JP2001031637A - New hydroxamic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound comprising a hydroxamic acid derivative, capable of inhibiting metalloproteinases and excellent in physiological activities such as percutaneous absorbability or oral absorbability. SOLUTION: This compound is represented by formula I [R1 is H, a (substituted) aralkyl or the like; R2 is H, a (substituted) aralkyloxycarbonyl or the like; R3, R7 and R8 are each H, OH, a (substituted) alkyl or the like; R4 is a (substituted) alkyl or the like; R5 is H, a (substituted) alkyl or the like; R6 is H, OH or the like, X is O, a (substituted) 1-6C alkylene or the like; Y is A-B or the like; A is a (substituted) 1-6C alkylene or the like; B is H, amino or the like], e.g. Na-[4-(N-hydroxyamino)-2(R)-isobutyl-3(S)-(3-phenylpropyl) succinyl]-L-4'-aminomethylphenylalamine. The compound represented by formula I is obtained by respectively converting R9 and R11 to R13 of a compound represented by formula II into the objective groups R3 to R6 and then converting the CO2R10 site of the compound into an amide bond-containing site.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound which inhibits metalloproteinase, an intermediate for producing the same, and a method for producing them. More preferably, the present invention relates to vertebrate-derived matrix metalloproteinases (MM
A novel compound which inhibits Ps) and / or tumor necrosis factor-α (TNF-α) converting enzyme, has excellent biological activity such as transdermal absorption and oral absorption, an intermediate for producing the same and a method for producing them .

[0002]

2. Description of the Related Art Among metalloproteinases, matrix metalloproteinases (MMPs) belong to zinc-containing endoproteinases and are involved in the degradation of extracellular matrix in connective tissues. To date, it is known that dozens of MMPs exist in MMPs, and the expression of these enzymes is strictly controlled in healthy individuals, but Alzheimer's, Parkinson's disease, pancreatitis, ulcerative colitis, aphthous Ulcer, autoimmune disease (rheumatoid arthritis, Crohn's disease, anemia in autoimmune disease), osteoarthritis, periodontal disease, corneal ulcer, uveitis, various bullous diseases (congenital epidermolysis bullosa, after Epidermolysis bullosa acquisita, tardive skin porphyria, pemphigus pemphigoid, pemphigus vulgaris), intractable skin ulcers (pressure ulcers, skin ulcers in radiation-treated patients, skin ulcers in diabetic patients, skin in patients with obstructive arteriosclerosis) Ulcers), osteoporosis, Behcet's disease, angiogenesis (lymphoma, ovarian cancer, metastasis and invasion associated with cancer growth), cachexia, various infectious diseases (malaria, hepatitis C, HIV infection, , Sepsis), multiple sclerosis, psoriasis, diabetes, schizophrenia,
In cases such as depression, abnormal elevation of MMPs is observed, and these are thought to be involved in the destruction of the extracellular matrix; Literature (D. Brown et al., Current Eye Research,
12, 571 (1993) / Y. Okada et al., Virchow Archiv B
Cell Pathol., 59, 305 (1990) / WGStetler-Stevenso
n, Cancer and Metastasis Reviews, 9,289 (1990) / H.
Birkedal-Hansen et al., Critical Reviews in Oral Bi
ology and Medicine, 4 (2), 197 (1993)].

[0003] On the other hand, TNF-α is produced as a membrane-bound precursor having a molecular weight of 26K, and is considered to cause diseases such as sepsis and rheumatoid arthritis if released extracellularly. Recently, an enzyme that causes the release of TNF-α (TNF-α
Conversion enzyme) is a metalloproteinase whose activity has been reported to be regulated by MMPs inhibitors [AJ
H. Gearing et al., Journal of Leukocyte Biology, 5
7, 774 (1995), KMMohler et al., Nature, 370, 218
(1994), GM NcGeehan et al., Nature, 370, 558 (19
94)]. Therefore, in the case of the above-mentioned diseases, inhibiting the action of these enzymes is an effective therapeutic means.
Conventionally, as compounds having MMPs inhibitory activity, compounds that are classified into four classes of phosphoric acid derivatives, hydroxamic acid derivatives, derivatives having a mercapto group, and derivatives having a carboxyl group are known. Particularly with respect to hydroxamic acid derivatives, compounds having various skeletons have been proposed (US Pat. No. 4,599,361, European Patent Application Publication No. 575844 A2, US Pat. No. 5,412,145,
WO 92/13831, U.S. Pat.No. 5,183,900,
WO 94/02447, EP 606046 A1
No. 2,268,933 A), and many of these compounds have inhibitory activity against various MMPs. On the other hand, WO 96/33968 discloses a compound having a remarkably improved solubility in water, which was a problem.

[0004]

When administering a medicine,
For example, injections and the like not only impose a heavy burden on patients, but also have a serious problem in terms of simplicity and the like from the viewpoint of ingestion of drugs by the patients themselves. In addition, diseases related to tissue degradation often become chronic, and require long-term drug application. In such cases, oral administration may be the most suitable route of administration. However, it is difficult to apply such a drug orally to a conventional compound, and at present it is not effectively used as a therapeutic agent.

[0005]

Means for Solving the Problems The present inventors have focused on hydroxamic acid derivatives having a high inhibitory activity on MMPs, and have conducted intensive studies in order to enhance their utilization. As a result, it not only has high metalloproteinase inhibitory activity, but also dramatically improves in vivo drug use and biological activity such as transdermal absorbability and oral absorbability compared to the above compounds. The present inventors have found a novel hydroxamic acid derivative and completed the present invention.

That is, the present invention provides: [1] The following general formula (I):

Embedded image

Wherein R ¹ is hydrogen, an aralkyl group which may be substituted, a silyl group having three substituents, a tetrahydropyranyl group, an aralkyloxycarbonyl group which may be substituted, Represents an alkyloxycarbonyl group which may be substituted, an alkyl group which may be substituted, or a protecting group for a hydroxyl group, wherein R ² is hydrogen, an aralkyloxycarbonyl group which may be substituted, A good alkyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, or an amino group-protecting group, and R ³ is hydrogen, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aralkyl. R ⁴ represents an alkyl group which may be substituted, or an aralkyl group which may be substituted; R ⁵ represents hydrogen,
Represents an alkyl group which may be substituted, an aralkyl group which may be substituted, or a protecting group for a carboxyl group, and R ⁶ represents
X represents hydrogen, hydroxyl, amino, or -XY;
Represents oxygen, an optionally substituted (C ₁ -C ₆ ) alkylene group, or an optionally substituted phenylene group,
Y represents -AB group or -B group, A is an optionally substituted (C ₁ -C ₆ ) alkylene group, oxygen, sulfur, imino group,
Or an optionally substituted (C ₁ -C ₆ ) alkyleneimino group, B is hydrogen, an amino group, an amidino group, a sulfonyl group, an acylimidoyl group, an optionally substituted imidazolyl group, Represents an optionally protected bisphosphonomethyl group, or an optionally protected bisphosphonohydroxymethyl group, and R ⁷ is hydrogen, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted Represents an aralkyl group, and R ⁸ represents hydrogen, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aralkyl group], or a pharmaceutically acceptable salt thereof. Or a solvate;

[2] In the general formula (I) described in the above [1],
And R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉)
Alkyl group, (C_Three-C₇) Cycloalkyl-substituted (C₁-C_Four) Low grade
Alkyl group, hydroxyl group, amino substitution (C₁-C₆) Alkyl group,
Phenyl (C₁-C_Four) Lower alkyl group, guanidino-substituted
Nil (C₁-C_Four) Lower alkyl group, amino-substituted phenyl (C₁-
C_Four) Lower alkyl group, carboxy-substituted phenyl (C₁-C_Four)
Lower alkyl group, carbamoyl-substituted phenyl (C₁-C_Four) Low
Lower alkyl group, hydroxy-substituted phenyl (C ₁-C_Four) Lower class
Alkyl group, guanidino substitution (C₁-C_Four) With lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, protected
Amino substitution (C₁-C_Four) Substituted with lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydro
Xy substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, (C₁-C_Four) Lower alkoxy
Carbonyl-substituted phenyl (C₁-C_Four) Lower alkyl group, (C ₁-
C_Four) Lower alkylimino substitution (C₁-C₆) Alkyl group, (C₁-
C_Four) Lower acylimidoyl imino substitution (C₁-C₆) Alkyl
Group, arylmethylimino substitution (C₁-C₆) Alkyl group, nitrogen
Substituted with an aryl-containing heterocyclic group (C₁-C_Four) Lower alk
Luimino substitution (C ₁-C₆) Alkyl group, nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkyl group, directly containing oxygen
Chain or branched chain (C₁-C₈) Alkyl group, aryl sulfone
Mid substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, alkyl sulfonamide
Replacement (C₁-C_Four) Phenyl substituted with a lower alkyl group
(C ₁-C_Four) Lower alkyl group, aryloxy substituted (C₁-C_Four)
A lower alkyl group, or hydroxy-substituted (C₁-C₈) Archi
R^FourIs (C_Three-C₉) Alkyl group, hydroxy group
Exchange (C_Three-C₈) An alkyl group or an optionally substituted
Reel (C₁-C_Four) A lower alkyl group;

R ⁵ is hydrogen, (C ₁ -C ₁₆ ) alkyl group, halogen-substituted (C ₁ -C ₁₆ ) alkyl group, hydroxy-substituted (C ₁ -C ₁₆ ) alkyl group, (C ₁ -C ₁₀ ) Alkoxy-substituted (C ₁ -C ₁₀ ) alkyl group, amino-substituted (C ₁ -C ₁₆ ) alkyl group, mono (C ₁ -C ₆ ) alkylamino-substituted (C ₁ -C ₁₆ ) alkyl group, di (C ₁ -C ₁₆ ) alkyl group (C ₆ ) alkylamino-substituted (C ₁ -C ₁₆ ) alkyl group, (C ₃ -C ₁₀ ) cycloalkyl group, (C ₃ -C ₁₀ ) cycloalkyl-substituted (C ₁ -C ₆ ) alkyl group, (C ₂ -C ₁₆ ) alkenyl group, (C ₂ -C ₁₆ ) alkynyl group, (C
₆ -C ₁₀₎ aryl group, (C ₆ -C ₁₀₎ aryl-substituted (C ₁ -C ₆₎ alkyl group, (C ₁ -C ₆₎ alkoxycarbonyloxy-substituted (C ₁ -
C ₆ ) alkyl group, (C ₂ -C ₇ ) alkanoyloxy-substituted (C _1-
C ₆ ) an alkyl group, a silyl group having three substituents, or a phthalimide-substituted (C ₁ -C ₆ ) alkyl group, wherein R ⁶ is
Hydrogen, hydroxyl, amino, or -XY; X
Is oxygen, a (C ₁ -C ₆ ) alkylene group, or a phenylene group; Y is an —AB group or a —B group; B is hydrogen,
Amino group, amidino group, sulfonyl group, (C ₁ -C ₄ ) lower acylimidoyl group, optionally substituted benzimidoyl group, bisphosphonomethyl group, tetra (C ₁ -C ₄ ) lower alkylbisphosphono Methyl group, tri (C ₁ -C ₄ ) lower alkylbisphosphonomethyl group, bisphosphonohydroxymethyl group, tetrabenzylbisphosphonohydroxymethyl group, or (C ₁ -C ₄ ) lower alkyl-substituted imidazole-3-
In the yl group, A is oxygen, (C ₁ -C ₄ ) lower alkylene group, imino group, or (C ₁ -C ₄ ) lower alkylene imino group, and R ⁷ is hydrogen, or (C ₁ -C 4 ₄ ) The compound of the above-mentioned [1], wherein the compound is a lower alkyl group, and R ⁸ is hydrogen or (C ₁ -C ₄ ) a lower alkyl group.

[3] In the general formula (I) according to the above [1], R ¹ and R ² are hydrogen, and R ³ is hydrogen, a hydroxyl group,
Methyl, isobutyl, aminopropyl, phenylpropyl, guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl , Hydroxymethylphenylpropyl group, aminomethylbenzyl group, toluenesulfonamidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group,
Phthalimidomethylbenzyl group, phenoxyethyl group,
Aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group, pyridylmethyliminopentyl group, methoxycarbonylphenylpropyl group, ethoxyethoxyethyl group, hydroxyoctyl group, butoxyethyl group, iso-butyroxyethyl group, morpholinopropyl Group, (3,4,4-trimethyl-2,5-dioxo
-Imidazolidine-1-yl) propyl, cyclohexylpropyl, or piperidinopropyl; R ⁴
Is a naphthylmethyl group, a phenylpropyl group, an isobutyl group, a tert-butyl group, an isopropyl group, or a hydroxyoctyl group;

R ⁵ is hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl, n-hexyl, n-pentyl, neopentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, Hexadecyl group, adamantyl group, 2,2,2-trichloroethyl group, 2-
Chloroethyl group, 2-hydroxyethyl group, methoxymethyl group, methoxyethyl group, benzyloxymethyl group, benzyloxyethyl group, 2-methoxyethoxyethyl group,
2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, cyclohexyl group, cyclohexylmethyl group, allyl group, cinnamyl group, 2-propynyl group,
Phenyl, 4-methoxyphenyl, 4-bromophenyl, trityl, benzhydryl, acetoxymethyl, acetoxyethyl, triethylsilyl, tert-
A butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or a phthalimidomethyl group; R ⁶ is hydrogen, a hydroxyl group, an amino group, or a -XY group; and X is
Oxygen, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group,
Or a phenylene group, Y is an -AB group or -B group, and B is an amino group, an amidino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, a bisphosphonomethyl group, Tetraethylbisphosphonomethyl group, triethylbisphosphonomethyl group,
Tetramethylbisphosphonomethyl group, trimethylbisphosphonomethyl group, bisphosphonohydroxymethyl group, tetrabenzylbisphosphonohydroxymethyl group, or
A 2-methylimidazol-3-yl group, wherein A is oxygen, imino, methyleneimino or methylene;
⁷ is hydrogen or a methyl group; R ⁸ is hydrogen or a methyl group; the compound of the above-mentioned [1];

[4] The following general formula (I):

Embedded image Wherein R ^{1 to} R ⁴ and R ^{6 to} R ⁸ have the same meaning as described in the above [1], and R ⁵ represents hydrogen. Salts or solvates acceptable for

[5] In the general formula (I) described in the above [4],
And R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉)
Alkyl group, (C_Three-C₇) Cycloalkyl-substituted (C₁-C_Four) Low grade
Alkyl group, hydroxyl group, amino substitution (C₁-C₆) Alkyl group,
Phenyl (C₁-C_Four) Lower alkyl group, guanidino-substituted
Nil (C₁-C_Four) Lower alkyl group, amino-substituted phenyl (C₁-
C_Four) Lower alkyl group, carboxy-substituted phenyl (C₁-C_Four)
Lower alkyl group, carbamoyl-substituted phenyl (C₁-C_Four) Low
Lower alkyl group, hydroxy-substituted phenyl (C ₁-C_Four) Lower class
Alkyl group, guanidino substitution (C₁-C_Four) With lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, protected
Amino substitution (C₁-C_Four) Substituted with lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydro
Xy substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, (C₁-C_Four) Lower alkoxy
Carbonyl-substituted phenyl (C₁-C_Four) Lower alkyl group, (C ₁-
C_Four) Lower alkylimino substitution (C₁-C₆) Alkyl group, (C₁-
C_Four) Lower acylimidoyl imino substitution (C₁-C₆) Alkyl
Group, arylmethylimino substitution (C₁-C₆) Alkyl group, nitrogen
Substituted with an aryl-containing heterocyclic group (C₁-C_Four) Lower alk
Luimino substitution (C ₁-C₆) Alkyl group, nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkyl group, directly containing oxygen
Chain or branched chain (C₁-C₈) Alkyl group, aryl sulfone
Mid substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, alkyl sulfonamide
Replacement (C₁-C_Four) Phenyl substituted with a lower alkyl group
(C ₁-C_Four) Lower alkyl group, aryloxy substituted (C₁-C_Four)
A lower alkyl group, or hydroxy-substituted (C₁-C₈) Archi
Group

R ⁴ is a (C ₃ -C ₉ ) alkyl group, a hydroxy-substituted (C ₃ -C ₈ ) alkyl group, or an optionally substituted aryl (C ₁ -C ₄ ) lower alkyl group; R ⁵ represents hydrogen, R ⁶ is hydrogen, a hydroxyl group, an amino group, or a -XY group, X is oxygen, a (C ₁ -C ₆ ) alkylene group, or a phenylene group, and Y is -AB group or -B group, and B
Is hydrogen, amino, amidino, sulfonyl, (C _1-
C ₄ ) a lower acylimidoyl group, an optionally substituted benzimidoyl group, a bisphosphonomethyl group, a tetra (C _1-
C ₄ ) lower alkylbisphosphonomethyl group, tri (C ₁ -C ₄ )
A lower alkylbisphosphonomethyl group, a bisphosphonohydroxymethyl group, a tetrabenzylbisphosphonohydroxymethyl group, or a (C ₁ -C ₄ ) lower alkyl-substituted imidazol-3-yl group, wherein A is oxygen, (C ₁ -C ₄ ) a lower alkylene group, an imino group, or a (C ₁ -C ₄ ) lower alkylene imino group, R ⁷ is hydrogen, or a (C ₁ -C ₄ ) lower alkyl group, and R ⁸ is The compound of the above-mentioned [4], which is hydrogen, hydrogen, or a (C ₁ -C ₄ ) lower alkyl group;

[6] In the general formula (I) according to the above [4], R ¹ and R ² are hydrogen, and R ³ is hydrogen, a hydroxyl group,
Methyl, isobutyl, aminopropyl, phenylpropyl, guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl , Hydroxymethylphenylpropyl group, aminomethylbenzyl group, toluenesulfonamidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group,
Phthalimidomethylbenzyl group, phenoxyethyl group,
Aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group, pyridylmethyliminopentyl group, methoxycarbonylphenylpropyl group, ethoxyethoxyethyl group, hydroxyoctyl group, butoxyethyl group, iso-butyroxyethyl group, morpholinopropyl Group, (3,4,4-trimethyl-2,5-dioxo
-Imidazolidine-1-yl) propyl, cyclohexylpropyl, or piperidinopropyl; R ⁴
Is a naphthylmethyl group, a phenylpropyl group, an isobutyl group, a tert-butyl group, an isopropyl group, or a hydroxyoctyl group; R ⁵ represents hydrogen; and R ⁶ represents hydrogen, a hydroxyl group, an amino group, or -XY. X is
Oxygen, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group,
Or a phenylene group, Y is an -AB group or -B group, and B is an amino group, an amidino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, a bisphosphonomethyl group, Tetraethylbisphosphonomethyl group, triethylbisphosphonomethyl group,
Tetramethylbisphosphonomethyl group, trimethylbisphosphonomethyl group, bisphosphonohydroxymethyl group, tetrabenzylbisphosphonohydroxymethyl group, or
A 2-methylimidazol-3-yl group, wherein A is oxygen, imino, methyleneimino or methylene;
⁷ is hydrogen or a methyl group; R ⁸ is hydrogen or a methyl group; the compound of the above-mentioned [4];

[7] The following general formula (I):

Embedded image [Wherein, R ^{1 to} R ⁴ and R ^{6 to} R ⁸ have the same meanings as described in the above [1], and R ⁵ is an alkyl group which may be substituted,
Represents an optionally substituted aralkyl group or a protecting group for a carboxyl group], or a pharmaceutically acceptable salt or solvate thereof;

[8] The general formula (I) described in the above [7]
And R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉)
Alkyl group, (C_Three-C₇) Cycloalkyl-substituted (C₁-C_Four) Low grade
Alkyl group, hydroxyl group, amino substitution (C₁-C₆) Alkyl group,
Phenyl (C₁-C_Four) Lower alkyl group, guanidino-substituted
Nil (C₁-C_Four) Lower alkyl group, amino-substituted phenyl (C₁-
C_Four) Lower alkyl group, carboxy-substituted phenyl (C₁-C_Four)
Lower alkyl group, carbamoyl-substituted phenyl (C₁-C_Four) Low
Lower alkyl group, hydroxy-substituted phenyl (C ₁-C_Four) Lower class
Alkyl group, guanidino substitution (C₁-C_Four) With lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, protected
Amino substitution (C₁-C_Four) Substituted with lower alkyl group
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydro
Xy substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, (C₁-C_Four) Lower alkoxy
Carbonyl-substituted phenyl (C₁-C_Four) Lower alkyl group, (C ₁-
C_Four) Lower alkylimino substitution (C₁-C₆) Alkyl group, (C₁-
C_Four) Lower acylimidoyl imino substitution (C₁-C₆) Alkyl
Group, arylmethylimino substitution (C₁-C₆) Alkyl group, nitrogen
Substituted with an aryl-containing heterocyclic group (C₁-C_Four) Lower alk
Luimino substitution (C ₁-C₆) Alkyl group, nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkyl group, directly containing oxygen
Chain or branched chain (C₁-C₈) Alkyl group, aryl sulfone
Mid substitution (C₁-C_Four) Fe substituted with a lower alkyl group
Nil (C₁-C_Four) Lower alkyl group, alkyl sulfonamide
Replacement (C₁-C_Four) Phenyl substituted with a lower alkyl group
(C ₁-C_Four) Lower alkyl group, aryloxy substituted (C₁-C_Four)
A lower alkyl group, or hydroxy-substituted (C₁-C₈) Archi
R^FourIs (C_Three-C₉) Alkyl group, hydroxy group
Exchange (C_Three-C₈) An alkyl group or an optionally substituted
Reel (C₁-C_Four) A lower alkyl group;

R^FiveIs (C₁-C₁₆) Alkyl group, halogen substitution
(C₁-C₁₆) Alkyl group, hydroxy-substituted (C₁-C₁₆) Alkyl
Group, (C₁-C_Ten) Alkoxy substituted (C₁-C_Ten) Alkyl group, amine
No substitution (C₁-C₁₆) Alkyl group, mono (C₁-C₆) Alkylam
No substitution (C₁-C₁₆) Alkyl group, di (C₁-C₆) Alkylamino
Replacement (C₁-C₁₆) Alkyl group, (C_Three-C_Ten) Cycloalkyl group,
(C_Three-C_Ten) Cycloalkyl-substituted (C₁-C₆) Alkyl group, (C_Two-
C₁₆) Alkenyl group, (C _Two-C₁₆) Alkynyl group, (C₆-C_TenA)
Reel base, (C₆-C_Ten) Aryl substituted (C₁-C₆) Alkyl group,
(C₁-C₆) Alkoxycarbonyloxy substitution (C₁-C₆) Al
Kill group, (C_Two-C₇) Alkanoyloxy substituted (C₁-C₆) Al
Kill group, silyl group having 3 substituents, or phthalate
Imide substitution (C₁-C₆) Represents an alkyl group, R⁶Is hydrogen, water
An acid group, an amino group, or a -X-Y group, wherein X is oxygen,
(C₁-C₆) An alkylene group or a phenylene group, and Y
Is a -A-B group or a -B group, and B is hydrogen, an amino group,
Amidino group, sulfonyl group, (C₁-C_Four) Lower acylimide
Group, an optionally substituted benzimidoyl group,
Suphosphonomethyl group, tetra (C₁-C_Four) Lower alkyl bis
Phosphonomethyl group, tri (C₁-C_Four) Lower alkyl bisphos
Honomethyl group, bisphosphonohydroxymethyl group, tet
Labenzylbisphosphonohydroxymethyl group, or (C
₁-C_Four) A lower alkyl-substituted imidazol-3-yl group represented by A
Is oxygen, (C₁-C_Four) Lower alkylene group, imino group,
Is (C₁-C_Four) A lower alkyleneimino group, R⁷Is the water
Elementary or (C₁-C_Four) A lower alkyl group;⁸Is the water
Elementary or (C₁-C_FourThe above [7], which is a lower alkyl group.
A compound as described above;

[0019]

[9] In the general formula (I) according to the above [7], R ¹ and R ² are hydrogen, and R ³ is hydrogen, a hydroxyl group,
Methyl, isobutyl, aminopropyl, phenylpropyl, guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl , Hydroxymethylphenylpropyl group, aminomethylbenzyl group, toluenesulfonamidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group,
Phthalimidomethylbenzyl group, phenoxyethyl group,
Aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group, pyridylmethyliminopentyl group, methoxycarbonylphenylpropyl group, ethoxyethoxyethyl group, hydroxyoctyl group, butoxyethyl group, iso-butyroxyethyl group, morpholinopropyl Group, (3,4,4-trimethyl-2,5-dioxo
-Imidazolidine-1-yl) propyl, cyclohexylpropyl, or piperidinopropyl; R ⁴
Is a naphthylmethyl group, a phenylpropyl group, an isobutyl group, a tert-butyl group, an isopropyl group, or a hydroxyoctyl group;

