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,
 tert-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl
 ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or
 2-)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkyl
 ester, (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,
 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
 (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
 (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester
 (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl
 ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least
 one suitable substituent (e.g., benzyl ester, 4-methoxybenzyl ester,
 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester,
 bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,
 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which may have
 at least one suitable substituent (e.g., phenyl ester, 4-chlorophenyl
 ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester,
 cumenyl ester, etc.); phthalidyl ester; and the like.
 More preferable examples of the protected carboxy thus defined may be
 C.sub.2 -C.sub.4 alkenyloxycarbonyl and phenyl(or nitrophenyl)(C.sub.1
 -C.sub.4)alkoxycarbonyl, and the most preferable one may be
 ethoxycarbonyl.
 Suitable "amino-protective group" includes "acyl" mentioned above.
 More preferable examples of "amino-protective group" are C.sub.2 -C.sub.4
 alkoxycarbonyl and phenyl(or nitrophenyl)(C.sub.1 -C.sub.4)alkoxycarbonyl,
 and the most preferable one is tert-butoxycarbonyl.
 Suitable "cyclo(lower)alkyl" is, for example, cyclopropyl, cyclobutyl,
 cyclopentyl, cyclohexyl, and the like.
 Suitable "leaving group" includes halogen as mentioned above, acyloxy such
 as sulfonyloxy (e.g., mesyloxy, tosyloxy, etc.), alkoxy (e.g.,
 tert-butoxy, etc.), aralkoxy (e.g., benzyloxy, etc.), and the like.
 Of the object compounds (I),
 (1) the preferred one may be the compound of the formula (I) wherein
 R.sup.2 is a hydrogen or an optionally substituted lower alkyl, and
 R.sup.4 is a hydrogen or an optionally substituted lower alkyl,
 (2) the more preferred one may be the compound of the formula (I)
 wherein
 A is a sulfonyl or a carbonyl;
 R.sup.1 is an aryl optionally substituted by a substituent selected from
 the group consisting of halogen, cyano, nitro, amino, acylamino, lower
 alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl
 and heterocyclic group; a heterocyclic group optionally substituted by a
 substituent selected from the group consisting of halogen, cyano, nitro,
 amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy,
 aryloxy, lower alkyl, aryl, heterocyclic group, haloaryl, hydroxyaryl,
 lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl, aryloxyaryl,
 trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl,
 cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower
 alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl,
 hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower
 alkoxycarbonyl(lower)alkoxyaryl, lower alkylsulfonyloxyaryl, aryl
 substituted by halogen and hydroxy, aryl substituted by halogen and
 alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower
 alkyl-heteromonocyclic group and aryl-heterocyclic group; a lower alkyl
 optionally substituted by halogen; or a lower alkenyl optionally
 substituted by aryl;
 R.sup.2 is a hydrogen or an optionally substituted lower alkyl;
 R.sup.3 is a lower alkyl optionally substituted by a substituent selected
 from the group consisting of halogen, heterocyclic group, carbamoyl, lower
 alkylcarbamoyl, carboxy, protected carboxy, heterocyclic-carbonyl,
 di(lower)alkylamino, protected amino, arylcarbonylamino,
 heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino,
 di(lower)alkylaminosulfonylamino, heterocyclic-sulfonyl amino,
