JPH09104672A - Hydroxamic acid derivative - Google Patents

Abstract

(57) [Summary] [Structure] A compound of formula (I) and a salt thereof (in the formula, R ¹ ,
R ² is H, an alkyl group or the like; E is —CONR ³ —, —NR ³
CO -, - COO -, - OCO -, - NR 3 CONR
_{^{3 -, - COCH 2 -,}} - CO -, - OCONR 3 -, -
^{NR 3 COO -, - OCOO -} , - CSNR 3 -, - NR
³ CS-, -NR ³ CSNR ^3- , -OCSNR ^3- , -N
^{R 3 CSO -, - CSO -} , - OCS -, - OCSO
-; J is a single bond, alkylene, alkenylene, group of formula (II), A is H, alkyl, cycloalkyl, Ar group, G is - (CH _{2) m} -, a group of formula (III)). Embedded image [Effect] The compound of formula (I) has a gelatinase inhibitory action, and has rheumatism, osteoarthritis, pathological bone resorption, osteoporosis,
Periodontal disease, interstitial nephritis, arteriosclerosis, emphysema, liver cirrhosis, corneal damage, cancer cell metastasis invasion and proliferation disease, autoimmune disease, leukocyte cell migration and invasion disease, angiogenesis prevention And / or is useful in therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to hydroxamic acid derivatives. More specifically, 1) General formula (I)

Embedded image (In the formula, all symbols have the same meanings as described below.) A hydroxamic acid derivative and a non-toxic salt thereof, 2) a process for producing them, and 3) a drug containing them.

[0002]

BACKGROUND OF THE INVENTION Matrix metalloproteinases (hereinafter abbreviated as MMPs) have zinc (hereinafter, Z) as an active center.
abbreviated as n ²⁺ ), and in a physiological situation, collagen, laminin,
By degrading proteoglycan, fibronectin, elastin, gelatin, etc., it acts on growth and tissue reconstruction of joint tissues, bone tissues, connective tissues and the like. MM
Up to now, 10 or more kinds of molecular species having different primary structures have been identified as P. The properties common to each of these enzymes are (1) having Zn ²⁺ in the active center and requiring calcium (Ca ²⁺ ) for enzyme activity, (2) being secreted as a latent enzyme, and extracellularly Undergoing activation, (3) having high homology in amino acid sequence, (4) having the ability to decompose various extracellular matrix components existing in vivo, (5) tissue metalloproteinase inhibitor which is a common inhibitor It is known that the activity is inhibited by (TIMP).

Recently, it has been reported in many cases that gelatinase, which is a neutral metalloproteinase degrading extracellular matrix such as gelatin, is involved in various diseases in this MMP. Therefore, inhibitors of gelatinase are considered to be useful for the prevention and / or treatment of various diseases. For example, rheumatism, osteoarthritis, pathological bone resorption, osteoporosis, periodontal disease, interstitial nephritis, arteriosclerosis, emphysema, liver cirrhosis, corneal damage, cancer cell metastatic invasion and proliferation disease, autoimmune disease (Crohn's disease, Sugren's disease, etc.), diseases caused by invasion and invasion of leukocyte cells, and angiogenesis.

[0004]

2. Description of the Related Art Several compounds having a gelatinase inhibitory action are known, and as such, many substrate analog matrix metalloproteinase inhibitors have been studied [Inhibitors of matrix metalloprot].
einases (MMP's), Nigel RA Beeley, Phillip RJ Ansel
l, Andrew JP Docherty et al. Curr. Opin. Ther. Patent
s., 4 , 7-16 (1994), Current Drugs Ltd ISSN 0962-25
94].

For example, the specification of EP 606046 describes the general formula (X)

Embedded image

[(A) wherein Ar ^X is carbocyclic or heterocyclic aryl; R ^X is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, etc .;

R ^1X is hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, etc .; R ^2X is hydrogen or lower alkyl; or

(B) R ^X and R ^1X together with the chain to which they are attached form a 1,2,3,4-tetrahydro-isoquinoline, piperidine ring, etc .; Ar ^X and R ^2X are (a ) Has the meaning defined in;

(C) R ^1X and R ^2X , together with the carbon atom to which they are attached, are C 3 -C 7 -cycloalkanes, which are unsubstituted or substituted by lower alkyl, oxa-cyclohexane, Ar ^X and R ^2X have the meaning defined in (a), such as thia-cyclohexane. ] It is disclosed that the aryl sulfonamide derivative represented by the formula [3] has a matrix metalloproteinase inhibitory action.

[0010]

DISCLOSURE OF THE INVENTION As a result of intensive studies to find a compound having a gelatinase inhibitory action, the present inventors have found that the hydroxamic acid derivative represented by the general formula (I) has a gelatinase inhibitory action. The hydroxamic acid derivative represented by the general formula (I) of the present invention is a novel compound which has never been known so far.

[0011]

DISCLOSURE OF THE INVENTION The present invention includes 1) general formula (I)

Embedded image

[In the formula, R ¹ is a hydrogen atom or C1 to
4 alkyl group, R ² represents 1) hydrogen atom, 2) C1-8 alkyl group, 3) phenyl group, or 4) C1-4 alkyl group substituted with phenyl group,

E is a 1) -CO-NR ³ -group (wherein R ³ is a hydrogen atom, C 1
Represents a C4 alkyl group, a phenyl group, or a C1-4 alkyl group substituted with a phenyl group. ), 2) -NR ³ -CO- group (wherein R ³ has the same meaning as described above), 3) -CO-O- group, 4) -O-CO- group, 5) -NR. ³ -CO-NR ³ - group (wherein, R ³ represents the same meaning as above.), 6) -CO-CH 2 - group, 7) -CO- group, 8) -O-CO-NR ³ -group (in the group, R ³ represents the same meaning as described above), 9) —NR ³ —CO—O— group (in the group, R ³ represents the same meaning as described above), 10). —O—CO—O— group, 11) —CS—NR ³ — group (in the group, R ³ represents the same meaning as described above), 12) —NR ³ —CS— group (in the group, R ³ Represents the same meaning as described above), 13) -NR ³ -CS-NR ³ -group (in the group, R ³ represents the same meaning as described above), 14) -O-CS-NR ^3-. in group (group, R ³ is as defined above ^{Wath.), 15) -NR 3 -CS} -O- group (wherein, R ³ represents the same meaning as above.), 16) -CS-O- group, 17) -O-CS- group, Or 18) represents an —O—CS—O— group,

A is 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, or 4) an Ar group (wherein the Ar group represents a carbocycle or a heterocyclic aryl, and 1 From 3 C1-15 alkyl groups, C1
~ 15 alkoxy group, halogen atom, nitro group, cyano group, guanidino group, amidino group, hydroxyl group, benzyloxy group, -NR ⁹ R ¹⁰ group (in the group, R ⁹ and R ¹⁰ are each independently a hydrogen atom or represents a C1~4 alkyl group), -.. COOR ¹¹ group (wherein, R ¹¹ is represents a hydrogen atom or a C1~4 alkyl group), a trifluoromethyl group, substituted with a phenyl group or a heterocyclic group, May be. )

J is 1) a single bond, 2) a C2-4 alkylene group, 3) a C2-4 alkenylene group, or

Embedded image (In the groups, R ⁴ and R ⁵ are each independently a (1) hydrogen atom, (2) C1-4 alkyl group, (3) C1-4 alkoxy group, or carbon to which R ⁴ and R ⁵ are bonded. Together with the atoms represent a C3-7 cycloalkyl group).