R ⁵ represents a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-
Butyl, tert-butyl, n-hexyl, n-pentyl, neopentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl , Adamantyl group, 2,2,2-trichloroethyl group, 2-chloroethyl group, 2-hydroxyethyl group, methoxymethyl group, methoxyethyl group, benzyloxymethyl group, benzyloxyethyl group, 2-methoxyethoxyethyl group, 2-
Aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, cyclohexyl group, cyclohexylmethyl group, allyl group, cinnamyl group, 2-propynyl group, phenyl group, 4-methoxyphenyl group, 4-bromophenyl group , Trityl, benzhydryl, acetoxymethyl, acetoxyethyl, triethylsilyl, tert-
A butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or a phthalimidomethyl group; R ⁶ is hydrogen, a hydroxyl group, an amino group, or a -XY group; and X is
Oxygen, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group,
Or a phenylene group, Y is an -AB group or -B group, and B is an amino group, an amidino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, a bisphosphonomethyl group, Tetraethylbisphosphonomethyl group, triethylbisphosphonomethyl group,
Tetramethylbisphosphonomethyl group, trimethylbisphosphonomethyl group, bisphosphonohydroxymethyl group, tetrabenzylbisphosphonohydroxymethyl group, or
A 2-methylimidazol-3-yl group, wherein A is oxygen, imino, methyleneimino or methylene;
⁷ is hydrogen or a methyl group; R ⁸ is hydrogen or a methyl group; the compound of the above-mentioned [7];

[10] The compound represented by the general formula (I) described in the above [1], or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable salt thereof. A pharmaceutical and / or veterinary composition comprising an acceptable carrier; [11] the compound represented by the general formula (I) according to the above [1], or a pharmaceutically acceptable salt thereof. A metalloproteinase inhibitor comprising a compound selected from the group consisting of salts or solvates; [12] a metalloproteinase belonging to one of the matrix metalloproteinases, [13] The inhibitor according to [11], wherein the metalloproteinase is a tumor necrosis factor-α.
(TNF-α) converting enzyme.
An inhibitor of the above-mentioned [11], which is an NF-α converting enzyme inhibitor; [14] an inhibitor of the general formula (I) of the above-mentioned [1] for prevention and / or treatment of a disease relating to tissue degradation. Using a compound;

[15] The following general formula (IV):

Embedded imageCO of the compound represented by_TwoR^TenSelectively contains amide bond
Convert to a site and, if desired, R⁹, R¹¹, R¹²And R¹³
Is the desired functional group R^Five, R^Three, R^FourAnd R⁶To each
Or a compound represented by the above general formula (IV)
And optionally R⁹, R¹¹, R¹²And R¹³The desired functional group
Is R^Five, R^Three, R^FourAnd R⁶And then convert it to
CO_TwoR^TenCharacterized by converting the site to an amide bond-containing site
The compound represented by the general formula (I) described in the above [1]
Substance, or a pharmaceutically acceptable salt or solvate thereof
A method for producing a compound selected from the group consisting of¹
~ R⁸Has the same meaning as described in the above [1], and R⁹Is
R above^FiveOr a protected hydroxyl group
(C₁-C_Ten) Alkyl group, protected amino substitution (C₁-
C₁₆) Alkyl group, or protected mono (C₁-C₆) Archi
Amino substitution (C₁-C₁₆) Represents an alkyl group, R^TenReplace
An optionally substituted alkyl group, an optionally substituted
Represents an aralkyl group or a carboxyl protecting group;
¹¹Is the above R^ThreeEquivalent to or protected water
Acid groups, protected guanidino-substituted phenyl (C₁-C_Four) Low grade
Alkyl group, protected amino-substituted phenyl (C ₁-C_Four) Low
Lower alkyl group, nitro-substituted phenyl (C₁-C_Four) Lower alk
Group, protected amino substitution (C₁-C₆) Alkyl group, nitro
B substitution (C₁-C₆) Alkyl group, protected carboxy substitution
Phenyl (C₁-C_Four) Lower alkyl group, protected hydroxy
Si-substituted phenyl (C₁-C_Four) Lower alkyl groups, protected groups
Anidino substitution (C₁-C_Four) Substituted with a lower alkyl group
Phenyl (C₁-C_Four) Lower alkyl group, protected amino group
Exchange (C₁-C_Four) Phenyl substituted with a lower alkyl group (C
₁-C_Four) Lower alkyl group, protected hydroxy substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl groups, protected carboxy substitution (C₁-C_Four) Low
Phenyl substituted with a lower alkyl group (C₁-C_Four) Lower class
Straight or branched chain containing alkyl group, protected hydroxyl group
(C₁-C₈) Alkyl group, or cyano-substituted phenyl (C₁-
C_Four) Represents a lower alkyl group, R¹²Is the above R^FourEquivalent to
Or protected hydroxy substitution (C₁-C₈) Al
Represents a kill group, R¹³Is the above R⁶Equivalent to, protected
Amino group, protected hydroxyl group, -X-E group or
 -X-A-E group (where X and A are as defined above,
E is nitro, cyano, amino, carboxyl
Group, hydroxy (C₁-C₁₁) Alkyl group, protected amino
Group, protected guanidino group, protected amidino
Group, protected acylimidoyl group, protected benz
Imidoyl group, protected bisphosphonomethyl group, protected
Bisphosphonohydroxymethyl group, or protected
(C₁-C₁₁) Represents an alkyl-substituted imidazol-3-yl group
]);

[16] The general formula (I) described in the above [15]
In V), R ⁹ has the same meaning as R ⁵ described above, or
Protected hydroxyethyl group, protected hydroxypropyl group, protected hydroxybutyl group, protected aminoethyl group, protected aminopropyl group, protected aminobutyl group, protected methylaminoethyl group, Represents a protected methylaminopropyl group or a protected methylaminobutyl group, wherein R ¹⁰ is a (C ₁ -C ₆ ) alkyl group, a benzyl group, a substituted benzyl group, a phenacyl group, or 2,2, Represents a 2-trichloroethyl group, R ¹¹
Is the same as R ³ or a protected guanidinophenylpropyl group, a protected aminophenylpropyl group, a nitrophenylpropylene group, a protected aminopropyl group, a nitropropyl group, a protected hydroxyphenylpropyl group Protected carboxyphenylpropyl group, protected aminomethylphenylpropyl group, protected guanidinomethylphenylpropyl group,
R ¹² represents a protected hydroxymethylphenylpropyl group, a protected aminomethylbenzyl group, a cyanophenylpropyl group, a protected aminopentyl group, a cyanobenzyl group, a protected hydroxyoctyl group, or a nitropentyl group; , Represents a group having the same meaning as R ⁴ or a protected hydroxyoctyl group, and R ¹³ has the same meaning as that of R ⁶ , a protected amino group, a protected hydroxyl group, a -XF group or a -XAF group ( Where X and A are
As defined above, F is a nitro group, a cyano group, an amino group, a carboxyl group, a hydroxymethyl group, a protected amino group, a protected guanidino group, a protected amidino group, a protected acetimidoyl Group, a protected propionimidoyl group, a protected benzimidoyl group, a protected bisphosphonomethylimino group, or a protected bisphosphonohydroxymethyl group). ;

[17] The following general formula (V):

Embedded image And a succinic acid derivative having a hydroxamic acid skeleton represented by the following general formula (III):

Embedded image With an amine derivative represented by the following general formula (VI):

[0025]

Embedded image Is obtained, and if necessary, R ⁹ , R ¹¹ , R ¹² and R ¹³ are each converted to a desired functional group R ⁵ , R ³ , R ⁴ and R ⁶ , A method for producing a compound selected from the group consisting of a compound represented by the general formula (I) according to the above [1] or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ To R ⁸ have the same meaning as described in the above [1], and R ⁹ , R ^{11 to} R ¹³ have the same meaning as described in the above [15]];

[18] The following general formula (VI):

Embedded image [Wherein, R ¹ , R ² , R ⁷ and R ⁸ have the same meaning as those described in the above [1], and R ⁹ , R ^{11 to} R ¹³ are the same as those described in the above [15]. Having significance] or a salt thereof;

[19] The following general formula (IV):

Embedded image [Wherein, R ⁷ and R ⁸ have the same meanings as described in the above [1], and R ^{9 to} R ¹³ have the same meanings as those described in the above [15].] Or a salt thereof;

[20] The following general formula (II):

Embedded image And a succinic acid derivative represented by the following general formula (III):

[0029]

Embedded image A method for producing a compound represented by the general formula (IV) or a salt thereof according to the above [15], wherein R ⁷ and R ⁸ are It has the same meaning as in the above [1], and R ^{9 to} R ¹³ have the same meaning as in the above [15]]; and [21] the following general formula (III):

Embedded image [Wherein, R ⁷ and R ⁸ have the same meaning as those described in the above [1], and R ⁹ and R ¹³ have the same meaning as those described in the above [15].] Or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention provides a compound represented by the formula (22): wherein R ¹ represents a protecting group for hydrogen or a hydroxyl group, R ² represents a protecting group for hydrogen or an amino group, ³ represents hydrogen, a hydroxyl group, an unsubstituted or substituted (C ₁ -C ₆ ) alkyl group, an unsubstituted or substituted aryl (C ₁ -C ₆ ) alkyl group, and R ⁴ represents an unsubstituted or substituted (C ₁ -C ₆ ) ₁ -C ₆₎ alkyl group,
Represents an unsubstituted or substituted aryl (C ₁ -C ₆ ) alkyl group,
R ⁵ is hydrogen, an unsubstituted or substituted (C ₁ -C ₁₆ ) alkyl group,
Represents an unsubstituted or substituted aryl (C ₁ -C ₆ ) alkyl group,
R ⁶ represents hydrogen, a hydroxyl group, an amino group, or a -XY group, X represents oxygen, a (C ₁ -C ₆ ) alkylene group or a phenylene group, and Y represents a -AB group or a -B group (here In A
Represents a (C ₁ -C ₆ ) alkylene group, an imino group or an (C ₁ -C ₆ ) alkyleneimino group, and B represents hydrogen, an amino group, an amidino group, a sulfonyl group, an acylimidoyl group, an unsubstituted or Represents a substituted imidazolyl group, an optionally protected bisphosphonomethyl group or an optionally protected bisphosphonohydroxymethyl group, R ⁷ is hydrogen, a hydroxyl group, unsubstituted or substituted (C ₁ -C ₆ ) Alkyl group, unsubstituted or substituted aryl
Represents a (C ₁ -C ₆ ) alkyl group, R ⁸ is hydrogen, a hydroxyl group, an unsubstituted or substituted (C ₁ -C ₆ ) alkyl group, an unsubstituted or substituted aryl (C ₁ -C ₆ ) alkyl group Represents a compound represented by
Or a stereoisomer thereof, and a pharmaceutically acceptable salt or solvate thereof;

[23] In the general formula (I), R ¹
And R ² is hydrogen; R ³ is hydrogen, hydroxyl, methyl, isobutyl, aminopropyl, 3-phenylpropyl, p-guanidinophenylpropyl, p-aminophenylpropyl, p-hydroxyphenylpropyl Group, p-carboxyphenylpropyl group, m-carboxyphenylpropyl group, p-aminomethylphenylpropyl group, p-guanidinomethylphenylpropyl group, p-hydroxymethylphenylpropyl group, p-aminomethylbenzyl group, m-amino Methylbenzyl group, o-aminomethylbenzyl group, p-
Toluenesulfonamidomethylbenzyl group, p-methanesulfonamidomethylbenzyl group, p-isobutyliminomethylbenzyl group, p-phthalimidomethylbenzyl group, phenoxyethyl group, o-aminomethylphenylpropyl group, aminopentyl group, acetimidoyl Iminopentyl group, isobutyliminopentyl group, (pyridin-4-yl) methyliminopentyl group, p-methoxycarbonylphenylpropyl group, ethoxyethoxyethyl group, 8-hydroxyoctyl group, n-butoxyethyl group, iso-butyroxy An ethyl group, an m-methoxycarbonylphenylpropyl group, a p-carbamoylphenylpropyl group, a morpholinopropyl group, or a piperidinopropyl group, and R ⁴ is an isobutyl group, a tert-butyl group, an isopropyl group, or
An 8-hydroxyoctyl group, wherein R ⁵ is hydrogen, a methyl group,
Ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-
Hexyl group, n-pentyl group, neopentyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group,
Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, adamantyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-hydroxyethyl, methoxymethyl, methoxyethyl, benzyloxymethyl Group, benzyloxyethyl group, 2-methoxyethoxyethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, cyclohexyl group, cyclohexylmethyl group, allyl group, cinnamyl group, 2-propynyl Group, phenyl group, 4-methoxyphenyl group, 4-bromophenyl group, trityl group, benzhydryl group, acetoxymethyl group, acetoxyethyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-
A butyldiphenylsilyl group or a phthalimidomethyl group, and R ⁶ is hydrogen, a hydroxyl group, an amino group, or -X-
X is oxygen, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or phenylene;
B is amino group, amidino group, acetimidoyl group, sulfonyl group, propionimidoyl group, benzimidoyl group, bisphosphonomethyl group, tetraethylbisphosphonomethyl group, triethylbisphosphonomethyl group, tetramethylbisphosphonomethyl A methyl group, a trimethylbisphosphonomethyl group, a bisphosphonohydroxymethyl group, a tetrabenzylbisphosphonohydroxymethyl group, a 2-methylimidazol-3-yl group, and when Y = -AB, A is oxygen, Imino group, methyleneimino group, methylene group,
R ⁷ is hydrogen or a methyl group; R ⁸ is hydrogen or a methyl group; the compound of the above-mentioned [22];

[24] A compound represented by the above general formula (I), or a stereoisomer thereof, and one or more compounds selected from pharmaceutically acceptable salts or solvates thereof. A metalloproteinase inhibitor, which is contained as an active ingredient and is characterized by inhibiting the activity of matrix metalloproteinases (MMPs) and / or tumor necrosis factor-α (TNF-α) converting enzyme; [25] For prevention and / or treatment, inhibiting the activity of matrix metalloproteinases (MMPs) and / or tumor necrosis factor-α (TNF-α) converting enzyme containing the compound represented by the general formula (I). Using a metalloproteinase inhibitor as follows:

[26] A process for producing the compound of the above general formula (I),

Embedded image

(I) A succinic acid derivative of the general formula (II)
(III) to give a diester compound represented by the general formula (IV), if desired, R ⁹ , R ¹¹ ,
R ¹² and R ¹³ are converted to the desired functional groups R ⁵ , R ³ , R ⁴ and R ⁶ respectively, and the CO ₂ R ¹⁰ site is converted to an amide compound, or (ii) the general formula (II) Succinic acid derivatives and general formulas
After reacting with an amine derivative of (III) to form a diester compound represented by the general formula (IV), the CO ₂ R ¹⁰ site is converted to an amide compound, and if desired, R ⁹ , R ¹¹ , R ¹² and A compound represented by the general formula (I) or a stereoisomer thereof, wherein R ¹³ is converted to a desired functional group R ⁵ , R ³ , R ⁴ and R ⁶ , and pharmaceutically A method for producing an acceptable salt or solvate thereof, wherein R ^{1 to} R ⁸ have the same meanings as described above, and R ⁹ has the same meaning as that of R ⁵ described above, or a protected hydroxyl group is substituted. A (C ₁ -C ₁₀ ) alkyl group, a protected amino-substituted (C ₁ -C ₁₆ ) alkyl group, or a protected mono
(C ₁ -C ₆ ) alkylamino-substituted (C ₁ -C ₁₆ ) alkyl group, wherein R ¹⁰ is a carboxyl-protecting group ((C ₁ -C ₆ ) alkyl group, benzyl group, substituted benzyl group, phenacyl Or a 2,2,2-trichloroethyl group), and R ¹¹ is the same as R ³ or a protected p-guanidinophenylpropyl group, a protected p-guanidinomethylphenylpropyl group, a protected p-guanidinomethylphenylpropyl group p-aminomethylphenylpropyl group, protected p-aminomethylbenzyl group, protected o-aminomethylbenzyl group, protected m-aminomethylbenzyl group, protected aminopentyl group, nitropentyl group, protected Protected hydroxyoctyl, protected p-hydroxyphenylpropyl, protected p-aminophenylpropyl, nitrophenylpropylene, protected aminopropyl, nitropro Represents Le radical, R
¹² is the same as R ⁴ or represents a protected hydroxyoctyl group, and R ¹³ is the same as R ⁶ , -XG group or -XA
-G represents a group wherein X and A are as defined above,
Is a nitro group, a cyano group, an amino group, a carboxyl group, a hydroxymethyl group, a protected amino group, a protected guanidino group, a protected amidino group, a protected acetimidoyl group, a protected propionimidoyl group Represents a protected benzimidoyl group, a protected bisphosphonomethyl group, or a protected bisphosphonohydroxymethyl group); and

[27] A process for producing the compound of the above general formula (I),

Embedded image Succinic acid derivatives having protected hydroxamic acid skeleton
After reacting (V) with an amine derivative of the general formula (III) to obtain a protected precursor represented by the general formula (VI), if desired, R ⁹ , R ¹¹ , R ¹² and R ¹³ R ⁵ which is a functional group of
A method for producing a compound represented by the general formula (I) or a stereoisomer thereof, and a pharmaceutically acceptable salt or solvate thereof, which is converted into R ³ , R ⁴ and R ⁶ , respectively. (Wherein, R ^{1 to} R ⁹ and R ^{11 to} R ¹³ are as defined above)
I will provide a.

It is clear that among the compounds of the above general formula (I), as shown by the following formula, an optically active carbon indicated by * is present. Thus, the scope of the concept of the compound of the present invention includes geometric isomers, stereoisomers, optically active isomers, racemates, tautomers, and metabolic derivatives thereof of the compound described in the above [1]. That must be understood.

Embedded image In one preferred embodiment of the present invention, the compound
Of the optically active carbons indicated by * in (I ′), the carbons of (1) and (4) have the R or S configuration, the carbon of (2) has the R configuration, and the carbon of (3) Carbon has an S configuration.

In another embodiment, the present invention provides a compound represented by the following general formula (I-1):

Embedded image Wherein R ^{1 to} R ³ , R ⁵ and Y have the same meanings as described in the above [1], wherein R ³ is preferably hydrogen, a hydroxyl group, or may be substituted Aryl (C
_1- C ₆ ) an alkyl group and -A- when Y is -AB group
Particularly preferred among the groups are a (C ₁ -C ₆ ) alkylene group, a (C ₁ -C ₆ ) alkyleneimino group, and an imino group. Acetimidyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, an amidino group, a bisphosphonohydroxymethyl group, or a bisphosphonomethyl group, and when Y is a -B group, Particularly preferred are an amino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, a bisphosphonohydroxymethyl group, or an amidino group, and ^Ra is hydrogen or the above-mentioned [1]. Substituent
X has the same meaning as the substituent of the optionally substituted phenylene group in X)).
Or a pharmaceutically acceptable salt or solvate thereof;

[29] The general formula (I) described in the above [28]
-1) A medicament comprising a compound selected from the group consisting of the compounds represented by -1) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. And / or a veterinary composition; [30] selected from the group consisting of the compound represented by the general formula (I-1) according to the above [28], or a pharmaceutically acceptable salt or solvate thereof. A metalloproteinase inhibitor comprising a compound as an active ingredient; [31] the metalloproteinase, which belongs to matrix metalloproteinases and is a matrix metalloproteinase inhibitor; [30] the metalloproteinase is a tumor necrosis factor-α;
(TNF-α) is one of those belonging to the converting enzyme, TNF-α
An inhibitor of the above-mentioned [30], which is a converting enzyme inhibitor; and [33] an inhibitor of the general formula (I-1) of the above-mentioned [28] for the prevention and / or treatment of a disease relating to tissue degradation. It is provided that a compound is used.

In still another aspect, the present invention provides a compound represented by the following general formula (I-2):

Embedded image [Wherein, R ^{1 to} R ³ , R ⁵ and Y have the same meanings as those described in the above [1], and the substituent of the [unsubstituted or substituted alkylene] group is the same as the above [1]. Having the same meaning as the substituent of the alkylene group which may be substituted in the substituent X 1), or a pharmaceutically acceptable salt or solvate thereof;

[35] The formula (I) described in the above [34]
A pharmaceutical comprising a compound represented by -2) or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable carrier. And / or a veterinary composition; [36] selected from the group consisting of the compound represented by the general formula (I-2) described in the above [34], or a pharmaceutically acceptable salt or solvate thereof. [37] a metalloproteinase inhibitor comprising a compound as an active ingredient; [37] the metalloproteinase is one of members of matrix metalloproteinases and is a matrix metalloproteinase inhibitor; 36] the inhibitor of [38], wherein the metalloproteinase is tumor necrosis factor-α;
(TNF-α) is one of those belonging to the converting enzyme, TNF-α
An inhibitor of the above-mentioned [36], which is a converting enzyme inhibitor; and [39] an inhibitor of the general formula (I-2) of the above-mentioned [34] for the prevention and / or treatment of a disease relating to tissue degradation. The use of a compound is provided.

In another embodiment, the present invention provides a compound represented by the general formula (III) described in the above [21] wherein R ⁷ and R ⁸ are the same as those in the above [1]. Has the same meaning as R ⁹ represents a hydrogen, an optionally substituted alkyl group, an optionally substituted aralkyl group or a carboxyl group protecting group, R ¹³ represents a protected hydroxyl group, Represents a protected amino group, -XG group or -XAG group (where X has the same meaning as described in the above [1], and A ₁ may be substituted (C ₁ -C ₆ ) An alkylene group, an oxygen, an imino group, or an optionally substituted (C _1-
C ₆ ) represents an alkylene imino group, G is a nitro group, a cyano group, a protected amino group, a protected carboxyl group, a protected guanidino group, a protected amidino group,
Represents a protected acylimidoyl group, a protected benzimidoyl group, a protected bisphosphonomethyl group, or a bisphosphonohydroxymethyl group)] or a pharmaceutically acceptable salt or solvate thereof;

[41] A method for producing a compound represented by the general formula (III) according to the above [21] or [40], or a pharmaceutically acceptable salt or solvate thereof; [42] (21) or (40).
A drug represented by the formula (I), comprising a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable carrier; And / or a veterinary composition; (43) the general formula (II) according to the above (21) or (40);
A bone destruction inhibitor, which comprises as an active ingredient a compound represented by I) or a compound selected from the group consisting of pharmaceutically acceptable salts and solvates thereof; General formula (II) described in [21] or [40]
An agent for preventing and / or treating osteoporosis, comprising as an active ingredient a compound represented by I) or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof; and [45] Use of the compound of the general formula (III) according to the above [21] or [40] for the prevention and / or treatment of a disease relating to bone tissue degradation; [46] The general formula (1) according to the above [1] I) (where R ^{1 to} R ⁸
Has the same meaning as described in the above [1]], or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. [47] a prophylactic and / or therapeutic agent for a tissue degradation-related disease; and [47] a tissue degradation-related disease is osteoarthritis, periodontal disease, corneal ulcer, multiple sclerosis, psoriasis, allergic disease (bronchial asthma, Allergic gastroenteritis, allergic rhinitis, atopic disease, and allergic conjunctivitis)
And / or a drug for preventing and / or treating the disease according to the above [46], which is selected from the group consisting of:

Other objects, features, advantages and aspects of the present invention will be apparent to those skilled in the art from the following description. However, it is understood that the description of the present specification, including the following description and the description of the specific examples, shows preferred embodiments of the present invention, and is given only for explanation. I want to. Various changes and / or alterations (or modifications) within the spirit and scope of the present invention disclosed herein will be apparent to those skilled in the art, based on the following description and knowledge from other portions of the present specification. Will be readily apparent. All patents and references cited in this specification are cited for explanatory purposes, and they are to be construed as being incorporated herein by reference. is there. In this specification,
The term “and / or” means that both (1) merged connection and (2) selective connection exist, eg, in the case of “prevention and / or treatment”, (1) It is used to include both prevention and treatment and (2) prevention or treatment. Elsewhere, the term “and / or” is similarly used to encompass both (1) merged connectivity and (2) selective connectivity.

