WO2000058304A1 - Heterocyclic sulfonamide derivatives - Google Patents

Abstract

Sulfonamide derivatives exhibiting matrix metalloprotease inhibiting effects, which are compounds represented by general formula (I), optical isomers thereof, pharmaceutically acceptable salts of both, or hydrates of them: wherein A is a group represented by the general formula (Ia): (wherein R5 is hydrogen or the like), or the like; R1 is hydroxyl or the like; R2 is a single bond, optionally substituted arylene, or optionally substituted heteroarylene; R3 is a single bond, -C C-, or the like; R4 is optionally substituted aryl, optionally substituted heteroaryl, or the like; and m is 0 or 1.

Description

 Specification

Heterocyclic sulfonamide derivative

Technical field

 The present invention relates to a sulfonamide derivative having a heterocycle and a meta-protease inhibitor containing the same.

Background art

Extracellular matrix is composed of collagen, fibronectin, laminin, proteoglycan, etc., and plays a role in tissue support, cell proliferation, differentiation, adhesion and the like. The degradation of extracellular matrix involves meta-oral proteases, which are proteases containing a metal ion in the active center, particularly matrix protease (MMP). Many families of MMPs, ranging from MMP-1 (type I collagenase) to MMP-23, have been reported to work on growth and tissue reform under the original physiological conditions. However, in various pathological conditions involving tissue destruction and fibrosis (osteoarthritis, rheumatoid arthritis, corneal ulcers, periodontitis, metastasis or invasion of tumors, viral infections (HIV infection)), the progression of the disease states and the aforementioned enzymes It has been reported that the increase in the expression (activity) of is correlated. Also, many MMP inhibitors tend to have an inhibitory effect on TNF- _α production.

 MMΡ inhibitors having a cyclic structure are described in W097 / 18194, WO98 / 088814, WO98 / 088815, WO98 / 088222, WO98 / 16650, W098 / 1 6 5 14 4, WO 98/16 52 0, WO 98 3/30 56, WO 98/349 18, WO 98/50 348, EP-7 6 94 9 8, EP-8 0 35050, EP-8181442, EP878467 and the like.

A compound having a similar side chain and MMP inhibitory activity is 00 / 1708-. Disclosure of the invention

 If the above-mentioned MMP activity can be inhibited, it is considered that it will greatly contribute to amelioration of the above-mentioned pathological conditions caused by or related to the activity or prevention of the progress thereof, and development of MMP inhibitors is desired. .

Means for Solving the Problems In view of the above points, the present inventors have conducted intensive studies, and as a result, have found that certain kinds of sulfonamide derivatives having a novel heterocyclic ring show strong MMP inhibitory activity. That is, the present invention provides a compound of the general formula (I):

 [Wherein the ring A is of the formula:

(Wherein, R ⁵ is a hydrogen atom, hydroxy, —Z—R ⁶ (where Z is —0—, —S—, or one N (R ^A ) —; R ⁶ may be substituted) Aryl; R ^A is a hydrogen atom, lower alkyl, aralkyl, or acyl);

R ¹ is NH〇H, hydroxy, or lower alkyloxy;

R ² is a single bond, optionally substituted arylene, or optionally substituted heteroarylene; -

R ³ is a single bond, - (CH ₂₎ p, one CH = CH, One C≡ C one, CO, one CO- NH-, - N = N-, - N (R B) one, single NH- CO — NH—, — NH— C o, one s—, S〇 ₂ , one SO. NH, one SO. One NH—N = CH—, or the formula:

Ν- ■ Ο Ο—— Ν

 If <is ^ ^ "

Wherein R ^B is hydrogen or lower alkyl, ρ is 1 or 2; R ⁴ is cycloalkyl which may be substituted, aryl which may be substituted, or aryl which may be substituted Heteroaryl, or an optionally substituted non-aromatic compound;

However, when R ² and R ³ are both a single bond, R ⁴ may be substituted but not aryl.], An optically active form thereof, or a pharmaceutically acceptable salt thereof. , Or hydrates thereof.

 More specifically, the present invention relates to II) to XIV) shown below.

I I) General formula (I I):

[Wherein, A ring and R ¹ are as defined above;

R ⁷ has the formula:

(Wherein R ⁸ is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower Alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle An optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, or an optionally substituted ureid;

R ⁹ is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxy. Carbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, substituted An optionally substituted non-aromatic heterocycle, an optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, or an optionally substituted ureide; q and r independently represent 0, 1, 2, or 3;

X is an oxygen or sulfur atom; P0001708-

Y i is one C≡C one or formula

A group represented by;

 X is an oxygen atom or a sulfur atom), an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

III) General formula (III):

[Wherein, A ring and R ¹ are as defined above;

R ^{1 Q} is the formula:

， または

, Or

(Wherein, R ⁹ and r are as defined above.

—— O O—— Y ² is one C≡C one or formula: -

—— OO——

 Or "^"

Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

IV) R ¹ ° is the formula:

(Wherein R ⁹ and r are the same as defined above) III), an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

V) Ring A has the formula: -

(Wherein R ⁵ is as defined above), the compound according to any one of I) to IV), an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

VI) The compound according to any one of I) to V), wherein R ¹ is hydroxy, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 (VII) A pharmaceutical composition comprising the compound according to any one of (I) to (VI) as an active ingredient.

 VI I I) A metastatic protease inhibitor comprising, as an active ingredient, the compound according to any one of I) to VI)).

 IX) A matrix protease inhibitor containing the compound according to any one of I) to VI) as an active ingredient.

