JPH11236369A - Sulfonamide derivative, method for producing the same, and pharmaceutical composition containing the same - Google Patents

Abstract

(57) [Summary] [Object] To provide an orally administrable MMPs inhibitor, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient. [Constitution] The following general formula (I): Wherein R ₁ is a lower alkyl group, a heterocyclic ring, a phenyl group,
Or a substituted phenyl group, R ₂ is a -COOH group, -CONH
An OH group, or -COOC ₂ H ₅ group. A is (1) -P
h-NHCO-R ₃ group (Ph is a phenyl group, R ₃ is a substituted or unsubstituted phenyl group, thienyl group, or pyridyl group), (2) -R ₄ -R ₅ group (R ₄ is a phenyl group or thienyl group) A group consisting of a group, R ₅ is a substituted or unsubstituted phenyl group or thienyl group), and (3) a —Ph—NHSO ₂ —R ₆ group (Ph is a phenyl group, and R ₆ is a substituted or unsubstituted phenyl group). This is a more selected group. Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sulfonamide derivative or a pharmaceutically acceptable salt thereof having a matrix metalloproteinases (hereinafter referred to as MMPs) inhibitory activity, a process for producing the same, and a method for producing the same. The present invention relates to a pharmaceutical composition containing the salt as an active ingredient.

[0002]

2. Description of the Related Art MMPs are prepared from extracellular matrix (Extr
It is a proteolytic enzyme involved in the decomposition of acellular matrix, and has Zn ²⁺ and Ca ²⁺ at its active center. Under normal physiological conditions, the constitutive
e) MMPs present in living organisms (in tissues) with low expression
Inhibitor (Tissue inhibitor of meralloproteinase: T
IMPs). However, under pathological conditions, such as in rheumatism and osteoarthritis, MMPs are elevated and cannot be controlled by TIMPs present in the body.
This condition further reduces articular cartilage glycoprotein and collagen (J. Trzaskos, et al., Acta Onthopaedica Scandi
navica, 66, 150 (1995)). MMPs are also said to play an important role in the development of arteriosclerosis and restenosis after angioplasty (CMDollery et al., Cric Res., 7).
7,863, (1995)).

[0003] Therefore, controlling the activity of MMPs produced and increased under such pathological conditions with an MMPs inhibitor (MMPs inhibitor) is effective for the treatment of the above-mentioned diseases, and also for prevention of cancer metastasis and repair of corneal ulcer. (RP
Beckett et al., DDT, 1, 16, (1996)), and the application of MMPs inhibitors to inflammatory bowel disease is also expected (Sylvia LF Pender et al., J. Immunol., 158, 1582, (1
997)). Accordingly, a number of substrate analog MMPs inhibitors have been studied (Inhibitors of matrix metalloproteinases).
(MMPs), Nigel RA Beeley, phillip RJ Ansell, A
ndrew JP Docherty et al., Curr.Opin.Ther.Patent., 4,7-1
6, (1994), Current Drugs Ltd ISSN 0962-2594), and reviews of various MMPs inhibitors have been reported (CM Dollery et al., Cric Res., 77, 863, (199).
Five)). Many patents for MMPs inhibitors have also been disclosed,
EP 606046 and JP-A-9-104672 disclose that arylsulfonamide derivatives have a matrix metalloproteinase inhibitory action.

[0004]

However, compounds which have been reported as inhibitors of MMPs have poor oral absorption and are therefore administered intrapleurally (Drug News & Perstectives, 8).
(4), 247, (1995)) or administration with eye drops (Drug of the
Future, 18,1101, (1993)), which was inconvenient. An object of the present invention is to provide a non-peptide MMPs inhibitor which has good oral absorption and can be orally administered, a method for producing the same, and a pharmaceutical composition containing the compound as an active ingredient.

[0005]

Means for Solving the Problems The present inventors have developed MMPs
As a result of intensive studies to find a compound having an inhibitory action, it was found that the sulfonamide derivative represented by the general formula (I) has an MMPs inhibitory action. The sulfonamide derivative represented by the general formula (I) of the present invention is
This is a novel compound that has never been known before. That is, the present invention provides the following general formula (I):

[0006]

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Wherein R ₁ is a lower alkyl group, a heterocyclic ring,
It is a phenyl group or a substituted phenyl group substituted with a lower alkyl group or a lower alkoxy group. R ₂ is -CO
OH group, a -CONHOH group or -COOC ₂ H ₅ group. A is a (1) -Ph-NHCO-R ₃ group (Ph is a phenyl group, R ₃ is a phenyl group, or a lower alkyl group, a lower alkoxy group or a —O— (CH ₂ ) _n NH ₂ group (n
= 1 to 3) substituted phenyl group, or thienyl group, or substituted thienyl group substituted with a lower alkyl group,
Or pyridyl group), (2) —R ₄ —R ₅ group (R ₄ is a phenyl group or thienyl group, R ₅ is a phenyl group, or a lower alkyl group, a lower alkoxy group, a hydroxy group, an amino group,
A substituted phenyl group substituted with a carboxyl group or a cyano group, or a thienyl group, or a substituted thienyl group substituted with a lower alkyl group), and (3) -Ph-NHSO ₂
A group selected from the group consisting of —R ₆ groups (Ph is a phenyl group, R ₆ is a phenyl group, or a substituted phenyl group substituted with a lower alkyl group or a lower alkoxy group). Or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition for treating and / or preventing a disease caused by the destruction of an extracellular matrix by a matrix metalloproteinase containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Things.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I) of the present invention, a lower alkyl group is an alkyl group having 1 to 6 carbon atoms, which may be linear or branched, methyl, ethyl, Propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, cyclopropyl, cyclohexyl and the like. The heterocyclic ring of R ₁ is, for example, pyridyl or pyrazolyl. Further, a lower alkoxy group is an alkoxy group containing 1 to 6 carbon atoms.

The compound of the general formula (I) of the present invention can be produced as follows. (1) In the compound of the general formula (I), R ₂ is —COO
A compound wherein the H group and A are -Ph-NHCO-R ₃ groups, that is, the compound of the general formula (V) according to claim 2. The compound of the general formula (V) is produced as follows.

[0010]

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That is, a compound of the general formula (II) and a compound of the general formula (III) are converted into an organic solvent such as chloroform or dichloromethane in the presence of an organic base such as triethylamine or pyridine or a base such as sodium carbonate or potassium carbonate. In, react by stirring at room temperature or under heating,
A compound of general formula (IV) is obtained. Then, this general formula (I
V) is alkali-hydrolyzed with sodium hydroxide or potassium hydroxide to obtain a compound of the general formula (V). (2) In the compound of the general formula (I), R ₂ is -CON
A compound wherein the HOH group and A are -Ph-NHCO-R ₃ groups, that is, the compound of the general formula (VI) according to claim 3. The compound of the general formula (VI) is produced as follows.

[0012]

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That is, the hydroxamic acid of the general formula (VI) can be obtained by reacting the carboxylic acid of the general formula (V) with hydroxylamine in the presence of a condensing agent. As a condensing agent, diphenylphosphoryl azide (DPP
A), diethylphosphoryl cyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), or 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide hydrochloride (WSCDI) can be used. The reaction is performed in a solvent under a base. Dimethylformamide (DMF) or tetrahydrofuran (THF) can be used as the solvent. As the base, triethylamine or N
-Methylmorpholine (NMM) can be used.
Further, to obtain a condensed with O- benzyl hydroxamic acid amide (XVII) using O- benzylhydroxylamine in place of the above hydroxylamine (NH ₂ O-Bn), this palladium - de carbon (Pd / C) Benzylation can also give the general formula (VI).

[0014]

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(3) In the compound of the general formula (I), R
₂ -COOH group, compounds wherein A is -R ₄ -R ₅ group, namely the preparation of compounds of the general formula according to claim 4 (XI). The compound of the general formula (XI) can be produced as follows.

[0016]

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That is, A. Suzuki (Synth. Org. Chem. Jp.
n., 1988, 46, 848.), E. Negishi (J. Org. Chem., 1977, 42, 182).
1.) or JKStille (J. Org. Chem., 1987, 52, 422.) with reference to a cross-coupling reaction using a palladium or nickel catalyst, and adding a compound of the general formula (VII) to a compound of the general formula (VIII). A compound or a compound of the general formula (IX) is cross-coupled to give a compound of the general formula (X). This cross-coupling reaction can be performed in a solvent containing a base in the presence of a catalyst. As the catalyst, a palladium compound represented by tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate or the like can be used. As the base, sodium carbonate, potassium carbonate and the like can be used. As the solvent, toluene, dimethylformamide, water and the like can be used. The reaction is performed at room temperature or with heating. Thereafter, the compound of the formula (X) is alkali-hydrolyzed with sodium hydroxide or potassium hydroxide to obtain the compound of the formula (XI). (4) In the compound of the general formula (I), R ₂ is -CON
Compound HOH group, A is -R ₄ -R ₅ group, namely the production of compounds of the general formula (XII) according to claim 5. The compound of the general formula (XII) can be produced as follows.

[0018]

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That is, the hydroxamic acid of the general formula (XII) can be obtained by reacting the carboxylic acid of the general formula (XI) with hydroxylamine in the presence of a condensing agent and a base. DPPA, DEPC, DCC, C
DI or WSCDI, and N-methylmorpholine (NMM), triethylamine [(C
₂ H ₅ ) ₃ N] and the like, and DMF or THF can be used as the solvent. In addition, O-benzylhydroxylamine (NH ₂ O-
(Bn) to give O-benzylhydroxamic acid amide (XVIII) after debenzylation to give a compound of the general formula (XII)
Can also be obtained.