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION R ¹ , R ³ , R ⁴ ,
In R ⁵ , R ⁷ , R ⁸ and R ¹⁰ , the “optionally substituted alkyl group” is one or more substituents (substituents can be selected from those described below) May be arbitrarily substituted, may be linear or branched, and preferably has 1 to 20 carbon atoms.
In, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group,
tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group,
Examples include a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, and an adamantyl group.

The compounds of the above general formula, in particular, R ¹ , R ³ , R ⁴ , and R ^{3 in} the compounds of the general formulas (I), (IV) and (VI)
In R ⁵ , R ⁷ , R ⁸ and R ¹⁰ , the “optionally substituted aralkyl group” refers to a group in which the aryl moiety and / or the alkylene moiety optionally has one or more substituents (the substituents are described below. And the aryl portion preferably has 6 carbon atoms.
To 10, more preferably 6, and the number of carbon atoms in the alkylene moiety is preferably 1 to 8, more preferably 1 to 8.
To 4, wherein the alkylene moiety may be straight-chain or branched, and a typical aralkyl group is an optionally substituted phenyl-substituted (C ₁ -C ₄ )
Lower alkyl groups (or also referred to as “phenyl- (C ₁ -C ₄ ) lower alkylene groups”), such as trityl, diphenylmethyl, phenyl, 4-methoxyphenyl, allyl, cinnamyl, benzyl, 2- or 4 -Optionally substituted benzyl, such as -nitrobenzyl, 4-bromobenzyl, 4-methoxybenzyl and the like, optionally substituted phenethyl, optionally substituted phenylpropyl (or " Phenyltrimethylene "
), Naphthylpropyl (also referred to as "naphthyltrimethylene"), and the like.

Further, R ¹ and R ² of the compound of the above general formula (I)
In R ² , “optionally substituted alkyl moiety” in “optionally substituted alkyloxycarbonyl group”
Is selected from the same as the aforementioned `` optionally substituted alkyl group '' in R <sup>1</sup> , R <sup>3</sup> , R <sup>4</sup> , R <sup>5</sup> , R <sup>7</sup> , R <sup>8</sup> or R <sup>10</sup> , wherein the `` substituted as also good alkyloxycarbonyl group "have, for example, (C ₁ -C ₆₎ alkyloxycarbonyl group such as tert- butyloxycarbonyl group. Of the compound of general formula (I)
In R ¹ and R ² , the `` optionally substituted aralkyl moiety '' in the `` optionally substituted aralkyloxycarbonyl group '' is the same as the above-mentioned `` optionally substituted aralkyl group '' And the "aralkyloxycarbonyl group which may be substituted" includes, for example, benzyloxycarbonyl, 2- or 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and the like. And benzyloxycarbonyl which may be optionally substituted, and phenethyloxycarbonyl which may be optionally substituted.

In R ¹ of the compound of the above general formula (I), the “silyl group having three substituents” is an alkyl group which may be substituted and / or Those having a good aryl group and / or an aralkyl group which may be substituted are mentioned, and the “aralkyl group which may be substituted” for these substitutions is selected from the same ones as described above. is there. In addition, the “optionally substituted alkyl group” of the substituent is also the above R ¹ ,
It is selected from the same as the “optionally substituted alkyl group” in R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ or R ¹⁰ . Further, the "optionally substituted aryl group" of the substituent is the "optionally substituted aralkyl group" of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ or R ^10. Selected from the same as the “aryl moiety” of the above, for example, a phenyl group, a naphthyl group and the like. Representative examples of the “silyl group having three substituents” include, for example, trimethylsilyl, triethylsilyl, tert-
Examples include a trialkylsilyl group such as a butyldimethylsilyl group, and an alkyldiarylsilyl group such as a tert-butyldiphenylsilyl group.

R ¹ of the compounds of the above general formulas (I) and (IV)
The `` protecting group of the hydroxyl group '' in the `` protecting group '' of the `` protected hydroxyl group '' in R ⁹ , R ¹¹ and R ¹³ are those known to those skilled in the art of organic synthesis, for example, peptide synthesis, penicillin It is selected from those which have been used in fields such as synthesis, cephalosporin synthesis, and sugar synthesis. Said and said "protecting group", "hydroxyl protecting group" is it capable removed by treatment with water, those removable by hydrogenolysis, for example, can be removed with a Lewis acid catalyst such as AlCl ₃ , Can be removed with zinc / acetic acid, can be removed with thiourea,
Those which can be removed with an acid or a weak base, such as benzyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, 2-methoxyethoxymethyl, formyl, acetyl, chloroacetyl, dichloroacetyl, and trityl. Can be The group may be a group capable of forming a hydroxyl group under a biological or physiological condition (for example, an in vivo reaction such as oxidation / reduction or hydrolysis by an in vivo enzyme) or a group capable of chemically forming a hydroxyl group. Any group can be used as long as it is a group. The “protecting group for hydroxyl group” and the “protecting group” include the above “silyl group having three substituents”, “optionally substituted aralkyl group”, tetrahydropyranyl group, “substituted And an alkyloxycarbonyl group which may be substituted, and an aralkyloxycarbonyl group which may be substituted.

R ² of the compounds of the above general formulas (I) and (IV),
In R ⁹ , R ¹¹ , R ¹³ , E or F, the `` protecting group for amino group '' may be any of those known to those skilled in the art of organic synthesis, for example, peptide synthesis, penicillin synthesis, cephalosporin synthesis, sugar It is selected from protecting groups that have been used in fields such as synthesis. Examples of the "protecting group for amino group" include those which can be removed by hydrogenolysis, those which can be removed by fluoride, those which can be removed by acid, and benzyloxycarbonyl, p-nitrobenzyloxy. Carbonyl, trityl, tert-butoxycarbonyl, for example, formyl, chloroacetyl, optionally substituted with halogen such as dichloroacetyl (C ₁ -C ₆ ) aliphatic acyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl And alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, 2-methoxyethoxymethyl and the like. As the group, an amino group which is free under a biological or physiological condition (for example, an in vivo reaction such as oxidation / reduction or hydrolysis by an in vivo enzyme or the like), or a protonated amino group thereof is used. Any group can be used as long as it is a group capable of forming a form or a group capable of changing to the form. Examples of the "protecting group for amino group" include the above-mentioned "optionally substituted alkyloxycarbonyl group", "optionally substituted aralkyloxycarbonyl group", 9-fluorenylmethyloxycarbonyl group and the like. Selected ones are also included.

Substitution in the above-mentioned "optionally substituted alkyl group", "optionally substituted aralkyl group", "optionally substituted aryl group", and "optionally substituted aralkyl group" Examples of the group include an alkyl group which may be substituted as described above, an aryl group as described above, a hydroxyl group, and an amino group which may be substituted (for example, amino, for example, methylamino, ethylamino, isopropylamino, etc. N-lower (C ₁ -C ₄ ) alkylamino, for example, N-arylamino such as phenylamino, for example, aralkylamino such as pyridylmethylamino, benzylamino, for example, guanidino group, etc., amidino group, acylimidoyl group (for example, was induced acetimidoyl group, a lower (C ₂ -C ₅₎ alkanoic acid such as propionic imidoyl group Of, such as benzimidoyl based on
(C ₇ -C ₁₁ ) derived from aromatic carboxylic acids),
Halogen (eg, F, Cl, Br, etc.), nitro, lower (C
₁ -C ₄₎ alkoxy group (e.g., methoxy, ethoxy, etc.),
Lower (C ₁ -C ₄ ) alkylthio groups (eg, methylthio, ethylthio, etc.), carboxyl groups, lower (C ₂ -C ₆ ) alkanoyloxy groups, lower (C ₁ -C ₆ ) alkoxycarbonyloxy groups, hydroxyl groups are protected Phosphono group which may be substituted (as the protecting group, the above-mentioned "protecting group for hydroxyl group", "alkyl group which may be substituted", "aralkyl group which may be substituted", "substituted An optionally substituted aryl group ", an" optionally substituted alkyloxycarbonyl group ", and an" optionally substituted aralkyloxycarbonyl group ").

Compounds of the above general formula, in particular, of the general formula (I)
And X, A and B in the compounds of (IV) and "(C ₁ -C ₆ ) alkylene group which may be substituted", "phenylene group which may be substituted", and "substituted (C ₁ -C ₆ ) alkyleneimino group '' and `` optionally substituted imidazolyl group '' as a substituent,
It can be selected from those exemplified as the substituents in the above-mentioned “optionally substituted alkyl group” and the like.

Compounds of the above general formula, in particular, of the general formula (I)
In B 2 of the compounds of the formulas (IV) and (IV), the protecting groups for the “optionally protected bisphosphonomethyl group” and the “optionally protected bisphosphonohydroxymethyl group” are as described above. `` Hydroxyl protecting group '', `` optionally substituted alkyl group '', `` optionally substituted aralkyl group '', `` optionally substituted aryl group '',
"Optionally substituted alkyloxycarbonyl group"
And "aralkyloxycarbonyl group which may be substituted".

Compounds of the above general formula, in particular, of the general formula (I)
In B and E in the compounds of (IV) and (IV), the “acyl imidoyl group” is, for example, a lower (C ₂ −) such as an acetimidoyl group or a propionimidoyl group,
C ₅ ) those derived from alkanoic acids, and those derived from (C ₇ -C ₁₁ ) aromatic carboxylic acids such as benzimidoyl groups.

The "protecting group for carboxyl group" in R ⁵ and R ¹⁰ in the compounds of the above general formula, especially the compounds of general formulas (I) and (IV), is known to those skilled in the art of organic synthesis. , For example, protecting groups that have been used in the fields of peptide synthesis, penicillin synthesis, cephalosporin synthesis, sugar synthesis, and the like. The “carboxyl group-protecting group” can be selected from those similar to the above “hydroxyl group-protecting group” and can be removed by hydrogenation or treatment with an acid or a weak base. And the like, the above-mentioned "optionally substituted alkyl group",
Such as "optionally substituted aralkyl group", "optionally substituted aryl group", "optionally substituted alkyloxycarbonyl group" and "optionally substituted aralkyloxycarbonyl group" You can choose from among them.

Compounds of the above general formula, in particular, of the general formula (IV)
R ⁹ in the ^{compounds, R 11, R 12, R} 1 3, in E and F,
`` Protected hydroxyl group '', `` protected guanidino-substituted phenyl (C ₁ -C ₄ ) lower alkyl group '', `` protected amino-substituted phenyl (C <sub>1</sub> -C <sub>4</sub> ) lower alkyl group '', `` protected amino group A substituted (C ₁ -C ₆ ) alkyl group, a `` protected carboxy-substituted phenyl (C <sub>1</sub> -C <sub>4</sub> ) lower alkyl group '', a `` protected hydroxy-substituted phenyl (C ₁ -C ₄ ) lower alkyl group '', `` Protected guanidino-substituted (C <sub>1</sub> -C <sub>4</sub> ) lower alkyl group-substituted phenyl (C <sub>1</sub> -C <sub>4</sub> ) lower alkyl group '', `` Protected amino-substituted (C ₁ -C ₄ ) lower alkyl group Phenyl (C ₁ -C ₄ ) lower alkyl group substituted with
"Phenyl substituted with protected hydroxy-substituted (C ₁ -C ₄₎ lower alkyl (C ₁ -C ₄₎ lower alkyl group"
"Phenyl substituted with protected carboxy substituted (C ₁ -C ₄₎ lower alkyl (C ₁ -C ₄₎ lower alkyl group"
`` A straight or branched chain containing a protected hydroxyl group (C ₁ -C ₈ )
Alkyl groups, protected hydroxy-substituted (C ₁ -C ₈ ) alkyl groups, protected amino groups, protected guanidino groups, protected amidino groups, protected acyl groups Imidoyl group, protected benzimidoyl group, protected bisphosphonomethyl group, protected bisphosphonohydroxymethyl group, protected (C ₁ -C ₁₁ ) alkyl-substituted imidazole Each of the protecting groups in the -3-yl group or the protected bisphosphonomethylimino group is the aforementioned protecting group for a hydroxyl group,
"Protecting group for amino group" and "Protecting group for carboxyl group"
The corresponding ones can be selected and used from among them. In the compound of the general formula (I), particularly preferably, R ¹ and R ² are hydrogen, R ³ is an aralkyl group which may be substituted, and R ⁴ is an alkyl group which may be substituted. There, R ⁵ is hydrogen, also aralkyl groups have been been an alkyl group or a substituted or optionally substituted, R ⁶
Is an optionally substituted aralkyl group, R ⁷ and R ⁸
Is hydrogen or a salt thereof.

The compounds of formula (I) of the present invention may exist as two tautomers. Further, the compounds of the present invention have an asymmetric carbon in the compounds of formula (I) and exist as stereoisomers with respect to that carbon. The present invention includes the mixtures of the isomers as well as each individual stereoisomer. The compounds of the present invention may be each enantiomer, racemate, diastereomer. The compound of the present invention may be a solvate or an acid addition salt thereof, and a compound having a carboxyl group and / or a compound having a hydroxyl group in a substituent and / or an amino group which may be substituted. It may be any prodrug of those having or derived therefrom. The prodrug form of the compound of the present invention includes those which can be converted into the compound of the general formula (I) in vivo by metabolism, for example, by hydrolysis, oxidation, reduction, transesterification and the like. , Esters, ethers, amides, alcohols, amine derivatives.

[0057] Among the compounds obtained by the present invention, the typical ones (but are not limited to) as follows can be mentioned: N ^a - [4- (N- hydroxyamino) -2 (R)-Isobutyl-3 (S)
- (3-phenylpropyl) succinyl] -L-4'-aminomethyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminophenylalanine N ^a- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-methyl-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'acetimidoyl methylphenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-propionic imidoyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -O- sulfo -L- tyrosine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-sulfo-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine

[0058] N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-
4'-aminomethyl-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-methyl-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'acetimidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-propionic imidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -O- sulfo -L- tyrosine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-sulfo-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4 '-[bis (phosphonyl) methylimino] phenylalanine methyl ester

[0059] N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-
4 '- [bis (phosphonyl) hydroxymethyl] phenylalanine methyl ester N ^a - [4-(N-hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-aminomethyl phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amino-phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-methyl-phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenyl methyl phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-acetimidoylmethylphenylalanine ethyl ester

[0060] N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-
4'-propionic imidoyl methyl phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -O- sulfo -L- tyrosine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-sulfo-phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) hydroxymethyl] phenylalanine ethyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-aminomethyl-phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amino-phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-methyl-phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'- amidinomethylphenylalanine isopropyl ester

[0061] N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-
4'acetimidoyl methyl phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-propionic imidoyl methyl phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -O- sulfo -L- tyrosine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-sulfo-phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine isopropyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine isopropyl ester

[0062] N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-
4'-aminomethyl phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-aminophenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-guanidino-methyl-phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-amidinophenyl methyl phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-acetimidoylmethylphenylalanine n-butyl ester

N ^a- [4- (N-hydroxyamino) -2 (R) -isobutyl-3 (S)-(3-phenylpropyl) succinyl] -L-
4'-propionimidoylmethylphenylalanine n-
Butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -O- sulfo -L- tyrosine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4'-sulfo-phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S )
- (3-phenylpropyl) succinyl] -L-4 '- [bis (phosphonyl) hydroxymethyl] phenylalanine n- butyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S) - Diisobutylsuccinyl] -L-4'-aminomethylphenylalanine

N ^a- [4- (N-hydroxyamino) -2 (R) 3 (S)-
Diisobutyl succinyl] -L-4'-amidinophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-aminophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-guanidino-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-guanidino-methyl-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-amidinophenyl methyl phenylalanine N ^a - [4 - (N-hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'acetimidoyl methylphenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 ( S) - diisobutyl succinyl] -L-4'-propionic imidoyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -O- sulfo -L- Tyrosine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-sulfo-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R ) 3 (S) - diisobutyl succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S) - diisobutyl succinyl] -L -4 '-[Bis (phosphonyl) hydroxymethyl] phenylalanine

[0065] N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) - Mechirusakushiniru] -L-4'-aminomethyl phenylalanine N ^a - [4- (N- hydroxyamino ) -2 (R) isobutyl-3 (S)-
Mechirusakushiniru] -L-4'-amidinophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-aminophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-guanidino-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-guanidino-methyl-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-amidinophenyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'acetimidoyl methylphenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-propionic imidoyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -O- sulfo -L- tyrosine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-sulfo-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Methylsuccinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine

[0066] N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-aminomethyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl succinyl] -L-4'-amidinophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-aminophenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-guanidino-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-guanidino-methyl-phenylalanine N ^a - [4 - (N-hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-amidinophenyl methyl phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4' acetimidoyl methylphenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-propionic imide Irume Le phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl succinyl] -O- sulfo -L- tyrosine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl succinyl] -L-4'-sulfo-phenylalanine N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine N ^a - [4- (N -Hydroxyamino) -2 (R) isobutylsuccinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine

[0067] N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) -
Diisobutyl succinyl] -L-4'-aminomethyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-amidinophenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-amino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R ) 3 (S) - diisobutyl succinyl] -L-4'-guanidino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4' guanidinomethyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-amidinophenyl methyl phenylalanine methyl ester N ^a - [4- (N- Hydroxyamino) -2 (R) 3 (S) -diisobutylsuccinyl] -L-4'-acetimidoylmethylphenyl Alanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-propionic imidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -O- sulfo -L- tyrosine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl ] -L-4'-sulfo-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S) - diisobutyl succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S) - diisobutyl succinyl] -L-4 '- [bis (phosphonyl) hydroxymethyl] phenylalanine methyl ester

[0068] N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) - Mechirusakushiniru] -L-4'-aminomethyl phenylalanine methyl ester N ^a - [4- (N- (Hydroxyamino) -2 (R) isobutyl-3 (S)-
Methylsuccinyl] -L-4'-amidinophenylalanine
Methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-amino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-guanidino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-guanidino-methyl-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-amidinophenyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'acetimidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-propionic imidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -O- sulfo -L- tyrosine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4'-sulfo-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Mechirusakushiniru] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl -3 (S) -
Methylsuccinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine methyl ester

[0069] N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-aminomethyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R ) isobutyl succinyl] -L-4'-amidinophenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-amino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-guanidino-phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4' guanidinomethyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-amidinophenyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutylsuccinyl] -L-4'-acetimidoylmethyl Ruaranin methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-propionic imidoyl methyl phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl succinyl] -O- sulfo -L- tyrosine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl-succinyl] -L-4'-sulfo-phenylalanine methyl ester N ^a - [ 4-(N-hydroxyamino) -2 (R) isobutyl-succinyl] -L-4 '- [bis (phosphonyl) methylimino] phenylalanine methyl ester N ^a - [4- (N- hydroxyamino) -2 (R) isobutyl Succinyl] -L-4 '-[bis (phosphonyl) hydroxymethyl] phenylalanine methyl ester or a pharmaceutically acceptable salt or solvate of the above compound, each enantiomer, racemate, diastereomer, prodrug Or in vivo metabolic derivatives (e.g., hydrolysis, oxidation, reduction, etc. transesterification derivative)

Next, the compound represented by the above general formula (I) according to the present invention and the synthetic intermediates thereof will be described in detail with reference to synthetic route diagrams. In the following description, according to a method commonly used in many chemical literatures, numbers are sequentially assigned to compound names, and the compounds are indicated with the numbers. First, a method for producing a compound of the general formula (II) useful as a production intermediate will be described.

[0071]

Embedded image (In the above synthetic route, R ¹⁰ , R ¹¹ and R ¹² are
Wherein are as defined, R ^{1 4,} R ¹⁵ and R ¹⁶ may be the same or different, a protecting group of the carboxyl group, for example optionally substituted (C ₁ -C ₆₎ alkyl group, Benzyl, substituted benzyl, phenacyl or
Represents a 2,2,2-trichloroethyl group, and D represents a substitutable group such as halogen. )

The route for synthesizing a compound of the general formula (II) useful as a production intermediate starting from a malonic acid diester of the general formula (VII) is suitable in all cases where R ¹¹ is not hydrogen or a hydroxyl group. is there. The compound of the general formula (X) is obtained by reacting an α-halogenocarboxylic acid ester (IX) in which D is a halogen with a compound of the general formula (VIII) obtained by anionizing a malonic diester of the general formula (VII). (Examples of halogen include fluorine, chlorine, bromine and iodine, with bromine being preferred). The malonic acid diester (V
Examples of the base used for the anionization of II) include those used in ordinary reactions, for example, alkali metal hydrides (eg, sodium hydride), lithium diisopropylamide (LDA), lithium bis (trimethylsilyl) Alcoholates such as amides and alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, sodium propoxide, potassium tert-butoxide, potassium ethoxide, etc.) can be used, but preferably sodium or potassium hydride -tert-butoxide. As the reaction solvent, an inert organic solvent can be used. For example, saturated hydrocarbons (eg, n-hexane and the like), ethers (eg, tetrahydrofuran (THF) and the like), aromatic hydrocarbons (eg, Benzene, toluene, etc.), amides (eg, dimethylformamide (DMF), dimethylacetamide (DMAc), etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.) can be used, but preferably DMF is used. is there. Reaction temperature is usually -78 ~ 50 ℃
And preferably from 0 to 20 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature, etc. used, but is from 30 minutes to 4 minutes.
Time is sufficient, usually 1 to 2 hours.

In order to subsequently react the compound (VIII) with the α-halogenocarboxylic acid ester of the general formula (IX), an inert organic solvent can be used as a reaction solvent.
Saturated hydrocarbons (eg, n-hexane etc.), ethers (eg, THF, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, DMF, DMAc
And the like, and halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and preferably DMF. The reaction temperature is usually from -10 to 50C, preferably from -5 to 0C. The reaction time depends on the starting materials, solvent,
Although it varies depending on the reaction temperature and the like, it is usually 2 hours to 24 hours, preferably 10 hours to 20 hours.

The compounds of general formula (XII), the general formula compound with the halogenated anion embodying (XI) of (X) (C ₁ -C ₆₎ alkyl (preferably iodide such as methyl iodide (C ₁ -C ₆ ) alkyl), substituted halogenated (C ₁ -C ₆ ) alkyl (preferably 1-benzyloxycarbonylamino-3-iodopropane, 1-benzyloxycarbonylamino-5-
Iodopentane, 1-tetrahydropyranyloxy-8-iodooctane, 1-ethoxyethoxy-2-iodoethane,
1-n-butyloxy-2-iodoethane, 1-iso-butyloxy-2-iodoethane, 1-phenoxy-2-iodoethane,
1-tetrahydropyranyloxy-3-iodopropane, etc.), alkenyl halides (preferably cinnamyl bromide (C ₆ H ₅ —CH = CH—CH ₂ —Br), methallyl iodide [C
H = C (CH ₃ ) —CH ₂ —I] or a substituted alkenyl halide (preferably nitrocinnamyl bromide (O ₂ NC ₄ H ₅ —CH = CH—CH ₂ —Br ₂ ), methoxy Carbonyl cinnamyl bromide, 1-methoxycarbonylphenyl-3-iodopropane, cyanosinnamyl bromide, 1-cyanophenyl-3-iodopropane, cyanobenzyl bromide,
1-benzyloxyphenyl-3-iodopropane, etc.] and then, if desired, hydrogenation.

As the base used in the synthesis of the compound of the general formula (XI), those usually used in this kind of reaction can be mentioned, for example, LDA, lithium bis (trimethylsilyl) amide, alkali metal hydride (for example, Alcoholates such as sodium hydride), alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, sodium propoxide, potassium-tert-butoxide, potassium ethoxide) and the like are used, and preferably sodium hydride is used. Used. As a reaction solvent, an inert organic solvent can be used. For example, saturated hydrocarbons (eg, n-hexane and the like), ethers (eg,
THF, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, DMF, DMAc, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and preferably DMF Is mentioned.
The reaction temperature is usually -10 to 50C, preferably 10 to 30C
It is. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 30 minutes to 4 hours, preferably 1 hour to 2 hours.