 X) An agent for treating or preventing cancer, comprising the compound according to any one of I) to VI) as an active ingredient.

 XI) A therapeutic or prophylactic agent for astritis comprising the compound according to any one of I) to VI) as an active ingredient.

 XI I) A therapeutic or prophylactic agent for osteoarthritis comprising the compound according to any one of I) to VI) as an active ingredient.

 XI I I) An agent for treating or preventing heart failure, comprising the compound according to any one of I) to VI) as an active ingredient.

 XI V) An agent for treating or preventing rheumatoid arthritis, comprising as an active ingredient the compound according to any one of I) to VI).

As used herein, alone or in combination with other terms, the term "lower alkyl J" includes straight-chain or branched monovalent hydrocarbon groups having 1 to 8 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, -Isobutynole, sec butynole, tert-butynole, n-pentynole, isopentyl, neo-"^ pentinole, n-hexynole, isohexynole, n-heptinole, n-octynole, etc. Preferably, C1-C6 alkyl More preferably, a C1-C3 alkyl is included.

 As used herein, the term "lower alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon having 2 to 8 carbon atoms and having one or more double bonds. Include groups. For example, butyl, aryl, propenyl, crotonyl, isopentenyl, various butenyl isomers and the like can be mentioned. Preferably, C2-C6 alkenyl is mentioned. More preferably, a C2-C4 alkenyl is mentioned.

 As used herein, the term "lower alkynyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 8 carbon atoms and having one or more triple bonds. And may have a double bond. For example, ethynyl, 2-probyl, 3-butyninole, 4-pentinole, 5-hexyninole, 6-heptininole, 7-octininole and the like can be mentioned. Preferably, a C2-C6 alkynyl is mentioned. Even more preferred are C2-C4 alkynyl.

 In the present specification, “cycloalkyl” includes cycloalkyl having 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably a C3-C6 cycloalkyl is mentioned.

 As used herein, "aryl", used alone or in combination with other terms, includes a monocyclic or condensed cyclic aromatic hydrocarbon. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.

In the present specification, the “aralkyl” is the same as the above “lower alkyl” substituted by the above “aryl”, and these may be substituted at all possible positions. For example, benzyl, phenylethyl (eg, 2-phenylethyl), phenylpropyl (eg, 3-phenylpropyl), naphthylmethyl (eg, 1-naphthylmethyl, 2) -Naphthylmethyl, etc.) and anthrylmethyl (for example, 91-anthrylmethyl etc.). Preferably, benzyl and phenylethyl are exemplified.

As used herein, the term "heteroaryl" used alone or in combination with other terms refers to an arbitrarily selected 5- to 6-membered ring containing at least one oxygen, sulfur or nitrogen atom. Which may be fused to a cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions. For example, pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), phenyl (eg, 2-phenyl, 3-phenyl) Chenyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl), vilazolyl (eg, 1- virazolyl, 3-birazolyl), isothiazolyl (eg, 3-isothiazolyl), isoxazolyl (eg, 3-) Isoxazolyl), oxazolyl (eg, 2-xazolyl), thiazolyl (eg, 2-thiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), virazinyl (eg, 2-pyrazinyl), Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (eg, 3-pyridazi ), Tetrazolyl (for example, 1H-tetrazolyl), oxazidazolyl (for example, 1,3,4-oxadiazolyl), thiadiazolyl (for example, 1,3,4-thiadiazolyl), indridinyl (for example, 2-indridinyl, 6 —Indolinyl), isoindrill (for example, 2-isoindrill), indolyl (for example, 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (for example, 3— Indazolyl), purinyl (for example, 8-purinyl), quinolinidinyl (for example, 2-quinolinyl), isoquinolyl (for example, 3-isoquinolyl), quinolyl (for example, 2-quinolyl, 5-quinolyl) ), Phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (eg, 2-naphthyridinyl) , Kinoraniru (e.g., 2-Kinoraniru), quinazolinyl (e.g., 2-Kinazori) yl, Niino Riniru (e.g., 3-Niino Riniru), Puteri Jiniru (e.g., -

2-pteridinyl), carbazolyl (for example, 2-caprolyl, 3-carbazolyl), phenanthridinyl (for example, 2-phenanthridinyl, 3-phenanthridinyl), atalidinyl (for example, 1-ataridinyl, 2-ataridinyl) ), Dibenzofuranyl (eg, 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzoimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), Benzoxazolyl (for example, 2-benzoxazolyl), Benzoxadiazolyl (for example, 4-benzobenzodiazolyl), Benzoisothiazolyl (for example, 3-benzoisothiazolyl) , Benzothiazolyl (eg, 2-benzothiazolyl), benzofuryl ( Eg to three to base Nzofuriru), Benzocheniru (e.g., 2 - base Nzoche sulfonyl), and the like et be.

As the “heteroaryl” for R ⁴ , phenyl, pyridyl, dibenzofurer, isoxazolyl, tetrazolyl and pyrrolyl are preferred.

 In the present specification, the term "heteroarylalkyl" is the same as the above "lower alkyl" substituted at any position with the above "heteroaryl", and these may be substituted at all possible positions. For example, thiazolylmethyl (for example, 4-monothiazolylmethyl), thiazolylethyl (for example, 5-thiazolyl-2-ethyl), benzothiazolylmethyl (for example, (benzothiazoluyl-2-yl) methyl), indolylmethyl (for example, (indole-3) —Yl) methyl), imidazolylmethyl (for example, 4-imidazolylmethyl), benzothiazolylmethyl (for example, 2-benzothiazolylmethyl), indazolylmethyl (for example, 1-indazolylmethyl), benzoto Lyazolylmethyl (eg, 1-benzotriazolylmethyl), benzoquinolylmethyl (eg, 2-benzoquinolylmethyl), benzimidazolylmethyl (eg, 2-benzoimidazolylmethyl), pyridylmethyl (eg, 4-pi Jirumechiru), and the like.