 heterocyclic-thio, lower alkylheterocyclic-thio and heterocyclic-thio; a
 lower alkoxy; an aryloxy; an aryl(lower)alkoxy; an optionally substituted
 lower alkenyl; an optionally substituted heterocyclic group; or a group of
 the formula:
 ##STR8##
 wherein
 R.sup.8 and R.sup.9 are the same or different and each is hydrogen, lower
 alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl,
 carbamoyl(lower)alkyl, hydroxy(lower)alkyl, aryl, cyclo(lower)alkyl or
 heterocyclic-(lower)alkyl;
 R.sup.4 is a hydrogen or an optionally substituted lower alkyl;
 R.sup.5 is a hydrogen, an optionally substituted lower alkyl, an optionally
 substituted aryl or an optionally substituted heterocyclic group and
 R.sup.10 is a hydroxy or a protected hydroxy; and
 (3) the most preferred one may be the compound of the formula (I)
 wherein
 A is a sulfonyl or a carbonyl;
 R.sup.1 is a thienyl substituted by a substituent selected from the group
 consisting of halogen, phenyl, halophenyl, hydroxyphenyl, lower
 alkoxyphenyl, lower alkylphenyl, nitrophenyl, biphenylyl, phenoxyphenyl,
 trihalo(lower)alkylphenyl, cyano(lower)alkoxyphenyl, cyanophenyl,
 cyano(lower)alkylphenyl, lower alkanoyloxyphenyl, lower
 alkanoyloxy(lower)alkylphenyl, di(lower)alkylaminosulfonylphenyl,
 hydroxy(lower)alkylphenyl, lower alkoxycarbonylphenyl, lower
 alkoxycarbonyl(lower)alkoxyphenyl, lower alkylsulfonyloxyphenyl, phenyl
 substituted by halogen and hydroxy, phenyl substituted by halogen and
 lower alkanoyloxy, phenyl substituted by halogen and lower alkoxy,
 thiazolyl, oxazolyl, pyridyl, benzodihydrofuranyl, benzodioxolenyl, lower
 alkyloxadiazolyl and phenyloxadiazolyl, a thiazolyl substituted by phenyl
 or a thiadiazolyl substituted by phenyl;
 R.sup.2 is a hydrogen;
 R.sup.3 is a lower alkyl, a halo(lower)alkyl, a morpholinyl(lower)-alkyl, a
 piperidinyl(lower)alkyl, a pyridyl(lower)alkyl, a carbamoyl(lower)alkyl, a
 lower alkylcarbamoyl(lower)alkyl, a carboxy(lower)alkyl, a
 phenyl(lower)alkoxycarbonyl(lower)alkyl, a
 morpholinylcarbonyl(lower)alkyl, a di(lower)alkylamino(lower)alkyl, a
 phenyl(lower)alkoxycarbonylamino(lower)alkyl, a lower
 alkoxycarbonylamino(lower)alkyl, a benzoylamino(lower)alkyl, a
 pyridyl-carbonylamino(lower)alkyl, a lower alkanoylamino(lower)alkyl, a
 lower alkylsulfonylamino(lower)alkyl, a
 di(lower)alkylaminosulfonylamino(lower)alkyl, a
 pyridyl-sulfonylamino(lower)alkyl, a triazolylthio(lower)alkyl, an
 imidazolylthio(lower)alkyl, a thiazolylthio(lower)alkyl, a
 benzimidazolylthio(lower)alkyl, a lower alkyltriazolylthio(lower)alkyl, a
 lower alkoxy, a fluorenyl(lower)alkoxy, a phenoxy, a
 pyridyl(lower)alkenyl, a pyridyl, a piperidinyl, a thienyl substituted by
 oxazolyl, a mono- (or di-)(lower)alkylamino, a carboxy(lower)alkylamino, a
 lower alkoxycarbonyl(lower)alkylamino, an
 N-(lower)alkyl-N-(lower)alkoxycarbonyl(lower)alkylamino, a
 carbamoyl(lower)alkylamino, a hydroxy(lower)alkylamino, a phenylamino or a
 cyclo(lower)alkylamino;
 R.sup.4 is a hydrogen;
 R.sup.5 is a hydrogen and
 R.sup.10 is a hydroxy.
 The processes for preparing the object compounds are explained in detail in
 the following.
 Process 1
 The compound (IV) or a salt thereof can be prepared by reacting the
 compound (II) or a salt thereof with the compound (III) or a salt thereof.
 Suitable salts of the compounds (II), (III) and (IV) may be the same as
 those exemplified with respect to the compound (I).
 The reaction is usually carried out in a conventional solvent such as
 water, acetone, dioxane, acetonitrile, chloroform, methylene chloride,
 ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
 pyridine and dichloromethane, a mixture thereof, or any other organic
 solvents which do not adversely affect the reaction.