For subsequent reaction with an alkyl halide, an inert organic solvent can be used as a reaction solvent. For example, saturated hydrocarbons (for example, n-hexane and the like) and ethers (for example, THF, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, DMF, DMAc, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), etc., are preferably used. DMF. Reaction temperature is usually -10 to 100
° C, preferably -5 to 70 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 2 to 48 hours, preferably 10 to 20 hours.
In order to further hydrogenate as desired and obtain a compound of the general formula (XII), a palladium catalyst such as palladium carbon or a catalyst such as platinum can be used as a hydrogenation catalyst.
Preferably it is palladium carbon. As the reaction solvent,
An inert organic solvent which does not become a catalyst poison can be used, and examples thereof include alcohols (methanol, ethanol, etc.), amides (eg, DMF, DMAc, etc.), acetic acid and water, and mixtures thereof. Is also used, preferably methanol or ethanol. The reaction temperature is usually 0-50 ° C, preferably 10-30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 10 hours.

The compound of the general formula (XIII) can be produced by deesterifying the general formula (XII). R ¹⁰ , R ¹⁴ ,
R ¹⁵ has the same meaning as described above, but R ¹⁰ is preferably a tert-butyl group, and R ¹⁴ and R ¹⁵ are preferably a benzyl group to obtain the compound of the general formula (XIII). For example, when R ¹⁴ and R ¹⁵ are benzyl groups, they can be deesterified by hydrogenation. As the hydrogenation catalyst, a catalyst such as palladium carbon or platinum can be used, but palladium carbon is preferable. As a reaction solvent, an inert organic solvent which does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), amides (eg, DMF, DMAc
Etc.), acetic acid or water, and mixtures thereof are also used, preferably methanol or ethanol. The reaction temperature is usually 0 to 50 ° C, preferably 10 to 50 ° C.
30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 10 hours.

Starting from the compound of the general formula (XIV)
A route for synthesizing a compound of the general formula (II) useful as a production intermediate is suitable when R ¹¹ is hydrogen or a hydroxyl group. The compound of the general formula (XV) can be obtained by converting the succinic acid derivative of the general formula (XIV) into (a) N, N′-dicyclohexylcarbodiimide (DC
C) reacting with alcohols in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC / HCl) and a base such as N, N-dimethylaminopyridine, (b) by converting formula (XVI) into a salt such as sodium, potassium, cesium, etc., and reacting with an alkyl halide or benzyl halide, or (c) reacting thionyl chloride with a complex of an alcohol. Can be manufactured. For example, in the case of reacting the compound of the general formula (XIV) with a thionyl chloride-alcohol complex, the alcohol used is not particularly limited, and for example, methanol,
Ethanol, n-propyl alcohol, iso-propyl alcohol, tert-butyl alcohol, phenol, benzyl alcohol, phenacyl alcohol, 2,2,2-trichloroethanol, etc. (preferably, methanol, ethanol, iso-propyl alcohol Tert-butyl alcohol, and more preferably iso-propyl alcohol.), Which is also used as a reaction solvent. The reaction temperature is usually -30 to 10 ° C, preferably -10 to 0 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 5 hours to 24 hours, preferably 10 hours to 15 hours.

The compound of the general formula (XVI) can be produced by anionizing the succinic diester of the general formula (XV) and reacting with methallyl iodide, followed by hydrogenation. Examples of the base used for anionization of the succinic diester (XV) include those used in ordinary reactions, such as alkali metal hydride (eg, sodium hydride), LDA, lithium bis (trimethylsilyl). ) Alcoholates such as amides and alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, sodium propoxide, potassium-tert-butoxide, potassium ethoxide, etc.) can be used, but LDA is preferable. The reaction solvent is an inert organic solvent, such as a saturated hydrocarbon (eg, n-hexane),
Ethers (eg, THF, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg,
DMF, DMAc, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.) can be used, but THF is preferred. Reaction temperature is usually -78 ~ 0 ℃
And preferably -70 to -10 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature, etc.
24 hours, usually 4 hours to 12 hours.

In order to react with methallyl iodide subsequent to this reaction, an inert organic solvent can be used as a reaction solvent. For example, saturated hydrocarbons (eg, n-hexane, etc.), ethers (eg, THF) ), Aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, DMF, DMAc, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and the like, preferably THF. is there. Reaction temperature is usually -78 ~ 0 ℃
And preferably -70 to -10 ° C. The reaction time depends on the starting material, solvent, reaction temperature, etc.
Hours to 48 hours, preferably 10 hours to 20 hours. Further, if desired, hydrogenation is performed to obtain a compound of the general formula (XVI). A catalyst such as palladium carbon or platinum can be used as a hydrogenation catalyst, but palladium carbon is preferred. As the reaction solvent, an inert organic solvent that does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, and the like), amides (eg, DMF, DMAc, and the like), acetic acid, and water are used. Is methanol. The reaction temperature is usually 0 to 50 ° C,
Preferably it is 10-30 degreeC. The reaction time depends on the raw materials used,
Although it depends on the solvent, the reaction temperature and the like, it is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

The compound of the general formula (XVII) can be produced by deesterifying the compound of the general formula (XVI). For example, when R ¹⁶ is an iso-propyl group, it can be deesterified by alkaline hydrolysis. The base used for the hydrolysis is not particularly limited as long as it is used as a base in a usual reaction, and examples thereof include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and lithium hydride. , Sodium hydride and the like, and preferably sodium hydroxide, potassium hydroxide and the like. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and can dissolve the raw materials, but amides (eg, DMF, DMAc, etc.), alcohols, ethers (eg, diethyl ether, tetrahydrofuran, Dioxane), water, ketones (eg, acetone, etc.), and preferably alcohols, water, dioxane, acetone, or a mixed solvent thereof. The reaction temperature is usually -20 to 150 ° C, preferably -10 to 100 ° C. The reaction time is usually 5 minutes to 36 hours, preferably,
10 minutes to 24 hours.

Compounds of general formula (II) useful as synthetic intermediates can be prepared by (a) decarboxylation of compounds of general formula (XIII) or (b)
It can be produced by reacting a dicarboxylic acid of the general formula (XVII) with an alcohol via an acid anhydride of the general formula (XVIII). (a) To decarboxylate the compound of the general formula (XIII), the compound is reacted in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or N-ethylmorpholine. As the reaction solvent, an inert organic solvent can be used, and examples thereof include saturated hydrocarbons (eg, n-hexane and the like), aromatic hydrocarbons (eg, benzene, toluene and the like), and the like. Is toluene. Reaction temperature is usually 70-15
0 ° C., preferably 100-120 ° C. The reaction time depends on the starting material, solvent, reaction temperature, etc.
Usually, it is 1 hour to 5 hours, preferably 2 hours to 3 hours. (b) A reaction for producing a production intermediate (II) from a dicarboxylic acid of the general formula (XVII) via an acid anhydride of the general formula (XVIII),
For example, it can be carried out with reference to [J. Org. Chem., 47, 4928 (1982)]. The alcohol to be reacted with the acid anhydride (XVIII) is not particularly limited, and for example, methanol, ethanol, n-propyl alcohol, iso-propyl alcohol,
tert-butyl alcohol, phenol, benzyl alcohol, phenacyl alcohol, 2,2,2-trichloroethanol and the like, preferably methanol, ethanol,
Benzyl alcohol, 2,2,2-trichloroethanol.

Next, a method for producing the intermediate (III) will be described.

Embedded image (In the above synthetic route, R ⁷ , R ⁸ , R ⁹ and R ¹³ are as defined above, and R ¹⁷ is, for example, a tert-butyloxycarbonyl (Boc) group, a benzyloxycarbonyl (Z) group or a substituted A urethane-type protecting group such as a benzyloxycarbonyl group or an acyl-type protecting group such as a formyl group, an acetyl group, a chloroacetyl group, a benzoyl group, or a substituted benzoyl group.)

In the production intermediate (III), R ¹³ is -XE
Group or -XAE group, E represents (a) a protected bisphosphonomethyl group or a protected guanidino group,
(b) a protected bisphosphonohydroxymethyl group and
(c) The compound in which the -AE group is a protected guanidinomethyl group, a protected aminomethyl group or a substituted imidazolylmethyl group is a compound of the general formula (XXII) in which E is a nitro group, a carboxyl group or a cyano group. Each can be manufactured. For example, when (a) E is a protected guanidino group, the protected 4′-nitrophenylalanine is converted to an α-amino group and a carboxylic acid protected 4′-aminophenylalanine, and then 1H-pyrazole-N, It can be produced by reacting with N'-bis-benzyloxycarbonyl-1-carboxamidine. When E is a protected bisphosphonomethyl group, the α-amino group and the carboxylic acid-protected 4′-aminophenylalanine are converted to a formate such as ethyl orthoformate and a phosphite such as diethyl phosphite. [Phos
phorous and Sulfur, 11, 311 (1981)]. (b) When E is a protected bisphosphonohydroxymethyl group, the protected 4'-carboxylphenylalanine can be converted to an acid halide and then reacted with a phosphite compound such as tribenzyl phosphite.
[Phosphorous, Sulfur, and Silicon, 113, 295 (1996)
See]. (c) when the -AE group is a protected guanidinomethyl group, after converting 4'-cyanophenylalanine to an α-amino group and a 4'-aminomethylphenylalanine in which a carboxylic acid is protected, 1H-pyrazole- It can be produced by reacting with N, N'-bis-benzyloxycarbonyl-1-carboxamidine. Also, when the -AE group is a protected aminomethyl group, Boc is added to the α-amino group and the 4'-aminomethylphenylalanine in which the carboxylic acid is protected.
A group, a Z group, a substituted benzyloxycarbonyl group or the like (a protecting group that can be selectively removed as a protecting group for an α-amino group) can be introduced by a conventional method. In addition, -A
When the -E group is a substituted imidazolylmethyl group, it can be produced by reacting a protected 4'-hydroxymethylphenylalanine with methanesulfonylation or p-toluenesulfonylation and then reacting with an anionized imidazole derivative [J. See Med. Chem., 31, 2193 (1988).
].

(A) When converting to a protected guanidino group, first, an α-amino group in which E is a nitro group and a 4′-nitrophenylalanine protected with a carboxylic acid are hydrogenated to form an α-amino group. And a carboxylic acid protected 4'-aminophenylalanine is obtained. As a hydrogenation catalyst for hydrogenation, a catalyst such as palladium carbon or platinum can be used, but palladium carbon is preferable. As a reaction solvent, an alcohol (methanol, ethanol, or the like), DMF, DMAc, acetic acid, or water, which is an inert organic solvent that does not cause catalyst poison, is used, and methanol is preferable. The reaction temperature is generally 0-50 ° C, preferably 10-30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours. Then, 1H-
Pyrazole-N, N-bis-benzyloxycarbonyl-1-
It can be converted to a protected guanidino group by reacting with carboxamidine. The reaction solvent is n-hexane, benzene, toluene, DMF, DM
Ac, dichloromethane, chloroform, etc. are used,
Preferably it is dichloromethane. Reaction temperature is usually -10
-50 ° C, preferably 0-30 ° C. The reaction time varies depending on the starting materials, solvent, reaction temperature, etc.
It is 10 minutes to 12 hours, preferably 30 minutes to 6 hours.
When converted to a protected bisphosphonomethyl group, for example, the α-amino group and the carboxylic acid can be obtained by mixing and heating the protected 4′-aminophenylalanine with ethyl orthoformate and diethyl phosphite, Generally, the reaction is performed without a solvent. The reaction temperature is usually from 100 to 180 ° C, preferably from 140 to 160 ° C. The reaction time varies depending on the starting materials used, the reaction temperature and the like, but is usually 1 hour to 8 hours, preferably 1 hour to 6 hours. (b) In the case of a protected bisphosphonohydroxymethyl group, the reaction for converting the protected 4'-carboxylphenylalanine to an acid halide is, for example, dimethyl chloride prepared using thionyl chloride or oxalyl chloride and DMF. Obtained by reacting with chloroformiminium. As the reaction solvent, an inert solvent can be used. For example, amides (eg, DMF), ethers (eg, diethyl ether), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.)
And the like. The reaction temperature is usually -20 to 100 ° C,
Preferably it is -5 to 80 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 8 hours. Subsequently, when converting to a protected bisphosphonohydroxymethyl group, it is reacted with a trialkyl phosphite in the presence of one equivalent of a proton donor (preferably, alcohol, acetic acid, etc.). As the reaction solvent, an inert solvent can be used, and examples thereof include amides (eg, DMF, etc.), ethers (eg, diethyl ether, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.). Can be The reaction temperature is usually from -20 to 100 ° C, preferably from -5 to 50 ° C. The reaction time is generally 10 minutes to 24 hours, preferably 30 minutes to 8 hours.

(C) When protected is a guanidinomethyl group, first, E is hydrogenated under acidic conditions by subjecting an α-amino group, which is a cyano group, and a 4′-cyanophenylalanine, in which a carboxylic acid is protected, to an acid. 4'-Aminomethylphenylalanine having an α-amino group and a carboxylic acid protected is obtained. As a hydrogenation catalyst for hydrogenation, a catalyst such as palladium carbon or platinum can be used, but palladium carbon is preferable. The reaction solvent depends on the protecting group of the α-amino group. In the case of the acetyl group, alcohol (methanol, ethanol, etc.), DMF, DMAc, acetic acid or water, which are inert organic solvents that do not poison the catalyst, are used. , Preferably ethanol. Hydrochloric acid, hydrohalic acid such as hydrobromic acid, sulfuric acid,
Examples thereof include mineral acids such as nitric acid, and organic acids such as formic acid, acetic acid, citric acid, and malic acid, and are preferably hydrochloric acid or acetic acid. When the protecting group for the α-amino group is a Boc group, acetic acid is preferred. The reaction temperature is generally 0-50 ° C, preferably 10-30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 8 hours. Subsequently, the resulting α-amino group and carboxylic acid protected 4'-aminomethylphenylalanine and 1H-pyrazole-N, N'-
Bis-benzyloxycarbonyl-1-carboxamidine can be converted to a protected guanidinomethyl group by reaction. The reaction solvent is an inert organic solvent, n-
Hexane, benzene, toluene, DMF, DMAc, dichloromethane, chloroform and the like are used, but dichloromethane is preferred. The reaction temperature is usually -10 to 50C, preferably 0 to 30C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 10 minutes to 12 hours, preferably 30 minutes to 6 hours. -When the AE group is a protected aminomethyl group and the protecting group is a Z group, the α-amino group and the carboxylic acid are protected 4′-
Aminomethylphenylalanine (α-E is a cyano group
Amino groups and carboxylic acids are derived from protected 4'-cyanophenylalanine) by (1) reacting with N- (benzyloxycarbonyloxy) -succinimide with the amino group free, or (2) using normally In the presence of a base (eg, carbonates such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, or organic amines such as triethylamine and N-ethylmorpholine that do not affect the protecting group of the carboxylic acid) It can be introduced by reacting with benzyl formate. (1) When N- (benzyloxycarbonyloxy) -succinimide is used, the reaction solvent is DMF, DMAc, dichloromethane,
Chloroform, ethers (for example, dioxane) and ketones (for example, acetone and the like) are preferred, but preferably
DMF. The reaction temperature is usually -5 to 50C, preferably 0 to 30C. The reaction time is usually 2 to 24 hours, preferably 6 to 15 hours. (2) When chlorobenzyl formate is allowed to act, examples of the reaction solvent include ethers (eg, dioxane), ketones (eg, acetone), water, and a mixed solvent thereof. The reaction temperature is usually -20 to 30C, preferably -5 to 5C. Reaction temperature is usually 2-24
Hours, preferably 6 to 15 hours. When the -AE group is a substituted imidazolylmethyl group, first, the protected 4'-aminomethylphenylalanine hydrochloride protected with an α-amino group and a carboxylic acid is subjected to a diazotization reaction in the presence of water to obtain the protected 4'-amino group. -Need to be converted to hydroxymethylphenylalanine. The reaction solvent is not particularly limited as long as the solvent dissolves the raw material and sodium nitrite, but water is most suitable. Reaction temperature is 50-130
° C, preferably 90 to 100 ° C. Reaction time is usually
It is 1 hour to 5 hours, preferably 3 hours. Next, after the obtained 4′-hydroxymethylphenylalanine derivative is led to a sulfonylated compound as an intermediate, by reacting with the anion of the imidazole derivative, the -AE group is a substituted imidazolylmethyl group (III). Obtainable. The intermediate sulfonylate is protected
It is obtained by adding 4'-hydroxymethylphenylalanine and a sulfonylating agent in the presence of a base. Examples of the sulfonylation reagent include methanesulfonyl chloride, chloride
alkylsulfonyl halides such as p-toluenesulfonyl, arylsulfonyl halides, and the like;
For example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like are preferable. Examples of the base include alkylamines such as trialkylamine, and nitrogen-containing heterocyclic compounds such as pyridine. Preferably, triethylamine is used. As the reaction solvent, an inert solvent can be used. For example, amides (eg, DMF, DMAc, etc.), aromatic hydrocarbons (eg, benzene, etc.), ethers (eg, diethyl ether, etc.), halogenation Although hydrocarbons (eg, dichloromethane, chloroform, etc.) can be used, dichloromethane is preferred.
The reaction temperature is usually -20 to 50 ° C, preferably -5 to 20 ° C
It is. The reaction time is generally 10 minutes to 4 hours, preferably 30 minutes to 2 hours.

By reacting the resulting sulfonylated intermediate with an anionized imidazole derivative, a compound of the general formula (XXII) in which the -AE group is a substituted imidazolylmethyl group can be obtained. For example, alkali metal hydrides (eg, sodium hydride), LDA, lithium bis (trimethylsilyl) amide, alkali metal alcoholates (eg, sodium methoxide, sodium ethoxide, sodium propoxy) And alcoholates such as potassium tert-butoxide, potassium ethoxide and the like, but sodium hydride is preferable.

The compound of the general formula (XX) can be produced by introducing a protecting group such as a Boc group, a Z group or a substituted benzyloxycarbonyl group into the amino group of the compound of the general formula (XIX) by a conventional method. I can do it. For example, in the case of a Z group, it can be introduced by reacting chlorobenzyl formate in the presence of a commonly used base (eg, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc.). . Examples of the reaction solvent include ethers (for example, dioxane and the like), ketones (for example, acetone and the like), water, and a mixed solvent thereof.
The reaction temperature is usually -20 to 30 ° C, preferably -5 to 5 ° C.
It is. The reaction time is usually 2 hours to 24 hours, preferably 6 hours to 15 hours.

The general formula (XXII) is obtained by converting the carboxylic acid of the general formula (XX) into (a) N, N′-dicyclohexylcarbodiimide (DCC),
In the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC · HCl) and a base such as N, N-dimethylaminopyridine, alcohols (HO-R ⁹ )
Or (b) converting formula (XX) into a salt such as sodium, potassium, cesium, etc., and then reacting with an alkyl halide or benzyl halide, or (c) thionyl chloride and an alcohol (HO-R ^It can be produced by reacting the complex of ⁹ ). For example, in the case of producing by the method (a), the alcohol used is not particularly limited, and for example, methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl Alcohol, tert-butyl alcohol,
n-pentyl alcohol, neopentyl alcohol, n-hexyl alcohol, heptanol, n-octyl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, dodecyl alcohol, tridecyl alcohol, tetradecyl alcohol, pentadecyl alcohol, hexadecyl alcohol, Phenol, 4-methoxyphenol, 4-bromophenol, trityl alcohol, benzhydryl alcohol, acetoxymethanol, acetoxyethanol, benzyl alcohol, phenacyl alcohol, 2-chloroethanol, 2,2,2-trichloroethanol, methoxymethanol, 2-methoxyethanol, benzyloxymethanol, 2-benzyloxyethanol, 2- (benzyloxycarbonylamino) ethanol, 2- (benzyloxycal Niruamino) -2-methyl-ethanol, 2-N, N-dimethylaminoethanol, cyclohexyl alcohol, cyclohexylmethanol,
Allyl alcohol, cinnamyl alcohol, 2-propynyl alcohol, triethylsilanol, tert-butyldimethylsilanol, tert-butyldiphenylsilanol, phthalimide methanol, and the like. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the raw materials, but includes DMF, DMAc, ethyl acetate, diethyl ether, dichloromethane, chloroform, dioxane, etc., and preferably dichloromethane and DMF. . The reaction temperature is usually -20 to 30C, preferably -10 to 15C. The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 15 hours.

Compounds of general formula (III) useful as intermediates can be prepared by (a) removing the amino protecting group of the compound of general formula (XXII) or (b) directly esterifying the amino acid of general formula (XIX) Can be manufactured. (a) As a method for removing the amino protecting group, a conventional method widely known to those skilled in the art is applied to each depending on the type. For example, when the protecting group is a Z group, a hydrogenation method is a preferable removal method. As the hydrogenation catalyst, a catalyst such as palladium carbon or platinum can be used, but palladium carbon is preferable.
The reaction solvent is not particularly limited as long as it is an inert organic solvent that does not become a catalyst poison. Alcohols (methanol, ethanol, etc.), amides (eg, DMF, DMAc, etc.), acetic acid or water are used. Preferably, it is methanol. The reaction temperature is generally 0 to 50 ° C, preferably 10 to 50 ° C.
~ 30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours. When the protecting group is a Boc group, the protecting group is also removed by a hydrogen halide such as hydrogen fluoride, hydrogen chloride or hydrogen bromide or an organic acid such as formic acid, trifluoroacetic acid or p-toluenesulfonic acid. When hydrogen chloride is used, the reaction can be performed using 5 to 50 equivalents of hydrogen chloride as a raw material using ethyl acetate or dioxane as a solvent,
Preferably, it is 20 to 30 equivalents. Reaction temperature is -10 to 50 ° C
And preferably 0 to 30 ° C.

(B) As a method of directly esterifying an amino acid, for example, the general formula (XIX) is reacted with an alcohol in the presence of p-toluenesulfonic acid hydrate to azeotropically distill off water produced by boiling. Can be manufactured. The alcohol used is not particularly limited, and for example, methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, se
c-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, neopentyl alcohol, n-hexyl alcohol, heptanol, n-octyl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, dodecyl alcohol, tridecyl alcohol, tetradecyl Alcohol, pentadecyl alcohol, hexadecyl alcohol, phenol, 4-methoxyphenol, 4-bromophenol, trityl alcohol, benzhydryl alcohol, acetoxymethanol, acetoxyethanol, benzyl alcohol, phenacyl alcohol, 2-chloroethanol, 2, 2,2-trichloroethanol, methoxymethanol, 2-methoxyethanol, benzyloxymethanol, 2-benzyloxyethanol,
2- (benzyloxycarbonylamino) ethanol, 2-
(Benzyloxycarbonylamino) -2-methylethanol, 2-N, N-dimethylaminoethanol, cyclohexyl alcohol, cyclohexyl methanol, allyl alcohol, cinnamyl alcohol, 2-propynyl alcohol, triethylsilanol, tert-butyldimethylsilanol, tert -Butyldiphenylsilanol, phthalimidemethanol and the like, preferably methanol, ethanol and benzyl alcohol. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction, but DMF, DM
Ac, benzene, toluene, xylene, dichloromethane,
Chloroform, dioxane and the like are preferred, and benzene and toluene are preferred. Reaction temperature is usually 50-20 ° C
And preferably 60 to 150 ° C. Reaction time is usually
It is 1 hour to 24 hours, preferably 2 hours to 15 hours. Next, the method for producing the intermediate (V) will be described.

Embedded image

The compound of the general formula (XXIII) is produced by deesterifying the compound of the general formula (XII).
R ¹⁰ , R ¹⁴ and R ¹⁵ have the same meanings as described above, but have the general formula (XXI
In order to obtain the compound of II), R ¹⁵ is preferably a 2,2,2-trichloroethyl group, and R ¹⁰ and R ¹⁴ are preferably a benzyl group. For example, R
^{When 10} and R ¹⁴ are benzyl groups, they can be deesterified by hydrogenation. Palladium on carbon as hydrogenation catalyst,
Although a catalyst such as platinum can be used, palladium carbon is preferred. As the reaction solvent, an inert organic solvent that does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), THF, DMF,
DMAc, acetic acid or water can be used, and a mixture thereof can be used, and THF is preferable. The reaction temperature is usually 0
-50 ° C, preferably 10-30 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

The compound of the general formula (XXIV) is a succinic acid derivative (I
I), N, N'-dicyclohexylcarbodiimide (DCC),
It can be produced by reacting with an alcohol in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC · HCl) and a base such as N, N-dimethylaminopyridine. The alcohol used is not particularly limited, and examples thereof include methanol, ethanol, n-propyl alcohol, iso-propyl alcohol, tert-butyl alcohol, phenol, benzyl alcohol, phenacyl alcohol, and 2,2,2-trichloroethanol. (Preferably, 2,2,2-trichloroethanol.) As the reaction solvent, an inert organic solvent can be used. For example, saturated hydrocarbons (eg, n-hexane, etc.), ethers (eg, THF, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) ), Amides (eg, DMF, DMAc, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and the like, with preference given to dichloromethane. The reaction temperature is usually -30 to 30C, preferably -10 to 20C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like to be used, but is usually 1 hour to 24 hours, preferably 3 hours to 15 hours.