As used herein, the term "non-aromatic compound" used alone or in combination with other terms. The term "primary ring" includes a non-aromatic 5- to 7-membered ring containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring, or a ring obtained by condensing two or more of these atoms. You. For example, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolyl (eg, 3-pyrrolidinyl), imidazolidinyl (eg, 2-imidazolidinyl), imidazolinyl (eg, Midazolinyl), birazolidinyl (eg, 1-virazolidinyl, 2-birazolidinyl), birazolinyl (eg, birazolinyl), piperidyl (eg, piperidino, 2-piperidyl), piperazinyl (eg, 1-piperazinyl), indolinyl (eg, 1-indolinyl) Indolininole), isoindolinyl (for example, isoindolinyl), morpholinyl (for example, morpholino, 3-morpholininole), 4H— [1,2,4] oxaziazione-l-one , 1, 2, 3, 4—Tetrahi draw [1,8] Naphchili Gin and the like.

Examples of the "non-aromatic heterocyclic ring" for R ⁴ include birazolidinyl, piperidyl, pivalinyl, morpholinyl, 4 H— [1,2,4] oxaziazolyl 5-one, 1,2,3,4-tetrahi Draw [1, 8] naphthyridine and the like are preferred.

 In the present specification, “arylene” means the divalent group of the above “aryl”. For example, phenylene, naphthylene and the like can be mentioned. More specifically, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and the like can be mentioned. Preferred is 1,4-phenylene.

 In the present specification, “heteroarylene” means the divalent group of the above “heteroaryl”. For example, thiofenzil, frangyl, pyridinezyl and the like can be mentioned. In more detail, 2,5-chofenzir, 2,5-furangyl and the like can be mentioned.

As used herein, the term “acyl” used alone or in combination with other terms refers to an alkylcarbonyl wherein the alkyl moiety is the above “lower alkyl” or an arylcarbonyl wherein the aryl moiety is the above “aryl”. Is included. example -For example, acetyl, propionyl, benzoyl and the like. “Lower alkyl” and “aryl” may be substituted by the respective substituents described below. In the present specification, “halogen” means fluorine, chlorine, bromine, and iodine, and preferably includes fluorine, chlorine, and bromine.

 In the present specification, examples of the “lower alkyloxy” include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and the like. Preferably, methyloxy, ethyloxy, n-propyloxy, isopropyloxy and n-butyloxy are exemplified.

 In the present specification, the “lower alkylthio” includes methylthio, ethylthio and the like.

 In the present specification, the “lower alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.

 As used herein, the term "halo lower alkyl" used alone or in combination with other terms includes the above "lower alkyl" substituted with 1 to 8, preferably 1 to 5 positions by the halogen. I do. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferably, trifluoromethyl is used. In the present specification, "halo-lower alkyloxy" includes trifluoromethyloxy and the like.

 In the present specification, “lower alkylsulfonyl j” includes methylsulfonyl, ethylsulfonyl, and the like. Methylsulfonyl is preferable.

 In the present specification, examples of "asyloxy" include acetyloxy, propionoxy, benzoyloxy and the like.

As used herein, "substituted amino" used alone or in combination with other terms. The term "lower alkyl", "aralkyl", "heteroarylalkyl", or amino substituted one or two times with said "acyl". For example, methylamino, dimethylamino, ethylmethylamino, getylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned. Preferably, methylamino, dimethylamino, ethylmethylamino, getylamino, and acetylamino are exemplified.

 In the present specification, examples of the “substituted aminocarbonyl” include methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, getylaminocarbonyl, and the like. Preferably, dimethylaminocarbonyl is used. In the present specification, examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, and lower alkyloxycarbonyl. Halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocycle, aryloxy (for example, Phenyloxy), aralkyloxy (for example, benzyloxy), lower alkylsulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions.

As the substituent for the “optionally substituted lower alkyl” in R ⁸ and R ⁹ , hydroxy and lower alkyloxy are preferable.

In the present specification, “optionally substituted arylene”, “optionally substituted heteroarylene”, “optionally substituted cycloalkyl”, “optionally substituted aryl”, “ "Optionally substituted heteroaryl", "optionally substituted non-aromatic heterocycle", "optionally substituted aralkyl", "optionally substituted heteroarylalkyl", and "substituted" The substituent in the “optionally substituted raido” is a lower alkyl which may be substituted, cyclo, -Alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, non-substituted or substituted Amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic, substituted And optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions.

As “optionally substituted arylene” and “optionally substituted heteroarylene” for R ^2, unsubstituted ones are preferred. Examples of the substituent include nitrogen, nitro, cyano, lower alkyloxy and the like.

“Optionally substituted cycloalkyl”, “optionally substituted aryl”, “optionally substituted heteroaryl”, and “optionally substituted non-aromatic heterocycle” for R ⁴ The lower alkyl, hydroxy lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, halogen, nitro, carboxy, halo lower alkyl, halo lower alkyloxy, unsubstituted or substituted amino, unsubstituted or Preferred are substituted aminocarbonyl, heteroaryl, non-aromatic heterocycle, and the like.

As the “optionally substituted aryl” in R ⁹ , an unsubstituted aryl is preferable. Examples of the substituent include an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkynoleoxycarbonyl, and lower halo. Examples include alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy.