 This reaction can be carried out in the presence of an organic or inorganic
 base such as alkali metal (e.g., lithium, sodium, potassium, etc.),
 alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g.,
 sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium
 hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium
 hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,
 potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium
 bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.,
 sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali
 metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g.,
 triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine,
 picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium
 diisopropylamide, and the like.
 The reaction temperature is not critical, and the reaction is usually
 carried out under cooling to heating.
 Process 2
 The compound (V) and a salt thereof can be prepared by eliminating the
 hydroxy protective group of the compound (IV) or a salt thereof.
 Suitable salts of the compounds (IV) and (V) may be the same as those
 exemplified above with regard to the compound (I).
 Suitable method of this elimination reaction includes conventional ones
 such as hydrolysis, reduction and the like.
 The hydrolysis is preferably carried out in the presence of a base or an
 acid including Lewis acid.
 Suitable base includes an inorganic base and an organic base such as an
 alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal
 (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or
 hydrogencarbonate thereof, trialkylamine (e.g., trimethylamine,
 triethylamine, etc.), picoline, 1,5-diazabicyclo[4.3.0]non-5-one, and the
 like.
 Suitable acid includes an organic acid (e.g., formic acid, acetic acid,
 propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), and an
 inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid,
 hydrogen chloride, hydrogen bromide, etc.).
 The elimination using Lewis acid such as trihaloacetic acid (e.g.,
 trichloroacetic acid, trifluoroacetic acid, etc.) and the like is
 preferably carried out in the presence of cation trapping agent (e.g.,
 anisole, phenol, etc.). This reaction is usually carried out without
 solvent.
 Alternatively, the reaction may be carried out in a conventional solvent
 such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.),
 tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene
 dichloride, chloroform, N,N-dimethylformamide and N,N-dimethylacetamide, a
 mixture thereof, or any other organic solvents which do not adversely
 affect the reaction.
 The reaction temperature is not critical and the reaction is usually
 carried out under cooling to warming.
 The reduction is carried out in a conventional manner, including chemical
 reduction and catalytic reduction.
 Suitable reducing reagents to be used in chemical reduction are a hydride
 (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium
 borohydride, sodium cyanoborohydride, etc.), or a combination of a metal
 (e.g., tin, zinc, iron, etc.) or a metallic compound (e.g., chromium
 chloride, chromium acetate, etc.) and an organic acid or an inorganic acid
 (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid,
 p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
 Suitable catalyst to be used in catalytic reduction is conventional one
 such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum
 black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium
 catalyst (e.g., spongy palladium, palladium black, palladium oxide,
 palladium on carbon, colloidal palladium, palladium on barium sulfate,
 palladium on barium carbonate, etc.), nickel catalyst (e.g., reduced
 nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced
 cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron, Raney
 iron, Ullman iron, etc.), and the like.
 The reduction is usually carried out in a conventional solvent such as
 water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.),
 tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene
 dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide and
 cyclohexane, a mixture thereof, or any other organic solvents which do not
 adversely affect the reaction.
 When the above-mentioned acids to be used in chemical reduction are liquid,
 they can also be used as a solvent.
 The reaction temperature of this reduction is not critical and the reaction
 is usually carried out under cooling to warming.
 Process 3
 The compound (IV) or a salt thereof can be prepared by reacting the
 compound (VI) or its reactive derivative at the carboxy group, or a salt
 thereof, with the compound (VII) or its reactive derivative at the amino
 group, or a salt thereof.
 Suitable salts of the compounds (VI) and (VII) may be the same as those
 exemplified for the compound (I).
 The reaction is usually carried out in a conventional solvent such as
 water, acetone, dioxane, acetonitrile, chloroform, methylene chloride,
 ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
 pyridine and dichloromethane, a mixture thereof, or any other organic
 solvents which do not adversely affect the reaction.