[0020]

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(5) In the compound of the general formula (I), R
₂ -COOH group, A is -Ph-NHSO ₂ -R ₆ group compounds, namely the production of compounds of general formula (XV) according to claim 6. The compound of the general formula (XV) can be produced as follows.

[0022]

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That is, a compound of the general formula (XIII) is added to a compound of the general formula (II) by adding triethylamine [(C ₂ H ₅ ) ₃
N], in the presence of an organic base such as pyridine or a base such as sodium carbonate or potassium carbonate, and reacted at room temperature or with heating and stirring in an organic solvent such as chloroform or dichloromethane,
The compound of the general formula (XIV) is obtained. Next, the general formula (XI
V) is alkali-hydrolyzed with sodium hydroxide or potassium hydroxide to obtain a compound of the general formula (XV). (6) In the compound of the general formula (I), R ₂ is -CON
HOH group, A is -Ph-NHSO ₂ -R ₆ group compounds, namely the preparation of compounds of the general formula of claim 7 (XVI). The compound of the general formula (XVI) can be produced as follows.

[0024]

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That is, the hydroxamic acid of the general formula (XVI) can be obtained by reacting the carboxylic acid of the general formula (XV) with hydroxylamine in the presence of a condensing agent and a base. DPPA, DEPC, DCC,
Using CDI or WSCDI, the base is NM
M, (C ₂ H ₅ ) ₃ N, etc., and DMF, TH
F can be used. In addition, O-benzylhydroxylamine (NH
O-benzylhydroxamic acid amide (XIX) can be obtained by using ₂ O-Bn), followed by debenzylation to obtain the general formula (XVI).

[0026]

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Next, a method for producing the compound of the general formula (II) and the compound of the general formula (VII) which are the starting materials in the synthesis process of the compound of the general formula (I) will be described. (A) Method for producing compound of general formula (II)

[0028]

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Compound (XX) and compound (XXI) are
The compound (XXII) is obtained by reacting in the presence of a base such as triethylamine or pyridine. This compound (XXII)
Nitrobenzenesulfonyl chloride (XXIII)
Is reacted in the presence of a base such as toluethylamine or pyridine to give compound (XXIV). Next, the compound (XXIV) is reduced in the presence of a palladium-carbon catalyst to obtain a compound of the general formula (II). (B) Method for producing compound of general formula (VII)

[0030]

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Compound (XXV) is replaced with compound (XXV)
The reaction is performed in the presence of a base such as toluethylamine or pyridine to obtain the general formula (VII).

The compounds represented by formula (I) are exemplified below. (1) 2-[(N-isobutyl-N- (4- (2-thenoylamino) benzenesulfonyl)) amino] acetic acid (compound 1) (2) 2-[(N-isobutyl-N- (4- (4 -Methylbenzoylamino) benzenesulfonyl)) amino]
Acetic acid (compound 2) (3) 2-[(N-cyclohexylmethyl-N- (4-
(4-methylbenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 3) (4) 2-[(N-cyclohexylmethyl-N- (4-
(4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 4) (5) 2-[(N- (4-methoxybenzyl) -N-
(2- (4-methylbenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 5) (6) 2-[(N-cyclohexylmethyl-N- (4-
(2-Thenoylamino) benzenesulfonyl)) amino] acetic acid (compound 6) (7) 2-[(N-isobutyl-N- (4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 7)

(8) 2-[(N-isobutyl-N- (4
-(3-cyanophenyl) benzenesulfonyl)) amino] acetic acid (compound 8) (9) 2-[(N-isobutyl-N-2- (5- (3-
(Cyanophenyl) thiophene) sulfonyl) amino] acetic acid (compound 9) (10) 2-[(N-isobutyl-N- (4- (2-pyrrolinoylamino) benzenesulfonyl)) amino] acetic acid (compound 10) (11) ) 2-[(N-isobutyl-N- (4- (5-methyl-2-thenoylamino) benzenesulfonyl)) amino] acetic acid (compound 11) (12) 2-[(N-isobutyl-N- (4- (4-
(2-aminoethoxy) benzoylamino) benzenesulfonyl)) amino] acetic acid / hydrochloride (compound 12) (13) 2-[(N-isobutyl-N- (4- (3-methylphenyl) benzenesulfonyl)) amino ] Acetic acid (compound 13) (14) 2-[(N-isobutyl-N- (4- (2-
(2-aminoethoxy) benzoylamino) benzenesulfonyl)) amino] acetic acid / hydrochloride (compound 14)

(15) 2-[(N- (3-picolyl)-
N- (4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 15) (16) 2-[(N-isobutyl-N- (4- (4-methylphenyl) benzenesulfonyl)) amino ] Acetic acid (compound 16) (17) 2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 17) (18) 2-[(N-isobutyl- N- (4-((2-
(2-aminoethoxy) -4-methoxy) benzenesulfonyl)) amino] acetic acid / hydrochloride (compound 18) (19) 2-[(N-isobutyl-N- (4- (3,4
-Dimethoxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 19) (20) 2-[(N-isobutyl-N- (4- (5-methyl-2-thienyl) benzenesulfonyl)) amino]
Acetic acid (compound 20) (21) 2-[(N-isobutyl-N- (3- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 21)

(22) 2-[(N-isobutyl-N-
(4- (3-methoxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 22) (23) 2-[(N-pyrazolemethyl-N- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 23) (24) 2-[(N-isobutyl-N- (4- (4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetic acid (compound 24) (25) N-hydroxy-2-[(N- Isobutyl-N
-(4- (2-thenoylamino) benzenesulfonyl)) amino] -acetamide (compound 25) (26) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-Methylbenzoylamino) benzenesulfonyl)) amino] acetamide (compound 26) (27) N-hydroxy-2-[(N-cyclohexylmethyl-N- (4- (4-methylbenzoylamino) Benzenesulfonyl)) amino] acetamide (compound 2
7) (28) N-hydroxy-2-[(N-cyclohexylmethyl-N- (4- (4-methoxybenzoylamino)
Benzenesulfonyl)) amino] acetamide (Compound 28)

(29) N-hydroxy-2-[(N-
(4-methoxybenzyl) -N- (2- (4-methylbenzoylamino) benzenesulfonyl)) amino] acetamide (Compound 29) (30) N-hydroxy-2-[(N-cyclohexylmethyl-N- (4 -(2-thenoylamino) benzenesulfonyl)) amino] acetamide (compound 30) (31) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetamide (compound 31) (32) N-hydroxy-2-[(N-isobutyl-N
-(4- (3-cyanophenyl) benzenesulfonyl)) amino] acetamide (compound 32) (33) N-hydroxy-2-[(N-isobutyl-N
-2- (5- (3-cyanophenyl) thiophene) sulfonyl) amino] acetamide (compound 33) (34) N-hydroxy-2-[(N-isobutyl-N
-(4- (2-pyrrolinoylamino) benzenesulfonyl)) amino] acetamide (compound 34) (35) N-hydroxy-2-[(N-isobutyl-N
-(4- (5-Methyl-2-thenoylamino) benzenesulfonyl)) amino] acetamide (Compound 35)

(36) N-hydroxy-2-[(N-isobutyl-N- (4- (4- (2-aminoethoxy) benzoylamino) benzenesulfonyl)) amino] acetamide hydrochloride (Compound 36) 37) N-hydroxy-2-[(N-isobutyl-N
-(4- (3-methylphenyl) -benzenesulfonyl)) amino] acetamide (compound 37) (38) N-hydroxy-2-[(N-isobutyl-N
-(4- (2- (2-aminoethoxy) benzoylamino)) benzenesulfonyl) isobutylamino] acetamide hydrochloride (compound 38) (39) N-hydroxy-2-[(N-picolyl-N-
(4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetamide (compound 39) (40) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-methylphenyl) benzenesulfonyl)) amino] acetamide (compound 40) (41) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetamide (compound 41) (42) N-hydroxy-2-[(N-isobutyl-N
-(4- (2- (2-aminoethoxy) -4-methoxy) benzoylamino) benzenesulfonyl) amino]
Acetamide hydrochloride (compound 42)

(43) N-hydroxy-2-[(N-isobutyl-N- (4- (3,4-dimethoxyphenyl)
(Benzenesulfonyl)) amino] acetamide (compound 43) (44) N-hydroxy-2-[(N-isobutyl-N
-(4- (5-methyl-2-thienyl) benzenesulfonyl)) amino] acetamide (compound 44) (45) N-hydroxy-2-[(N-isobutyl-N
-(3- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetamide (compound 45) (46) N-hydroxy-2-[(N-isobutyl-N
-(4- (3-Methoxyphenyl) benzenesulfonyl)) amino] acetamide (compound 46) (47) N-hydroxy-2-[(N-pyrazolemethyl-N- (4-methoxybenzoylamino) benzenesulfonyl)) Amino] acetamide (compound 47) (48) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetamide (compound 4
8) (49) 2-[(N-isobutyl-N- (4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid ethyl ester (Compound 49)