“Optionally substituted heteroaryl”, “optionally substituted non-aromatic heterocycle”, “optionally substituted aralkyl”, and R ⁸ and R ⁹ -

As the “urea which may be substituted”, an unsubstituted one is preferable. Examples of the substituent include optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogeno, nitro, cyano, carboxy, lower alkyloxycarbonyl, and lower halo. Examples include alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy. BEST MODE FOR CARRYING OUT THE INVENTION

 The compound (I) of the present invention can be prepared by using the following starting materials by the methods described in WO97 / 27174 (methods A to F) and methods similar to known methods. Can be done. This will be described in detail below.

 As starting materials, commercially available compounds containing a nitrogen atom in the ring and having a (protected) carboxyl group as a substituent and compounds described in the literature are used. Compounds obtained by introducing further substituents into the above-mentioned known compounds by a known reaction can also be used as starting materials.

 Examples of commercially available starting materials include a proline derivative, a 2-carboxyindolin derivative, a 2-carboxyindoline derivative, a 3-carboxy-1,3,4-dihydroisoquinoline derivative, and a 3-carboxypiperidine derivative.

The WO 9 7/0 5 1 3 5, 2 - c which Karubokishipurori down derivatives are described

(式中、 A環、 R ²、 R ³、 R⁴、 および mは前記と同意義、 R ^{1 1}は低級アルキル、 H a lはハロゲンを示す）

(Wherein, A ring, R ² , R ³ , R ⁴ and m are as defined above, R ¹¹ is lower alkyl, and Hal is halogen)

 (First step)

 In this step, the starting material (IV) is converted to a sulfonamide derivative (V). The method can be carried out in the same manner as described in W09 7/2 7174 (Method A-1st step).

 (2nd step)

In this step, the protecting group for the carboxyl group of the compound (V) is deprotected to obtain a compound (VI) in which R ¹ is —COOH. Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc.

 When referring to the "compound of the present invention", a pharmaceutically acceptable salt or a hydrate thereof is also conjugated. For example, alkali metal (lithium, sodium, potassium, etc.), alkaline earth metal (magnesium, calcium, etc.), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid) , Phosphoric acid, sulfuric acid, etc.) and salts with organic acids (acetic acid, cunic acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.). These salts can be formed by a commonly used method. When forming a hydrate, it may be coordinated with any number of water molecules.

 The compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates.

 The compound of the present invention exhibits excellent MMP-2 inhibitory activity and inhibits matrix degradation, as described in Experimental Examples described later.

Specifically, osteoarthritis, rheumatoid arthritis, corneal ulcer, periodontitis, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerotic aneurysms, atherosclerosis Disease, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, Scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, bullous epidermis, psoriasis, diabetes, nephritis, neurological disease, inflammation, osteoporosis, Bone resorption, gingivitis, tumor growth, tumor angiogenesis, ocular tumors, angiofibromas, hemangiomas, fever, bleeding, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, It can be used as a treatment for Crohn's disease, meningitis, heart failure, asthmatic airway inflammation, arteriosclerosis, and gastrointestinal ulcer.

 When the compound of the present invention is administered to humans for the treatment of the above-mentioned diseases, it is administered orally as powders, granules, tablets, capsules, pills, liquids, etc., or as injections, suppositories, transdermals It can be administered parenterally as an absorbent, inhalant or the like. In addition, a pharmaceutical formulation can be prepared by mixing an effective amount of the compound with excipients, binders, wetting agents, disintegrating agents, lubricants and other pharmaceutical additives suitable for the dosage form, if necessary. it can. In the case of injections, they should be sterilized with a suitable carrier to produce the preparation.

 Dosages will vary depending on disease state, route of administration, age of patient, or body weight, but for oral administration to adults, usually 0.1 to 100 mg / kg / day, preferably 1 ~ 20 mg / kg / day.

 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

 In the examples, the following abbreviations are used.

 M e: Methyl

E t: ethyl

¹ Pr: isopropyl

n B u: n—butyl

t B u: t e r t —butyl

 P h: phenyl

Example

Example 1 Preparation of Compound (A-1) -CO Me

Go to C0 ₂ Me CISO.

N First step S. 5 ~ N0 ₂

^H HCI

 (First step)

 dl-2-Methoxycarbonylindoline hydrochloride (1) (1.45 g, 6.79 mmol) was suspended in dichloromethane (20 mL), and N-methylmorpholine (2.2 mL, 20.0 mmol) was added at room temperature under a nitrogen atmosphere. And 4-nitrobenzenesulfonino rechloride (2) (lg, 4.51 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into ice-cold 2N hydrochloric acid, extracted twice with ethyl acetate, and the organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then depressurized. Concentration gave a brown paste (1.97 g). The resulting mixture was subjected to silica gel gel chromatography, eluted with ethyl acetate / n-hexane = 1/5, and concentrated under reduced pressure to obtain a crystalline residue (1.46 g). Recrystallization from ethyl acetate / n-hexane gave compound (3) (pale yellow columnar crystals, 1.02 g). Yield 62%.

IR V max (cm-i) (KBr): 1749, 1606, 1529, 1360, 1350, 1173.

iH-NMR (6 ppm) (CDCh) 3.14 (dd, J = 5.2, 16.4 Hz, 1H), 3.29 (rid, J = 10.2, 16.4 Hz, 1H), 3.80 (s, 3H). , J = 5.3, 10.2 Hz, 1H), 6.95-7.30 (3H), 7.53 (d, J = 8.0 Hz.1H), 8.03 (d, J = 9.2 Hz, 211), 8.30 (d, J = 8.6 Hz 2H). 708 - by the elemental analysis C _ls Hi4N ₂ 0 ₆ S

 Calculated: C, 53.03; H, 3.89; N, 7.73; S, 8.85.