 This reaction can be carried out in the presence of an organic or inorganic
 base such as alkali metal (e.g., lithium, sodium, potassium, etc.),
 alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g.,
 sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium
 hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium
 hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,
 potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium
 bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.,
 sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali
 metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g.,
 triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine,
 picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium
 diisopropylamide, and the like.
 Suitable reactive derivative at the amino group of the compound (VII) may
 include Schiff's base type imino or its tautomeric enamine type isomer
 formed by the reaction of the compound (VII) with a carbonyl compound such
 as aldehyde, ketone or the like; a silyl derivative formed by the reaction
 of the compound (VII) with a silyl compound such as
 bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,
 bis(trimethylsilyl)urea or the like; a derivative formed by the reaction
 of the compound (VII) with phosphorus trichloride or phosgene, and the
 like.
 Suitable reactive derivative at the carboxy group of the compound (VI) may
 include an acid halide, an acid anhydride, an activated amide, an
 activated ester, and the like. Suitable examples of the reactive
 derivative may be an acid chloride; an acid azide; a mixed acid anhydride
 with acid such as substituted phosphoric acid (e.g., dialkylphosphoric
 acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric
 acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid,
 sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g.,
 methanesulfonic acid, etc.), aliphatic carboxylic acid (e.g., acetic acid,
 propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic
 acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.)
 or aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid
 anhydride; an activated amide with imidazole, 4-substituted imidazole,
 dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.,
 cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl
 [(CH.sub.3).sub.2 N.sup.+ =CH--] ester, vinyl ester, propargyl ester,
 p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
 pentachlorophenyl ester, mesylphenyl ester, phenyl azophenyl ester, phenyl
 thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl
 thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl
 thioester, etc.), or an ester with a N-hydroxy compound (e.g.,
 N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,
 N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,
 etc.), and the like. These reactive derivative can be optionally be
 selected from them according to the kind of the compound (VI) to be used.
 The reaction is preferably carried out in the presence of a conventional
 condensing agent such as N,N'-dicyclohexylcarbodiimide;
 N-cyclohexyl-N'-morpholinoethylcarbodiimide;
 N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
 N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
 N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
 N,N'-carbonylbis-(2-methylimidazole);
 pentamethyleneketene-N-cyclo-hexylimine; diphenylketene-N-cyclohexylimine;
 ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl
 polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
 chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl
 chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl
 chloroformate, isopropyl chloroformate); triphenylphosphine;
 2-ethyl-7-hydroxybenzisoxazolium salt;
 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the
 reaction of N,N-dimethylforamide with thionyl chloride, phosgene,
 trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
 The reaction temperature is not critical, and the reaction is usually
 carried out under cooling.
 Process 4
 The compound (X) or a salt thereof can be prepared by reacting the compound
 (VIII) or a salt thereof with the compound (IX) or a salt thereof.
 Suitable salts of the compounds (VIII), (IX) and (X) may be the same as
 those exemplified for the compound (I).
 The reaction is usually carried out in a conventional solvent such as
 water, acetone, dioxane, acetonitrile, chloroform, methylene chloride,
 ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
 pyridine and dichloromethane, a mixture thereof, or any other organic
 solvents which do not adversely affect the reaction.
 This reaction can be carried out in the presence of an organic or inorganic
 base such as alkali metal (e.g., lithium, sodium, potassium, etc.),
 alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g.,
 sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium
 hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium
 hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,
 potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium
 bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.,
 sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali
 metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g.,
 triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine,
 picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium
 diisopropylamide, and the like.
 The reaction is carried out in the presence of alkali metal halide (e.g.,
 sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g.,
 sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl
 azodicarboxylate (e.g., diethyl azodicarboxylate, diisopropyl
 azodicarboxylate, etc.), and the like.