(50) 2-[(N-isobutyl-N-
(4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetic acid ethyl ester (compound 50) (51) 2-[(N-isobutyl-N- (4- (4-hydroxyphenyl) benzenesulfonyl)) amino] Acetic acid (compound 51) (52) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-hydroxyphenyl) benzenesulfonyl)) amino] acetamide (compound 52) (53) 2-[(N-isobutyl-N- (4- (3,4
-Dihydroxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 53) (54) N-hydroxy-2-[(N-isobutyl-N
-(4- (3,4-dihydroxyphenyl) benzenesulfonyl)) amino] acetamide (compound 54) (55) 2-[(N-isobutyl-N- (4- (3-aminophenyl) benzenesulfonyl)) amino ] Acetic acid (compound 55) (56) N-hydroxy-2-[(N-isobutyl-N
-(4- (3-Aminophenyl) benzenesulfonyl)) amino] acetamide (Compound 56)

(57) 2-[(N-isobutyl-N-
(4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 57) (58) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-Carboxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 58) (59) 2-[(N-isobutyl-N- (4- (4-methoxy-3-methylphenyl) benzenesulfonyl) )
Amino] acetic acid (Compound 59) (60) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-Methoxy-3-methylphenyl) benzenesulfonyl)) amino] acetamide (Compound 60) (61) 2-[(N-isobutyl-N- (4- (4-hydroxy-3-methylphenyl) ) Benzenesulfonyl)) amino] acetic acid (compound 61) (62) N-hydroxy-2-[(N-isobutyl-N
-(4- (4-Hydroxy-3-methylphenyl) benzenesulfonyl)) amino] acetamide (Compound 62)

The sulfonamide derivative of the present invention can be used
It is used as a pharmaceutical composition for the treatment and / or prevention of diseases caused by the destruction of the extracellular matrix due to the administration of tablets, capsules, granules,
It can be administered orally as a syrup, and can be administered parenterally in the form of a direct injection or the like. The dose varies depending on the patient's condition, age, and body weight, but an effect can be expected by, for example, administering 10 to 1000 mg per day for an adult in one or several divided doses.

[0042]

The compound represented by the general formula (I) of the present invention has an excellent inhibitory effect on MMPs, as is clear from the following pharmacological tests. The outline of the pharmacological test of the compound of the present invention is shown below. Pharmacological test 1: Inhibitory activity of MMP-1 (type I collagenase) MMP-1 (type I collagenase) inhibitory activity was determined by using human skin fibroblast-derived MMP-1 (Yagai Co., Ltd.) and type I collagenase activity measurement kit (stock (Ed Harris, Jr. et. Al., M)
ethod Enzymol., 82, 423, (1982)). That is, 0.01
U / ml of MMP-1,10 ~ ¹⁰ ~10 compound at a concentration of ~ ⁵ M and FITC fluorescence-labeled type I collagen (50.mu.
g) in 0.05 M Tris / HCl buffer (pH 7.5) containing 200 mM NaCl and 5 mM CaCl ₂ in 50
Incubated for 4 hours at 37 ° C. in 0 μl.
The reaction was stopped with 200 μl of 0.05 M Tris / HCl buffer (pH 9.5) containing 200 mM NaCl, 50 mMo-phenanthroline and ethanol.
Centrifuged at 5000 g for 10 minutes. The fluorescence intensity of the supernatant at an excitation wavelength of 495 nm and a fluorescence wavelength of 520 nm was measured and compared with the fluorescence intensity of the heat-denatured substrate to determine the substrate decomposition rate. The substrate degradation inhibition rate when the compound was added was determined in comparison with the substrate degradation rate of a control to which no compound was added, and the 50% inhibitory concentration (IC ₅₀ value) was calculated. Table 1 shows the results.

Pharmacological test 2: Inhibitory effect of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) MMP-2 is proM on COS-1 cells (RIKEN)
The proMMP-2 in the culture supernatant obtained by transfecting MP-2 cDNA and culturing for 3 days
Those activated with mM 4-aminophenylmercuric acetic acid, MMP-9 derived from human fibrosarcoma cells (Yagai Co., Ltd.), and inhibitory activity using a type IV collagenase activity measurement kit (Yagai Co., Ltd.) (Biswaz, C. et al., J. Cell. Biochem., 2).
8,39, (1984)). 0.01 U / ml MMP-2 or MMP-9, compound in a certain concentration range and FITC fluorescently labeled type IV collagen (from bovine placenta, 25 μg)
With 100 mM 0.05 M Tris / HCl buffer (pH 7.5) containing 200 mM NaCl and 5 mM CaCl _2.
Incubated in μl at 42 ° C. for 4 hours. M
By the same operation as in the case of the enzyme assay using MP-1,
Only native type IV collagen was precipitated by centrifugation, and the substrate degradation rate was determined from the fluorescence intensity of the supernatant. Compared with the control substrate degradation rate without the compound, the substrate degradation inhibition rate when the compound was added was determined, and the 50% inhibition concentration (IC ₅₀
Value) was calculated. Table 1 shows the results.

Pharmacological test 3: Membrane type MMP (MMP-14)
MMP-14 stimulated HT1080 fibrosarcoma cells with 40 μM of concanavalin A and cultured for 12 hours. The cell suspension collected was used as an enzyme solution. MMP-14 and MOCAc-Pro-Leu- as a compound and a substrate in a certain concentration range.
_{Gly-Leu-A 2 pr (} Dnp) -Ala-Arg
-NH ₂ (Peptide Institute, 3163-v) 0.2MNaCl the 10μM, 10mM CaCl _2, 0.02%
50 mM T with NaN ₃ and 0.05% Brij35
Incubation was carried out at 37 ° C. for 2 hours in a ris · HCl buffer (pH 7.4). 4 volumes of sodium acetate buffer
(PH 4.0) to stop the reaction,
The fluorescence intensity at an excitation wavelength of 328 mm and a fluorescence wavelength of 393 mm was measured, and the substrate decomposition rate was determined from the fluorescence intensity. Compared with the control substrate decomposition rate without the compound, the substrate decomposition inhibition rate when the compound was added was determined, and the 50% inhibition concentration (I
_C50 value) was calculated. Table 1 shows the results.

[0045]

[Table 1-1]

[0046]

[Table 1-2]

[0047]

EXAMPLES AND COMPARATIVE EXAMPLES Production examples are given below, but it goes without saying that the present invention is not limited to the examples. Reference Example Production method of ethyl 2-[(N-isobutyl-N- (4-aminobenzenesulfonyl)) amino] acetic acid. (A) A method for producing 2- (isobutyl) aminoacetic acid ethyl ester (Chemical Formula 30).

[0048]

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Isobutylamine (7.8 g) and N-ethyldiisopropylamine (13.7 g) were dissolved in dimethylformamide (30 ml) and stirred at 0 ° C. Ethyl bromoacetate (15 g) was added thereto, and the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 3.5 hours. The mixture was poured into 50 ml of ice water and extracted with ethyl acetate (20 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 3) to obtain 8.4 g of the target compound as an oil. MS (m / e): 159 (M ⁺ ) (B) 2-[(N-isobutyl-N- (4-nitrobenzenesulfonyl)) amino] acetic acid ethyl ester
Production method of 1).

[0050]

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The amine (4.0) obtained in (A) of the above reference example was used.
g) and N-ethyldiisopropylamine (3.2 g) were dissolved in dimethylformamide (30 ml) and stirred at 0 ° C. This was dissolved in 70 ml of MeOH solution, and 10%
NaOH (30 ml) was added and the mixture was stirred at room temperature for 2 hours. To this, p-nitrobenzenesulfonyl chloride (4.7 g)
Was added, and the mixture was stirred at 0 ° C. for 20 minutes and then at room temperature for 30 minutes. It was poured into 30 ml of ice water and extracted with ethyl acetate (20
ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 2) to obtain the desired product.
2 g were obtained as pale yellow crystals. 75-76 ° C IR (cm- ¹ ): 3100, 2950, 2866, 17
43, 1608 MS (m / e): 301 (M ⁺ -43), 271, 25
^{1,186,59 (BP) 1 H-NMR} (CDCl 3): 0.92 (6H, d, (C
_{H 3) 2), 1.20 (} 3H, t, CH 3), 1.85
(1H, sept, CH), 3.08 (2H, d, C
_{H 2), 4.05 (2H,} q, CH 2), 4.12 (2
_{H, s, CH 2),} 8.02 (2H, d, aromatic ring),
8.35 (2H, d, aromatic ring) (C) 2-[(N-isobutyl-N- (4-aminobenzenesulfonyl)) amino] acetic acid ethyl ester
2) Manufacturing method.

[0052]

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The compound (6.0) obtained in the above Reference Example (B)
g), ethanol (10 ml) and palladium / carbon (0.6 g) were added thereto, and catalytically reduced with hydrogen gas. Filter through Celite, concentrate and concentrate on a silica gel column (ethyl acetate:
Purification with n-hexane = 1: 3) gave 4.9 g of the desired product as pale yellow crystals. Melting point ^{58-60 ℃ IR (cm ~ 1)} : 3472,3376,2950,17
37,1599 MS (m / e): 314 (M ⁺ ) ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.20 (} 3H, t, CH 3), 1.85
(1H, sept, CH), 3.00 (2H, d, C
_{H 3), 3.95 (2H,} s, CH 2), 4.10 (2
H, q, CH ₂ ), 6.65 (2H, d, aromatic ring),
7.60 (2H, d, aromatic ring)

Embodiment 1 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
(4-Methylbenzoylamino) benzenesulfonyl)) amino] acetamide (Compound 31). (A) Production method of 2-[(N-isobutyl-N- (4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid ethyl ester (Compound 49).