The compound of the general formula (XXV) can be prepared by:
The compound of the formula (II) is decarboxylated or (b) the compound of the general formula (XXIV) is partially deesterified. (a) To decarboxylate the compound of the general formula (XXIII), heat in an inert solvent. Examples of the inert organic solvent include, for example, saturated hydrocarbons (for example, n-hexane and the like), aromatic hydrocarbons (for example, toluene and benzene), and toluene is preferable. Reaction temperature is usually 70-15
0 ° C., preferably 100-120 ° C. The reaction time varies depending on the starting material, solvent, reaction temperature and the like used, but is usually 1 hour to 5 hours, preferably 2 hours to 3 hours.

(B) Partial deesterification of the compound of the general formula (XXIV) can be achieved, for example, by hydrogenation when R ¹⁰ is a benzyl group or by treatment with an acid when R ¹⁰ is a tert-butyl group. . Although a catalyst such as palladium carbon or platinum can be used as the hydrogenation catalyst, palladium carbon is preferred. As the reaction solvent, an inert organic solvent which does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), ethers (eg, THF, etc.), amides (eg, DMF, DMAc, etc.) ,
Acetic acid or water is used, preferably THF. The reaction temperature is usually from 0 to 50 ° C, preferably from 10 to 30 ° C.
The reaction time varies depending on the starting material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 24 hours, preferably 1 hour to 24 hours.
6 hours. The acid used is trifluoroacetic acid
(TFA), a hydrochloric acid solution or the like dissolved in an organic solvent (ethyl acetate, dioxane, etc.) is used, but preferably TFA is used as the solvent. The reaction temperature is usually -10
-50 ° C, preferably 0-30 ° C. The reaction time varies depending on the diester (XXIV) used, the acid, the reaction temperature and the like, but is usually 30 minutes to 24 hours, preferably 1 hour to 15 hours.

The compound of the general formula (XXVII) can be produced by converting the half ester (XXV) into an acid halide and then reacting with a protected hydroxyamine (XXVI).
R ¹⁵ is preferably a 2,2,2-trichloroethyl group for the purpose of selectively removing the protecting groups of R ¹ and R ^{2 and} the protecting group of R ¹⁵ . The reaction for converting into an acid halide is obtained by reacting thionyl chloride or oxalyl chloride with dimethylchloroformiminium chloride prepared using DMF. As the reaction solvent, an inert solvent can be used. For example, aromatic hydrocarbons (eg, benzene, toluene, etc.), amides (eg, DMF, DMAc, etc.), ethers (eg, diethyl ether, etc.) , Halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.)
And the like, preferably dichloromethane. The reaction temperature is usually -20 to 100 ° C, preferably -5
~ 80 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 8 hours. The obtained intermediate is obtained by reacting with a protected hydroxyamine (XXVI) in the presence of a base. As a reaction solvent, an inert solvent can be used. For example, aromatic hydrocarbons (for example, Benzene, toluene, etc.), amides (eg, DMF, DMAc
Etc.), ethers (eg, diethyl ether, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and the like, with preference given to dichloromethane. Examples of the base include tertiary amines such as trialkylamine and pyridine, and triethylamine is preferred. The reaction temperature is generally -20 to 50C, preferably -5 to 30C. The reaction time is usually from 5 minutes to
24 hours, preferably 10 minutes to 5 hours.

The compound of the general formula (V) can be obtained by deesterifying the compound of the general formula (XXVII). For example,
When R ¹⁵ is a 2,2,2-trichloroethyl group, it can be removed by treating with zinc using acetic acid as a reaction solvent.
The reaction temperature is generally 0 to 50 ° C, preferably 5 to 40 ° C.
It is. The reaction time is generally 30 minutes to 15 hours, preferably 1 hour to 5 hours.

Next, methods for producing the intermediates (IV) and (VI) and the desired compound (I) will be described.

Synthesis route of intermediates (IV), (VI) and target compound (I)

Embedded image In the above synthesis route, each group of R ^{1 to} R ¹³ has the same meaning as described above.

The compound of the general formula (IV) is prepared by preparing the intermediates (II) and (I
It is produced by reacting II) by conventional coupling techniques (R ¹⁰ is as defined above, protecting groups for carboxyl group, for example an optionally substituted alkyl group, optionally substituted Aralkyl groups and the like, preferably tert-butyl group, benzyl group, substituted benzyl group, phenacyl group, 2,2,2-trichloroethyl group, particularly preferably tert-butyl group or benzyl group .). As the condensing agent used in this reaction, for example, DCC, EDC.HCl, EEDQ, HOBT derivative, HONB derivative, HOSu derivative, isobutyloxycarbonyl chloride, monoalkyl ester carbonate derivative formed by reaction with ethyloxycarbonyl chloride, DPPA And the like, and preferably EDC.HCl. The reaction solvent does not hinder the progress of the reaction,
There is no particular limitation as long as the solvent dissolves the raw materials. Examples thereof include amides (eg, DMF and DMAc), esters (eg, ethyl acetate), ethers (eg, diethyl ether, dioxane, etc.), halogenated Hydrocarbons (for example, dichloromethane, chloroform, etc.); The reaction temperature is usually -20 to 50 ° C, preferably -15
~ 30 ° C. The reaction time is usually 1 hour to 24 hours,
Preferably, it is 2 hours to 15 hours.

The compound of the general formula (XXVIII) is prepared by partially deesterifying the compound of the formula (IV) and optionally converting R ¹³ to the desired functional group R ⁶ . For example, in the case of tert-butyl ester, deesterification can be achieved by treatment with trifluoroacetic acid (TFA), a solution of hydrogen chloride in ethyl acetate or dioxane, or zinc bromide. The reaction temperature is usually -10 to 20C, preferably -5 to 5C. The reaction time varies depending on the starting material, acid, reaction temperature and the like used, but is usually 1 to 24 hours, preferably 1 to 15 hours.

Subsequently, when R ¹³ is converted to R ⁶ or R ¹¹ is converted to R ³ , for example, R ¹³ is a group containing a protected amino group and R ⁶ is a group containing an acetimidoyl imino group. In some cases, it can be converted by deprotecting the amino group and reacting with ethylacetimidate. When the amino-protecting group is a Boc group, it is removed simultaneously with the tert-butyl ester by treatment with TFA. In the case of Z group, it can be deprotected by a hydrogenation method. Although a catalyst such as palladium carbon or platinum can be used as the hydrogenation catalyst, palladium carbon is preferred. As the reaction solvent, an inert organic solvent which does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), ethers (eg, THF, etc.), amides (eg, DMF, DMAc, etc.), Acetic acid or water is used, preferably methanol. The reaction temperature is usually 0 to 50 ° C,
Preferably it is 10-30 degreeC. The reaction time depends on the raw materials used,
Although it depends on the solvent, the reaction temperature and the like, it is usually 1 hour to 24 hours, preferably 1 hour to 15 hours. To introduce an acetimidoyl group into the deprotected amino group, a commonly used base (inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or trialkylamine, N-methylmorpholine, Pyridine, N, N-
In the presence of an organic base such as dimethylaminopyridine). The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the raw materials, but amides (eg, DMF, DMAc, etc.), esters (eg, ethyl acetate, etc.), ethers (eg, Examples thereof include diethyl ether, dioxane, etc.), and halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), preferably DMF. Reaction temperature is usually -20 ~
The temperature is 50 ° C, preferably -5 to 30 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 15 hours. Further, in the general formula (IV), when E is a cyano group, in another embodiment, a protected guanidinomethyl group,
After conversion to a protected amidinomethyl group, protected aminomethyl group, etc., partial deesterification, or
The general formula (IV) is partially de-esterified and the -AE group is converted into another embodiment such as a protected guanidinomethyl group, a protected amidinomethyl group, a protected aminomethyl group, etc. (XXVIII).
For example, when R ¹⁰ is a tert-butyl group and R ¹³ is converted to a protected amino group, the compound of formula (IV) is hydrogenated, and after introducing a protecting group for the amino group, trifluoroacetic acid ( TFA), a solution of hydrogen chloride in ethyl acetate or dioxane or treatment with zinc bromide. In the case of hydrogenation, a catalyst such as palladium carbon or platinum can be used as a hydrogenation catalyst, but palladium carbon is preferred. As the reaction solvent, an inert organic solvent which does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), ethers (eg, THF, etc.), amides (eg, DMF, DMF, etc.)
Ac), acetic acid or water is used, preferably acetic acid. The reaction temperature is usually 0 to 50 ° C, preferably 10 to 50 ° C.
４０40 ° C. The reaction time varies depending on the starting material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 24 hours.
Preferably, it is 1 hour to 15 hours. Subsequently, when the protecting group for the amino group is a benzyloxycarbonyl group in the introduction of the protecting group, the protecting group can be introduced by reacting with N- (benzyloxycarbonyl) succinimide or benzyl chloroformate in the presence of a base. As the base to be used, commonly used bases (inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, or trialkylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine and the like) Organic base), and is preferably triethylamine. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the starting materials.
F, DMAc, etc.), esters (eg, ethyl acetate, etc.), ethers (eg, diethyl ether, methyl tert-butyl ether, dioxane, etc.), and halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), preferably DMF. is there. Reaction temperature is usually -20 to 50 ° C
And preferably -5 to 30 ° C. Reaction time is usually
It is 5 minutes to 24 hours, preferably 10 minutes to 15 hours.
Further, when trifluoroacetic acid (TFA) is used to remove the tert-butyl ester group, the reaction temperature is preferably -5 to 5 ° C. The reaction time is 1-5 hours.

The compound of the general formula (XXIX) has the general formula (XXVIII)
Can be produced by reacting a carboxylic acid with a hydroxyl group protected or unprotected with a hydroxyl group by a conventional coupling technique. (The protecting group for the hydroxyl group is selected from those known in the art. Examples thereof include an unsubstituted or substituted benzyl group, a trialkylsilyl group, a tert-butyldiphenylsilyl group, a tetrahydropyranyl group, and a tert-butyl group, with a benzyl group being preferred. As the condensing agent to be used, for example, DCC, EDC.HCl, EEDQ,
Examples include HOBT derivatives, HONB derivatives, HOSu derivatives, isobutyloxycarbonyl chloride, monoalkyl ester carbonate derivatives formed by reaction with ethyloxycarbonyl chloride, DPPA, etc., and preferably EDC.HCl. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the raw materials.
And the like, esters (eg, ethyl acetate, etc.), ethers (eg, diethyl ether, dioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and preferably DMF.
The reaction temperature is usually -20 to 20 ° C, preferably -15 to 0
° C. The reaction time is generally 1 hour to 72 hours, preferably 2 hours to 48 hours.

The compound of the general formula (VI) is prepared as follows:
(V) is reacted by a conventional coupling technique (R ¹ , R ² are as defined above, but preferably R ¹ is a tert-butyl group, a benzyl group, a substituted benzyl group, Boc Group, particularly preferably a benzyl group,
R ² is a Boc group or a Z group. ). As the condensing agent used in this reaction, for example, DCC, EDC.HCl, EEDQ, HOBT derivative, HONB derivative, HOSu derivative, isobutyloxycarbonyl chloride, monoalkyl ester carbonate derivative formed by reaction with ethyloxycarbonyl chloride, DPPA And the like, and preferably EDC.HCl. The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the raw materials, but amides (eg, DMF, DMAc, etc.), esters (eg, ethyl acetate, etc.), ethers (eg, Diethyl ether, dioxane, etc.), and halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.). The reaction temperature is usually -20 to 20 ° C, preferably -15 to 0 ° C. The reaction time is generally 1 hour to 24 hours, preferably 2 hours to 15 hours.

The compound of the general formula (I) can be prepared by removing the protecting group for the hydroxyl group and the amino group of the compound of the general formula (VI) or the compound of the general formula (XXIX), or, if desired, by converting R ¹¹ to R ³ , R ¹² to R ⁴ , R ⁹ to R ⁵ , or R ¹³
The obtained by converting the R ^6. When the protecting group for a hydroxyl group is a benzyl group and the protecting group for an amino group or a guanidino group is a Z group or (Cl-Z), they can be simultaneously deprotected by a hydrogenation method. Also, when the protecting group for the hydroxyl group is a benzyl group and R ¹³ is a cyano group, the conversion from R ¹³ to R ⁶ is completed by conversion to an aminomethyl group simultaneously with deprotection of the hydroxyl group. When the benzyl group is removed by the hydrogenation method, a catalyst such as palladium carbon or platinum can be used as the hydrogenation catalyst, but palladium carbon is preferred. As the reaction solvent, an inert organic solvent which does not become a catalyst poison can be used. For example, alcohols (methanol, ethanol, etc.), amides (eg, DM
F, DMAc, etc.), acetic acid or water, preferably methanol. When R ¹³ is a cyano group, acetic acid is preferred. The reaction temperature is usually from 0 to 100 ° C, preferably from 10 to 50 ° C. The reaction time varies depending on the starting materials, solvent, reaction temperature and the like used, but is usually 1 hour to 24 hours, preferably 1 hour to 15 hours.

Subsequently, when converting R ¹³ to R ⁶ , for example, R
^{When 13} is a group containing a protected amino group and R ⁶ is a group containing an acetimidoyl imino group, conversion can be carried out by deprotecting the amino group and reacting with ethylacetimidate. To introduce an acetimidoyl group into the deprotected amino group, a commonly used base (inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or trialkylamine, N-methylmorpholine, Reaction with ethyl acetimidate in the presence of pyridine, an organic base such as N, N-dimethylaminopyridine). The reaction solvent is not particularly limited as long as it does not hinder the progress of the reaction and dissolves the raw materials, but amides (eg, DMF, DMAc, etc.), esters (eg, ethyl acetate, etc.), ethers (eg, Diethyl ether, dioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and preferably DM
F. The reaction temperature is generally -20 to 50C, preferably -5 to 30C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 15 hours.

After completion of the reaction, the reaction product obtained as described above is subjected to a usual isolation and purification method, for example, a method such as extraction with water or an organic solvent, concentration, neutralization, distillation, column chromatography and recrystallization. Can be easily isolated. The resulting compounds may be in the form of their solvates or salts (including acid addition salts), which are derived from pharmaceutically or pharmaceutically or physiologically acceptable acids or bases. It may be. These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, bromic acid, iodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid; Are salts with organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, citric acid, ascorbic acid, lactic acid, p-toluenesulfonic acid, methanesulfonic acid, fumaric acid, tartaric acid and maleic acid; sodium, potassium, Salts with alkali metals or alkaline earth metals such as calcium and magnesium, salts with inorganic bases such as ammonium, organic bases (eg, dialkylamines such as dimethylamine and diethylamine, trialkylamines, Benzylamine, ethanolamine, triethanolamine, morpholine, N-methylmorpholine,
Salt with piperidine). Further, these compounds (I)
Salts with pharmaceutically or physiologically acceptable acids or bases by conventional methods, for example, salts with inorganic acids such as hydrochlorides, sulfates, nitrates, acetates and oxalates depending on the compound,
Salts with organic acids such as succinates and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts can be derived.

Diseases relating to tissue degradation to which the compound obtained by the present invention is applied include osteoarthritis, periodontal disease,
Corneal ulcer, multiple sclerosis, psoriasis, allergic diseases (bronchial asthma, allergic gastroenteritis, allergic rhinitis,
Atopic disease, and allergic conjunctivitis).

The compound (I) and the salt thereof produced as described above are, for example, low irritating to the skin, low toxic, excellent in percutaneous absorption and oral absorption, and have a vertebrate-derived matrix metalloproteinase (MMP). Potently inhibits the activity and / or potently inhibits the activity of tumor necrosis factor-α (TNF-α) -converting enzyme, and is useful for animals, particularly mammals (eg, humans, dogs, rabbits, rats, etc.). The present invention is useful as an inhibitor of matrix metalloproteinases (MMPs) such as a tissue of the present invention and / or an inhibitor of tumor necrosis factor-α (TNF-α) converting enzyme. Thus, the compounds of the invention
(I) and salts thereof are vertebrate-derived MMPs and / or TN
Diseases associated with F-α converting enzyme, such as osteoarthritis,
Prevention of diseases related to tissue degradation such as periodontal disease, corneal ulcer, multiple sclerosis, psoriasis, allergic diseases (bronchial asthma, allergic gastrointestinal tract, allergic rhinitis, atopic disease, and allergic conjunctivitis) Promising as therapeutic agents. In particular, the compound (I) of the present invention and a salt thereof not only have excellent inhibitory activity against MMPs and / or TNF-α converting enzyme, but also have bioavailability in transdermal administration, oral administration and the like (for example, transdermal administration). Skin absorption, oral absorption, etc.), and is easy to apply for prevention and / or treatment of diseases related to tissue degradation and further prevention of further deterioration of symptoms, and is excellent as a medicine.

Among the compounds obtained in the present invention, those containing a phosphono group which may be protected as a functional group thereof are expected to exhibit an activity of inhibiting bone destruction, and are used as agents for preventing and / or treating osteoporosis and the like. And is expected to be used for the prevention and / or treatment of diseases related to bone tissue degradation.

Next, the method for measuring the biological activity of the compound according to the present invention, the dosage form, the dosage and the like will be described. The inhibitory activity of the compound represented by the general formula (I) of the present invention on human fibroblast-derived collagenase (metalloproteinase for tissue destruction) was determined by the method of Y. Murawaki et al. [Journal of Hepatolog
y, 18, p328-334 (1993)] and human fibroblast-derived stromelysin inhibitory activity is tested by the method of SS Twining [Anal. Biochem, 143, p30 (1984)]. The result of this test will be described later as a test example together with its specific measurement method. When used as a medicament, the compound (I) or a salt thereof may be in any dosage form (including inhalation or rectal administration) depending on the purpose, such as oral administration, topical administration, or parenteral administration,
Pharmaceutical compositions or preparations (eg, powders, granules,
Tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions, gel preparations, etc.), each containing at least one compound of the present invention alone. Alternatively, it can be used in admixture with a pharmaceutically acceptable carrier, adjuvant, excipient, excipient and / or diluent. Pharmaceutical compositions can be formulated according to the usual methods.

The solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills and capsules. In such dosage forms, the active ingredient compound may comprise at least one additive, such as sucrose,
Lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein,
It can be mixed with albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also comprise, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid, ascorbic acid, Examples include antioxidants such as α-tocopherol and cysteine, disintegrants, binders, thickeners, buffering agents, sweeteners, flavoring agents, and perfumes. Tablets and pills can also be prepared with enteric coating.

[0113] Typically, tablets and capsules for oral administration are presented in the form of a single dose, and the usual additives shown below can be contained by ordinary means. it can. Tablets are coated according to methods well known in normal pharmaceutical practice. (1) Syrup, acacia, gelatin, sorbitol,
Common excipients as bridging substances such as tragacanth gum or polyvinylpyrrolidone, (2) lactose, sugar, corn starch, calcium phosphate,
Fillers such as sorbitol or glycine; (3) tableted lubricants such as magnesium stearate, talc, polyethylene glycol or silica; (4) disintegrants such as potato starch or acceptable such as sodium lauryl sulfate. A damp chemical that can be used.

The oral liquid preparation may contain, for example, an inert diluent commonly used in the art, for example, water and the like, and typically includes a suspension, solution, emulsion containing water or oil. It can be formed in the form of a liquid, syrup, or elixir, or provided as a dry product for reconstitution with water or other suitable excipients before use. Such liquid formulations include suspensions, such as sorbitol, syrup, methylcellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifiers, such as lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (including edible oils); Oily esters such as, for example, tonsil oil, fractionated coconut oil, glycerin, propylene glycol or ethyl alcohol; preservatives, conventional additives such as, for example, methyl or propyl p-hydroxybenzoate or sorbic acid and, if necessary, conventional additives. Seasonings or coloring agents can also be included.

A single dose for oral administration is about 1 mg to
10 g, preferably about 10 mg to 1 g of the general formula (I)
Containing the compound of Dosage varies depending on the target disease, symptoms, administration target, administration method, etc., and the appropriate daily dose varies greatly depending on the patient's condition.
When administered to mammals, e.g., adults, 0.1 mg / kg body weight.
An oral dose of 01-500 mg, especially 0.1-300 mg / kg body weight, of a compound of general formula (I) is suitable. The dosage for a particular patient will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, drug combination, and the extent of the condition the patient is treating at the time. , Taking into account these and other factors.

Drugs for topical application to the skin can be formulated as solutions or suspensions in suitably sterilized aqueous or non-aqueous vehicles. Additives include, for example, buffers such as sodium bisulfite or disodium edetate; preservatives including bactericidal and antifungal agents such as phenylmercuric acetate or benzalkonium chloride or chlorohexidine; And thickeners. The dosage used for topical dosing depends on the size of the area to be treated, but a single (one eye) dose for the eye is in the range from 0.01 to 100 mg of the compound of general formula (I).

The active ingredients can be administered parenterally using a sterile medium. As used herein, parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Acceptable vehicles or solvents that can be used include:
Water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides.

Suppositories for rectal administration include the drug and appropriate nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at intestinal temperature and melt in the rectum. However, it can be manufactured by mixing with a substance that releases a drug. The drug, depending on the excipient and concentration used, can either be suspended or dissolved in the excipient. Adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle. For use in the treatment of arthritis, such as osteoarthritis and rheumatoid arthritis, the compounds of the invention can be administered by oral administration or by injection into the affected joint. The daily dose for a 70 kg mammal is of the general formula
Compound (I), in the range of 0.001 mg to 6 g. The invention further relates to pharmaceutically acceptable packs (and / or containers or packages) and kits comprising one or more containers filled with one or more of the aforementioned composition components of the invention. Related. Such is, together with the container (s), a notice (document) in the form prescribed by a governmental body regulating the manufacture, use or sale of pharmaceuticals or biological products, It may be accompanied by a notice (package) indicating the approval of the government agency for the manufacture, use or sale of the product for human administration.

[0119]

Next, the present invention will be described in more detail with reference to Examples, that is, Production Examples, Test Examples and Formulation Examples, but the present invention is not limited to these Examples. All examples, except as otherwise described in detail,
It has been or can be implemented using standard techniques, which are well known and routine to those skilled in the art. The following abbreviations are used in the present examples (manufacturing examples and the like) to mean the following. DMF; N, N-dimethylformamide, EDC; 1- (3-
Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, HOBT; 1-hydroxybenzotriazole, TEA;
Triethylamine, THF; tetrahydrofuran, Et;
Ethyl, Boc; tert-butyloxycarbonyl, Bn;
Benzyl, Me; methyl, Cl-Z; 2-chlorobenzyloxycarbonyl, Z: benzyloxycarbonyl, tBu; t
ert-butyl, Tce; 2,2,2-trichloroethyl, Na; sodium

Production Example 1 3 (RS) -tert-butyloxycarbonyl-6-phenyl-2
(R) -Isobutylhexanoic acid (Compound 1) a) Benzyl 2 (R) -bromo-4-methylpentanoate (Compound 1-a) 2 (R) -Bromo-4-methylpentanoic acid (28.5 g, 146 mmo
l), benzyl alcohol (18.1 mL, 175 mmol), and 4-dimethylaminopyridine (1.90 g, 14.6 mmol)
Was dissolved in dichloromethane (140 mL), and E
DC (35.6 g, 175 mmol) was added. After stirring for 1 hour under ice-cooling and further overnight at room temperature, the mixture was separated and washed twice with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline in this order. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the column chromatogram (silica gel; 700
g, eluted with a mixed solvent of n-hexane: AcOEt = 40: 1)
The title compound was obtained as a colorless oil (32.0 g,
77%). Specific rotation [α] _D = +31.8 ^o (c = 1.0, MeO
H), Rf value; 0.48 (AcOEt: n-hexane = 1: 5). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.9 (6H, 2 × d, J = 6.5 H)
z, CH (CH ₃ ) ₂ ), 1.67 (1H, m, (CH ₃ ) ₂ CH ), 1.90 (2
H, m, (CH ₃ ) ₂ CH- CH ₂ ), 4.30 (1H, t, J = 7 Hz, -CH
-Br), 5.2 (2H, s , CH 2 -Ph), 7.32 (5H, s, aromatic -H).