 The reaction is preferably carried out in the presence of a conventional
 condensing agent such as N,N'-dicyclohexylcarbodiimide;
 N-cyclohexyl-N'-morpholinoethylcarbodiimide;
 N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
 N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
 N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
 N,N'-carbonylbis-(2-methylimidazole);
 pentamethyleneketene-N-cyclo-hexylimine; diphenylketene-N-cyclohexylimine;
 ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl
 polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
 chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl
 chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl
 chloroformate, isopropyl chloroformate); triphenylphosphine;
 2-ethyl-7-hydroxybenz-isoxazolium salt;
 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the
 reaction of N,N-dimethylforamide with thionyl chloride, phosgene,
 trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
 The reaction temperature is not critical, and the reaction is usually
 carried out under cooling.
 Process 5
 The compound (XII) or a salt thereof can be prepared by eliminating the
 hydroxy protective group of the compound (XI) or a salt thereof.
 Suitable salts of the compounds (XI) and (XII) may be the same as those
 exemplified for the compound (I).
 The reaction of this process can be carried out in a manner similar to that
 in Process 2.
 Process 6
 The compound (XIII) or a salt thereof can be prepared by subjecting the
 compound (XII) or a salt thereof to amidation reaction.
 Suitable salts of the compounds (XII) and (XIII) may be the same as those
 exemplified for the compound (I).
 The reaction of this process can be carried out in a manner similar to that
 in Process 4.
 Process 7
 The compound (IV) or a salt thereof can be prepared by reacting the
 compound (XIV) or a salt thereof with the compound (XV) or a salt thereof.
 Suitable salts of the compounds (XIV) and (XV) may be the same as those
 exemplified for the compound (I).
 The reaction of this process can be carried out in a manner similar to that
 in Process 1.
 Process 8
 The compound (XVIII) or a salt thereof can be prepared by reacting the
 compound (XVI) or a salt thereof with the compound (XVII) or its reactive
 derivative at the carboxy group, or a salt thereof.
 Suitable salts of the compounds (XVI), (XVII) and (XVIII) may be the same
 as those exemplified for the compound (I).
 Suitable reactive derivative at the amino group of the compound (XVII) may
 include Schiff's base type imino or its tautomeric enamine type isomer
 formed by the reaction of the compound (XVII) with a carbonyl compound
 such as aldehyde, ketone or the like; a silyl derivative formed by the
 reaction of the compound (XVII) with a silyl compound such as
 bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,
 bis(trimethylsilyl)urea or the like; a derivative formed by the reaction
 of the compound (XVII) with phosphorus trichloride or phosgene, and the
 like.
 The reaction is usually carried out in a conventional solvent such as
 water, acetone, dioxane, acetonitrile, chloroform, methylene chloride,
 ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,
 pyridine and dichloromethane, a mixture thereof, or any other organic
 solvents which do not adversely affect the reaction.
 This reaction can be carried out in the presence of an organic or inorganic
 base such as alkali metal (e.g., lithium, sodium, potassium, etc.),
 alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g.,
 sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium
 hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium
 hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate,
 potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium
 bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.,
 sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali
 metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g.,
 triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine,
 picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium
 diisopropylamide, and the like.
 The reaction is carried out in the presence of alkali metal halide (e.g.,
 sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g.,
 sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl
 azodicarboxylate (e.g., diethyl azodicarboxylate, diisopropyl
 azodicarboxylate, etc.), and the like.
 The reaction is preferably carried out in the presence of a conventional
 condensing agent such as N,N'-dicyclohexylcarbodiimide;
 N-cyclohexyl-N'-morpholinoethylcarbodiimide;
 N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;
 N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide;
 N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
 N,N'-carbonylbis-(2-methylimidazole);
 pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine;
 ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl
 polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl
 chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl
 chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl
 chloroformate, isopropyl chloroformate); triphenylphosphine;
 2-ethyl-7-hydroxybenz-isoxazolium salt;
 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;
 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;
 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the
 reaction of N,N-dimethylforamide with thionyl chloride, phosgene,
 trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
 The reaction temperature is not critical, and the reaction is usually
 carried out under cooling.
 Process 9
 The compound (XX) or a salt thereof can be prepared by eliminating the
 hydroxy protective group of the compound (XIX) or a salt thereof.