 Found: C, 53.36; H, 3.84; N, 7.78; S, 8.74.

 (2nd step)

Compound (3) (918 mg, 2.53 mmol) was dissolved in 10 ml of dimethylformamide, and 110 mg of palladium hydroxide was added to perform catalytic reduction. After completion of the reaction, the catalyst was removed, the mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.08 g of a pale brown paste. Recrystallization from ethanol / water gave compound (4) (818 _{mg of} pale brown granular crystals). 97% yield

Melting point 161-163 ° C

 IR V max (cm-i) (KBr): 3479, 3371, 1749, 1624, 1593, 1348, 1329, 1153.

iH-NMR (0 ppm) (CDCl ₃ ) 3.07 (dd, J = 5.3, 16.4 Hz, 1H), 3.21 (dd, J = 10.4, 15.8 Hz, 1H), 3.2-3.70 (2H), 3.79 ( s, 3H), 4.75 (dd, J = 5.5, 10.4 Hz, 1H), 6.59 (d, J = 8.8 Hz, 2H), 6.9-7.25 (3H), 7.55 (d, J = 8.8 Hz, 2H).

Elemental analysis Ci ₆ Hi ₆ N ₂ 04S

 Calculated: C, 57.82; H, 4.85; N, 8.43; S, 9.65.

 Found: C, 57.85; H, 4.86; N, 8.31; S, 9.44.

 (3rd step)

Compound (4) (788 mg, 2.37 mmol) was suspended in 20 ml of a 50% aqueous ethanol solution, 1.5 ml of concentrated hydrochloric acid was added, and the mixture was cooled to an internal temperature of 0 to 5 ° C. Then, sodium nitrite (0.35 g, 5.07 mmol) was added. Was dissolved in 3 ml of water, added dropwise so that the temperature did not exceed 5 ° C, and stirred at the same temperature for 20 minutes (preparation of diazonium salt). Compound (5) (750 mg, 2.37 mmol) was dissolved in pyridine (15 ml), cooled to 120-130 ° C, and the previously prepared suspension of diazonium salt of compound (4) was added quickly to room temperature. The mixture was returned and stirred overnight. The reaction solution was poured into 100 ml of 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed successively with a 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and concentrated under reduced pressure. 1.63 g of a dark red paste was obtained. Silica gel power -Lam chromatography, elution with ethyl acetate / toluene = 1/10, followed by recrystallization from toluene gave compound (6) (385 mg of pale red granular crystals). Yield 31%. 145-7 (dec) ° C

 IR V max (cm-i) (KBr): 1743, 1595, 1309, 1281, 1165.

iH-NMR (δ ppm) (CDCl ₃ ) 0.95 (t, J = 7.2 Hz, 3H), 1.39 (m, 2H), 1.65 (m, 2H), 2.69 (t, J = 7.5 Hz, 2H), 3.05 -3.35 (2H), 4.88 (dd, J = 5.3, 9.8 Hz, 1H), 7.0-7.4 (5H), 7.6 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 9.2 Hz, 2H) , 8.13 (d, J = 8.4 Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H)

 (4th step)

 Compound (6) (200 mg, 0.39 mmol) was dissolved in methanol (2.4 ml) / tetrahydrofuran (2.4 ml), and a 1N aqueous solution of sodium hydroxide (1.2 ml, 1.2 mmol) was added at room temperature. The mixture was stirred for 4 hours. The reaction solution was poured into iced 2N hydrochloric acid, extracted twice with ethyl acetate, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.18 g of a pale red substance. Recrystallization from acetone / n-hexane gave compound (A-1) (153 mg of pale red needles). 79% yield.

Melting point 185-186 ° C.

 (IR v max cm- CKBr): 3433, 1718, 1658, 1498, 1381, 1227, 1163

iH-NMR (6 ppm) (DMSO) 0.91 (t, J = 7.3 Hz, 3H), 1.33 (m, J = 6.9 Hz, 2H), 1.6 l (m, 2H), 2.67 (t, J = 7.5 Hz , 2H), 3.07 (dd, J = 4.1, 16.4 Hz, 1H), 3.3-3.5 (lH), 5.05 (dd, J = 4.4, 10.6 Hz, 1H), 6.6-7.3 (3H), 7.43 (d, J = 8.0 Hz, 3H), 8.07 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 8.6 Hz, 2H), 13.0-13.4 (br s , 1H)

Elemental analysis As C26H25N5O4S

 Calculated: C, 62.01; H, 5.00; N, 13.91; S, 6.37

 Found: C, 61.89; H, 4.84; N, 14.16; S, 6.59.

As in Example 1 and as described in Hoffman, RV Org. Synth. 1981, 60, 121. Compounds (A-2) to (A-5) were synthesized by the method _of-

Example 6

 (Step 1)

 Compound (7) was allowed to react with 5-promothiophen-2-sulfoluc mouth ride (8) in the same manner as described in the first step of Example 1 to give compound (9).

 (2nd step)

 Compound (11) was obtained in the same manner as described in Tamura, Y. et al., J. Med. Chem. 1998, 41, 640.

 (3rd step)

Compound (A-6) was obtained in the same manner as in the method described in the fourth step of Example 1. Compounds (A-7) and (A-8) were synthesized in the same manner as described in Example 6. Example 9 P00 / 01708

 A-9

 (First step)

 Compound (13) was obtained in the same manner as described in Tamura, Y. et al., J. Med. Chem. 1998, 41, 640.