G is

Embedded image 1)-(CH ₂ ) _m -group (wherein m represents 2, 3 or 4) or

Embedded image (In the group, R ⁶ and R ⁷ are each independently (i)
Hydrogen atom, (ii) C1-8 alkyl group, (iii) -CO
OR ⁸ group (wherein R ⁸ is a hydrogen atom, a C 1-8 alkyl group, a phenyl group, or a C 1-8 substituted with a phenyl group)
Represents a 4-alkyl group. ), (Iv) Ar group (in the group, A
The r group has the same meaning as described above. ), (V) heterocyclic group, (vi) —COOR ⁸ group (wherein R ⁸ has the same meaning as described above), C1-4 alkoxy group, hydroxyl group, benzyloxy group, —NR ¹² R ¹³ group. (In the group, R ¹² and R ¹³
Each independently represent a hydrogen atom or a C1-4 alkyl group. ), A —NR ¹⁴ COOR ¹⁵ group (in which R ¹⁴ represents a hydrogen atom or a C1-4 alkyl group, R ¹⁵ represents a hydrogen atom, a C1-8 alkyl group, a phenyl group or a C1-4 substituted with a phenyl group). Represents an alkyl group), A
a C1-8 alkyl group substituted with an r group or a heterocyclic group (provided that one of the carbon atoms of the C1-8 alkyl group may be replaced with one sulfur atom), or R ⁶ and R ⁷ together with the carbon atom bonded represent C3~7 cycloalkyl group. ). However, E is ^{-O-CO-NR 3 -,} - O-CO-
O -, - O-CS- NR 3 - , or -O-CS-O-a and, J excluding compounds and A is a single bond is a hydrogen atom. ]

The present invention relates to a hydroxamic acid derivative represented by and a nontoxic salt thereof, 2) a method for producing them, and 3) a drug containing the nontoxic salt as an active ingredient.

In the present invention, all isomers are included unless otherwise specified. For example, the alkyl group, the alkoxy group and the alkylene group include straight-chain and branched ones. Also included are isomers formed by the presence of asymmetric carbon atoms, such as the presence of branched alkyl, alkoxy and alkylene groups.

In the general formula (I), R ¹ , R ³ , R ⁴ , R ⁵ and R
^The C1-4 alkyl group represented by ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ is methyl, ethyl, propyl,
A butyl group and isomers thereof.

In the general formula (I), R ² , R ⁶ , R ⁷ , R ⁸ and R
^The C1-8 alkyl group represented by ¹⁵ , A is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.

In the general formula (I), a C1-4 alkyl group substituted by a phenyl group represented by R ² , R ³ , R ⁸ and R ¹⁵ means methyl and ethyl substituted by one phenyl group. , Propyl, butyl groups and their isomers.

In the general formula (I), the C1-4 alkoxy group represented by R ⁴ , R ⁵ , R ⁶ and R ⁷ is methoxy,
Ethoxy, propoxy, butoxy groups and their isomers.

In the general formula (I), C as a substituent of Ar
1-15 alkyl group means methyl, ethyl, propyl,
A butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl group and isomers thereof.

In the general formula (I), C as a substituent of Ar
1-15 alkoxy group means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,
Heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy groups and isomers thereof.

In the general formula (I), the halogen atom in the substituent of the Ar group is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

C represented by J in the general formula (I)
The 2-4 alkylene group means ethylene, trimethylene, tetramethylene group and isomers thereof.

C represented by J in the general formula (I)
2-4 alkenylene groups include vinylene, propenylene,
Butenylene, butadinylene groups and their isomers.

In the general formula (I), a C3-7 cycloalkyl group represented by R ⁴ and R ⁵ together with the carbon atom to which it is bound, and a C3 represented by R ⁶ and R ⁷ together with the carbon atom to which it is attached. ~ 7 cycloalkyl group and C3-7 cycloalkyl group represented by A is cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

In the general formula (I), the carbocyclic aryl represented by the Ar group in the A, R ⁶ and R ⁷ groups means C 5
Represents 10 carbocyclic aryl. For example, C5-10 carbocyclic aryl includes benzene, pentalene, indene, naphthalene, azulene and the like.

In the general formula (I), the heterocyclic aryl represented by the Ar group in the A, R ⁶ and R ⁷ groups is 1 to 2
Represents a 5- to 15-membered monocyclic or bicyclic heterocyclic aryl containing one nitrogen atom, one oxygen atom and / or one sulfur atom. For example, a 5- to 15-membered monocyclic or bicyclic heterocyclic aryl containing 1 to 2 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom is pyrrole, imidazole, pyrazole, pyridine, Pyrazine,
Pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepine, thiophene,
Thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxaazepine, oxadiazepine, thiadiazole, thiazine,
Thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole ring, etc. Can be mentioned.

In the general formula (I), the heterocycle represented by the R ⁶ and R ⁷ groups in the G group and the heterocycle of the substituent of Ar are 1 to 2 nitrogen atoms, 1 oxygen atom and And / or a 5- to 15-membered monocyclic or bicyclic heterocycle containing one sulfur atom. A 5- to 15-membered monocyclic or bicyclic heterocycle containing 1 to 2 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom means 1 to 2 nitrogen atoms, 1 5 to 15 membered monocyclic heterocyclic aryl containing 1 oxygen atom and / or 1 sulfur atom is partially or fully saturated.

For example, a 5- to 15-membered monocyclic or bicyclic heterocycle containing 1-2 nitrogen atoms, 1 oxygen atom and / or 1 sulfur atom is pyrroline, pyrrolidine, imidazoline, Imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran) ), Dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydo Loisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, Dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, Dihydroquinoxaline,
Tetrahydroquinoxaline, perhydroquinoxaline,
Dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole ring And the like.

The E group in the present invention has a benzene ring on the right side,
It is assumed that the J group is bonded to the left side. For example, E group -CO-NR ³ - in the case of J-CO-NR ³ - and represents a benzene ring. The non-toxic salt in the present invention includes all salts. For example, common salt, acid addition salt,
A hydrate salt etc. are mentioned.

[Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.),
Ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine , N-methyl-D-
Glucamine and the like).

[Acid Addition Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding acid addition salt by a known method. Non-toxic, water-soluble salts are preferred. Suitable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate or acetate, trifluoroacetate, lactate, Tartrate,
Oxalate, fumarate, maleate, citrate,
Examples thereof include organic acid salts such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate and gluconate. Further, the compound of the present invention represented by the general formula (I) or a salt thereof can be converted into a hydrate by a known method.

Among the compounds of the present invention represented by the general formula (I), preferred compounds are the general formula I (1)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (2)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (3)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (4)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (5)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (6)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (7)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (8)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (9)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (10)

Embedded image (In the formula, A and G have the same meanings as described above.),

Formula I (11)

Embedded image (In the formula, A and G have the same meanings as described above.),

Formula I (12)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (13)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (14)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (15)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (16)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (17)

Embedded image (In the formula, A and G have the same meanings as described above.),

Formula I (18)

Embedded image (In the formula, A and G have the same meanings as described above.),

General formula I (19)

Embedded image (In the formula, R ¹ and E have the same meanings as described above.),

General formula I (20)

Embedded image (In the formula, R ¹ and E have the same meanings as described above.),

General formula I (21)

Embedded image (In the formula, R ¹ and E have the same meanings as described above.),

Formula I (22)

Embedded image (In the formula, R ¹ and E have the same meanings as described above.),

General formula I (23)

Embedded image (In the formula, R ¹ and E each have the same meaning as described above.), And a non-toxic salt thereof.