[0055]

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The compound (1.0 g) obtained in (C) of the above Reference Example was dissolved in pyridine (10 ml) and stirred at 0 ° C. To this was added p-methoxybenzoyl chloride (0.6 g), and the mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated, acidified with 10% hydrochloric acid, and extracted with ethyl acetate (20 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1) to obtain 1.2 g of the desired product as white crystals. Melting point 122-1
^{23 ℃ IR (cm ~ 1)} : 3448,2950,1749,15
06,1341 MS (m / e): 405 (M ⁺ -43), 375, 30
^{0 (BP) 1 H-NMR} (CDCl 3): 0.90 (6H, d, (C
_{H 3) 2), 1.20 (} 3H, t, CH 3), 1.82
(1H, sept, CH), 3.03 (2H, d, C
_{H 2), 3.88 (3H,} s, OCH 3), 3.98 (2
_{H, s, CH 2),} 4.05 (2H, q, CH 2), 6.
90 to 7.90 (8H, m, aromatic ring), 8.02 (1
(H, s, NH) (b) A method for producing 2-[(N-isobutyl-N- (4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetic acid (compound 7).

[0057]

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2-[(N-isobutyl-N- (4- (4
-Methoxybenzoylamino) benzenesulfonyl))
Amino] acetic acid ethyl ester (Compound 49) (1.0
g) was dissolved in ethanol (5 ml), sodium hydroxide (0.13 g) and water (2 ml) were added, and the mixture was stirred at room temperature for 2 hours. Concentration and acidification with 10% hydrochloric acid yielded white crystals. The crystals were recrystallized from ethanol to obtain 0.91 g of the desired product. Melting point ^{180-181 ℃ IR (cm ~ 1)} : 3388,2962,1728,16
65, 1530 ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 3.05
_{(2H, d, CH 2)} , 3.89 (3H, s, OC
_{H 3), 3.98 (2H,} s, CH 2), 6.90~7.
90 (8H, m, aromatic ring) (c) N-benzyloxy-2- [N-isobutyl-N
-(4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetamide.

[0059]

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2-[(N-isobutyl-N- (4- (4
-Methoxybenzoylamino) benzenesulfonyl))
Amino] acetic acid (compound 7) (0.8 g) was dissolved in dimethylformamide (30 ml) and stirred at 0 ° C. 1-Hydroxy-1H-benzotriazole monohydrate (HOBt) (0.36 g) and N-ethylmorpholine (NEM) (0.52 g) were added thereto and stirred for 30 minutes. Add benzylhydroxylamine (0.37
g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (WSCDI)
(0.44 g) was added and the mixture was stirred at room temperature for 4 hours. Ice water (1
0 ml) and extracted with ethyl acetate (20 ml ×
3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1) to obtain 0.9 g of the desired product.
Was obtained as white crystals. 145-150 ° C IR (cm ~ ¹ ): 3250, 2980, 1659, 16
05, 1506 ¹ H-NMR (CDCl ₃ ): 0.85 (6H, d, (C
_{H 3) 2), 1.75 (} 1H, sept, CH), 2.85
_{(2H, d, CH 2)} , 3.60 (2H, s, CH 2),
3.88 (3H, s, OCH ₃ ), 4.91 (2H,
_{s, CH 2), 6.90~7.90 (} 8H, m, aromatic ring), 8.15 (1H, s, NH), 9.15 (1H,
s, NH) (d) N-hydroxy-2-[(N-isobutyl-N-
(4- (4-methoxybenzoylamino) benzenesulfonyl)) amino] acetamide (Compound 31).

[0061]

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The compound (0.9 g) obtained in the above (c) was dissolved in tetrahydrofuran (10 ml), and 5%
Palladium / carbon (90 mg) was added, and the mixture was catalytically reduced with hydrogen gas. Filtration through Celite, concentration and recrystallization from ethanol gave 0.51 g of the desired product as white crystals. Melting point ^{169-170 ℃ IR (cm ~ 1)} : 3320,2950,1659,15
93,1335 ¹ H-NMR (CDCl ₃ ): 0.92 (6H, d, (C
_{H 3) 2), 1.90 (} 1H, sept, CH), 3.00
_{(2H, d, CH 2)} , 3.75 (2H, s, CH 2),
_{3.90 (3H, sOCH 3),} 7.00~8.00
(8H, m, aromatic ring)

Embodiment 2 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
Preparation of (4-methoxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 41). (A) Method for producing 2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetic acid ethyl ester (Compound 50).

[0064]

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A sample 2 obtained by the same method as shown in the reference example
-[(N-isobutyl-N- (4-bromobenzenesulfonyl)) amino] acetic acid ethyl ester (0.8 g),
P-methoxyphenylboronic acid (0.32 g), sodium carbonate (0.45 g), water (2 ml), tetrakis (triphenylphosphine) palladium (10 mg) and toluene (10 ml) were added and heated to reflux (3.5). time). Saturated sodium hydrogen carbonate (10 ml) was added to the reaction solution, and the mixture was extracted with toluene (20 ml × 2). The toluene layer was washed several times with a saturated saline solution and dehydrated with sodium sulfate. Filtered,
It was concentrated and purified by a silica gel column (ethyl acetate: n-hexane = 1: 3) to obtain 0.66 g of the desired product as white crystals. Melting point 76-78 ° C IR (cm- ¹ ): 3418, 1725, 1341, 11
88,1161 MS (m / e): 406 (M ⁺⁺ l) 363,333 ,.
^{183,84 (BP) 1 H-NMR} (CDCl 3): 0.90 (6H, d, (C
_{H 3) 2), 1.18 (} 3H, t, CH 3), 1.88
(1H, sept, CH), 3.08 (2H, d, C
_{H 2), 3.88 (3H,} s, OCH 3), 4.04 (2
_{H, s, CH 2),} 4.05 (2H, q, CH 2), 6.
90 to 7.96 (8H, m, aromatic ring) (b) Method for producing 2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 17).

[0066]

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2-[(N-isobutyl-N- (4- (4
-Methoxyphenyl) benzenesulfonyl)) amino]
Ethyl acetate (compound 50) (0.66 g) in ethanol (5 ml), sodium hydroxide (0.13 g)
And water (1 ml) were added, followed by stirring at room temperature for 3 hours. It was concentrated and acidified by adding 10% hydrochloric acid. The white crystals generated at this time were recrystallized with ethanol to obtain the target compound 0.40.
g was obtained. Melting point 161-162 ° C IR (cm ~ ¹ ): 3430, 2956, 1728, 16
05,1338 MS (m / e): 378 (M ⁺⁺ 1), 347,183.
(BP) 139 ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 3.03
_{(2H, d, CH 2)} , 3.87 (3H, s, CH 3),
_{3.98 (2H, s, CH 2} ), 6.95~7.90
(8H, m, aromatic ring) (c) N-benzyloxy-2-[(N-isobutyl-
Production method of N- (4- (4-methoxyphenyl) -benzenesulfonyl)) amino] acetamide.

[0068]

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2-[(N-isobutyl-N- (4- (4
-Methoxyphenyl) benzenesulfonyl)) amino]
Acetic acid (compound 17) (0.30 g) was dissolved in dimethylformamide (20 ml) and HOBt (0.24 g)
And NEM (0.36 g) were added and stirred for 30 minutes. This was combined with benzylhydroxylamine hydrochloride (0.25 g), W
SCDI (0.30 g) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water (20 ml) and extracted with ethyl acetate (20 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. Filtered and concentrated. 370 mg of the desired product was obtained as white crystals. 129-130 ° C IR (cm ¹ ): 3418, 2950, 1683, 15
99,1389 MS (m / e): 375 (M ⁺ -107), 332,2
^{47,183,91 (BP) 1 H-NMR} (CDCl 3): 0.80 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 2.94
_{(2H, d, CH 2)} , 3.65 (2H, s, CH 2),
3.87 (3H, s, OCH ₃ ), 4.95 (2H,
_{s, CH 2), 6.90~7.80 (} 13H, m, aromatic ring), 9.20 (1H, s, NH) (d) N- hydroxy -2 - [(N-isobutyl -N-
(4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 41).

[0070]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetamide (0.37 g) was dissolved in tetrahydrofuran (10 ml). 5%
1. Palladium / carbon (30 mg) was added, and hydrogen gas was used for 2.
Catalytic reduction was carried out for 5 hours. Filtered through celite and concentrated. The resulting crystals were recrystallized from ethanol to give the desired product 0.25
g was obtained. Melting point 144-145 ° C IR (cm- ¹ ): 3226,1665,1335,12
90, 1152 MS (m / e): 375 (M ⁺ -17), 332, 24
7,183,91 (BP) ¹ H-NMR (CDCl ₃ ): 0.94 (6H, d, (C
_{H 3) 2), 1.86 (} 1H, sept, CH), 3.00
_{(2H, d, CH 2)} , 3.74 (2H, s, CH 2),
_{3.87 (3H, s, OCH 3} ), 7.00~7.85
(8H, m, aromatic ring), 9.40 (1H, bs, NH)

Embodiment 3 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
(5-methyl-2-thienyl) benzenesulfonyl))
Production of [amino] acetamide (compound 44). (A) Production method of ethyl 2-[(N-isobutyl-N- (4- (5-methyl-2-thienyl) benzenesulfonyl)) amino] acetic acid.