 (2nd step)

Compound (A-9) was obtained in the same manner as in the method described in the fourth step of Example 1. Tables 1 to 3 show physical constants of the compounds obtained above.

Z

80 mu lO / OOdfAI d ΙΌε8δ / 00 OAV

 ζ 挲

-80Z, I0 / 00 <If / I3d tOe8S / 00 OAV

 £ 挲

-80Ll / 00 / 00df / I3d tOC8S / 00 OAV -By using the same method, a compound represented by the following combination of substituents in the following general formula can be synthesized.

However, the symbols Q 1 Q 7 used below mean the following substituents.

 = Ν Ν = Ν π —— Ν

Ql = — Ν _Ν ^ — Q2 = -Λ, .Ν— Q3 = — lL _s J— Q4 =, NNN—— OO—— N

Q5 = ~ L ", Q6 = and Q

(R ² R ³ R ⁴ ) = (1,4-phenylene, -CH _2- , Ph), (1,4-phenylene, -CH _2- , 4-Me-Ph), (1,4-phenylene, -CH2-, 4-Et-Ph), (1,4-phenylene, -CH2-, 4-nPr-Ph), (1,4-phenylene, -CH2-, 4-iPr-Ph), (1, 4-phenylene, -CH2-, 4-nBu-Ph), (1,4-phenylene, -CH2-, 4-tBu-Ph), (1,4-phenylene, -CH2-, 4-OMe-Ph) , (1,4-phenylene, -CH2-, 4-OEt-Ph), (1,4-phenylene, -CH2-, 4-SMe-Ph), (1, 4-phenylene, -CH2-, 4- F-Ph), (1,4-phenylene, -CH2-, 4-Cl-Ph), (1, 4-phenylene, -CH2-, 4-Br-P), (1,4-phenylene, -CH _{2 -, 4-CF 3 -Ph} ), (1, 4-phenylene, -CH2-, 4-N0 2 -Ph), (1, 4- phenylene, -CH2-, 4-NH2-Ph), (1 , 4-phenylene, -CH _2-4 -NHMe-Ph), (1,4-phenylene, -CH2-, 4-NMe ₂ -Ph), (1,4-phenylene, -CH2-, 4-NHEt- Ph), (1, 4-phenylene, -CH _2-4 -NMeEt-Ph), (1, 4-phenylene, -CH = CH-, Ph), (1,4- phenylene, -CH = CH-, 4-Me-Ph), (1,4-phenylene, -CH = CH-, 4-Et-Ph), (1,4-phenylene, -CH = CH-, 4-nPr-Ph), (1, 4-phenylene, -CH = CH-, 4-iPr-Ph), (1,4-phenylene, -CH = CH-, 4-nBu-Ph), (1, 4-phenylene, -CH = CH-. 4-t, Bu-Ph), (1, 4- -phenylene, -CH = CH-, 4-OMe-Ph), (1,4-phenylene, -CH = CH-, 4-OEt-Ph), (1,4-phenylene, -CH = CH-, 4 -SMe-Ph), (1,4-phenylene, -CH = CH-, 4-F-Ph), (1,4-phenylene, -CH = CH-, 4-Cl-Ph), (1,4 -phenylene, -CH = CH-, 4-Br-Ph), (1,4-phenylene, -CH = CH-, 4-CFa-Ph), (1,4-phenylene, -CH = CH-, 4 _{-N0 2 -Ph), (1,4- phenylene} , -CH = CH-, 4-NH 2 -Ph), (1,4-phenylene, -CH = CH -, 4-NHMe-Ph), (1 , 4-phenylene, -CH = CH-, 4-NMe ₂ -Ph), (1,4-phenylene, -CH = CH-, 4-NHEt-Ph), (1,4-phenylene, -CH = CH -, 4-NMeEt-Ph), (1,4-phenylene, -C≡C-, Ph), (1,4-phenylene, -C≡ C-, 4-Me-Ph), (1,4- phenylene, -C≡C-, 4-Et-Ph), (1,4-phenylene, -C≡C-, 4-nPr-Ph), (1,4-phenylene, -C≡C-, 4- iPr-Ph), (1,4-phenylene, -C≡C-, 4-nBu-Ph), (1,4-phenylene, -C≡ C-, 4-tBu-Ph), (1,4- phenylene, -C≡ C-, 4- OMe-Ph), (1,4-phenylene, -C≡ C-, 4-OEt-Ph), (1,4-phenylene, -C≡C-, 4- SMe- Ph), (1,4-phenylene, -C≡ C-, 4-F-Ph), (1,4-phenylene, -C≡ C-, 4-Cl-Ph), (1,4- phenylene, -C≡ C-, 4-Br-Ph), (1,4-phenylene, -C tri-C- '4-CFs-Ph), (1,4- p henylene, -C≡ C-, 4-N02-Ph), (1,4-phenylene, -C≡ C- '4-NH ₂ -Ph), (1,4- phenylene, -C≡C-, 4 -NHMe-Ph), (1,4-phenylene, -C≡ C-, 4-NMe ₂ -Ph), (1,4-phenylene, -C≡C-, 4-NHEt-Ph), (1, 4-phenylene, -C≡C-, 4-NMeEt-Ph), (1,4-phenylene, -CONH-, Ph), (1,4-phenylene, -CONH-, 4-Me-Ph), ( 1,4-phenylene, -CONH-, 4-Et-Ph), (1,4-phenylene, -CONH-, 4-nPr-Ph), (1,4-phenylene,-CONH-, 4-iPr- Ph), (1,4-phenylene, -CONH-, 4-nBu-Ph), (1,4-phenylene,-CONH-, 4-tBu-Ph), (1,4-phenylene, -CONH-, 4-OMe-Ph), (1,4-phenylene,-CONH-, 4-OEt-Ph), (1,4-phenylene, -CONH-, 4-SMe-Ph), (1,4-phenylene, -CONH-, 4-F-Ph), (1,4-phenylene, -CONH-, 4-Cl-Ph), (1,4-phenylene, -CONH-, 4-Br-Ph), (1, 4-phenylene, -CONH-, 4- CF 3 -Ph), (1,4-phenylene, -CONH-, 4- N0 2 -Ph), (1,4-phenylene, -CONH-, 4-NH 2 -Ph), (1, 4-phenylene, -CONH-, 4-NHMe-Ph), (1, 4-phenylene, -CONH-, 4-NMe. ₂ -Ph), (1,4-phenylene,- CONH-, 4-NHEt-Ph), (1,4-phenylene, -CO H-, 4-NMeEt-Ph), (1,4-phenylene, -NHCO-, t