Specific preferred examples of the compounds represented by formula (I) include the compounds shown in Tables 1 to 23 below.
Examples thereof include non-toxic salts thereof and compounds described in Examples.

[0060]

[Table 1]

[0061]

[Table 2]

[0062]

[Table 3]

[0063]

[Table 4]

[0064]

[Table 5]

[0065]

[Table 6]

[0066]

[Table 7]

[0067]

[Table 8]

[0068]

[Table 9]

[0069]

[Table 10]

[0070]

[Table 11]

[0071]

[Table 12]

[0072]

[Table 13]

[0073]

[Table 14]

[0074]

[Table 15]

[0075]

[Table 16]

[0076]

[Table 17]

[0077]

[Table 18]

[0078]

[Table 19]

[0079]

[Table 20]

[0080]

[Table 21]

[0081]

[Table 22]

[0082]

[Table 23]

[0083]

[Table 24]

[0084]

[Table 25]

[0085]

[Table 26]

[0086]

[Table 27]

[0087]

[Table 28]

[0088]

[Table 29]

[0089]

[Table 30]

[0090]

[Table 31]

[0091]

[Table 32]

[0092]

[Table 33]

[0093]

[Table 34]

[0094]

[Table 35]

[0095]

[Table 36]

[0096]

[Table 37]

[0097]

[Table 38]

[0098]

[Table 39]

[0099]

[Table 40]

[0100]

[Table 41]

[0101]

[Method for producing the compound of the present invention]

(A) Of the compounds of the present invention represented by the general formula (I), R
² does not represent a hydrogen atom, and the A-J-E- group, the substituent of Ar in A, and R ⁶ and R ⁷ in the G group are -COO.
A compound which does not represent an H group, an amino group, a hydroxyl group or a group containing them, and the AJE-group does not represent a -CS-OH group, that is, a compound represented by the general formula (IA):

[0102]

Embedded image

(Wherein G ¹ , E ¹ , J ¹ and A ¹ are G,
It has the same meaning as E, J, and A. However, A ¹ -J ¹ -E
^1- , the substituent of Ar in A ¹ and R ⁶ and R ⁷ in the G ¹ group do not represent a —COOH group, an amino group, a hydroxyl group or a group containing them, and A ¹ —J ¹ —E ¹ -Is -CS-O
R ^{2 -A} is a C1-8 alkyl group, a phenyl group, or C1 substituted with a phenyl group.
~ 4 alkyl groups, and other symbols have the same meanings as described above. The compound of the present invention represented by the general formula (II):

[0104]

Embedded image

(Wherein all symbols have the same meanings as described above) and a compound of the general formula (III)

Embedded image It can be produced by subjecting a compound represented by H ₂ N—OR ^2-A (III) (wherein all symbols have the same meanings as described above) to an amidation reaction.

The amidation reaction is known and, for example, (1)
Examples thereof include a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent.

The following is a detailed description of these methods.
(1) The method using an acid halide is, for example, carboxylic acid in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without solvent, with an acid halide (oxalyl chloride, thionyl chloride, etc.) and −20 ° C. ~ At the reflux temperature, the resulting acid halide in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.),
0-40 ° C in amine and organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)
It is carried out by reacting with. (2) The method using a mixed acid anhydride is, for example, carboxylic acid in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) or without solvent,
In the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate, isobutyl chloroformate, etc.), -20 to 40 ° C The obtained mixed acid anhydride is reacted with the corresponding amine in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0 to 40 ° C. (3) Method using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 2-chloro-1-methylpyridinium iodine, etc.) Is
For example, a carboxylic acid and an amine may be used in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether, etc.) or without a solvent to form a tertiary amine (pyridine,
(Triethylamine, dimethylaniline, dimethylaminopyridine, etc.) with or without a condensing agent. These reactions (1), (2) and (3) are desirably performed under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

(B) Among the compounds of the present invention represented by the general formula (I), R ² represents a hydrogen atom, or A--J
-E- group, a substituent of Ar in A, or at least one group of R ⁶ or R ^{7 in} G group represents -COOH group, amino group, hydroxyl group or a group containing them,
A compound in which the A-J-E- group represents a -CS-OH group, that is, general formula (IB):

[0109]

Embedded image

(Wherein G ² , E ² , J ² and A ² are G,
It has the same meaning as E, J, and A. However, A ² -J ² -E
² - group, at least one group is -COOH group of the R ⁶ or R ⁷ in the substituent or G ² radicals, of Ar in A ^2, amino group, or represents a hydroxyl group or a group containing them, A
² -J ² -E ² - group, or represents a -CS-OH group, or R ² represents a hydrogen atom, the other symbols are the same meanings as described above. The compound of the present invention represented by the formula (1) can be prepared by deprotecting or hydrogenolytically decomposing the compound represented by the general formula (IA) prepared by the above method under alkaline or acidic conditions.

Deprotection under alkaline conditions is known,
For example, in organic solvents (methanol, tetrahydrofuran, dioxane, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (calcium hydroxide, etc.) or carbonates (sodium carbonate). , Potassium carbonate, etc.) or an aqueous solution thereof, or a mixture thereof, at 0 to 40 ° C.

Deprotection under acidic conditions is well known and includes, for example, solvents (methylene chloride, dioxane, ethyl acetate, acetic acid,
It is carried out at 0 to 120 ° C. in an organic acid (such as trifluoroacetic acid) or an inorganic acid (such as hydrogen chloride or hydrogen bromide) in water or a mixed solvent thereof.

Hydrogenolysis is known, and examples thereof include solvents (ethers (tetrahydrofuran, dioxane, diemethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes (benzene, toluene, etc.), amides. Inorganic acid in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum dioxide, Raney nickel, etc.) in a system (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof. (Hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or organic acid (acetic acid, p
-Toluenesulfonic acid, oxalic acid, trifluoroacetic acid,
0 to 20 in the presence or absence of formic acid or the like, in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate.
It is performed at a temperature of 0 ° C.

As can be easily understood by those skilled in the art, t-butyl group, benzyl group and the like can be mentioned as the protective group for the carboxyl group and the hydroxyl group, but other than these, they can be eliminated easily and selectively. It is not particularly limited as long as it is a group. For example, TW Greene, Protective Groups in Orga
The one described in nic Synthesis, Wiley, New York, 1991 is used. Examples of the amino-protecting group include a benzyloxycarbonyl group and a t-butoxycarbonyl group, but are not particularly limited as long as they can be easily and selectively eliminated. Examples of the protecting group for hydroxamic acid include a t-butyl group and a benzyl group, but other groups are not particularly limited as long as they can be easily and selectively removed. For example -C (CH _{3) 2} -OCH
₃ etc. are used. By properly using these protecting groups, the desired compound of the present invention can be easily produced.

Further, the above-mentioned compound represented by the general formula (II) is reacted with 1,1'-carbonyldiimidazole and hydroxylamine, and if necessary, a subsequent deprotection reaction (under alkaline or acid conditions is carried out). It can also be produced by subjecting it to deprotection or hydrogenolysis). This reaction is known, and is carried out, for example, in an organic solvent (dimethylformamide, tetrahydrofuran, etc.) in the presence or absence of an amine (triethylamine, pyridine, etc.) at 0 to 40 ° C. The compound represented by the general formula (II) can be produced by a known method, a method represented by the following reaction process schemes 1 to 7 or a method described in Examples.