[0073]

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2-Methylthiophene (0.9 g) was placed in dry tetrahydrofuran (5 ml) and stirred at -20.degree. To this, n-butyllithium (5.8 ml) was added dropwise and stirred at 0 ° C. for 30 minutes. Next, zinc chloride (1.
25 g) and stirred at room temperature for 1 hour. Next, ethyl 2-[(isobutyl)-(4-bromobenzenesulfonyl) -amino] acetic acid (1.70 g) and tetrakis (triphenylphosphine) palladium (10 mg) obtained by the method shown in Reference Example were added, Heated to reflux (3.5 hours). Concentrate and extract with ethyl acetate (20
ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated and purified by a silica gel column (ethyl acetate: n-hexane = 1: 5) to obtain the desired product 73.
0 mg was obtained as crystals. IR (cm- ¹ ): 2950, 1755, 1332, 11
88,1149 MS (m / e): 396 (M ⁺ -13) 353, 32
2,237,173 (BP) 129 ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.15 (} 3H, t, CH 3), 1.85
(1H, sept, CH), 2.52 (3H, s, C
_{H 3), 3.05 (2H,} d, CH 2), 4.03 (2
_{H, s, CH 2),} 4.04 (3H, q, CH 2), 6.
78 (1H, d, aromatic ring), 7.18 (1H, d, aromatic ring), 7.60 (2H, d, aromatic ring), 7.80 (2
(H, d, aromatic ring) (b) A method for producing 2-[(N-isobutyl-N- (4- (5-methyl-2-thienyl) benzenesulfonyl)) amino] acetic acid (compound 20).

[0075]

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2-[(N-isobutyl-N- (4- (5
-Methyl-2-thienyl) benzenesulfonyl)) amino] acetic acid ethyl ester (0.7 g) in ethanol (1 g).
0 ml), sodium hydroxide (0.14 g) and water (5
ml) and stirred at room temperature for 2 hours. Concentrate 10%
Acidified with hydrochloric acid. The crystals generated at this time were filtered and recrystallized with ethanol to obtain 0.58 g of the desired product as white crystals. Melting point ^{178-180 ℃ IR (cm ~ 1)} : 3058,2944,1722,14
01 MS (m / e): 368 (M ⁺⁺ 1) 324, 237,
^{173 (BP) 1 H-NMR} (CDCl 3): 0.89 (6H, d, (C
_{H 3) 2), 1.86 (} 1H, sept, CH), 2.52
_{(3H, s, CH 3)} , 3.05 (2H, d, CH 2),
_{3.98 (2H, s, CH 2} ), 6.75 (1H, d,
7.20 (1H, d, aromatic ring), 7.65
(2H, d, aromatic ring), 7.80 (2H, d, aromatic ring) (c) N-hydroxy-2-[(N-isobutyl-N-
(4- (5-Methyl-2-thienyl) benzenesulfonyl)) amino] acetamide (Compound 44).

[0077]

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2-[(N-isobutyl-N- (4- (5
-Methyl-2-thienyl) benzenesulfonyl)) amino] acetic acid (0.4 g) in dimethylformamide (10 m
1), HOBt (0.24 g) and NEM
(0.58 g) and stirred at 0 ° C. for 30 minutes. To this, hydroxylamine hydrochloride (0.15 g), WSCDI
(0.42 g) was added and the mixture was stirred at room temperature for 12 hours. Pour into ice water (10 ml) and extract with ethyl acetate (20 ml
× 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1). The resulting crystals were recrystallized from ethanol to obtain 50 mg of the desired product. 139-140 ° C IR (cm- ¹ ): 3274,2950,1659,14
64,1332 MS (m / e): 309 (M ⁺ -73) 266,23
^{7,173 (BP) 1 H-NMR} (CDCl 3): 0.90 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 2.52
_{(3H, s, CH 3)} , 2.95 (2H, d, CH 2),
_{3.75 (2H, s, CH 2} ), 6.78 (1H, d,
Aromatic ring), 7.22 (1H, d, aromatic ring), 7.70
(2H, d, aromatic ring), 7.80 (2H, d, aromatic ring)

Embodiment 4 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
(4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetamide (Compound 48). (A) Method for producing ethyl 2-[(N-isobutyl-N- (4- (4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetate.

[0080]

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The compound (1.0 g) obtained in Reference Example (C) was dissolved in pyridine (10 ml) and stirred at 0 ° C. This was added to P-methoxybenzenesulfonyl chloride (0.7
g) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, acidified with 10% hydrochloric acid, and extracted with ethyl acetate (20%).
ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1) to obtain 1.48 g of the desired product as an oil. IR (cm- ¹ ): 3256, 2950, 1743, 15
96,1493 MS (m / e): 484 (M ⁺ ) 441,326 (B
^{P) 262 1 H-NMR (} CDCl 3): 0.88 (6H, d, (C
_{H 3) 2), 1.18 (} 3H, t, CH 3), 1.80
(1H, sept, CH), 3.00 (2H, d, C
_{H 2), 3.85 (3H,} s, OCH 3), 4.00 (2
_{H, q, CH 2),} 6.90~7.80 (8H, m, aromatic ring) (b) 2 - [( N- isobutyl -N- (4- (4- methoxybenzenesulfonyl amino) benzenesulfonyl) ) Preparation of amino] acetic acid (compound 24).

[0082]

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2-[(N-isobutyl-N- (4- (4
-Methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetic acid ethyl ester (1.48 g) was dissolved in ethanol (5 ml), sodium hydroxide (0.18 g) and water (2 ml) were added, and the mixture was added at room temperature for 2 hours. Stirred. The mixture was concentrated, acidified by adding 10% hydrochloric acid, and extracted with ethyl acetate (10 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. Filtered,
It was concentrated and purified by a silica gel column (chloroform: methanol = 3: 1) to obtain 1.25 g of the desired product as crystals. 58-59 ° C. IR (cm- ¹ ): 3500, 3262, 2950, 17
25,1592 MS (m / e): 456 (M ⁺ ) 413,326,17.
1 (BP) 123 ¹ H-NMR (CDCl ₃ ): 0.89 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 3.05
_{(2H, d, CH 2)} , 3.85 (3H, s, OC
_{H 3), 4.10 (2H,} s, CH 2), 6.80~7.
80 (8H, m, aromatic ring), 8.35 (1H, s, N
H) (c) N-benzyloxy-2-[(N-isobutyl-
N- (4- (4-methoxybenzenesulfonylamino)
Preparation of benzenesulfonyl)) amino] acetamide.

[0084]

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2-[(N-isobutyl-N- (4- (4
-Methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetic acid (0.85 g) was dissolved in dimethylformamide (20 ml) and HOBt (0.34 g)
And NEM (0.51 g) were added and stirred for 30 minutes. To this, benzylhydroxylamine (0.35 g), WSCD
I (0.42 g) was added, and the mixture was stirred at room temperature for 4 hours. Pour into ice water (20 ml) and extract with ethyl acetate (10 ml
× 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1) to give the target compound (1.07).
g were obtained as crystals. Melting point 58-59 ° C IR (cm ~ ¹ ): 3256, 2950, 1680, 15
96, 1497 ¹ H-NMR (CDCl ₃ ): 0.82 (6H, d, (C
_{H 3) 2), 1.75 (} 1H, sept, CH), 2.85
_{(2H, d, CH 2)} , 3.60 (2H, s, CH 2),
3.85 (3H, s, OCH ₃ ), 4.92 (2H,
_{s, CH 2), 6.80~7.90 (} 13H, m, aromatic ring) (d) N-hydroxy -2 - [(N-isobutyl -N-
(4- (4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetamide (compound 4
8) Manufacturing method.

[0086]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (4-methoxybenzenesulfonylamino) benzenesulfonyl)) amino] acetamide (1.0 g) was dissolved in tetrahydrofuran (20 ml). Put 5% palladium on carbon (10mg)
It was catalytically reduced with hydrogen gas for 1 hour at room temperature. Filter through Celite, concentrate and concentrate on a silica gel column (ethyl acetate: n-
Purification with hexane = 3: 1) gave 750 mg of the desired product as white crystals. 61-62 ° C IR (cm- ¹ ): 3256, 2950, 1677, 15
96,1497 MS (m / e): 400 (M ⁺ -39) 355,326
^{(BP) 262,171 1 H-NMR} (CDCl 3): 0.88 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 2.90
_{(2H, d, CH 2)} , 3.70 (2H, s, CH 2),
_{3.86 (3H, s, OCH 3} ), 6.90~7.90
(8H, m, aromatic ring)

Embodiment 5 FIG. N-hydroxy-2-[(N-cyclohexylmethyl-
Production method of N- (4- (2-thenoylamino) benzenesulfonyl)) amino] acetamide (compound 30). (A) 2-[(N-cyclohexylmethyl-N- (4-
Preparation of (2-thenoylamino) benzenesulfonyl)) amino] acetic acid ethyl ester.

[0089]

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The 2-method obtained by the same method as shown in the reference example
[(N-cyclohexylmethyl-N- (4-aminobenzenesulfonyl)) amino] acetic acid ethyl ester (1.
0 g) was dissolved in pyridine (10 ml) and stirred at 0 ° C. Tonoyl chloride (0.41 g) was added thereto, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, acidified with 10% hydrochloric acid, and extracted with ethyl acetate (20 ml ×
3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated and purified by a silica gel column (ethyl acetate: n-hexane = 1: 1) to obtain 0.8 g of the desired product.
Was obtained as white crystals. 148-149 ° C. IR (cm- ¹ ): 3501, 3357, 2919, 16
64,1592 MS (m / e): 464 (M ⁺ ) 392,198 (B
P) ¹ H-NMR (CDCl ₃ ): 0.80 to 0.90 (2
_{H, m, CH 2),} 1.10~1.30 (6H, m),
1.50 (1H, bs, CH), 1.60 to 1.80
(5H, m), 3.05 ( 2H, d, CH 2), 4.0
_{2 (2H, s, CH 2} ), 4.10 (2H, q, C
_{H 2), 7.05~7.80 (7H,} m, aromatic ring),
8.00 (1H, bs, NH) (b) 2-[(N-cyclohexylmethyl-N- (4-
Preparation of (2-thenoylamino) benzenesulfonyl)) amino] acetic acid (compound 6).