B) Dibenzyl 3 (RS) -tert-butyloxycarbonyl-2 (R) -isobutylsuccinate (Compound 1
-b) Benzyl tert-butyl malonate (24.9 g, 99.6 mmo
l) was dissolved in DMF (60 mL), and potassium tert-butoxide (13.4 g, 120 mmol) was added little by little under stirring at 0 ° C. After stirring at room temperature for 1 hour, the temperature was returned to 0 ° C, and compound 1-a
A solution of (28.4 g, 99.6 mmol) in DMF (60 mL) was added dropwise over 1 hour. After stirring at 5 ° C for 15 hours, AcOEt (2 L) was added,
The mixture was separated and washed twice with a saturated saline solution, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution in this order.
After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the column chromatogram (silica gel; 750 g, n-
The compound was purified by elution with a mixed solvent of hexane: AcOEt = 20: 1) to give the title compound (40.0 g, 89%) as a colorless oil. Specific rotation [α] _D = +16.7 ^o (c = 1.0, MeOH), Rf value;
56 (AcOEt: n-hexane = 1: 5). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.82 (6H, 2 × d, J = 10 Hz,
CH (CH ₃ ) ₂ ), 1.15-1.8 (12H, 2 xs + m, (CH ₃ ) ₂ CH-CH
_{2, + C (CH 3)} 3), 3.2 (1H, m, CH 2 - CH -CO), 3.7 (1H
, M, CO- CH -CO), 5.1 (4H, m, CH 2 -Ph x 2), 7.3
2 (10H, s, aromatic-H).

C) dibenzyl 3 (RS) -tert-butyloxy
Cicarbonyl-3-cinnamyl-2 (R) -isobutylsuccine
(Compound 1-c) Dissolve compound 1-b (9.49 g, 20.9 mmol) in DMF (100 mL).
Then, 60% sodium hydride (1.0 g,
(25.1 mmol) was added in small portions. After stirring at room temperature for 2 hours,
Cool to 0 ° C and cinnamyl bromide (5.35 g, 27.2 mmo
l) was added little by little, and the mixture was stirred at 5 ° C for 15 hours. Decompress the solvent
After evaporation, AcOEt (500 mL) was added, and saturated saline and 1N salt were added.
Acid, saturated aqueous sodium bicarbonate, and saturated saline
Separation washing was performed twice each. Organic layer anhydrous magnesium sulfate
After drying with nesium, the solvent is distilled off under reduced pressure and column chromatography is performed.
Ram (silica gel; 700 g, n-hexane: AcOEt = 20:
(Eluted with the mixed solvent of 1)) to give a colorless oil.
The title compound (10.9 g, 91%) was obtained. Rf value: 0.34 (AcOEt: n-hexane = 1: 9).¹ H-NMR (CDCl_Three) δ ppm; 0.7-1.0 (6H, m, CH(CH ₃ ) ₂ )
 , 1.1-2.1 (12H, m, (CH_Three)_Two CH-CH ₂ , + C(CH ₃ ) ₃ ), 2.8
 (2H, bd, J = 5.4 Hz,CH ₂ -CH = CH), 3.0-3.3 (1H, m
 , CH_Two-CH-CO), 5.0-5.2 (4H, m,CH ₂ -O x 2), 6.1-
6.4 (2H, m, CH _Two-CH = CH), 7.1-7.5 (15H, m, aromatic
-H).

D) 3 (RS) -tert-butyloxycarbonyl-6
-Phenyl-2 (R) -isobutylhexanoic acid (Compound 1) Compound 1-c (4.2 g, 7.36 mmol) in ethanol (35 mL)
And 10% palladium on carbon (50% wet, 1.3 g) was added, followed by vigorous stirring at room temperature for 7 hours while flowing hydrogen.
After the catalyst was filtered off, ethanol was distilled off under reduced pressure, and N-methylmorpholine (0.81 mL, 7.36 mmol) and toluene (50 m
L) was added and refluxed for 2 hours. The reaction solution was separated and washed twice each in the order of 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the column chromatogram (silica gel; 150 g, chloroform: methanol = 200) : 1), and the title compound was obtained as a colorless oil (1.1 g, 43%). Rf value: 0.60 (chloroform: methanol: acetic acid = 95:
5: 3). _{^{1 H-NMR (CDCl 3)}} δppm; 0.88 (6H, bd, J = 5.7 Hz, CH
_{(CH 3) 2), 1.0-2.0} (16H, m, (CH 3) 2 CH-CH 2, + C (CH 3)
_Three + CH ₂ -CH ₂ -CH ₂ -Ph), 2.4-2.8 (4H, m, CH -CO x 2
_{+ CH 2 -Ph), 7.0-7.4 (} 5H, m, aromatic -H).

[0124] Production Example 2 N ^{a-tert-butyloxycarbonyl} -L-4'-cyanophenylalanine methyl ester (Compound 2) N ^{a-tert-butyloxycarbonyl} -L-4'-cyanophenylalanine (0.99 g, 517 mmol ) In dichloromethane (2.
5 L) and stirred at −2 ° C. with methanol (62.8 mL,
1.55 mol), N, N-dimethylaminopyridine (326 mg, 5.
17 mmol) and EDC (109 g, 569 mmol) were added sequentially. After stirring at 0 ° C. for 3 hours and further at room temperature for 12 hours, the solvent was distilled off. AcOEt (2 L) was added, and the mixture was separated and washed twice with 1N hydrochloric acid, saturated saline, a saturated aqueous solution of NaHCO ₃ , and saturated saline in this order. After the organic layer was dried over anhydrous MgSO ₄ , the solvent was distilled off under reduced pressure, and the obtained yellow solid was recrystallized from methyl-tert-butyl ether to give the title compound as a white solid (137 g, 451 mm
ol, yield 87%). Melting point: 104-106 ° C, [α] _D ²⁵ = -8.3 ^o (c = 1.0, MeOH)
. ¹ H-NMR (CDCl ₃ ) δ ppm; 1.40 (9H, s, C (CH ₃ ) ₃ ), 3.03
and 3.20 (1H each, m, CH- CH 2 -C 6 H 4), 3.72 (3H, m
, OCH ₃ ), 4.60 (1H, m, CH), 5.01 (1H, m, NH)
, 7.25 and 7.59 (2H each, m, aromatic-H).

Production Example 3 L-4'-cyanophenylalanine methyl ester monohydrochloride (Compound 3) Compound 2 (137 g, 451 mmol) was added to 4N HCl (AcOEt) under ice-cooling.
Solution, 800 mL) and stirred at room temperature for 1 hour. Et ₂ O (500 mL) was added to the reaction solution (white suspension), and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (quantitative) as white crystals.

[0126] Production Example 4 N ^a - [4-tert- butoxy -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-4'-cyanophenylalanine methyl ester (Compound 4) Compound 3 (108 g, 451 mmol) was added to DMF (1400 mL) -CH ₂ Cl ₂
(700 mL) and stirred at -15 ° C under stirring for Compound 1 (146 g,
418 mmol), HOBt (67.8 g, 502 mmol), EDC (96.1 g
, 502 mmol) and TEA (62 mL, 446 mmol) were added sequentially. After stirring at -15 ° C for 1 hour and at room temperature for 15 hours,
The solvent was distilled off under reduced pressure. AcOEt (2 L) was added, and the mixture was separated and washed twice in the order of a saturated saline solution, 1N hydrochloric acid, a saturated saline solution, a saturated aqueous solution of NaHCO ₃ , and a saturated saline solution. The organic layer was dried over anhydrous MgSO ₄ and the solvent was distilled off under reduced pressure. The resulting reaction mixture was purified by column chromatography (silica gel; 10 kg, eluted with a mixed solvent of chloroform: methanol = 100: 1) to give a white color. The title compound as a solid (109 g, 20
3 mmol, 46%). Melting point: 97-100 ° C, [α] _D ²⁵ = -19.3 ^o (c = 1.0, MeOH)
. ¹ H-NMR (CDCl ₃ ) δ ppm; 0.84 (6H, m, CH (CH ₃ ) ₂ ), 1.
0-1.75 (16H, m, (CH ₂ ) ₂ -CH ₂ -Ph + CH ₂ -CH (CH ₃ ) ₂ + C
(CH ₃ ) ₃ ), 2.2-2.7 (4H, m, CH- CO x 2 + CH ₂ -Ph),
3.07 (2H, m, CH- CH 2 -C 6 H 4), 3.72 (3H, m, OCH 3),
4.92 (1H, m, CH -CH 2 -C 6 H 4), 6.07 (1H, m, NH), 7.
1-7.6 (9H, m, aromatic-H).

[0127] Production Example 5 N ^a - [4-hydroxy -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-4'-cyanophenylalanine methyl ester (Compound 5) Compound 4 (146 g, 272 mmol) was added with ice-cooled 95% trifluoroacetic acid (containing 5% of water, 300 mL), and the mixture was stirred at 5 ° C. for 30 minutes and further at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and Et ₂ O
(100 mL) -N-hexane (600 mL) was added, and the precipitated solid was collected by filtration and dried to give the title compound (118 g, 245 mmol, 90%) as a white solid. Melting point: 166-169 ° C, [α] _D ²⁵ = -16.4 ^o (c = 1.0, MeO
H). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.84 (6H, m, CH (CH ₃ ) ₂ ), 1.
0-1.8 (7H, m, (CH 2) 2 -CH 2 -Ph + CH 2 -CH (CH 3) 2), 2.
41 (1H, m, CH -CO ), 2.58 (3H, m, CH -CO + CH 2 -Ph)
, 3.11 (2H, m, CH- CH 2 -C 6 H 4), 3.73 (3H, m, OCH 3)
, 4.91 (1H, m, CH -CH 2 -C 6 H 4), 6.20 (1H, m, NH),
7.1-7.6 (9H, m, aromatic-H).

[0128]Production Example 6 N^a-[4- (N-benzyloxyamino) -2 (R) -isobutyl-
3 (S)-(3-Phenylpropyl) succinyl] -L-4'-sia
Nophenylalanine methyl ester (Compound 6) Compound 5 (118 g, 245 mmol) was dissolved in DMF (700 mL).
After cooling to 15 ° C, HOBt (39.6 g, 293 mmol), O-benzyl
Hydroxylamine hydrochloride (58.4 g, 366 mmol), EDC
(56.1 g, 293 mmol) and TEA (51 mL, 366 mmol).
Added in order. After stirring at room temperature for 15 hours, additional HOBt (16.5
 g, 122 mmol), O-benzylhydroxylamine hydrochloride
 (19.5 g, 122 mmol), EDC (23.4 g, 122 mmol) and
And TEA (17 mL, 122 mmol) in that order, and add 3 hours at room temperature.
Stirred. The reaction solution is dropped into water (7 L) while stirring.
The precipitated white crystals were collected by filtration, water, 1N hydrochloric acid, water, 10%
Na _TwoCO_ThreeWashing was performed twice each in the order of an aqueous solution and water. Profit
The obtained crystals were dried under reduced pressure in the presence of diphosphorus pentoxide to give white crystals.
The title compound (126 g, 216 mmol, 88%) was obtained. Melting point: 195-206 ° C, [α]_D ^{twenty five}= +11.1^o(c = 1.0, MeOH)
 .¹ H-NMR (CDCl_Three) δppm; 0.82 (6H, m, CH(CH ₃ ) ₂ ), 1.
0-1.6 (7H, m,(CH ₂ ) ₂ -CH_Two-Ph +CH ₂ -CH(CH_Three)_Two), 2.
12 (1H, m,CH-CO), 2.43 (3H, m,CH-CO +CH ₂ -Ph)
 , 3.04 (2H, m, CH-CH ₂ -C₆H_Four), 3.69 (3H, m, OCH_Three)
 , 4.85 (1H, m,CH-CH_Two-C₆H_Four), 4.90 (2H, s, O-CH ₂ -
Ph), 6.37 (1H, m, NH), 7.0-7.6 (14H, m, aromatic
-H).

[0129] Production Example 7 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminomethylphenylalanine methyl ester monoacetate (Compound 7) Compound 6 (41.9 g, 71.7 mmol) was dissolved in acetic acid (700 mL) and 5% palladium After addition of carbon (50% wet, 20 g), the mixture was vigorously stirred at 35 ° C. for 1 hour while flowing hydrogen, and further at room temperature for 2 hours. After filtering off the catalyst, acetic acid was distilled off under reduced pressure, and AcOEt (180 mL) -Et ₂ O (360 mL) was added to the obtained residue. The precipitated crystals were collected by filtration and dried under reduced pressure. This crude product was analyzed by reversed-phase column chromatography (Fuji Silysia Chemical Chromatorex O
DS-1020T; 2.5 kg, eluted with 10% to 15% methanol / 0.1% acetic acid aqueous solution) and lyophilized to give the title compound as a white solid (23.7 g, 44.4 mmol, 62
%). Melting point: 194-197 ° C, [α] _D ²⁵ = −9.82 ^o (c = 1.0, MeO
H). ¹ H-NMR (CD ₃ OD) δ ppm; 0.85 (6H, m, CH (CH ₃ ) ₂ ), 1.
_{01 (2H, m, CH 2} -CH (CH 3) 2), 1.3-1.6 (5H, m, (C
H ₂ ) ₂ -CH ₂ -Ph + CH ₂ -CH (CH ₃ ) ₂ ), 1.95 (3H, s, CH ₃ CO ₂
H), 2.08 (1H, m, CH- CO), 2.2-2.5 (3H, m, CH- C
O + CH ₂ -Ph), 2.91and 3.16 (1H each, m, CH- CH ₂ -C _{6
H 4), 3.66 (3H,} m, OCH 3), 3.99 (2H, s, CH 2 -NH 2),
4.73 (1H, m, CH -CH 2 -C 6 H 4), 7.05-7.4 (9H, m, aromatic -H).

[0130] Production Example 8 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminomethylphenylalanine monohydrochloride (Compound 8) Compound 7 (16 g, 28.7 mmol) was suspended in methanol (150 mL) and stirred with 1N NaOH Aqueous solution (115 mL) at 0 ° C
Was dropped. After stirring at room temperature for 1 hour, the mixture was neutralized with 6N hydrochloric acid and methanol was distilled off under reduced pressure. The obtained solution was subjected to reverse phase column chromatography (Fuji Silysia Chemical Chromatorex ODS-1020).
T; 900 g, eluted with 0% to 30% methanol / 0.1% hydrochloric acid aqueous solution), followed by lyophilization to give the title compound (10.8 g, 20.7 mmol, 72%) as a white solid. _{Mp; 156 ℃, [α] D} 25 = -3.4 o (c = 1.0, MeOH). _{^{1 H-NMR (CD 3 OD}} ) δppm; 0.86 (6H, m, CH (CH 3) 2), 1.
_{00 (2H, m, CH 2} -CH (CH 3) 2), 1.2-1.6 (5H, m, (C
H ₂ ) ₂ -CH ₂ -Ph + CH ₂ -CH (CH ₃ ) ₂ ), 2.09 (1H, m, CH -CO
), 2.2-2.6 (3H, m, CH -CO + CH 2 -Ph), 2.92 and
3.19 (1H each, m, CH- CH 2 -C 6 H 4), 3.98 (2H, s, CH 2
_{-NH 2), 4.71 (1H,} m, CH -CH 2 -C 6 H 4), 7.0-7.5 (9H, m
, Aromatic-H).

[0131] Production Example 9 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-acetimidoyliminomethylphenylalanine methyl ester monohydrochloride (Compound 9) Compound 7 (500 mg, 0.9 mmol) was dissolved in DMF (10 mL).
After cooling to 0 ° C., TEA (263 μL, 1.89 mmol) and ethylacetimidate hydrochloride (126 mg, 0.99 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Add 1N hydrochloric acid to the reaction solution and adjust the pH.
Was adjusted to 1 and the solvent was distilled off under reduced pressure. The obtained residue was subjected to reverse phase column chromatography (Fuji Silysia Chemical Chromatorex).
Purification using ODS-1020T; 25 g, eluted with 0% to 25% methanol) and lyophilization gave the title compound as a white solid (336 mg, 0.585 mmol, 65%). Melting point: 136-139 ° C, [α] _D ²⁵ = -10.3 ^o (c = 1.0, MeO
H). ¹ H-NMR (CD ₃ OD) δ ppm; 0.85 (6H, m, CH (CH ₃ ) ₂ ), 1.
_{0 (2H, m, CH 2} -CH (CH 3) 2), 1.3-1.6 (5H, m, (CH 2) 2
-CH ₂ -Ph + CH ₂ -CH (CH ₃ ) ₂ ), 2.10 (1H, m, CH- CO),
2.16 (3H, s, C- CH 3), 2.3-2.6 (3H, m, CH -CO + CH
_{2 -Ph), 2.92 and3.15 (1H} each, m, CH- CH 2 -C 6 H 4),
_{3.67 (3H, m, OCH 3} ), 4.36 (2H, s, C 6 H 4 - CH 2 -NH),
4.70 (1H, m, CH -CH 2 -C 6 H 4), 7.0-7.4 (9H, m, aromatic -H).

[0132] Production Example 10 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-acetimidoyliminomethylphenylalanine monoacetate (Compound 10) Compound 8 (500 mg, 0.9 mmol) was dissolved in DMF (10 mL).
After cooling to 0 ° C., TEA (470 μL, 3.36 mmol) and ethylacetoimidate hydrochloride (180 mg, 1.44 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to reverse phase column chromatography (Fuji Silysia Chemical Ltd.).
Chromatorex ODS-1020T; 50 g, 0% to 25% methanol
/ Elution with 0.1% acetic acid aqueous solution) and freeze-dried to give the title compound as a white solid (200 mg, 0.35 m
mol, 37%). ¹ H-NMR (CD ₃ OD) δ ppm; 0.85 (6H, m, CH (CH ₃ ) ₂ ), 1.
_{0 (2H, m, CH 2} -CH (CH 3) 2), 1.3-1.6 (5H, m, (CH 2) 2
-CH ₂ -Ph + CH ₂ -CH (CH ₃ ) ₂ ), 1.90 (3H, s, CH ₃ CO ₂ H),
2.10 (1H, m, CH -CO ), 2.15 (3H, s, C- CH 3), 2.3-
2.6 (3H, m, CH -CO + CH 2 -Ph), 2.93 and 3.18 (1H
_{each, m, CH- CH 2 -C} 6 H 4), 4.35 (2H, s, C 6 H 4 - CH 2 -N
H), 4.68 (1H, m , CH -CH 2 -C 6 H 4), 7.0-7.4 (9H, m,
Aromatic-H).

[0133] Production Example 11 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminomethylphenylalanine (Compound 11) Compound 8 (20 g, 38.5 mmol) was dissolved in 2N sodium hydroxide (48 ml), and 2N hydrochloric acid was added while cooling with ice. Was added dropwise to adjust the pH to 7. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (17.3) as a colorless solid.
g, 35.8 mmol, 93%). Melting point: 180-193 ° C, [α] _D ²⁵ = + 22.3 ⁰ (c = 1.0, 0.1N
NaOH), ¹ H-NMR (D ₂ O + NaOD) δ ppm; 0.82 (3H, d, J =
6.2 Hz), 0.85 (3H, d, J = 6.4 Hz), 1.04 (1H, m), 1.1
-1.5 (5H, m), 2.01 (1H, m), 2.2-2.5 (3H, m), 2.82
(1H, dd, J = 10.1 and 14.1 Hz), 3.11 (1H, dd, J = 4.3
and 14.1 Hz), 3.67 (2H, s), 4.50 (1H, dd, J = 4.3 an
d 10.1 Hz), 7.1-7.4 (9H, m).

[0134] Production Example 12 N ^a - [4-tert- butoxy -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-4 '- (benzyloxycarbonylaminomethyl) phenylalanine Methyl ester (Compound 12) Compound 4 (20 g, 37.4 mmol) was dissolved in acetic acid (300 ml), and 5% palladium on carbon (50% wet, 10 g) was added. And vigorously stirred at room temperature for 2 hours. After the catalyst was removed by filtration, acetic acid was distilled off under reduced pressure, and toluene was added to the residue obtained, followed by distillation under reduced pressure again. The obtained colorless oil was dissolved in DMF (200 ml), and neutralized by adding triethylamine.N- (benzyloxycarbonyloxy)
Succinimide (7.44 g, 29.9 mmol) and triethylamine (4.16 ml) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was diluted with ethyl acetate, it was washed successively with saturated saline, 1N hydrochloric acid, saturated saline, saturated sodium hydrogen carbonate, and saturated saline. After drying the organic layer over anhydrous magnesium sulfate,
The title compound (23.8) was obtained as a pale yellow oil by concentration under reduced pressure.
g, 35.4 mmol, 95%). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.83 (6H, d, J = 6.5 Hz),
1.03 (1H, m), 1.2-1.8 (15H, m), 2.30 (1H, m), 2.4-
2.7 (3H, m), 3.04 (2H, m), 3.71 (3H, s), 4.33 (2H,
d, J = 5.88 Hz), 4.91 (1H, m), 5.01 (1H, m), 5.12 (2
H, s), 5.97 (1H, d, J = 8.08 Hz), 7.0-7.4 (14H, m).

[0135] Production Example 13 N ^a - [4- hydroxy -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-4 '- (benzyloxycarbonylaminomethyl) phenylalanine methyl ester (Compound 13) To compound 12 (15 g, 17.7 mmol) was added ice-cooled 95% trifluoroacetic acid (containing 5% water, 100 ml), and the mixture was stirred at 5 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was treated with ethyl acetate (400
ml), washed successively with saturated sodium hydrogen carbonate solution, saturated saline, 1N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. Et ₂ O in the residue
(100 ml), and the precipitated crystals were collected by filtration and dried to give the title compound (12.9 g, 16.3 mmol, 92%) as a white solid.
%). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.83 (6H, d, J = 6.4 Hz),
1.11 (1H, m), 1.3-1.8 (6H, m), 2.39 (1H, m), 2.45-
2.7 (3H, m), 3.06 (2H, m), 3.73 (3H, s), 4.30 (2H,
d, J = 5.88 Hz), 4.87 (1H, m), 5.0-5.2 (3H, s + m),
6.15 (1H, d, J = 7.71 Hz), 6.95-7.5 (14H, m).

[0136] Production Example 14 N ^a - [4- (N- benzyloxyamino) -2 (R) - isobutyl -
3 (S)-(3-Phenylpropyl) succinyl] -L-4 '-(benzyloxycarbonylaminomethyl) phenylalanine methyl ester (Compound 14) Using compound 13, the same operation as in Production Example 6 was carried out to give a white solid. Compound (85%) was obtained. ¹ H-NMR (CDCl ₃ ) δppm; 0.86 (6H, m), 1.0-1.6 (7H, m),
2.16 (1H, m), 2.45-2.7 (3H, m), 3.01 (2H, m), 3.70 (3
H, s), 4.34 (2H, d, J = 5.9 Hz), 4.82 (1H, m), 4.95-5.
25 (5H, s + m), 6.41 (1H, d, J = 7.8 Hz), 7.0-7.5 (20H,
m).

[0137] Production Example 15 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminomethylphenylalanine methyl ester monoacetate (Compound 7) Compound 14 (50 g, 69.3 mmol) in methanol (750 ml)
And 5% palladium on carbon (50%
(20 g) was stirred vigorously at 35 ° C. for 1 hour while flowing hydrogen, and further at room temperature for 1 hour. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue obtained was AcOEt (200 ml)-
Et ₂ O (400 ml) was added, and the precipitated crystals were collected by filtration and dried under reduced pressure. Reverse-phase column chromatogram (Fuji Silysia Chemical Chromatorex ODS-1020T; 3.0 kg, 10%
After purification using 15% methanol / 0.1% acetic acid aqueous solution) and freeze-drying, the title compound (8
0%).

[0138] Production Example 16 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-aminomethylphenylalanine isopropyl ester monoacetate (Compound 16) Production Example 4 using L-4'-cyanophenylalanine isopropyl ester monohydrochloride and Compound 1 , 5, 6, and 7 were performed to give the title compound as a white solid. ¹ H-NMR (MeOH-d ₄ ) δppm; 0.86 (6H, m), 1.02 (1H, m),
1.3-1.6 (12H, m), 1.96 (3H, s), 2.12 (1H, m), 2.2-2.5
(3H, m), 2.96 (2H, m), 3.98 (2H, s), 4.75 (1H, m), 5.
01 (1H, m), 7.1-7.4 (9H, m).