[0116]

Embedded image

[0117]

Embedded image

[0118]

Embedded image

[0119]

Embedded image

[0120]

Embedded image

[0121]

Embedded image

[0122]

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In the above reaction scheme, the R ^P group represents a protecting group for a carboxyl group (eg, benzyl group, t-butyl group, etc.), n represents 0 or 1, and other symbols have the same meanings as described above. Represent.

Each reaction in the above reaction scheme is carried out by a known method. The compounds represented by the general formula (IV), the general formula (V), the general formula (VI), the general formula (VII) and the general formula (VIII) used as the starting materials in the above process formulas are known per se. Alternatively, it can be easily manufactured by a known method.

In each reaction in the present specification, the reaction product is subjected to a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or It can be purified by a method such as column chromatography, washing, or recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions. Other starting materials and each reagent in the present invention are known per se or can be produced by a known method.

[0126]

[Pharmacological activity] It was proved by the following experiment that the compound of the present invention represented by the general formula (I) has gelatinase A inhibitory activity.

[Experimental Method] Human normal skin fibroblasts (H
Progelatinase A (7 μl) purified from NDF)
Assay buffer solution (90 μl) containing 10 mM p
-Aminophenyl mercury acetate (APMA) (10μ
1) was added and preincubated at 37 ° C. for 1 hour to activate the enzyme.

(1) The activating enzyme (7
μl / tube, 98 μl), solutions of various concentrations of test compounds (compounds of Examples 2 and 2 (3)) or solutions without addition of test compound (2 μl), 0.05% fluorein isothiocyanate (FITC) -gelatin ( 100μ
1) was added and incubated at 37 ° C. for 2 hours. After 0.1 M Tris-hydrochloric acid (pH 9.5; containing 94.7% ethanol) (750 μl) was added to stop the enzyme reaction, the mixture was stirred and allowed to stand at 0 ° C. for 30 minutes to separate non-degraded substrate.
The reaction mixture was centrifuged at 900 xg for 30 minutes. The fluorescence intensity of the gelatinase activity in the supernatant (Ex = 495 nm and Em
= 520 nm). The results for the compounds of Examples 2 and 2 (3) are shown in Table 24.

(2) Synthetic substrate (MOCAc-Pro-Leu-Gly-A ₂ pr
(Dnp) -Ala-Arg-NH ₂ ) (890 μl; final concentration 13.5 μM)
Then, solutions of various concentrations of the test compounds (compounds of Examples 2 (4) and 3 (2)) or solutions without addition of the test compound (10 μl) were preincubated at 37 ° C. for 5 minutes. There, the activated enzyme (7
μl / tube, 100 μl) was added and incubated at 37 ° C. for 20 minutes, after which the enzyme reaction was stopped by adding 0.1 M sodium acetate buffer (2 ml; pH 4.0). The gelatinase activity was measured by the fluorescence intensity (Ex =
It was calculated by measuring 328 nm and Em = 393 nm). The results for the compounds of Examples 2 (4) and 3 (2) are shown in Table 24.

[0130]

[Table 42] Table 24: Gelatinase A inhibitory activity Example number IC ₅₀ (μM) 2 0.0017 2 (3) 0.0010 2 (4) 0.00061 3 (2) 0.00023

[0131]

[Toxicity] On the other hand, the toxicity of the compound of the present invention is very low, and it can be judged that the compound is sufficiently safe for use as a medicament.

[0132]

[Application to pharmaceuticals] In animals including humans, especially in humans, by inhibiting gelatinase, rheumatism, osteoarthritis, pathological bone resorption, osteoporosis, periodontal disease, interstitial nephritis, arteriosclerosis, emphysema, liver cirrhosis. Useful for the prevention and / or treatment of corneal damage, metastatic invasion and proliferation of cancer cells, autoimmune diseases (Crohn's disease, Schuren's disease, etc.), diseases caused by leukocyte cell migration and invasion, angiogenesis, etc. Is.

In order to use the compound of the present invention represented by the general formula (I), its non-toxic acid addition salt, or its hydrate for the above purpose, it is usually systemically or topically, orally or parenterally. It is administered in the form of The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc.
Usually 1 mg to 100 per adult per dose
Orally administered in the range of 0 mg once to several times a day,
Or 1 mg to 100 per adult
In the range of mg, administered parenterally (preferably intravenously) once to several times a day, or from 1 hour to 24 times a day
It is continuously administered intravenously for a time range. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or may be required beyond the range. When the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration and an injection, an external preparation, a suppository and the like for parenteral administration.

Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such a solid composition, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose,
It is mixed with hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate. The composition is prepared according to a standard method.
Additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium fibrin glycolate, stabilizers such as lactose, solubilizers such as glutamic acid or aspartic acid. May be contained. Tablets or pills as needed
It may be coated with a film of a gastric or enteric substance such as gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like. In such liquid compositions, one or more active substances are contained in commonly used inert diluents (eg, purified water, ethanol). This composition is:
In addition to inert diluents, wetting agents, auxiliary agents such as suspending agents,
Sweetening agents, flavoring agents, fragrances and preservatives may be contained. Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. This composition contains, in addition to the inert diluent, buffers such as sodium bisulfite, which provide isotonicity with stabilizers, e.g., isotonic agents such as sodium chloride, sodium citrate, or citric acid. You may. The method of manufacturing the spray is
For example, U.S. Pat.Nos. 2,868,691 and 3,095,355
It is described in detail in the issue.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solution and suspension include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (registered trademark) and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). . These are sterilized by filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions, for example, sterilized or dissolved in sterile distilled water for injection or other solvents before use of the lyophilized product. Other compositions for parenteral administration include external solutions, ointments, liniments, suppositories for intrarectal administration, and vagina that contain one or more active substances and are formulated by a conventional method. Includes pessaries and the like for administration.

[0136]

EXAMPLES The present invention will now be described in detail with reference to Examples and Examples, but the present invention is not limited thereto. Chromatographic separation point and TLC
The solvent in parentheses shown in the above indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. The solvent in parentheses shown in the NMR section indicates the solvent used for the measurement.

Reference Example 1 N-[(4-nitrophenyl) sulfonyl] glycine
t-butyl ester

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To a solution of glycine t-butyl ester hydrochloride (35 g) in pyridine (200 ml) at 0 ° C. 4-
Nitrobenzenesulfonyl chloride (46.3 g) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture is concentrated and the residue is water, then hexane: ethyl acetate = 9: 1.
The solid was washed with a mixed solution of and dried to obtain the title compound (61.4 g) having the following physical properties. TLC: Rf 0.18 (hexane: ethyl acetate = 4:
1).

Reference Example 2 N-[(4-aminophenyl) sulfonyl] glycine
t-butyl ester

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The compound (57.1 g) produced in Reference Example 1 was dissolved in ethanol (200 ml) and tetrahydrofuran (200 ml).
ml) solution was added 10% palladium-carbon (2.2 g). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite (trade name),
The filtrate was concentrated. The obtained crystals were washed with a mixed solution of hexane: ethyl acetate = 4: 1 and dried to give the title compound (50 g) having the following physical data. TLC: Rf 0.36 (hexane: ethyl acetate = 1: 1
1).