[0091]

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2-[(N-cyclohexylmethyl-N-
(4- (2-thenoylamino) benzenesulfonyl))
Amino] acetic acid ethyl ester (0.8 g) was dissolved in ethanol (5 ml) and sodium hydroxide (0.2 g)
And water (3 ml) were added and the mixture was stirred at room temperature for 2 hours. Concentration and acidification with 10% hydrochloric acid yield white crystals. This was filtered and recrystallized from ethanol to obtain the desired product.
7 g were obtained as crystals. 158-159 ° C. IR (cm- ¹ ): 3400, 2950, 1750, 16
80,1600 MS (m / e): 391 (M ⁺ -45) 381,26.
^{6,111 (BP) 1 H-NMR} (CDCl 3): 0.80~0.90 (2
H, m, CH ₂ ), 1.10 to 1.20 (3H, m),
1.55 (1H, bs, CH), 1.60-1.80
(5H, m), 3.05 ( 2H, d, CH 2), 3.9
_{5 (2H, s, CH 2} ), 7.00~7.90 (7H,
m, aromatic ring) (c) A method for producing N-hydroxy-2-[(N-cyclohexylmethyl-N- (4- (2-thenoylamino) benzenesulfonyl)) amino] acetamide (Compound 30).

[0093]

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2-[(N-cyclohexylmethyl-N-
(4- (2-thenoylamino) benzenesulfonyl))
Amino] acetic acid (compound 6) (0.5 g) was dissolved in dimethylformamide (10 ml) and HOBt (0.26
g) and NEM (0.4 g) were added and stirred for 30 minutes. To this, hydroxylamine hydrochloride (0.12 g), WSCD
I (0.33 g) was added, and the mixture was stirred at room temperature for 12 hours. It was poured into ice water (10 ml) and extracted with ethyl acetate (20 m
1 × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated, and purified by a silica gel column (chloroform: methanol = 10: 1).
9 g were obtained. 165-166 ° C IR (cm- ¹ ): 3298,2920,1593,14
52,1317 MS (m / e): 378 (M ⁺ -73) 295,266
(BP) ¹ H-NMR (CDCl ₃ ): 0.80-1.00 (2
_{H, m, CH 2),} 1.10~1.30 (3H, m),
1.55 (1H, bs, CH), 1.60-1.80
(5H, m), 3.00 ( 2H, d, CH 2), 3.7
_{5 (2H, s, CH 2} ), 7.10~7.90 (7H,
m, aromatic ring)

Embodiment 6 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
Preparation of (4-methylphenyl) benzenesulfonyl)) amino] acetamide (compound 40). (A) A method for producing ethyl 2-[(N-isobutyl-N- (4- (4-methylphenyl) benzenesulfonyl)) amino] acetate.

[0096]

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[0097] 2- obtained by the same method as shown in the reference example.
[(N-isobutyl-N- (4-bromobenzenesulfonyl)) amino] acetic acid ethyl ester (1.2 g), p
-Methylphenylboronic acid (0.42 g), sodium carbonate (0.44 g), water (2 ml), tetrakis (triphenylphosphine) palladium (10 mg) and toluene (10 ml) were added and heated to reflux (3.5 hours). .
Saturated sodium bicarbonate (10 ml) was added to the reaction solution,
Extracted with toluene (20 ml × 2). The toluene layer was washed several times with a saturated saline solution and dehydrated with sodium sulfate. Filter, concentrate and concentrate on a silica gel column (ethyl acetate: n-hexane =
1: 3) to give 1.2 g of the desired product as a liquid. IR (cm- ¹ ): 3448, 2950, 1746, 13
41, 1191 MS (m / e): 390 (M ⁺⁺ 1) 337, 221,
^{158 (BP) 1 H-NMR} (CDCl 3): 0.80 (6H, d, (C
_{H 3) 2), 1.15 (} 3H, t, CH 3), 1.85
(1H, sept, CH), 2.50 (3H, s, C
_{H 3), 3.05 (2H,} d, CH 2), 4.05 (2
_{H, s, CH 2),} 4.06 (2H, q, CH 2), 6.
60 to 7.90 (8H, m, aromatic ring) (b) Method for producing 2-[(N-isobutyl-N- (4- (4-methylphenyl) benzenesulfonyl)) amino] acetic acid (compound 16).

[0098]

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2-[(N-isobutyl-N- (4- (4
-Methylphenyl) benzenesulfonyl)) amino] acetic acid ethyl ester (1.2 g) in ethanol (5 m
l), sodium hydroxide (0.24 g) and water (1 m
l) was added and the mixture was stirred at room temperature for 3 hours. It was concentrated and acidified by adding 10% hydrochloric acid. At this time, white crystals were formed.
This was filtered and recrystallized with ethanol to obtain 0.74 of the desired product.
g were obtained as crystals. 150-151 ° C. IR (cm- ¹ ): 2950, 1722, 1392, 12
30,1152 MS (m / e): 362 (M ⁺⁺ 1) 318,231,
^{152 (BP) 1 H-NMR} (CDCl 3): 0.90 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 2.40
_{(3H, s, CH 2)} , 3.00 (2H, d, CH 2),
_{4.00 (2H, s, CH 2} ), 7.20~7.90
(8H, m, aromatic ring) (c) N-benzyloxy-2-[(N-isobutyl-
N- (4- (4-methylphenyl) benzenesulfonyl)) amino] acetamide.

[0100]

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2-[(N-isobutyl-N- (4- (4
-Methylphenyl) benzenesulfonyl)) amino] acetic acid (compound 16) (0.3 g) was dissolved in dimethylformamide (20 ml), and HOBt (0.25 g) and N
EM (0.38 g) was added and stirred for 30 minutes. To this, benzylhydroxylamine hydrochloride (0.26 g), WSC
DI (0.31 g) was added and the mixture was stirred at room temperature. Extracted with ethyl acetate (20 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. Filtration and concentration gave 0.26 g of the desired product as white crystals. Melting point 143-14
^{4 ℃ IR (cm ~ 1)} : 3274,2920,1683,14
82,1338 MS (m / e): 466 (M ⁺ ) 316, 235 (B
P) ¹ H-NMR (CDCl ₃ ): 0.86 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 2.41
_{(3H, s, CH 3)} , 2.93 (2H, d, CH 2),
3.65 (2H, s, CH ₂ ), 4.95 (2H, s, CH ₂ )
_{CH 2), 7.20~7.90 (13H,} m, aromatic ring), 9.20 (1H, bs, NH) (d) N- hydroxy -2 - [(N-isobutyl -N-
(4- (4-methylphenyl) benzenesulfonyl))
Production of [amino] acetamide (compound 40).

[0102]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (4-methylphenyl) benzenesulfonyl)) amino] acetamide (0.25 g) was dissolved in tetrahydrofuran (10 ml). 5% palladium / carbon (20 mg) was added, and the mixture was catalytically reduced with hydrogen gas for 2 hours, filtered through celite, and concentrated. The crystals generated by this concentration are recrystallized with ethanol to obtain the target compound, 0.1.
14 g were obtained. 155-156 ° C IR (cm- ¹ ): 3214,2950,1659,15
96,1338 MS (m / e): 360 (M ⁺ -16) 303,23
^{1,167 (BP) 1 H-NMR} (CDCl 3): 0.94 (6H, d, (C
_{H 3) 2), 1.88 (} 1H, sept, CH), 2.41
_{(3H, s, CH 3)} , 3.00 (2H, d, CH 2),
_{3.74 (2H, s, CH 2} ), 7.20~7.90
(8H, m, aromatic ring), 9.39 (1H, bs, NH)

Embodiment 7 FIG. Method for producing 2-[(N-isobutyl-N- (4- (4-hydroxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 51)

[0105]

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The 2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 17) obtained in (b) of Example 2 (0.25)
g) was dissolved in methylene chloride (10 ml), and boron tribromide (0.4 ml) was added thereto, followed by stirring at room temperature for 30 minutes. It was concentrated and extracted with ethyl acetate (20 ml × 2).
The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate.
Then, the mixture was filtered, concentrated, and purified by silica gel calcium (chloroform: methanol = 3: 1). Object 0.
20 g were obtained as white crystals. 170-171 ° C IR (cm- ¹ ): 3358, 3168, 1728, 16
11,1140 MS (m / e): 363 (M ⁺ ), 305, 233, 1
69 (BP) 139, ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 3.08
_{(2H, d, CH 2)} , 4.01 (2H, s, CH 2),
6.90-7.90 (8H, m, aromatic ring)

Embodiment 8 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
Method for producing (4-hydroxyphenyl) benzenesulfonyl)) amino] acetamide (compound 52)

[0108]

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The N-hydroxy- obtained in Example 2 (d)
2-[(N-isobutyl-N- (4- (4-methoxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 41) (0.10 g) was treated with methylene chloride (5 m
l), boron tribromide (0.3 ml) was added thereto at room temperature, and the mixture was stirred for 3.5 hours. It was concentrated and purified with silica gel calcium (chloroform: methanol = 3: 1). 0.08 g of the desired product was obtained as white crystals. Melting point 56-5
^{7 ℃ IR (cm ~ 1)} : 3262,2956,1674,15
90,1392 MS (m / e): 305 (M ⁺ -73), 262,23
3 (BP), 167,115 ¹ H-NMR (CD ₃ OD): 0.92 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 2.95
_{(2H, d, CH 2)} , 3.74 (2H, s, CH 2),
6.90-7.90 (8H, m, aromatic ring)

Embodiment 9 FIG. 2-[(N-isobutyl-N- (4- (3-aminophenyl) benzenesulfonyl)) amino] acetic acid (compound 5
5) Production method (a) Production method of ethyl 2-[(N-isobutyl-N- (4- (3-nitrophenyl) benzenesulfonyl)) amino] acetic acid.