〇

y (e1! inffico§eptlN 4 --- to

 〇 〇

 y py? py) ¾ Q4enlelhlinl34〇Mtphilen: 4 --- 4

Q¾¾yy¾ (,), ee3:? Inlneen 4iprlili npr ;? : lll <---, --- y) ¾y Q ¾, t:? ee Elillnlehnl34Mh;? ---- pJ)) ethlle1 NHtNMM:? rLEph 4 ---- t

y¾ Oy) tHt Eh: llene 4N: B :: PJlel: plnIin .--- o

yy)) p 〇ch〇NH pdh nrIhinoen Ihi ---- y, ((., COHt 5tNH 4 h2dihh25th nl ------

〇

〇 〇

y) (,) p (C〇5 CaH Et:? ii2〇H NHtlotlenilNNMpi tlll ---- yp ((py, 5thioendl CN ph2hi p2oedl〇NH 4li lllh-nl ---- yp «y), 〇2olledi CNH¾llln lnoedl CO 4Hil .tnnNffiN ----- py (, y (,, 〇oed C0N32 hiliniNH 45Ch ndC2 4FpilONffi -------: p) (y (,,, COpii5tohNH Br5dC ch2lii2 nilONHlp-- --- yp ) (ColldilONhlienH ¾p CONffi ph2l --- yy (p ,, (, O 5 d Ced CNHilO05tohnilNH 4 ph2hi --- py (p ,, (,, COCONH Buph5thioliNHnraph5tendl24u2holiii-- ------ 〇 〇

yyp)) (p ,,,,,,, od5td 4tli thilienil 4i2hioeil 4up 4nuplhn---------- y¾y¾p) ,,), (,,,, oiedil45tliodl44illii tn fnprpti2iiieniprp << ---- ----- yQpy) p) ,,, (,,,, dtdohenil4e5hioenil 44tpli thi 4! viph2liE- --------- yypQp (5 ,,) ,,,,, ddil3tph5tohenil4 tiolien 4NMeE2hi Ph-- ------y¾ypp) ,,) (,,,, 3od35tioedHtpli tihenilph2hhnil 4NMh 4 <--------- y¾y¾pp () ,,) ,,, 3odl3 toediHe thihenitliiinl fNM: pll ^: < * --- ------ yypp ,,) () ,,,,, 3d2odil 3C tioe 340 thilien 4FhlinilN-------- yyp (p) ,,) ,,,,, odoidil 3c5thien 34Bl thilen 4lll2llilrpip- --- ------- y¾y¾pp),), (,,,,, odil3S5thoendl34 t: hdllen 4Meph2ihiFph <*---- -------.

 y¾y¾,) p) ,, (,,,, dOohedil3〇e5thioenil 34t thin 4ivlph2hEph <---- ------ yy¾pp) ,,) (,,,,, ddl 35toen34t thiolieninBUJlhiliilBUpli 4P2 <---- ------- y¾y) (p,) ,,,,, 3ed ωoiiedilnpr thiolinil iprph i! in 4pli--------- yyp) p,) ,, (,,,, 3ted 3 tohedile5hiolinil 4Etphhin 4ph2, ------- --- ¾yQpyp ()) ,,,,, 5d3odt2thioheni1I thilienil24Nivephl Pl <---- ----- y¾yp) (p) ,,,,, 2oed tohedil 2e5thihnil24NHEtPhhin 4Nph2 <--- ----- --- Qy¾pyp (,) ,,,,, ododieni2 NHe: ph tailienil2h hlil fM! Fp <-------— QQypyp)) ,,, ,,,,, d23toen 4N0 tohedil2CF25hihil2hin 4- ----- --- ttttttt to to

 Cn Cn

yQpyp) () ,,,,,,, doe tohedlc5thihnil 24Brplihini24lph2 ------ ---- yQpyQp,),), (,,,, eod5thohndil24PIi thihenil24SAleph2iF- --- ------- y¾yQp) p) ,, (,,,,, tedO tohd〇e5hiohnil24Etphhienil24 ^ ph2 <------ ---- y¾y) pp,), (,,,,, ed 4t tohed5thiollnil 2BUPIlhinil24nBUph2 <---- ------ yy) pp,), (,,,,, ed 4i tod5thiohnil 2prpiihilienil 24npr2-- ------- y¾ypp,),) (,,,,, ed 4oe5thiollnil 2Etpll thihendil24Jvihp2 <-- ---- ----- yppy), (,,,) ,, toiendi 2li toliedilt: pl25hiil phin 4NMeEi ----.-- yyp (p, x) ,,, odNffit tod5tihenil 4M:? lihihenilhh 4p2- ----- pypy,)) (，,， diHe tolied tioenl 4NMphiiinil 42iihph ------ o O o OO Ο oo O oo O