Reference Example 3 N-[[4- (p-toluoylamino) phenyl] sulfonyl] glycine t-butyl ester

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P-Toluoyl chloride (0.5 ml) was added to a pyridine (10 ml) solution of the compound (1.2 g) produced in Reference Example 2 under ice cooling. Reaction mixture at room temperature for 3
Stirred for 0 minutes. 1N hydrochloric acid (100 ml) in the reaction mixture
And extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was washed with ether and dried to give the title compound (1.52 g) having the following physical data.

TLC: Rf 0.56 (hexane: ethyl acetate = 1: 1), NMR (CDCl ₃ ): δ 8.08-8.00 (1H, br.s), 7.86 (2H, d,
J = 9.2Hz), 7.82 (2H, d, J = 9.2Hz), 7.78 (2H, d, J = 8.2Hz),
7.31 (2H, d, J = 8.2Hz), 5.04 (1H, t, J = 5.4Hz), 3.67 (2H, d,
J = 5.4Hz), 2.44 (3H, s), 1.37 (9H, s).

Reference Examples 3 (1) to 3 (7) By the same operation as in Reference Example 3 using the corresponding compounds,
The compound of the present invention having the following physical properties was obtained.

Reference Example 3 (1) N-[[4- (benzoylamino) phenyl] sulfonyl] glycine t-butyl ester

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TLC: Rf 0.70 (ethyl acetate), NMR (CDCl ₃ ): δ 8.02 (1H, s), 7.9-7.8 (6H, m), 7.6-
7.3 (3H, m), 5.02 (1H, t, J = 5.4Hz), 3.68 (2H, d, J = 5.4Hz),
1.37 (9H, s).

Reference Example 3 (2) N-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycine t-butyl ester

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TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1), NMR (CDCl ₃ ): δ 7.94-7.90 (1H, br.s), 7.86 (2H, d, J =
9.2Hz), 7.85 (2H, d, J = 8.8Hz), 7.79 (2H, d, J = 9.2Hz), 6.
99 (2H, d, J = 8.8Hz), 5.00 (1H, t, J = 5.4Hz), 3.89 (3H, s),
3.67 (2H, d, J = 5.4Hz), 1.37 (9H, s).

Reference Example 3 (3) N-[[4- (4-Pentylbenzoylamino) phenyl] sulfonyl] -D-phenylalanine t-butyl ester

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TLC: Rf 0.66 (hexane: ethyl acetate = 3: 2), NMR (CDCl ₃ ): δ 7.95 (1H, s), 7.84-7.68 (6H, m), 7.3
5-7.08 (7H, m), 5.10 (1H, d, J = 10.0Hz), 4.14-4.00 (1H,
m), 3.02 (2H, d, J = 6.0Hz), 2.67 (2H, t, J = 7.8Hz), 1.72-1.
56 (2H, m), 1.48-1.25 (4H, m), 1.21 (9H, s), 0.89 (3H, t, J
= 5.0Hz).

Reference Example 3 (4) N-[[4- (p-toluoylamino) phenyl] sulfonyl] -D-tryptophan benzyl ester

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TLC: Rf 0.32 (hexane: ethyl acetate = 1: 1), NMR (CDCl ₃ + CD ₃ OD): δ 7.81 (2H, d, J = 8Hz), 7.56 (4H,
s), 7.43 (1H, d, J = 7Hz), 7.35-7.25 (6H, m), 7.15-7.00 (4
H, m), 6.81 (1H, s), 4.92 (2H, s), 4.25 (1H, m), 3.18 (2H,
m), 2.45 (3H, s).

Reference Example 3 (5) N-[[3- (benzoylamino) phenyl] sulfonyl] glycine t-butyl ester

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TLC: Rf 0.65 (hexane: ethyl acetate = 1: 1), NMR (CDCl ₃ ): δ 8.26-8.16 (2H, m), 8.00 (1H, t, J = 1.8H)
z), 7.94-7.87 (2H, m), 7.66-7.46 (5H, m), 5.24 (1H, t, J =
5.4Hz), 3.70 (2H, d, J = 5.4Hz), 1.35 (9H, s). Reference Example 3 (6) N-[[2- (benzoylamino) phenyl] sulfonyl] glycine t-butyl ester

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TLC: Rf 0.51 (hexane: ethyl acetate = 3: 2), NMR (CDCl ₃ ): δ 10.27 (1H, s), 8.73 (1H, d, J = 8.4Hz),
8.05-7.94 (2H, m), 7.90 (1H, dd, J = 1.8Hz, 8.0Hz), 7.70-
7.45 (4H, m), 7.30-7.18 (1H, m), 5.20 (1H, t, J = 5.2Hz),
3.61 (2H, d, J = 5.4Hz), 1.33 (9H, s).

Reference Example 3 (7) N-[[4- (2-thienylcarbonylamino) phenyl] sulfonyl] -D-alanine t-butyl ester

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TLC: Rf 0.25 (hexane: ethyl acetate = 2: 1), NMR (DMSO-d ₆ ): δ 10.51 (1H, s), 8.12-8.05 (2H, m),
7.94-7.88 (3H, m), 7.74 (2H, d, J = 8.8Hz), 7.24 (1H, t, J =
3.8Hz), 3.72 (1H, quint, J = 7.4Hz), 1.27 (9H, s), 1.14 (3
H, d, J = 7.4Hz).

Reference Example 4 N-[[4- (p-toluoylamino) phenyl] sulfonyl] glycine

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A solution of the compound (1.45 g) produced in Reference Example 3 in trifluoroacetic acid (10 ml) and water (1 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, the residue was washed with ether and dried to obtain the compound of the present invention (1.16 g) having the following physical data. TLC: Rf 0.48 (chlorophorm: methanol: acetic acid = 16: 3: 1), NMR (d ₆ -DMSO): δ 10.46 (1H, s), 8.02-7.84 (1H), 7.
97 (2H, d, J = 9.0Hz), 7.88 (2H, d, J = 8.0Hz), 7.75 (2H, d, J =
9.0Hz), 7.34 (2H, d, J = 8.0Hz), 3.55 (2H, d, J = 6.2Hz), 2.
40 (3H, s).

Reference Examples 4 (1) to 4 (7) Instead of the compound produced in Reference Example 3, Reference Examples 3 (1) to 4 (7)
Using the compound prepared in 3 (7), the same operation as in Reference Example 4 or the same purpose as that (for example, hydrogenolysis)
Thus, the compound of the present invention having the following physical properties was obtained.

Reference Example 4 (1) N-[[4- (benzoylamino) phenyl] sulfonyl] glycine

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TLC: Rf 0.19 (chloropholom: methanol: acetic acid: water = 50: 10: 1: 1), NMR (CD ₃ OD): δ 8.0-7.8 (6H, m), 7.6-7.5 (3H, m) , 3.
70 (2H, s).

Reference Example 4 (2) N-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycine

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TLC: Rf 0.43 (chlorophorm: methanol: acetic acid = 16: 3: 1), NMR (d ₆ -DMSO): δ 10.39 (1H, s), 7.97 (2H, d, J = 8.8H
z), 7.95 (2H, d, J = 9.0Hz), 7.89 (1H, t, J = 6.2Hz), 7.75 (2
H, d, J = 9.0Hz), 7.70 (2H, d, J = 8.8Hz), 3.84 (3H, s), 3.55
(2H, d, J = 6.2Hz).