[0111]

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A 2 obtained by the same method as shown in the reference example
-[(N-isobutyl-N- (4-bromobenzenesulfonyl)) amino] acetic acid ethyl ester (1.0 g),
m-Nitrophenylboronic acid (0.8 g), sodium carbonate (1.0 g), water (5 ml), tetrakis (triphenylphosphine) palladium (15 mg) and toluene (30 ml) were added and heated to reflux (3.5 hours). ). Saturated sodium hydrogen carbonate (20 ml) was added to the reaction solution, and the mixture was extracted with toluene (20 ml × 2). The toluene layer was washed several times with a saturated saline solution and dehydrated with sodium sulfate. Filter, concentrate and concentrate on a silica gel column (ethyl acetate: n-hexane = 1: 1).
Purification in 3) gave 1.4 g of the desired product as a liquid. Melting point 76
-78 ° C IR (cm- ¹ ): 2950, 2866, 1737, 15
30,1467 MS (m / e): 421 (M ⁺ ), 377,347,2
67, 89 (BP) ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.20 (} 3H, t, CH 2), 1.88
(1H, sept, CH), 3.10 (2H, d, C
_{H 2), 4.08 (2H,} q, CH 2), 4.10 (2
_{H, s, CH 2),} 7.60-8.50 (8H, m, aromatic ring) (b) 2 - [( N- isobutyl -N- (4- (3- nitrophenyl) benzenesulfonyl)) amino Acetic acid production method;

[0113]

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2-[(N-isobutyl-N- (4- (3
-Nitrophenyl) benzenesulfonyl)) amino] acetic acid ethyl ester (1.0 g) in ethanol (10 m
l), sodium hydroxide (0.14 g) and water (5 m
l) was added and the mixture was stirred at room temperature for 3 hours. It was concentrated and acidified by adding 10% hydrochloric acid. Extract with ethyl acetate (20 ml
× 2), the ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. Filtered and concentrated. 0.8 of the target substance (white crystals)
g was obtained. Melting point ^{180-181 ℃ IR (cm ~ 1)} : 3076,2950,2914,17
25, 1704 MS (m / e): 231 (M ⁺ -161), 152 (B
P), 84, 45 ¹ H-NMR (CDCl ₃ ): 0.92 (6H, d, (C
_{H 3) 2), 1.88 (} 1H, sept, CH), 3.10
_{(2H, d, CH 2)} , 4.08 (2H, s, CH 2),
7.60 to 8.60 (8H, m, aromatic ring) (c) Method for producing 2-[(N-isobutyl-N- (4- (3-aminophenyl) benzenesulfonyl)) amino] acetic acid (compound 55) .

[0115]

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2-[(N-isobutyl-N- (4- (3
-Nitrophenyl) benzenesulfonyl)) amino] acetic acid (0.5 g) was dissolved in tetrahydrofuran (10 ml), 5% palladium on carbon (10 mg) was added thereto, and the mixture was catalytically reduced with hydrogen gas for 1 hour. Filtered through celite and concentrated. The resulting crystals were recrystallized from ethanol.
0.3 g of the desired product was obtained. Melting point 78-80 ° C IR (cm- ¹ ): 3406,2944,1740,16
00, 1180 MS (m / e): 363 (M ⁺⁺ 1), 233, 16
8,141,80 (BP) ¹ H-NMR (CD ₃ OD): 0.90 (6H, d, (C
_{H 3) 2), 1.85 (} 1H, sept, CH), 3.08
_{(2H, d, CH 2)} , 4.00 (2H, s, CH 2),
6.80 to 7.90 (8H, m, aromatic ring)

Embodiment 10 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
Preparation of (3-aminophenyl) benzenesulfonyl)) amino] acetamide (Compound 56) (a) N-benzyloxy-2-[(N-isobutyl-
Method for producing N- (4- (3-nitrophenyl) benzenesulfonyl)) amino] acetamide

[0118]

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The 2-[(N-isobutyl-N- (4- (3-nitrophenyl) benzenesulfonyl)) amino] acetic acid (0.8 g) obtained in (b) of Example 9 was treated with dimethylformamide (20 ml). And dissolved in HOBt (0.37
g) and NEM (0.47 g) were added and stirred for 30 minutes. Add benzylhydroxylamine hydrochloride (0.39
g) and WSCDI (0.46 g) were added, and the mixture was stirred at room temperature for 6 hours. The mixture was poured into ice water (50 ml) and extracted with ethyl acetate (30 ml × 3). The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. Filtered and concentrated. The resulting crystals were recrystallized from ethyl acetate to give 0.7 g of the desired product as white crystals. 133-134 ° C IR (cm- ¹ ): 2944,2866,1674,15
30,1344 MS (m / e): 388 (M ⁺ -109), 358,3
^{04,244,168 (BP) 1 H-NMR} (CDCl 3): 0.92 (6H, d, (C
_{H 3) 2), 1.86 (} 1H, sept, CH), 3.02
_{(2H, d, CH 2)} , 3.35 (2H, s, CH 2),
3.80 (2H, s, CH ₂ ), 4.85 (2H, s, CH ₂ )
_{CH 2), 7.30~8.40 (13H,} m, aromatic ring), 8.50 (1H, bs, NH)

(B) Method for producing N-hydroxy-2-[(N-isobutyl-N- (4- (3-aminophenyl) benzenesulfonyl)) amino] acetamide (Compound 56)

[0121]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (3-nitrophenyl) benzenesulfonyl)) amino] acetamide (0.7 g) was dissolved in tetrahydrofuran (30 ml). 5% palladium / carbon (20 mg) was added, and the mixture was catalytically reduced with hydrogen gas for 2.5 hours. The mixture was filtered through Celite, concentrated, and purified by a silica gel column (chloroform: methanol = 3: 1) to obtain 0.3 g of the desired product as crystals. Melting point 65-66
° C IR (cm- ¹ ): 3340, 3208, 2944, 16
74, 1593 MS (m / e): 318 (M ⁺ -59), 304, 23
2,168 (BP), 152 ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.70 (} 2H, bs, NH 2), 1.85
(1H, sept, CH), 3.00 (2H, d, C
_{H 2), 3.75 (2H,} s, CH 2), 6.60~7.
90 (8H, m, aromatic ring), 9.42 (1H, bs, N
H)

Embodiment 11 FIG. Method for producing 2-[(N-isobutyl-N- (4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetic acid (compound 57). (A) Production method of ethyl 2-[(N-isobutyl-N- (4- (4-cyanophenyl) benzenesulfonyl)) amino] acetic acid.

[0124]

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A sample 2 obtained by the same method as shown in the reference example
-[(N-isobutyl-N- (4-bromobenzenesulfonyl)) amino] acetic acid ethyl ester (2.5 g),
4-Cyanophenylboronic acid (1.15 g), sodium carbonate (1.68 g), water (10 ml) and toluene (30 ml) were added, and the mixture was heated under reflux (3.5 hours). Saturated sodium hydrogen carbonate (30 ml) was added to the reaction solution, and extracted with toluene (30 ml × 3). The toluene layer was washed several times with a saturated saline solution and dehydrated with sodium sulfate. Filter, concentrate and concentrate on a silica gel column (ethyl acetate: n-hexane = 1: 1).
Purification in 3) gave 2.4 g of the desired product as a liquid. IR (cm- ¹ ): 2950, 2866, 2224, 17
37, 1592 MS (m / e): 357 (M ⁺ -43), 327, 24
^{2,178 (BP), 151 1 H} -NMR (CDCl 3): 0.92 (6H, d, (C
_{H 3) 2), 1.20 (} 3H, t, CH 3), 1.88
(1H, sept, CH), 3.10 (2H, d, C
_{H 2), 4.08 (2H,} q, CH 2), 4.09 (2
_{H, s, CH 2),} 7.60~7.90 (8H, m, aromatic ring) (b) 2 - [( N- isobutyl -N- (4- (4- cyanophenyl benzenesulfonyl)) amino] Acetic acid production method.

[0126]

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2-[(N-isobutyl-N- (4- (4
-Cyanophenyl) benzenesulfonyl)) amino] acetic acid ethyl ester (2.40 g) in ethanol (10 m
l), sodium hydroxide (0.36 g) and water (5 m
l) was added and stirred at room temperature for 1.5 hours. Concentrate 10%
Acidified with hydrochloric acid. Extract with ethyl acetate (20 ml ×
3) The ethyl acetate layer was washed with saturated saline and dehydrated with sodium sulfate. The mixture was filtered, concentrated and purified by a silica gel column (chloroform: methanol = 7: 1). The desired product was obtained as white crystals (1.79 g). 129-130 ° C IR (cm- ¹ ): 3058, 2956, 2218, 17
22,1596 MS (m / e): 356 (M ⁺ -16), 329, 24
^{2,178 (BP), 151 1 H} -NMR (CDCl 3): 0.90 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 3.05
_{(2H, d, CH 2)} , 4.05 (2H, s, CH 2),
7.60 to 8.90 (8H, m, aromatic ring) (c) Method for producing 2- [N-isobutyl-N- (4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetic acid (Compound 57).