[0139]Production Example 17 N^a-[4- (N-hydroxyamino) -2 (R) -isobutyl-3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-amino
Tylphenylalanine n-butyl ester monoacetate
(Compound 17) L-4′-cyanophenylalanine n-butyl ester · 1
As in Production Examples 4, 5, 6, and 7 using hydrochloride and compound 1
Was performed to obtain the title compound as a white solid. ¹H-NMR (M
eOH-d_Four) δppm; 0.84 (6H, m), 0.95-1.1 (4H, m), 1.3-1.
6 (10H, m), 1.95 (3H, s), 2.14 (1H, m), 2.2-2.5 (3H,
m), 2.90 (2H, m), 3.99 (2H, m), 4.08 (2H, s), 4.80 (1
H, m), 5.12 (1H, m), 7.1-7.5 (9H, m).

[0140] Production Example 18 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-guanidinophenylalanine methyl ester · 1 acetate (Compound 18) Compound 1 and L-4 '-[N, N'-bis (benzyloxycarbonyl) guanidino] phenylalanine The same procedure as in Production Examples 4, 5, 6, and 7 was carried out using methyl ester hydrochloride to obtain the title compound as pale yellow crystals. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.83 (3H, d, J = 6.2 Hz),
0.86 (3H, d, J = 6.2 Hz), 1.08 (1H, m), 1.2-1.6 (6H,
m), 1.89 (3H, s), 2.05 (1H, m), 2.2-2.5 (3H, m),
2.96 (2H, m), 3.70 (3H, s), 4.46 (1H, dd, J = 4.3 Hz
and 10.1 Hz), 6.8-7.5 (9H, m).

[0141] Production Example 19 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-guanidinophenylalanine monohydrochloride (Compound 19) The same operation as in Production Example 8 was carried out using Compound 18 to obtain the title compound as a pale yellow solid. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.82 (3H, d, J = 6.1 Hz),
0.87 (3H, d, J = 6.1 Hz), 1.10 (1H, m), 1.24 (2H,
m), 1.4-1.6 (4H, m), 2.10 (1H, m), 2.2-2.5 (3H,
m), 3.01 (2H, m), 4.58 (1H, dd, J = 4.3 Hz and 10.1
Hz), 6.9-7.6 (9H, m).

[0142] Production Example 20 N ^a - [4- hydroxy -2 (R) - isobutyl -3 (S) - (3- phenylpropyl) succinyl] -L-4 '- [N , N'- bis (benzyloxy Carbonyl) guanidinomethyl] phenylalanine methyl ester (Compound 20) Compound 5 (30 g, 62.7 mmol) was dissolved in acetic acid (450 ml), and 5% palladium on carbon (50% wet, 15 g) was added.
The mixture was vigorously stirred at 35 ° C. for 3 hours while flowing hydrogen. After removing the catalyst by filtration, acetic acid was distilled off under reduced pressure, and the residue obtained was AcOEt (30 m
l) -Et ₂ O (120 ml) was added, and the precipitated crystals were collected by filtration and dried under reduced pressure. This crude product was dissolved in DMF (150 ml), and triethylamine (18.3 ml, 132 mmol) and 1H-pyrazole-N, N'-bis (benzyloxycarbonyl) carboxamidine (25.4 g, 62.7 mmol) were added at 0 ° C. The mixture was added and stirred overnight while returning to room temperature. Ethyl acetate (300 ml)
After washing with 1N hydrochloric acid, 5% sodium bicarbonate and saturated saline in this order, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure, the title compound (45.6
g, 57.6 mmol, 92%). ¹ H-NMR (CDCl ₃ ) δ ppm; 0.80 (3H, d, J = 6.3 Hz), 0.
84 (3H, d, J = 6.3 Hz), 1.05 (1H, m), 1.1-1.5 (6H,
m), 2.15 (1H, m), 2.3-2.7 (3H, m), 3.04 (2H, m), 3.
73 (3H, s), 4.35 (2H, m), 4.50 (1H, m), 5.03 (2H,
s), 5.19 (2H, s), 6.42 (1H, m), 6.8-7.5 (20H, m),
7.81 (1H, m).

[0143] Production Example 21 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-guanidinomethylphenylalanine methyl ester monoacetate (Compound 21) The same operation as in Production Examples 6 and 7 was carried out using Compound 20 to give the title compound as pale yellow crystals. Obtained. ¹ H-NMR (DMSO-d ₆ ) δ ppm; 0.52 (3H, d, J = 6.4 Hz),
0.69 (3H, d, J = 6.4 Hz), 1.05-1.55 (7H, m), 1.70 (3
H, s), 2.04 (1H, m), 2.2-2.6 (3H, m), 2.9-3.0 (2H,
m), 3.70 (3H, s), 4.10 (2H, m), 4.50 (1H, m), 6.8
-7.5 (9H, m).

[0144] Production Example 22 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
-(3-Phenylpropyl) succinyl] -L-4'-guanidinomethylphenylalanine monohydrochloride (Compound 22) The same operation as in Production Example 8 was performed using Compound 21 to obtain the title compound as a colorless solid. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.81 (3H, d, J = 6.1 Hz),
0.85 (3H, d, J = 6.1 Hz), 1.08 (1H, m), 1.28 (2H,
m), 1.4-1.6 (4H, m), 2.06 (1H, m), 2.2-2.5 (3H,
m), 3.06 (2H, m), 4.12 (2H, s), 4.58 (1H, m), 6.9-
7.6 (9H, m).

[0145] Production Example 23 N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-aminomethyl phenylalanine
Methyl ester monoacetate (compound 23) 3 (S) -tert-butyloxycarbonyl-2 (R) -isobutyl-5
-Production example 4, using methylhexanoic acid and compound 3,
The same operation as in 5, 6, and 7 was performed to obtain the title compound as white crystals. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.7-0.9 (12H, m), 1.0-1.
1 (2H, m), 1.3-1.6 (4H, m), 1.94 (3H, s), 2.31 (1
H, m), 2.52 (1H, m), 3.06 (2H, m), 3.70 (3H, s), 4.
37 (2H, s), 4.58 (1H, m), 7.28 (4H, m).

[0146] Production Example 24 N ^a - [4- (N- hydroxyamino) -2 (R) 3 (S ) - diisobutyl succinyl] -L-4'-aminomethyl phenylalanine
Hydrochloride (Compound 24) The same operation as in Production Example 8 was carried out using Compound 23 to obtain the title compound as white crystals. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.6-0.9 (12H, m), 1.0-1.
2 (2H, m), 1.4-1.6 (4H, m), 2.4-2.6 (2H, m), 3.05
(2H, m), 4.36 (2H, s), 4.52 (1H, m), 6.9-7.5 (4H,
m).

[0147] Production Example 25 N ^a - [4- (N- hydroxyamino) -2 (R) - isobutyl -3 (S)
Methylsuccinyl] -L-4'-aminomethylphenylalanine methyl ester monoacetate (compound 25) 2 (R)-[1 (S)-(tert-butyloxycarbonyl) ethyl] -4-methylpentanoic acid and compound 3 The same operation as in Production Examples 4, 5, 6, and 7 was carried out to obtain the title compound as a pale yellow solid. ¹ H-NMR (MeOH-d ₄ ) δ ppm; 0.7-0.9 (6H, m), 0.94 (3
H, d, J = 7.0 Hz), 1.01 (1H, m), 1.2-1.5 (2H, m), 1.8
1 (3H, s), 2.15 (1H, m), 2.48 (1H, m), 3.09 (2H,
m), 3.71 (3H, s), 4.32 (2H, s), 4.55 (1H, m), 7.4-
7.7 (4H, m).

[0148]Production Example 26 N^a-[4- (N-hydroxyamino) -2 (R) -isobutyl-3 (S)
 Methylsuccinyl] -L-4'-aminomethylphenylara
Nin monohydrochloride (Compound 26) Using Compound 25, the same operation as in Production Example 8 was performed to give white crystals.
The title compound was obtained. ¹ H-NMR (MeOH-d_Four) δ ppm; 0.7-0.9 (6H, m), 0.95 (3
H, d, J = 7.1 Hz), 1.04 (1H, m), 1.2-1.5 (2H, m), 2.2
1 (1H, m), 2.53 (1H, m), 2.9-3.1 (2H, m), 4.30 (2
H, s), 4.58 (1H, m), 7.17 and 7.29 (2H each, m).

[0149] Production Example 27 N ^a - [4- (N- hydroxyamino) - 2 (R) - isobutyl succinyl] - L-4'-aminomethyl phenylalanine methyl ester 1 acetate (Compound 27) 2 (R) - Production Examples 4, 5, and 5 using (tert-butyloxycarbonyl) methyl-4-methylpentanoic acid and Compound 3
The same operation as in 6, 7 was performed to obtain the title compound as a pale yellow oil. ¹ H-NMR (MeOH-d ₄ ) δppm; 0.83 (6H, m), 1.05 (1H, m),
1.2-1.5 (2H, m), 1.81 (3H, s), 2.15 (1H, m), 2.4-2.5
(2H, m), 3.10 (2H, m), 3.72 (3H, s), 4.28 (2H, s), 4.
60 (1H, m), 7.4-7.7 (4H, m).

[0150]Production Example 28 N^a-[4- (N-hydroxyamino) -2 (R)-isobutylsac
Cynyl] -L-4'-aminomethylphenylalanine monohydrochloride
Salt (Compound 28) Using compound 27, perform the same operation as in Production Example 8 to give white crystals.
The title compound was obtained. ¹ H-NMR (MeOH-d_Four) δppm; 0.7-0.8 (6H, m), 1.10 (1H,
m), 1.42 (2H, m), 2.10 (1H, m), 2.4-2.5 (2H, m), 3.07
(2H, m), 4.22 (2H, s), 4.68 (1H, m), 7.4-7.7 (4H, m)
 .

Production Example 29 N-tert-butyloxycarbonyl-L-4 '-(benzyloxycarbonylaminomethyl) phenylalanine methyl ester (Compound 29) Compound 2 (30 g, 98.6 mmol) was dissolved in acetic acid (300 ml). 5%
After adding palladium carbon (50% wet, 10 g), the mixture was vigorously stirred at room temperature for 2 hours while flowing hydrogen. After filtering off the catalyst, acetic acid was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (200 ml). The diluted solution was washed with cooled saturated aqueous NaHCO ₃ (until pH = 8-9) and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was diluted with DMF (250
n- (Benzyloxycarbonyloxy) succinimide (21.8 g, 87.7 mmol) was added thereto with stirring, and the mixture was reacted at room temperature for 16 hours. The reaction solution was treated with ethyl acetate (500 m
l) diluted with 1N hydrochloric acid, saturated saline, saturated NaHCO ₃ aqueous solution, washed with saturated saline in this order, dried over anhydrous magnesium sulfate,
The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; 2 L, eluted with a mixed solvent of n-hexane: ethyl acetate = 2: 1) to give the title compound (31.4 g, 72%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm; 1.41 (9H, s), 2.95-3.15 (2H,
m), 3.71 (3H, s), 4.36 (2H, d, J = 5.9 Hz), 4.57 (1H, m),
4.95 (1H, brd, J = 7.9 Hz), 5.03 (1H, m), 5.14 (2H, s),
7.07 (2H, m), 7.21 (2H, m), 7.3-7.4 (5H, m).

[0152] Production Example 30 N ^a - [4-tert- butoxy -2 (R) - isobutyl - 3 (S) - (3- phenylpropyl) succinyl] -L-4 '- (benzyloxycarbonylaminomethyl) phenylalanine Methyl ester (Compound 12) Compound 29 (50 g, 113 mmol) was treated in the same manner as in Production Example 3 to give L-
4 '-(benzyloxycarbonylaminomethyl) phenylalanine methyl ester monohydrochloride was quantitatively obtained.
Subsequently, the compound 1 (39.4 g, 113 mmol) and L-4 ′-(benzyloxycarbonylaminomethyl) phenylalanine methyl ester monohydrochloride were reacted in the same manner as in Production Example 4 to give the title compound as a pale yellow oil (69.9%). g, 92%).

Test Example 1 Measurement of Collagenase Inhibitory Activity Collagenase inhibitory activity of the compound of the present invention obtained from human fibroblasts was determined by the method of Y. Murawaki et al. [Journal of Hepa
tology, 18, p.328-334 (1993)]. Procollagenase was activated by incubation at 35 ° C. with 2 mM mercury aminophenylacetate for 2 hours.
Inhibitory activity was measured using fluorescein-labeled bovine type I collagen as a substrate. Activated collagenase was added to a solution of substrate (0.5 mg / ml) in 50 mM Tris-HCl buffer pH 7.5 containing 0.4 M sodium chloride, 10 mM calcium chloride. The resulting solution was incubated at 35 ° C. for 2 hours. 80 Enzymatic digestion of substrate
Stopped by the addition of mM o-phenanthroline, 25 μg /
A solution prepared by dissolving ml porcine pancreatic elastase in the above-mentioned Tris-HCl buffer was added, and the mixture was incubated at 37 ° C for 10 minutes. 70% ethanol, 0.67 M in the resulting solution
170 mM Tris-HCl buffer with sodium chloride, pH 9.5
Was added and the undigested substrate was precipitated by centrifugation at 3000 g for 20 minutes. The supernatant was collected, and the fluorescence intensity at an excitation wavelength of 495 nm and a measurement wavelength of 520 nm was measured to determine the inhibitory activity. IC ₅₀ is the concentration of the compound assayed at the digestive enzyme that reduces the cleavage of the substrate by 50% the cleavage achieved by the enzyme alone. The compounds of the present invention showed inhibitory activity (Table 1).

[0154]

[Table 1]

Test Example 2 Measurement of stromelysin inhibitory activity The stromelysin inhibitory activity of the compounds of the present invention obtained from human fibroblasts was determined by the twining method [Analytical Biochem. 143, p30 (198)
4)]. Prostromelysin at 37 ° C for 20
After incubation with μg / ml human plasmin for 2 hours, a 2.8 mg / ml diisopropylfluorophosphate solution was added to stop the reaction and activate. Inhibitory activity was measured using fluorescein-labeled casein as a substrate.
50 mM Tris-HCl buffer containing 10 mM calcium chloride, pH
Activated stromelysin was added to a solution of substrate (1 mg / ml) in 7.8. The resulting solution was incubated at 37 ° C. for 2 hours. Stop enzymatic digestion of substrate by adding 5% trichloroacetic acid and remove undigested substrate by 3000 g
And centrifuged for 20 minutes. Collect the supernatant, add 0.5 M Tris-HCl buffer pH 8.5, and excite
The inhibitory activity was determined by measuring the fluorescence intensity at 495 nm and a measurement wavelength of 520 nm. IC ₅₀ is the concentration of the compound assayed at the digestive enzyme that reduces the cleavage of the substrate by 50% the cleavage achieved by the enzyme alone. The compounds of the present invention showed inhibitory activity (Table 2).

[0156]

[Table 2]

Test Example 3 Measurement of TNF-α Production Inhibitory Effect Human monocyte leukemia cell line U937 [37% using RPMI1640 (Nissui Pharmaceutical) supplemented with 5% fetal bovine serum (Immunobiological Laboratories)
After culturing in a 5% CO ₂ incubator at 1 ° C, 1 × 10 ⁶ cells / 1 ml is dispensed into each well of the multiwell plate,
-myristate 13-acetate (Wako Pure Chemical Industries) was cultured overnight in the presence of 10 ^-7 M to differentiate into macrophage-like cells.] E. coli O127: Lipopolysaccaride (Sigma) derived from B8 strain
Add 1 μg / ml alone or simultaneously with the compound of the present invention, and culture at 37 ° C. in a 5% CO ₂ incubator for 6 hours. After completion of the culture, the medium is collected, centrifuged at 3000 rpm for 10 minutes, and the supernatant is diluted with purified water.TNF-α measurement kit (Genzyme)
Measure using

Test Example 4 Acute toxicity test The compound of the present invention is dissolved in distilled water for injection at a concentration of 10 mg / ml. This solution is injected at 10 mg / kg through the tail vein of the mouse, and the condition of the mouse is observed for 8 days.

Next, the general formula provided by the present invention
1 shows a pharmaceutical preparation containing the compound of (I).

Formulation Example 1 (Ointment) An ointment containing the following components could be produced by a conventional method. A; ingredient dose white petrolatum 93 g liquid paraffin 5 g compound 7 2 g total 100 g B; ingredient dose white petrolatum 94 g purified lanolin 5 g compound 8 1 g total 100 g C; ingredient dose white petrolatum 96 g compound 114 g 100 g total

Formulation Example 2 (Eye drops) An eye drop containing the following ingredients could be produced by a conventional method. A; Ingredient Dose compound 7 2 g Sodium chloride 0.33 g Sterilized purified water qs 100 ml B; Ingredient Dose compound 8 5 g Sodium chloride 0.26 g Sodium dihydrogen phosphate 0.56 g Sodium monohydrogen phosphate 0.28 g 0.002% chloride Benzalkonium solution qs 100 ml C; ingredient dose compound 7 1 g sodium chloride 0.33 g anhydrous sodium sulfite 0.10 g sterile purified water qs 100 ml D; ingredient dose compound 8 1 g sodium chloride 0.33 g sterile purified water qs 100 ml

Formulation Example 3 (Injection) An injection containing the following components could be produced by a conventional method. A; Ingredient Dose Compound 7 1 g Distilled water for injection qs 100 ml B; Ingredient Dose Compound 8 2 g Sodium chloride 0.9 g Distilled water for injection qs 100 ml C; Ingredient Dose Compound 9 1 g Sodium dihydrogen phosphate anhydrous 28 mg anhydrous disodium hydrogen phosphate 167 mg sodium chloride 0.9 g distilled water for injection qs 100 ml

Formulation Example 4 (Tablets) Tablets containing the following ingredients could be produced by a conventional method. A; Content of one component tablet 11 Compound 100 mg Lactose 98 mg Corn starch 46 mg Hydroxypropylcellulose 2 mg Magnesium stearate 4 mg Total 250 mg B; Content of one component tablet 7 Compound 50 mg Lactose 120 mg Corn starch 15 mg Hydroxy Propyl cellulose 4 mg Carboxymethyl cellulose calcium 10 mg Magnesium stearate 1 mg Total amount 200 mg

Formulation Example 5 (Granules) A granule containing the following components could be produced by a conventional method. Ingredients Dose Compound 8 2 g Lactose 1.85 g Corn starch 1.1 g Hydroxypropylcellulose 50 mg Total 5 g Formulation Example 6 (Capsules) Capsules containing the following ingredients could be manufactured by a conventional method. Ingredient Dose Compound 11 100 mg Lactose 35 mg Corn starch 60 mg Magnesium stearate 5 mg Total amount 200 mg

The following symbols have the following meanings in the present specification and claims, respectively.

Embedded image

[0166]

The compound provided by the present invention, for example, the compound of the general formula (I) exhibits metalloproteinase inhibitory activity and has excellent inhibitory activity against MMPs and / or TNF-α converting enzyme, In addition, bioavailability is dramatically improved as compared with conventional compounds. Therefore, these compounds, when applied to diseases related to tissue degradation,
An excellent effect is obtained, and a therapeutic and / or preventive effect can be expected. Obviously, the present invention can be practiced other than as specifically described in the foregoing description and examples. Many modifications and variations of the present invention are possible in light of the above teachings, and so are within the scope of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 1/02 A61P 1/02 11/06 11/06 17/06 17/06 19/02 19/02 25 / 00 101 25/00 101 27/02 27/02 27/16 27/16 37/00 37/00 43/00 105 43/00 105 111 111 C07C 239/20 C07C 239/20 251/06 251/06 257 / 14 257/14 317/04 317/04 (72) Inventor Moto Ito 530 Chokeiji, Takaoka City, Toyama Prefecture Inside Fuji Pharmaceutical Co., Ltd. (72) Inventor Junko Yasuda 530 Chokeiji Temple, Takaoka City, Toyama Prefecture Fuji Pharma Co. Inside (72) Inventor Miwa Otani 530 Chokeiji Temple, Takaoka City, Toyama Prefecture Inside Fuji Pharmaceutical Co., Ltd. (72) Inventor Tadanori Morikawa 530 Chokeiji Temple, Takaoka City, Toyama Prefecture F-term (reference) 4C206 AA01 AA02 AA03 AA04 GA13 GA37 HA10 HA16 HA31 NA05 NA11 ZA02 ZA33 ZA34 ZA59 ZA66 ZA67 ZA89 ZA96 ZB13 ZC20 ZC61 4H006 AA01 AA02 AB20 TA02

Claims (21)