Reference Example 4 (3) N-[[4- (4-Pentylbenzoylamino) phenyl] sulfonyl] -D-phenylalanine

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TLC: Rf 0.21 (chloroform: methanol: acetic acid = 95: 4: 1), NMR (DMSO-d ₆ ): δ 13.00-12.20 (1H, br.s), 10.40 (1
H, s), 8.11 (1H, d, J = 9.0Hz), 7.88 (2H, d, J = 8.6Hz), 7.84
(2H, d, J = 8.4Hz), 7.52 (2H, d, J = 8.6Hz), 7.34 (2H, d, J = 8.
4Hz), 7.28-7.08 (5H, m), 3.92-3.78 (1H, m), 2.93 (1H, d
d, J = 5.8,13.4Hz), 2.71 (1H, dd, J = 8.8,13.4Hz), 2.66 (2H,
t, J = 8.2Hz), 1.70-1.50 (2H, m), 1.44-1.18 (4H, m), 0.87
(3H, t, J = 6.8Hz).

Reference Example 4 (4) N-[[4- (p-toluoylamino) phenyl] sulfonyl] -D-tryptophan

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TLC: Rf 0.13 (chloroform: methanol: acetic acid: water = 100: 10: 1: 1), NMR (DMSO-d ₆ ): δ 12.57 (1H, br.s), 10.8 (1H, s), 1
0.42 (1H, s), 8.13 (1H, d, J = 8.8Hz), 7.9-7.8 (4H, m), 7.5
9 (2H, d, J = 8.8Hz), 7.4-7.25 (4H, m), 7.1-6.9 (3H, m), 3.
95-3.85 (1H, m), 3.04 (1H, dd, J = 6.18Hz), 2.84 (1H, dd, J =
7.4,18Hz), 2.39 (3H, s).

Reference Example 4 (5) N-[[3- (benzoylamino) phenyl] sulfonyl] glycine

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TLC: Rf 0.36 (chloroform: methanol: acetic acid = 16: 3: 1), NMR (DMSO-d ₆ ): δ 10.54 (1H, s), 8.33 (1H, s), 8.14-
7.90 (4H, m), 7.68-7.44 (5H, m), 3.60 (2H, d, J = 6.0Hz).

Reference Example 4 (6) N-[[2- (benzoylamino) phenyl] sulfonyl] glycine

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TLC: Rf 0.34 (chloroform: methanol: acetic acid = 90: 10: 1), NMR (DMSO-d ₆ ): δ 13.00-12.60 (1H, br.s), 10.26 (1H,
s), 8.67-8.56 (1H), 8.52-8.44 (1H, m), 8.02-7.92 (2H,
m), 7.87 (1H, dd, J = 1.4,7.8Hz), 7.74-7.54 (4H, m), 7.38
-7.27 (1H, m), 3.65 (2H, d, J = 4.6Hz).

Reference Example 4 (7) N-[[4- (2-thienylcarbonylamino) phenyl] sulfonyl] -D-alanine

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TLC: Rf 0.21 (chloroform: methanol: water = 4: 1: 0.1), NMR (DMSO-d ₆ ): δ 12.60 (1H, br.s), 10.49 (1H, s), 8.
05-7.98 (2H, m), 7.91-7.85 (3H, m), 7.73 (2H, d, J = 8.8H
z), 7.21 (1H, t, J = 3.8Hz), 3.77-3.68 (1H, m), 1.13 (3H,
d, J = 7.2 Hz).

Example 1 N-benzyloxy-N- [N '-[[4- (p-toluylamino) phenyl] sulfonyl] glycyl] amide

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Compound produced in Reference Example 4 (348 mg)
In N, N-dimethylformamide (5 ml) solution of N-
Benzylhydroxylamine hydrochloride (192 mg) and 1-ethyl-3- [3- (dimethylamino) propyl]
Carbodiimide (230 mg), 1-hydroxybenzotriazole (199 mg) and triethylamine (0.34
(ml) were sequentially added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, ethyl acetate was added to the obtained residue, and the mixture was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue was washed with ether and dried to obtain the compound of the present invention (417 mg) having the following physical data.

TLC: Rf 0.52 (chlorophorm: methanol: acetic acid = 9: 1: 0.5), NMR (d ₆ -DMSO + CCl ₄ ): δ 11.17 (1H, s), 10.48 (1H,
s), 7.98 (2H, d, J = 8.8Hz), 7.87 (2H, d, J = 7.8Hz), 7.76 (2
H, d, J = 8.8Hz), 8.1-7.7 (1H, brs), 7.50-7.25 (7H, m), 4.
66 (2H, s), 2.40 (2H, s).

Examples 1 (1) -1 (4) Instead of the compound prepared in Reference Example 4, Reference Examples 4 (1)-
By the same operation as in Example 1 using the compound prepared in 4 (4), the compound of the present invention having the following physical properties was obtained.

Example 1 (1) N-benzyloxy-N- [N '-[[4- (benzoylamino) phenyl] sulfonyl] glycyl] amide

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TLC: Rf 0.38 (chlorophorm: methanol: acetic acid: water = 100: 10: 1: 1), NMR (CDCl ₃ + CD ₃ OD): δ 7.95-7.8 (6H, m), 7.6-7.45
(3H, m), 7.37 (5H, s), 4.79 (2H, s), 3.50 (2H, s).

Example 1 (2) N-benzyloxy-N- [N '-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycyl] amide

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TLC: Rf 0.52 (chlorophorm: methanol = 9: 1), NMR (d ₆ -DMSO): δ 11.17 (1H, s), 10.41 (1H, s), 8.04
-7.84 (1H), 7.97 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz),
7.75 (2H, d, J = 8.8Hz), 7.42-7.28 (5H, m), 7.07 (2H, d, J =
8.8Hz), 4.66 (2H, s), 3.84 (3H, s), 3.40-3.30 (2H).

Example 1 (3) N-benzyloxy-N- [N '-[[4- (4-pentylbenzoylamino) phenyl] sulfonyl] -D-
Phenylalanyl] amide

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TLC: Rf 0.54 (chloroform: methanol = 19: 1), NMR (DMSO-d ₆ ): δ 11.21 (1H, s), 10.43 (1H, s), 8.23
(1H, d, J = 9.0Hz), 7.89 (2H, d, J = 8.8Hz), 7.83 (2H, d, J = 8.
4Hz), 7.62 (2H, d, J = 8.8Hz), 7.40-7.08 (12H, m), 4.41 (1
H, d, J = 11.0Hz), 4.34 (1H, d, J = 11.0Hz), 3.85-3.68 (1H,
m), 2.79 (1H, dd, J = 6.8, 13.6Hz), 2.73-2.60 (1H), 2.65
(2H, t, J = 8.2Hz), 1.70-1.50 (2H, m), 1.45-1.20 (4H, m),
0.86 (3H, t, J = 6.6Hz).

Example 1 (4) N-benzyloxy-N- [N '-[[2- (p-toluoylamino) phenyl] sulfonyl] -D-tryptophyllamide

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TLC: Rf 0.36 (chloroform: methanol = 9: 1), NMR (DMSO-d ₆ ): δ 11.19 (1H, s), 10.80 (1H, s), 10.41
(1H, s), 8.16 (1H, d, J = 8.2HZ), 7.84 (4H, m), 7.65 (2H, d, J
= 8.8Hz), 7.36-6.92 (12H, m), 4.39 (1H, d, J = 13.9Hz), 4.
30 (1H, d, J = 13.9Hz), 3.78 (1H, q, J = 8.2Hz), 3.05-2.70 (2
H, m), 2.40 (3H, s).