 Suitable salts of the compounds (XIX) and (XX) may be the same as those
 exemplified for the compound (I).
 The reaction of this process can be carried out in a manner similar to that
 in Process 2.
 Process 10
 The compound (XXII) or a salt thereof can be prepared by subjecting the
 compound (XXI) or a salt thereof to solvolysis.
 Suitable salts of the compounds (XXII) and (XXI) may be the same as those
 exemplified for the compound (I).
 The solvolysis is carried out in a conventional solvent such as water,
 alcohol (e.g., methanol, ethanol, etc.), a mixture thereof, or any other
 organic solvents which do not adversely affect the reaction.
 The reaction temperature is not critical, and the reaction is usually
 carried out under cooling to heating.
 The compounds obtained can be isolated and purified by a conventional
 method such as pulverization, recrystallization, column chromatography,
 reprecipitation and the like.
 The object compounds can be transformed into their salts in a conventional
 manner.
 It is to be noted that the object compounds may include one or more
 stereoisomers due to asymmetric carbon atoms, and all of such isomers and
 mixtures thereof are included within the scope of this invention.
 Collagenases initiate the degradation of collagen in vertebrates and, in
 addition to their normal function in the metabolism of connective tissue
 and wound healing, they have been implicated to be involved in a number of
 pathological conditions such as joint destruction in rheumatoid arthritis,
 periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis,
 decubitus restenosis after percutaneous transluminal coronary angiopsty,
 osteoporosis, proriasis, chronic active heatitis, autoimmune keratitis,
 and the like, and therefore the compounds of the present invention are
 useful for treating and/or preventing such pathological conditions.
 For therapeutic purposes, the compounds and pharmaceutically acceptable
 salts thereof of the present invention can be used in the form of a
 pharmaceutical preparation containing, as an active ingredient, one of
 said compounds in admixture with a pharmaceutically acceptable carrier
 such as an organic or inorganic solid or liquid excipient suitable for
 oral, parenteral or external administration. The pharmaceutical
 preparations may be capsules, tablets, dragees, granules, solutions,
 suspensions, emulsions, sublingual tablets, suppositories, ointments, and
 the like. If desired, there may be included, in these preparations,
 auxiliary substances, stabilizing agents, wetting agents, emulsifying
 agents, buffers and other commonly used additives.
 While the dose of the compound will vary depending upon the age and
 condition of patient and the like, in the case of intravenous
 administration, a daily dose of 0.01-100 mg of the active ingredient per
 kg weight of a human being, and in the case of intramuscular
 administration, a daily dose of 0.05-100 mg of the same per kg weight of a
 human being, or in the case of oral administration, a daily dose of
 0.1-100 mg of the same per kg weight of a human being, is generally given
 for the treatment of MMP or TNF.alpha. mediated diseases.
 In order to illustrate the usefulness of the object compound, the
 pharmacological test data of a representative compound of the compound are
 shown in the following.
 Inhibitory Activity of Collagenase
 1. Test Method
 Human collagenase was prepared from the culture medium of human skin
 fibroblast stimulated with interleukin-1.beta. (1 ng/ml). Latent
 collagenase was activated by incubation with trypsin (200 .mu.g/ml) at
 37.degree. C. for 60 minutes and the reaction was stopped by adding
 soybean trypsin inhibitor (800 .mu.g/ml). Collagenase activity was
 determined using FTTC-labeled calf skin type I collagen. FITC-collagen
 (2.5 mg/ml) was incubated at 37.degree. C. for 120 minutes with the
 activated collagenase and test compound in 50 mM Tris buffer (containing 5
 mm CaCl.sub.2, 200 mM NaCl and 0.02% NaN.sub.3, pH 7.5). After stopping
 the enzyme reaction by adding the equal volume of 70% ethanol-200 /mM Tris
 buffer (pH 9.5), the reaction mixture was centrifuged, and collagenase
 activity was estimated by measuring the fluorescence intensity of
 supernatant at 495 nm (excitation) and 520 nm (emission).
 2. Test Compound
 Compound of Example 5
 3. Test Result