[0128]

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2-[(N-isobutyl-N- (4- (4
-Cyanophenyl) benzenesulfonyl)) amino] acetic acid (0.1 g) was dissolved in ethanol (3 ml), and potassium hydroxide (0.07 g) and water (2 ml) were added thereto and the mixture was heated under reflux (3 hours). Concentrate and add water (10m
1) and acidified with 10% hydrochloric acid. White crystals form. The crystals were filtered and recrystallized from ethanol to obtain the desired product as white crystals (0.6 g). Melting ^{point> 250 ℃ IR (cm ~ 1} ): 2950,2662,1719,16
89, 1425 MS (m / e): 349 (M ⁺ -42), 230, 19
7,152,80 (BP) ¹ H-NMR (DMSO): 0.88 (6H, d, (C
_{H 3) 2), 1.95 (} 1H, sept, CH), 3.05
_{(2H, d, CH 2)} , 4.02 (2H, s, CH 2),
7.80 to 8.20 (8H, m, aromatic ring)

Embodiment 12 FIG. N-hydroxy-2-[(N-isobutyl-N- (4-
(4-carboxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 58). (A) N-benzyloxy-2-[(N-isobutyl-
Production of N- (4- (4-cyanophenyl) benzenesulfonyl)) amino] acetamide.

[0131]

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The 2-[(N-isobutyl-N- (4- (4-cyanophenylbenzenesulfonyl)) amino] acetic acid (1.5 g) obtained in Example 11 (b) was added to dimethylformamide (30 ml). Dissolve and add HOBt (0.74
g) and NEM (1.11 g) were added and stirred for 30 minutes.
Then benzylhydroxyamine hydrochloride (0.77
g) and WSCDI (0.93 g) were added, and the mixture was stirred at room temperature for 8 hours. Pour into ice water (50 ml). White crystals precipitated. The crystals were filtered, washed with water and dried to give the desired product (1.86 g) as white crystals. Melting point 154-155
° C IR (cm ~ ¹ ): 2950, 2218, 1683, 15
96, 1485 MS (m / e): 327 (M ⁺ -150), 242,1
78, 105, 77 (BP) ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 2.95
_{(2H, d, CH 2)} , 3.70 (2H, s, CH 2),
_{4.95 (2H, s, CH 2} ), 7.30~7.90
(13H, m, aromatic ring), 9.20 (1H, bs, N
H) (b) N-benzyloxy-2-[(N-isobutyl)
-N- (4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetamide.

[0133]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (4-cyanophenyl) benzenesulfonyl)) amino] acetamide (1.0 g) was dissolved in ethanol (10 ml), and the solution was added thereto. Potassium hydroxide (0.58 g) and water (5 ml) were added and heated to reflux (5
time). The mixture was concentrated, water (20 ml) was added thereto, and the mixture was acidified with 10% hydrochloric acid. White crystals precipitated. Filter the crystals,
After washing with water and drying, the target product (0.4 g) was obtained as white crystals. Melting point 192-193 ° C IR (cm ~ ¹ ): 3172, 2950, 1686, 16
08, 1422 MS (m / e): 291 (M ⁺ -205), 261,1
97, 105, 77 (BP) ¹ H-NMR (CDCl ₃ ): 0.90 (6H, d, (C
_{H 3) 2), 1.80 (} 1H, sept, CH), 3.00
_{(2H, d, CH 2)} , 3.80 (2H, s, CH 2),
_{4.90 (2H, s, CH 2} ), 7.20~8.20
(13H, m, aromatic ring) (c) N-hydroxy-2-[(N-isobutyl-N-
(4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetamide (Compound 58).

[0135]

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N-benzyloxy-2-[(N-isobutyl-N- (4- (4-carboxyphenyl) benzenesulfonyl)) amino] acetamide (0.4 g) was dissolved in tetrahydrofuran (30 ml). 5%
Palladium / carbon (100 ml) was charged and catalytically reduced with hydrogen gas for 1 hour. Filtered through celite and concentrated. White crystals precipitated. Recrystallization was performed with 5 ml of ethanol to obtain the desired product (0.25 g) as white crystals. Melting point 214-21
^{5 ℃ IR (cm ~ 1)} : 3256,2950,1683,16
08,1425 MS (m / e): 333 (M ⁺ -73), 290, 26
^{1,199,152 (BP) 1 H-NMR} (DMSO): 0.95 (6H, d, (C
_{H 3) 2), 1.75 (} 1H, sept, CH), 3.00
_{(2H, d, CH 2)} , 3.79 (2H, s, CH 2),
7.90 to 8.20 (8H, m, aromatic ring), 8.98
(1H, bs, NH)

[0137]

[Table 2]

[0138]

Industrial Applicability The novel compound of the present invention has an excellent inhibitory effect on matrix metalloproteinases (MMPs) and is useful as a therapeutic or preventive agent for diseases caused by destruction of extracellular matrix by MMPs. It can be expected to have the medicinal effect by oral administration.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/38 A61K 31/38 31/63 31/63 ADU ADU C07C 303/38 C07C 303/38 311/19 311/19 311 / 29 311/29 C07D 333/18 C07D 333/18 333/38 333/38 (72) Inventor Yoshinori Kobayashi 2526 Mori Omori Mori, Nagano Prefecture

Claims (8)

[Claims] 1. A compound represented by the following general formula (I): Wherein R ₁ is a lower alkyl group, a heterocyclic ring, a phenyl group,
Or a substituted phenyl group substituted with a lower alkyl group or a lower alkoxy group. R ₂ is a -COOH group, -C
ONHOH a group or -COOC ₂ H ₅ group. A is
(1) -Ph-NHCO-R ₃ group (Ph is a phenyl group,
R ₃ is a phenyl group, a lower alkyl group, a lower alkoxy group or a —O— (CH ₂ ) _n NH ₂ group (n = 1 to 3)
A substituted phenyl group or a thienyl group, or a substituted thienyl group or a pyridyl group substituted with a lower alkyl group), (2) -R ₄ -R ₅ group (R ₄ is a phenyl group or a thienyl group, R ₅ is a phenyl group, or a lower alkyl group, a lower alkoxy group, a hydroxy group, a substituted phenyl group substituted with a carboxyl group or a cyano group, or a thienyl group, or a substituted thienyl group substituted with a lower alkyl group), and _{(3) -Ph-NHSO 2 -R} 6 group (P
h is a phenyl group; R ₆ is a phenyl group or a substituted phenyl group substituted with a lower alkyl group or a lower alkoxy group). Or a pharmaceutically acceptable salt thereof. 2. A compound represented by the following general formula (II): (Wherein R ₁ is the same as described above; R ₇ is an alkyl group containing 1 to 3 carbon atoms);
General formula (III) of the following formula: (Wherein R ₃ is the same as described above, and R ₈ is a halogen atom). A compound represented by the following general formula (IV) is reacted in the presence of a base. (Wherein R ₁ , R ₃ and R ₇ are the same as described above), and then the compound of the general formula (IV) is hydrolyzed. ): (Wherein, R ₁ and R ₃ are the same as described above). 3. A compound represented by the general formula (V) according to claim 2, wherein the compound represented by the general formula (V) is reacted with NH ₂ OH in the presence of a condensing agent. (Wherein, R ₁ and R ₃ are the same as described above). 4. A compound represented by the following general formula (VII): (Wherein R ₁ , R ₄ and R ₇ are the same as described above, and R ₈ is a halogen atom), and a compound represented by the following general formula (VIII) or (IX): ] (In the formula, R ₅ is the same as described above, and R ₈ represents a halogen atom.) (Wherein R ₅ is the same as described above), and reacted with a palladium compound as a catalyst in the presence of a base to obtain a compound represented by the following general formula (X): (In the formula, R ₁ , R ₄ , R ₅ and R ₇ are the same as described above.)
And then hydrolyzing the compound of the general formula (X), wherein the compound of the general formula (X) is hydrolyzed.
I): embedded image (Wherein, R ₁ , R ₄ and R ₅ are the same as described above). 5. A compound represented by the general formula (XI) according to claim 4, wherein NH ₂ OH is reacted with the compound represented by the general formula (XI) in the presence of a condensing agent. (Wherein, R ₁ , R ₄ and R ₅ are the same as described above). 6. A compound represented by the following general formula (II): (Wherein, R _1, R ₇ is the same as defined above) with a compound represented by the general formula R ₈ -SO ₂ -R ₆ (Formula XIII, in the formula R ₆
Is the same as described above, and R ₈ represents a halogen atom. Is reacted in the presence of a base to give a compound of the following general formula (XIV): (Wherein R ₁ , R ₆ and R ₇ are the same as defined above), and then the compound of the general formula (XIV) is hydrolyzed. ): (In the formula, R ₁ and R ₆ are the same as described above.) 7. A compound represented by the general formula (XVI) according to claim 6, wherein the compound represented by the general formula (XV) is reacted with NH ₂ OH in the presence of a condensing agent. (In the formula, R ₁ and R ₆ are the same as described above.) 8. A compound represented by the following general formula (I): (Wherein R ₁ , R ₂ and A are as defined above) or a disease caused by the destruction of the extracellular matrix by a matrix metalloproteinase containing a compound or a pharmaceutically acceptable salt thereof as an active ingredient. And / or a pharmaceutical composition for the prevention and / or prevention of the disease.