Example 2 N-Hydroxy-N- [N '-[[4- (p-toluoylamino) phenyl] sulfonyl] glycyl] amide

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Compound prepared in Example 1 (150 mg)
To N, N-dimethylformamide (10 ml) solution of
0% Palladium-carbon (30 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hr. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated. Ether was added to the residue, the crystals were filtered and dried to obtain the compound of the present invention (80 mg) having the following physical data. TLC: Rf 0.21 (chlorophorm: methanol: acetic acid = 9: 1: 0.5), NMR (CD ₃ OD + d ₆ -DMSO): δ 8.10-7.70 (6H, m), 7.34 (2
H, d, J = 7.81Hz), 3.48 (2H, s), 2.43 (3H, s).

Examples 2 (1) to 2 (4) Instead of the compound prepared in Example 1, Examples 1 (1) to 2 (4)
The compound of the present invention having the following physical properties was obtained by the same procedure as in Example 2 using the compound prepared in 1 (4).

Example 2 (1) N-hydroxy-N- [N '-[[4- (benzoylamino) phenyl] sulfonyl] glycyl] amide

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TLC: Rf 0.04 (chlorophorm: methanol: acetic acid: water = 100: 10: 1: 1), NMR (d ₆ -DMSO): δ 10.58 (1H, s), 10.53 (0.5H, s), 8 .
86 (0.5H, s), 8.0-7.95 (4H, m), 7.9-7.75 (2H, m), 7.6-7.
5 (3H, m), 3.33 (2H, s).

Example 2 (2) N-hydroxy-N- [N '-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycyl]
Amide

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TLC: Rf 0.38 (chlorophorm: methanol: acetic acid = 16: 3: 1), NMR (d ₆ -DMSO): δ 10.52 (1H, s), 10.40 (1H, s), 8.86
(1H, s), 7.97 (4H, d, J = 8.8Hz), 7.90-7.70 (1H), 7.76 (2
H, d, J = 8.8Hz), 7.07 (2H, d, J = 8.8Hz), 3.85 (3H, s), 3.40
-3.10 (2H).

Example 2 (3) N-Hydroxy-N- [N '-[[4- (4-pentylbenzoylamino) phenyl] sulfonyl] -D-phenylalanyl] amide

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TLC: Rf 0.42 (chloroform: methanol = 9: 1), NMR (DMSO-d ₆ ): δ 10.41 (1H, s), 7.88 (2H, d, J = 8.4H)
z), 7.84 (2H, d, J = 8.4Hz), 7.54 (2H, d, J = 8.4Hz), 7.35 (2
H, d, J = 8.4Hz), 7.26-7.00 (5H, m), 3.77 (1H, t, J = 6.6Hz),
2.90-2.72 (1H, m), 2.72-2.56 (3H, m), 1.70-1.50 (2H,
m), 1.50-1.10 (4H, m), 0.87 (3H, t, J = 6.8Hz).

Example 2 (4) N-hydroxy-N- [N '-[[2- (p-toluoylamino) phenyl] sulfonyl] -D-tryptophyllamide

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TLC: Rf 0.59 (chloroform: methanol = 4: 1), NMR (DMSO-d ₆ ): δ 10.74 (1H, s), 10.59 (1H, s), 10.38
(1H, s), 8.80 (1H, s), 8.02-7.80 (5H, m), 7.58 (2H, d, J = 8.
6Hz), 7.38-7.23 (4H, m), 7.00-6.85 (1H, m), 3.90-3.74
(1H, m), 3.04-2.90 (1H, m), 2.75-2.61 (1H, m), 2.40 (3H,
s).

Example 3 N-Hydroxy-N- [N '-[[3- (benzoylamino) phenyl] sulfonyl] glycyl] amide

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The compound prepared in Reference Example 4 (5) (500
mg) in tetrahydrofuran (15 ml),
1'-Carbonyldiimidazole (265 mg) was added. The mixture was stirred at room temperature for 7 hours. Hydroxylamine hydrochloride (213 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
Stir for 8 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried and concentrated. The obtained compound was washed with ether and dried to obtain the compound of the present invention (391 mg) having the following physical data. TLC: Rf 0.46 (chloroform: methanol: acetic acid = 16: 3: 1), NMR (DMSO-d ₆ ): δ 10.55 (2H, s), 8.88 (1H, s), 8.33 (1)
H, s), 8.09-7.90 (4H, m), 7.64-7.48 (5H, m), 3.40-3.30
(2H).

Examples 3 (1) -3 (2) Reference Example 4 instead of the compound prepared in Reference Example 4 (5).
Using the compounds produced in (6) and 4 (7), the compound of the present invention having the following physical properties was obtained by the same procedure as in Example 3.

Example 3 (1) N-hydroxy-N- [N '-[[2- (benzoylamino) phenyl] sulfonyl] glycyl] amide

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TLC: Rf 0.40 (ethyl acetate), NMR (DMSO-d ₆ ): δ 10.60 (1H, s), 10.32 (1H, s), 9.05-
8.80 (1H, br.s), 8.57 (1H, t, J = 6.0Hz), 8.50-8.41 (1H,
m), 8.03-7.93 (2H, m), 7.90-7.82 (1H, m), 7.74-7.52 (4
H, m), 7.40-7.28 (1H, m), 3.41 (2H, d, J = 6.0Hz).

Example 3 (2) N-Hydroxy-N- [N '-[[2- (2-thienylcarbonylamino) phenyl] sulfonyl] -D, L-
Alanyl] amide

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TLC: Rf 0.48 (chloroform: methanol = 4: 1), NMR (DMSO-d ₆ ): δ 10.57 (1H, br.s), 8.84 (1H, d, J = 2.2)
Hz), 8.11 (1H, d, J = 3.6Hz), 7.97-7.88 (5H, m), 7.76 (2H,
d, J = 8.8Hz), 7.24 (1H, t, J = 3.6Hz), 3.68-3.61 (1H, m),
1.02 (3H, d, J = 7.2Hz).

[0205]

[Formulation example]

Formulation Example 1 The following components were mixed in a conventional manner and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient. -N-hydroxy-N- [N '-[[4- (p-toluoylamino) phenyl] sulfonyl] glycyl] amide ... 5.0 g-Carboxymethyl cellulose calcium (disintegrant) ... 0.2 g-Magnesium stearate ( Lubricant) …… 0.1 g ・ Microcrystalline cellulose …… 4.7 g

Formulation Example 2 The following components were mixed by a conventional method, the solution was sterilized by a conventional method, 5 ml each was filled in an ampoule, and freeze-dried by a conventional method, and 20 mg of the active ingredient was contained in 1 ampoule. I got 100 ampoules. -N-hydroxy-N- [N '-[[4- (p-toluoylamino) phenyl] sulfonyl] glycyl] amide: 2.00 g-mannitol: 20 g-distilled water: 1000 ml