[Claims] (1) The following general formula (I): Wherein R ¹ is hydrogen, an aralkyl group which may be substituted, a silyl group having three substituents, a tetrahydropyranyl group, an aralkyloxycarbonyl group which may be substituted, R ² represents hydrogen, an optionally substituted aralkyloxycarbonyl group, an optionally substituted alkyloxycarbonyl group, an optionally substituted alkyl group, or a protecting group for a hydroxyl group. A carbonyl group, a 9-fluorenylmethyloxycarbonyl group, or an amino group-protecting group; R ³ represents hydrogen, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aralkyl group; , R ⁴ is an optionally substituted alkyl group or an optionally substituted aralkyl group, R ⁵ is hydrogen, optionally substituted alkyl group, Represents conversion by aralkyl group which may or protecting group of carboxyl group,, R ⁶ represents hydrogen, hydroxyl group, an amino group, or -XY group,, X is oxygen, optionally substituted (C ₁ - C ₆ ) an alkylene group, or an optionally substituted phenylene group, Y represents an -AB group or -B group, A is an optionally substituted (C ₁ -C ₆ ) alkylene group, Oxygen, sulfur, imino group, or optionally substituted (C _1-
C ₆ ) represents an alkyleneimino group, B is hydrogen, an amino group, an amidino group, a sulfonyl group, an acylimidoyl group, an optionally substituted imidazolyl group, an optionally protected bisphosphonomethyl group, or Represents an optionally protected bisphosphonohydroxymethyl group, R ⁷ represents hydrogen, a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aralkyl group, R ⁸ represents hydrogen, Represents a hydroxyl group, an optionally substituted alkyl group, or an optionally substituted aralkyl group]
Or a pharmaceutically acceptable salt or solvate thereof. 2. In the general formula (I) according to claim 1, R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉) Alkyl group, (C_Three-C₇) Cycloal
Kill replacement (C₁-C_Four) Lower alkyl group, hydroxyl group, amino substitution
 (C₁-C₆) Alkyl group, phenyl (C₁-C_Four) Lower alkyl
Group, guanidino-substituted phenyl (C₁-C_Four) Lower alkyl group,
Amino substituted phenyl (C₁-C_Four) Lower alkyl group, carboxy
Si-substituted phenyl (C₁-C_Four) Lower alkyl group, carbamoyl
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydroxy-substituted
Phenyl (C ₁-C_Four) Lower alkyl group, guanidino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, optionally protected amino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, hydroxy-substituted (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C₁-C_Four) Lower alkyl group,
(C₁-C_Four) Lower alkoxycarbonyl-substituted phenyl (C₁-
C_Four) Lower alkyl group, (C ₁-C_Four) Lower alkylimino substitution
(C₁-C₆) Alkyl group, (C₁-C_Four) Lower acylimidoyl
Mino substitution (C₁-C₆) Alkyl group, arylmethylimino
Exchange (C₁-C₆) Substituted with an alkyl group or a nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkylimino substitution (C ₁-C₆) Archi
Substituted with a nitrogen-containing heterocyclic group (C₁-C_Four) Low
Lower alkyl group, oxygen-containing straight or branched chain (C₁-C₈) Archi
Group, arylsulfonamide substitution (C₁-C_Four) Lower alk
Substituted with a phenyl group (C₁-C_Four) Lower alkyl
Group, alkylsulfonamide substitution (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C ₁-C_Four) Lower alkyl group,
Aryloxy substitution (C₁-C_Four) A lower alkyl group or
Droxy substitution (C₁-C₈) Alkyl group,^FourIs (C_Three-C₉) Alkyl group, hydroxy-substituted (C_Three-C₈A)
Alkyl group, or optionally substituted aryl (C₁-
C_Four) A lower alkyl group;^FiveIs hydrogen, (C₁-C₁₆) Alkyl group, halogen-substituted (C₁-C
₁₆) Alkyl group, hydroxy-substituted (C₁-C₁₆) Alkyl group,
(C₁-C_Ten) Alkoxy substituted (C₁-C_Ten) Alkyl group, amino group
Exchange (C₁-C₁₆) Alkyl group, mono (C₁-C₆) Alkylamino
Exchange (C₁-C₁₆) Alkyl group, di (C₁-C₆) Alkylamino substitution
(C₁-C₁₆) Alkyl group, (C_Three-C_Ten) Cycloalkyl group, (C_Three-
C_Ten) Cycloalkyl-substituted (C₁-C₆) Alkyl group, (C_Two-C₁₆)
Alkenyl group, (C_Two-C₁₆) Alkynyl group, (C₆-C_Ten) Ally
Group, (C₆-C_Ten) Aryl substituted (C₁-C₆) Alkyl group, (C₁-
C₆) Alkoxycarbonyloxy substitution (C₁-C₆) Alkyl
Group, (C_Two-C₇) Alkanoyloxy substituted (C₁-C₆) Alkyl
Group, silyl group having 3 substituents, or phthalimi
Replacement (C₁-C₆) Represents an alkyl group, R⁶Is hydrogen, hydroxyl, amino, or -X-Y
X is oxygen, (C₁-C₆) Alkylene group or phenylene
Y is -A-B or -B, and B is hydrogen, amino, amidino, sulfonyl, (C
₁-C_Four) Lower acylimidoyl group, which may be substituted
Benzimidoyl group, bisphosphonomethyl group, tetra (C
₁-C_Four) Lower alkyl bisphosphonomethyl group, tri (C₁-
C_Four) Lower alkyl bisphosphonomethyl group, bisphosphono
Hydroxymethyl group, tetrabenzylbisphosphonohydride
Roxymethyl group, or (C₁-C_Four) Lower alkyl-substituted imi
Azol-3-yl group, where A is oxygen, (C₁-C_Four) Lower alkylene, imino,
Or (C₁-C_Four) A lower alkyleneimino group, R⁷Is hydrogen, or (C₁-C_Four) A lower alkyl group;⁸Is hydrogen, or (C₁-C_Four) A lower alkyl group
The compound according to claim 1. 3. In the general formula (I) according to claim 1, R ¹ and R ² are hydrogen, and R ³ is hydrogen, hydroxyl, methyl, isobutyl, aminopropyl, phenylpropyl, Guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl, hydroxymethylphenylpropyl, aminomethylbenzyl, toluenesulfone Amidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group, phthalimidomethylbenzyl group,
Phenoxyethyl group, aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group,
Pyridylmethyliminopentyl, methoxycarbonylphenylpropyl, ethoxyethoxyethyl, hydroxyoctyl, butoxyethyl, iso-butyroxyethyl, morpholinopropyl, (3,4,4-trimethyl
-2,5-dioxo-imidazolidine-1-yl) propyl group, cyclohexylpropyl group, or piperidinopropyl group; R ⁴ is naphthylmethyl group, phenylpropyl group, isobutyl group, tert-butyl group, An isopropyl group or a hydroxyoctyl group, and R ⁵ is hydrogen, a methyl group, an ethyl group, an n-propyl group, an iso-
Propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-hexyl, n-pentyl, neopentyl, heptyl, octyl, nonyl, decyl, undecyl , Dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, adamantyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-hydroxyethyl, methoxymethyl, methoxyethyl, benzyloxy Methyl group, benzyloxyethyl group, 2-methoxyethoxyethyl group, 2-aminoethyl group, 2-methylaminoethyl group, 2-dimethylaminoethyl group, cyclohexyl group, cyclohexylmethyl group,
Allyl, cinnamyl, 2-propynyl, phenyl, 4-methoxyphenyl, 4-bromophenyl, trityl, benzhydryl, acetoxymethyl, acetoxyethyl, triethylsilyl, tert-butyldimethylsilyl , Tert-butyldiphenylsilyl group, or phthalimidomethyl group; R ⁶ is hydrogen, hydroxyl, amino, or -XY; X is oxygen, methylene, ethylene, trimethylene, tetramethylene , A pentamethylene group, a hexamethylene group, or a phenylene group; Y is an -AB group or a -B group; B is an amino group, an amidino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, Benzimidoyl group, bisphosphonomethyl group, tetraethylbisphosphonomethyl group, triethylbisphospho A methyl group, a tetramethylbisphosphonomethyl group, a trimethylbisphosphonomethyl group, a bisphosphonohydroxymethyl group, a tetrabenzylbisphosphonohydroxymethyl group, or a 2-methylimidazol-3-yl group; The compound according to claim 1, wherein R ⁷ is hydrogen or a methyl group, and R ⁸ is hydrogen or a methyl group. 4. The following general formula (I): Wherein R ^{1 to} R ⁴ and R ^{6 to} R ⁸ have the same meaning as described in claim 1, and R ⁵ represents hydrogen.
Or a pharmaceutically acceptable salt or solvate thereof. 5. In the general formula (I) according to claim 4, R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉) Alkyl group, (C_Three-C₇) Cycloal
Kill replacement (C₁-C_Four) Lower alkyl group, hydroxyl group, amino substitution
 (C₁-C₆) Alkyl group, phenyl (C₁-C_Four) Lower alkyl
Group, guanidino-substituted phenyl (C₁-C_Four) Lower alkyl group,
Amino substituted phenyl (C₁-C_Four) Lower alkyl group, carboxy
Si-substituted phenyl (C₁-C_Four) Lower alkyl group, carbamoyl
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydroxy-substituted
Phenyl (C ₁-C_Four) Lower alkyl group, guanidino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, optionally protected amino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, hydroxy-substituted (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C₁-C_Four) Lower alkyl group,
(C₁-C_Four) Lower alkoxycarbonyl-substituted phenyl (C₁-
C_Four) Lower alkyl group, (C ₁-C_Four) Lower alkylimino substitution
(C₁-C₆) Alkyl group, (C₁-C_Four) Lower acylimidoyl
Mino substitution (C₁-C₆) Alkyl group, arylmethylimino
Exchange (C₁-C₆) Substituted with an alkyl group or a nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkylimino substitution (C ₁-C₆) Archi
Substituted with a nitrogen-containing heterocyclic group (C₁-C_Four) Low
Lower alkyl group, oxygen-containing straight or branched chain (C₁-C₈) Archi
Group, arylsulfonamide substitution (C₁-C_Four) Lower alk
Substituted with a phenyl group (C₁-C_Four) Lower alkyl
Group, alkylsulfonamide substitution (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C ₁-C_Four) Lower alkyl group,
Aryloxy substitution (C₁-C_Four) A lower alkyl group or
Droxy substitution (C₁-C₈) Alkyl group,^FourIs (C_Three-C₉) Alkyl group, hydroxy-substituted (C_Three-C₈A)
Alkyl group, or optionally substituted aryl (C₁-
C_Four) A lower alkyl group;^FiveRepresents hydrogen; R⁶Is hydrogen, hydroxyl, amino, or -X-Y
X is oxygen, (C₁-C₆) Alkylene group or phenylene
Y is -A-B or -B, and B is hydrogen, amino, amidino, sulfonyl, (C
₁-C_Four) Lower acylimidoyl group, which may be substituted
Benzimidoyl group, bisphosphonomethyl group, tetra (C
₁-C_Four) Lower alkyl bisphosphonomethyl group, tri (C₁-
C_Four) Lower alkyl bisphosphonomethyl group, bisphosphono
Hydroxymethyl group, tetrabenzylbisphosphonohydride
Roxymethyl group, or (C₁-C_Four) Lower alkyl-substituted imi
Azol-3-yl group, where A is oxygen, (C₁-C_Four) Lower alkylene, imino,
Or (C₁-C_Four) A lower alkyleneimino group, R⁷Is hydrogen, or (C₁-C_Four) A lower alkyl group;⁸Is hydrogen, or (C₁-C_Four) A lower alkyl group
A compound according to claim 4. 6. In the general formula (I) according to claim 4, R ¹ and R ² are hydrogen, and R ³ is hydrogen, hydroxyl, methyl, isobutyl, aminopropyl, phenylpropyl, Guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl, hydroxymethylphenylpropyl, aminomethylbenzyl, toluenesulfone Amidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group, phthalimidomethylbenzyl group,
Phenoxyethyl group, aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group,
Pyridylmethyliminopentyl, methoxycarbonylphenylpropyl, ethoxyethoxyethyl, hydroxyoctyl, butoxyethyl, iso-butyroxyethyl, morpholinopropyl, (3,4,4-trimethyl
-2,5-dioxo-imidazolidine-1-yl) propyl group, cyclohexylpropyl group, or piperidinopropyl group; R ⁴ is naphthylmethyl group, phenylpropyl group, isobutyl group, tert-butyl group, An isopropyl group or a hydroxyoctyl group, R ⁵ represents hydrogen, R ⁶ is hydrogen, a hydroxyl group, an amino group, or a -XY group, and X is oxygen, a methylene group, an ethylene group, a trimethylene group, A tetramethylene group, a pentamethylene group, a hexamethylene group, or a phenylene group, Y is -AB group or -B group, and B is amino group, amidino group, acetimidoyl group, sulfonyl group, propionimide Yl, benzimidoyl, bisphosphonomethyl, tetraethylbisphosphonomethyl, triethylbisphosphonomethyl, tetramethylbi A phosphonomethyl group, a trimethylbisphosphonomethyl group, a bisphosphonohydroxymethyl group, a tetrabenzylbisphosphonohydroxymethyl group, or a 2-methylimidazol-3-yl group, wherein A is oxygen, imino, methyleneimino or The compound according to claim 4, wherein the compound is a methylene group, R ⁷ is hydrogen or a methyl group, and R ⁸ is hydrogen or a methyl group. 7. The following general formula (I): Wherein R ^{1 to} R ⁴ and R ^{6 to} R ⁸ have the same meaning as described in claim 1, and R ⁵ is an optionally substituted alkyl group, an optionally substituted aralkyl group, Or a carboxyl-protecting group], or a pharmaceutically acceptable salt or solvate thereof. 8. In the general formula (I) according to claim 7, R¹And R^TwoIs hydrogen and R^ThreeIs hydrogen, (C₁-C₉) Alkyl group, (C_Three-C₇) Cycloal
Kill replacement (C₁-C_Four) Lower alkyl group, hydroxyl group, amino substitution
 (C₁-C₆) Alkyl group, phenyl (C₁-C_Four) Lower alkyl
Group, guanidino-substituted phenyl (C₁-C_Four) Lower alkyl group,
Amino substituted phenyl (C₁-C_Four) Lower alkyl group, carboxy
Si-substituted phenyl (C₁-C_Four) Lower alkyl group, carbamoyl
Substituted phenyl (C₁-C_Four) Lower alkyl group, hydroxy-substituted
Phenyl (C ₁-C_Four) Lower alkyl group, guanidino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, optionally protected amino substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl group, hydroxy-substituted (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C₁-C_Four) Lower alkyl group,
(C₁-C_Four) Lower alkoxycarbonyl-substituted phenyl (C₁-
C_Four) Lower alkyl group, (C ₁-C_Four) Lower alkylimino substitution
(C₁-C₆) Alkyl group, (C₁-C_Four) Lower acylimidoyl
Mino substitution (C₁-C₆) Alkyl group, arylmethylimino
Exchange (C₁-C₆) Substituted with an alkyl group or a nitrogen-containing heterocyclic group
(C₁-C_Four) Lower alkylimino substitution (C ₁-C₆) Archi
Substituted with a nitrogen-containing heterocyclic group (C₁-C_Four) Low
Lower alkyl group, oxygen-containing straight or branched chain (C₁-C₈) Archi
Group, arylsulfonamide substitution (C₁-C_Four) Lower alk
Substituted with a phenyl group (C₁-C_Four) Lower alkyl
Group, alkylsulfonamide substitution (C₁-C_Four) Lower alkyl
Phenyl substituted with a group (C ₁-C_Four) Lower alkyl group,
Aryloxy substitution (C₁-C_Four) A lower alkyl group or
Droxy substitution (C₁-C₈) Alkyl group,^FourIs (C_Three-C₉) Alkyl group, hydroxy-substituted (C_Three-C₈A)
Alkyl group, or optionally substituted aryl (C₁-
C_Four) A lower alkyl group;^FiveIs (C₁-C₁₆) Alkyl group, halogen-substituted (C₁-C₁₆) Al
Kill group, hydroxy substitution (C₁-C₁₆) Alkyl group, (C₁-C_Ten)
Alkoxy substitution (C₁-C_Ten) Alkyl group, amino-substituted (C₁-C
₁₆) Alkyl group, mono (C₁-C₆) Alkylamino substitution (C₁-C
₁₆) Alkyl group, di (C₁-C₆) Alkylamino substitution (C₁-
C₁₆) Alkyl group, (C_Three-C_Ten) Cycloalkyl group, (C_Three-C_Ten)
Cycloalkyl substitution (C₁-C₆) Alkyl group, (C_Two-C₁₆) Al
Kenyl group, (C _Two-C₁₆) Alkynyl group, (C₆-C_Ten) Aryl
Group, (C₆-C_Ten) Aryl substituted (C₁-C₆) Alkyl group, (C₁-
C₆) Alkoxycarbonyloxy substitution (C₁-C₆) Alkyl
Group, (C_Two-C₇) Alkanoyloxy substituted (C₁-C₆) Alkyl
Group, silyl group having 3 substituents, or phthalimi
Replacement (C₁-C₆) Represents an alkyl group, R⁶Is hydrogen, hydroxyl, amino, or -X-Y
X is oxygen, (C₁-C₆) Alkylene group or phenylene
Y is -A-B or -B, and B is hydrogen, amino, amidino, sulfonyl, (C
₁-C_Four) Lower acylimidoyl group, which may be substituted
Benzimidoyl group, bisphosphonomethyl group, tetra (C
₁-C_Four) Lower alkyl bisphosphonomethyl group, tri (C₁-
C_Four) Lower alkyl bisphosphonomethyl group, bisphosphono
Hydroxymethyl group, tetrabenzylbisphosphonohydride
Roxymethyl group, or (C₁-C_Four) Lower alkyl-substituted imi
Azol-3-yl group, where A is oxygen, (C₁-C_Four) Lower alkylene, imino,
Or (C₁-C_Four) A lower alkyleneimino group, R⁷Is hydrogen, or (C₁-C_Four) A lower alkyl group;⁸Is hydrogen, or (C₁-C_Four) A lower alkyl group
A compound according to claim 7. 9. In the general formula (I) according to claim 7, R ¹ and R ² are hydrogen, and R ³ is hydrogen, hydroxyl, methyl, isobutyl, aminopropyl, phenylpropyl, Guanidinophenylpropyl, aminophenylpropyl, hydroxyphenylpropyl, carboxyphenylpropyl, carbamoylphenylpropyl, aminomethylphenylpropyl, guanidinomethylphenylpropyl, hydroxymethylphenylpropyl, aminomethylbenzyl, toluenesulfone Amidomethylbenzyl group, methanesulfonamidomethylbenzyl group, isobutyliminomethylbenzyl group, phthalimidomethylbenzyl group,
Phenoxyethyl group, aminopentyl group, acetimidoyliminopentyl group, isobutyliminopentyl group,
Pyridylmethyliminopentyl, methoxycarbonylphenylpropyl, ethoxyethoxyethyl, hydroxyoctyl, butoxyethyl, iso-butyroxyethyl, morpholinopropyl, (3,4,4-trimethyl
-2,5-dioxo-imidazolidine-1-yl) propyl group, cyclohexylpropyl group, or piperidinopropyl group; R ⁴ is naphthylmethyl group, phenylpropyl group, isobutyl group, tert-butyl group, R ⁵ is a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group, a tert group.
-Butyl, n-hexyl, n-pentyl, neopentyl, heptyl, octyl, nonyl, decyl,
Undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, adamantyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-
Hydroxyethyl group, methoxymethyl group, methoxyethyl group, benzyloxymethyl group, benzyloxyethyl group, 2-methoxyethoxyethyl group, 2-aminoethyl group,
2-methylaminoethyl group, 2-dimethylaminoethyl group,
Cyclohexyl group, cyclohexylmethyl group, allyl group, cinnamyl group, 2-propynyl group, phenyl group, 4-methoxyphenyl group, 4-bromophenyl group, trityl group,
A benzhydryl group, an acetoxymethyl group, an acetoxyethyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or a phthalimidomethyl group, and R ⁶ is hydrogen, a hydroxyl group, an amino group, or -XY X is oxygen, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, or phenylene; Y is -AB or -B; Represents an amino group, an amidino group, an acetimidoyl group, a sulfonyl group, a propionimidoyl group, a benzimidoyl group, a bisphosphonomethyl group, a tetraethylbisphosphonomethyl group, a triethylbisphosphonomethyl group, and a tetramethylbisphosphonomethyl group. Group, trimethylbisphosphonomethyl group, bisphosphonohydroxymethyl Group, tetrabenzyl bis phosphono hydroxymethyl group or 2-methyl-imidazol-3-yl group,, A is oxygen, imino group, a Mechiren'imino group or a methylene group, R ⁷ is hydrogen or a methyl group, The compound according to claim 7, wherein R ⁸ is hydrogen or a methyl group. 10. The following general formula (IV):CO of the compound represented by_TwoR^TenSelectively contains amide bond
Convert to a site and, if desired, R⁹, R¹¹, R¹²And R¹³
Is the desired functional group R^Five, R^Three, R^FourAnd R⁶To each
Or a compound represented by the above general formula (IV)
And optionally R⁹, R¹¹, R¹²And R¹³The desired functional group
Is R^Five, R^Three, R^FourAnd R⁶And then convert it to
CO_TwoR^TenCharacterized by converting the site to an amide bond-containing site
The following general formula (I):Or a pharmaceutically acceptable salt thereof
Or production of a compound selected from the group consisting of solvates
Method (where R¹~ R⁸Has the same meaning as in claim 1.
Has, R⁹Is the above R^FiveEquivalent to or protected hydroxyl
Group is substituted (C₁-C_Ten) Alkyl group, protected amino group
Exchange (C₁-C₁₆) Alkyl group, or protected mono (C₁-C₆)
Alkylamino substitution (C₁-C₁₆) Represents an alkyl group, R^TenIs an alkyl group which may be substituted,
Protection of optional aralkyl or carboxyl groups
Represents a group, R¹¹Is the above R^ThreeEquivalent to or protected water
Acid groups, protected guanidino-substituted phenyl (C₁-C_Four) Low grade
Alkyl group, protected amino-substituted phenyl (C ₁-C_Four) Low
Lower alkyl group, nitro-substituted phenyl (C₁-C_Four) Lower alk
Group, protected amino substitution (C₁-C₆) Alkyl group, nitro
B substitution (C₁-C₆) Alkyl group, protected carboxy substitution
Phenyl (C₁-C_Four) Lower alkyl group, protected hydroxy
Si-substituted phenyl (C₁-C_Four) Lower alkyl groups, protected groups
Anidino substitution (C₁-C_Four) Substituted with a lower alkyl group
Phenyl (C₁-C_Four) Lower alkyl group, protected amino group
Exchange (C₁-C_Four) Phenyl substituted with a lower alkyl group (C
₁-C_Four) Lower alkyl group, protected hydroxy substitution (C₁-
C_Four) Phenyl substituted with a lower alkyl group (C₁-C_Four)
Lower alkyl groups, protected carboxy substitution (C₁-C_Four) Low
Phenyl substituted with a lower alkyl group (C₁-C_Four) Lower class
Straight or branched chain containing alkyl group, protected hydroxyl group
(C₁-C₈) Alkyl group, or cyano-substituted phenyl (C₁-
C_Four) Represents a lower alkyl group, R¹²Is the above R^FourEquivalent to or protected
Droxy substitution (C₁-C₈) Represents an alkyl group, R¹³Is the above R⁶With the same meaning, protected amino group,
Protected hydroxyl, -X-E or -X-A-E groups (where
 X and A are as defined above, and E is a nitro group,
Ano group, amino group, carboxyl group, hydroxy (C₁-C
₁₁) Alkyl, protected amino, protected gua
Nidino group, protected amidino group, protected acylyl
Midoyl group, protected benzimidoyl group, protected
Bisphosphonomethyl group, protected bisphosphonohydride
Loxymethyl group, or protected (C₁-C₁₁) Alkyl
Represents an substituted imidazol-3-yl group). 11. In the general formula (IV) according to claim 10, R ⁹ has the same meaning as R ⁵ described above, or a protected hydroxyethyl group, a protected hydroxypropyl group, or a protected hydroxybutyl. Represents a group, a protected aminoethyl group, a protected aminopropyl group, a protected aminobutyl group, a protected methylaminoethyl group, a protected methylaminopropyl group, or a protected methylaminobutyl group; R ¹⁰ represents a (C ₁ -C ₆ ) alkyl group, a benzyl group, a substituted benzyl group, a phenacyl group, or a 2,2,2-trichloroethyl group, and R ¹¹ has the same meaning as R ³ Or protected guanidinophenylpropyl, protected aminophenylpropyl, nitrophenylpropylene, protected aminopropyl, nitropropyl, protected Protected hydroxyphenylpropyl group, protected carboxyphenylpropyl group, protected aminomethylphenylpropyl group, protected guanidinomethylphenylpropyl group, protected hydroxymethylphenylpropyl group,
Represents a protected aminomethylbenzyl group, a cyanophenylpropyl group, a protected aminopentyl group, a cyanobenzyl group, a protected hydroxyoctyl group, or a nitropentyl group; R ¹² has the same meaning as R ⁴ , Or a protected hydroxyoctyl group, wherein R ¹³ is the same as R ⁶ , a protected amino group, a protected hydroxyl group, a -XF group or a -XAF group (where X
And A are as defined above, and F is a nitro group, a cyano group, an amino group, a carboxyl group, a hydroxymethyl group, a protected amino group, a protected guanidino group, a protected amidino group, a protected amidino group, Acetimidyl group,
The method according to claim 10, which represents a protected propionimidoyl group, a protected benzimidoyl group, a protected bisphosphonomethylimino group, or a protected bisphosphonohydroxymethyl group. 12. The following general formula (V): And a hydroxamic acid skeleton-containing succinic acid derivative represented by the following general formula (III): With an amine derivative represented by the following formula (VI): Is obtained, and if necessary, R ⁹ , R ¹¹ , R ¹² and R ¹³ are each converted to a desired functional group R ⁵ , R ³ , R ⁴ and R ⁶ , The following general formula (I): Or a method for producing a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof, wherein R ^{1 to} R ⁸ are the same as those described in claim 1. R ⁹ , R ^{11 to} R ¹³ have the same meaning as described in claim 10]. 13. The following general formula (I): Wherein R ^{1 to} R ⁸ have the same meaning as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical and / or veterinary composition comprising a compound and a pharmaceutically acceptable carrier. 14. A compound of the formula (I) according to claim 1, wherein R ^{1 is}
To R ⁸ have the same meaning as in claim 1), or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. A metalloproteinase inhibitor characterized by the following: 15. A metalloproteinase belonging to the class of matrix metalloproteinases,
The inhibitor according to claim 14, which is a matrix metalloproteinase inhibitor. 16. The inhibitor according to claim 14, wherein the metalloproteinase belongs to tumor necrosis factor-α (TNF-α) converting enzyme and is a TNF-α converting enzyme inhibitor. . 17. The compound represented by the general formula (I) according to claim 1, wherein R ^{1 is}
To R ⁸ have the same meaning as in claim 1), or a compound selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. A preventive and / or therapeutic agent for a disease relating to a characteristic tissue degradation. 18. The following general formula (VI): Wherein R ¹ , R ² , R ⁷ and R ⁸ have the same meaning as in claim 1, and R ⁹ , R ^{11 to} R ¹³ have the same meaning as in claim 10 Or a salt thereof. 19. The following general formula (IV): Wherein R ⁷ and R ⁸ have the same meanings as in claim 1, and R ^{9 to} R ¹³ have the same meanings as in claim 10, or Its salt. 20. The following general formula (II): And a succinic acid derivative represented by the following general formula (III): Characterized by reacting with an amine derivative represented by the following general formula (IV): Wherein R ⁷ and R ⁸ have the same meanings as in claim 1, and R ^{9 to} R ¹³ have the same meanings as in claim 10, or A method for producing the salt. 21. The following general formula (III): Wherein R ⁷ and R ⁸ have the same meaning as in claim 1, and R ⁹ and R ¹³ have the same meaning as in claim 10, or A pharmaceutically acceptable salt or solvate thereof.