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/18 ACS A61K 31/18 ACS ACV ACV ADU ADU AED AED 31/38 ABG 31/38 ABG 31 / 40 ADF 31/40 ADF 31/405 31/405 31/44 ACK 31/44 ACK 31/63 31/63 31/635 31/635 C07C 311/19 7419-4H C07C 311/19 311/37 311/37 311/46 311/46 311/47 7419-4H 311/47 327/26 7106-4H 327/26 327/48 327/48 329/10 7106-4H 329/10 333/08 7106-4H 333/08 335 / 16 7106-4H 335/16 C07D 209/20 C07D 209/20 213/82 213/82 333/38 333/38 (72) Inventor Toru Miyazaki 3-1-1 Sakurai, Shimamoto Town, Mishima District, Osaka Prefecture Ono Pharmaceutical Co., Ltd. Minase Research Institute, Inc. (72) Inventor Hiroyuki Ohno 3 Sakurai, Shimamoto-cho, Mishima-gun, Osaka Prefecture 1-1 Ono Pharmaceutical Industry Co., Ltd. Minase the laboratory

Claims (5)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ is a hydrogen atom or a C1-4 alkyl group, R ² is 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a phenyl group, or 4) a C1 substituted with a phenyl group. represent ~ 4 alkyl group, E is, 1) -CO-NR ³ - in group (group, R ³ represents a hydrogen atom, C1
Represents a C4 alkyl group, a phenyl group, or a C1-4 alkyl group substituted with a phenyl group. ), 2) -NR ³ -CO- group (wherein R ³ has the same meaning as described above), 3) -CO-O- group, 4) -O-CO- group, 5) -NR. ³ -CO-NR ³ - group (wherein, R ³ represents the same meaning as above.), 6) -CO-CH 2 - group, 7) -CO- group, 8) -O-CO-NR ³ -group (in the group, R ³ represents the same meaning as described above), 9) —NR ³ —CO—O— group (in the group, R ³ represents the same meaning as described above), 10). —O—CO—O— group, 11) —CS—NR ³ — group (in the group, R ³ represents the same meaning as described above), 12) —NR ³ —CS— group (in the group, R ³ Represents the same meaning as described above), 13) -NR ³ -CS-NR ³ -group (in the group, R ³ represents the same meaning as described above), 14) -O-CS-NR ^3-. in group (group, R ³ is as defined above ^{Wath.), 15) -NR 3 -CS} -O- group (wherein, R ³ represents the same meaning as above.), 16) -CS-O- group, 17) -O-CS- group, Or 18) -O-CS-O- group is represented, A is 1) hydrogen atom, 2) C1-8 alkyl group, 3) C3-7 cycloalkyl group, or 4) Ar group (Ar group in the group). Represents a carbocyclic or heterocyclic aryl, and has 1 to 3 C1-15 alkyl groups, C1
~ 15 alkoxy group, halogen atom, nitro group, cyano group, guanidino group, amidino group, hydroxyl group, benzyloxy group, -NR ⁹ R ¹⁰ group (in the group, R ⁹ and R ¹⁰ are each independently a hydrogen atom or represents a C1~4 alkyl group), -.. COOR ¹¹ group (wherein, R ¹¹ is represents a hydrogen atom or a C1~4 alkyl group), a trifluoromethyl group, substituted with a phenyl group or a heterocyclic group, May be. And J is 1) a single bond, 2) a C2-4 alkylene group, 3) a C2-4 alkenylene group, or (In the group, R ⁴ and R ⁵ are each independently, (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a C1-4 alkoxy group, or R ⁴ and R ⁵ are carbons to which they are bonded. . representing the C3~7 cycloalkyl groups together with the atoms) represents, G is embedded image _{1) - (CH 2) m} - in group (group, m represents 2, 3 or 4. ), Or (In the group, R ⁶ and R ⁷ are each independently (i)
Hydrogen atom, (ii) C1-8 alkyl group, (iii) -CO
OR ⁸ group (wherein R ⁸ is a hydrogen atom, a C 1-8 alkyl group, a phenyl group, or a C 1-8 substituted with a phenyl group)
Represents a 4-alkyl group. ), (Iv) Ar group (in the group, A
The r group has the same meaning as described above. ), (V) heterocyclic group, (vi) —COOR ⁸ group (wherein R ⁸ has the same meaning as described above), C1-4 alkoxy group, hydroxyl group, benzyloxy group, —NR ¹² R ¹³ group. (In the group, R ¹² and R ¹³
Each independently represent a hydrogen atom or a C1-4 alkyl group. ), A —NR ¹⁴ COOR ¹⁵ group (in which R ¹⁴ represents a hydrogen atom or a C1-4 alkyl group, R ¹⁵ represents a hydrogen atom, a C1-8 alkyl group, a phenyl group or a C1-4 substituted with a phenyl group). Represents an alkyl group), A
a C1-8 alkyl group substituted with an r group or a heterocyclic group (provided that one of the carbon atoms of the C1-8 alkyl group may be replaced with one sulfur atom), or R ⁶ and R ⁷ together with the carbon atom bonded represent C3~7 cycloalkyl group. ). However, E is ^{-O-CO-NR 3 -,} - O-CO-
O -, - O-CS- NR 3 - , or -O-CS-O-a and, J excluding compounds and A is a single bond is a hydrogen atom. ] The hydroxamic acid derivative shown by these, and those nontoxic salts. 2. E is —CO—NR ³ —, —NR ³ —CO
^{-, - NR 3 -CO-NR} 3 -, - O-CO-NR 3 -,
^{-NR 3 -CO-O -, -} CS-NR 3 -, - NR 3 -C
^{S -, - NR 3 -CS-} NR 3 -, - O-CS-NR
The compound according to claim 1, which is ^3- , -NR ³ -CS-O- (wherein R ³ has the same meaning as described in claim 1). 3. E is —CO—O—, —O—CO—, —
_{CO-CH 2 -, - CO} -, - O-CO-O -, - CS
The compound according to claim 1, which is -O-, -O-CS-, or -O-CS-O-. 4. The compound is N-benzyloxy-N- [N ′-[[4- (p-toluylamino) phenyl] sulfonyl] glycyl] amide, N-benzyloxy-N- [N ′-[[ 4- (benzoylamino) phenyl] sulfonyl] glycyl] amide, N-benzyloxy-N- [N '-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycyl] amide, N-benzyloxy-N -[N '-[[4- (4-pentylbenzoylamino) phenyl] sulfonyl] -D-
Phenylalanyl] amide, N-benzyloxy-N- [N '-[[2- (p-toluoylamino) phenyl] sulfonyl] -D-tryptophyllamide, N-hydroxy-N- [N'-[ [4- (p-Toluoylamino) phenyl] sulfonyl] glycyl] amide, N-hydroxy-N- [N '-[[4- (benzoylamino) phenyl] sulfonyl] glycyl] amide, N-hydroxy-N- [N '-[[4- (4-methoxybenzoylamino) phenyl] sulfonyl] glycyl]
Amido N-hydroxy-N- [N '-[[4- (4-pentylbenzoylamino) phenyl] sulfonyl] -D-phenylalanyl] amide, N-hydroxy-N- [N'-[[2- ( p-toluoylamino) phenyl] sulfonyl] sulfonyl] -D-tryptophyll] amide, N-hydroxy-N- [N ′-[[3- (benzoylamino) phenyl] sulfonyl] glycyl] amide, N-hydroxy-N- [ N '-[[2- (benzoylamino) phenyl] sulfonyl] glycyl] amide, N-hydroxy-N- [N'-[[2- (2-thienylcarbonylamino) phenyl] sulfonyl] -D, L-
The compound according to claim 1, which is an alanyl] amide or a non-toxic salt thereof. 5. A gelatinase inhibitor containing the compound represented by the general formula (I) according to claim 1 and a non-toxic salt thereof as an active ingredient.