 ¾ ¾ ¾ ¾ ¾ ¾

 S3

 P- Ρ--P- P-. *

 t t b t bO t t to

 cn

yQpoedthihnil4 --- yp) (, edi 4O05tohnlE Ρ1 4Ai? ph2hiΪ ---- -thiophen-diyl, -Q6-, 4-NMeEt-Ph), (2,5-thiophen-diyl, -Q7-, Ph), (2,5-thiophen-diyl, -Q7-, 4-Me-Ph ), (2,5-thiophen-diyl, -Q7-, 4-Et-Ph), (2,5-thiophen-diyl, -Q7-, 4-nPr-Ph), (2,5-thiophen-diyl) , -Q7-, 4-iPr-Ph), (2,5-thiophen-diyl, -Q7-, 4-nBu-Ph), (2,5-thiophen-diyl, -Q7-, 4-tBu-Ph ), (2,5-thiophen-diyl, -Q7-, 4-OMe-Ph), (2,5-thiophen-diyl, -Q7-, 4-OEt-Ph), (2,5-thiophen-diyl) , -Q7-, 4-SMe-Ph), (2,5-thiophen-diyl, -Q7-, 4-F-Ph), (2,5-thiophen-diyl, -Q7-, 4-Cl-Ph ), (2,5-thiophen-diyl, -Q7-, 4-Br-Ph), (2,5-thiophen-diyl, -Q7-, 4-CFs-Ph), (2,5-thiophen-diyl) _{, -Q7-, 4-N0 2 -Ph} ), (2,5- thiophen-diyl, -Q7-, 4-NH2-PI1), (2,5-thiophen-diyl, -Q7-, 4-NHMe- Ph), (2,5-thiophen-diyl, -Q7-, 4-NMe ₂ -Ph), (2,5-thiophen-diyl, -Q7-, 4-NHEt-Ph), (2,5-thiophen) -diyl, -Q7-, 4-NMeEt-Ph)

Test Example 1 Isolation and purification of MMP-2

 MMP-2 was purchased from Calbiochem-Novabiochem International, Inc.

Test Example 2 Method for measuring the enzyme inhibitory activity of various MMPs

The method for measuring the enzyme activity of MMP is described in C. Graham Knight, Frances Willenbrock and Gillian Murphy: A novel coumar in-labelled peptide for sensitive continuous assays of the matrix metalloproteinases: FEBS LETT., 296, (1992), .263-266. According to the method. Substrate: MOCAc-Pro-Leu-Gly -Leu-A 2 Pr (DNP) -Ala-Arg-NH2 was used Peptide Institute, Inc. Osaka, the Japan. The following four assays are performed for one inhibitory compound (inhibitor).

 (A) Substrate (synthetic substrate), enzyme (MMPs), inhibitor

 (B) Substrate (synthetic substrate), inhibitor

 (C) Substrate (synthetic substrate), enzyme (MMPs)

 (D) Substrate (synthetic substrate)

The fluorescence intensity was measured for each, and the inhibition (%) was determined by the following equation.

Inhibition (%) = {1 (A—B) Z (C-D)} × 100 -

ICso indicates the concentration at which the inhibition (%) becomes 50%.

Table 4 shows the inhibitory activities measured by the above method.

-Table 4 Compound No. ICso (μΜ) Compound No. ICso (μΜ)

 A-l 0.386 A-8 1.8

 A-2 0.0108 A-9 0.00234

 A-4 0.11 A- 10 0.98

 A-5 0.00153 A- 12 0.275

A-7 0.0455 A-13 8.87

-Formulation examples

Formulation Example 1

A granule containing the following ingredients is produced.

 Ingredient 10 mg of the compound represented by the formula (I)

 Lactose 700 mg Corn starch 274 mg

H P C-L —16 mg

 1000 mg of the compound represented by the formula (I) and lactose are passed through a 60-mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HP C-L (low viscosity hydroxypropyl cellulose) is added to the mixed powder, kneaded, granulated (extrusion granulated with a pore size of 0.5 to lmm), and dried. The resulting dried granules are combed through a vibrating sieve (128 mesh) to obtain granules.

Formulation Example 2

A powder for capsule filling containing the following ingredients is produced.

 Ingredient 10 mg of the compound represented by the formula (I)

 Lactose 79 mg Corn starch 10 mg Magnesium stearate 1 mg

 100 mg Lactose, a compound represented by the formula (I), is passed through a 60-mesh sieve. Cornstarch is passed through a 120 mesh sieve. These and magnesium stearate are mixed with a V-type mixer. Fill 100 mg of 100 mg into a No. 5 hard gelatin capsule.

Formulation Example 3

A capsule-filling granule containing the following ingredients is produced. -Ingredient 15 mg of compound represented by formula (I)

 Lactose 90 mg Corn starch 42 mg

H P C—L 3 mg

 150 mg Lactose, a compound represented by the formula (I), is passed through a 60-mesh sieve. Pass the filter through a 120-mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder, and the mixture is kneaded, granulated, and dried. After the obtained dried granules are sized, 150 mg of the dried granules is filled into a No. 4 hard gelatin capsule.

Formulation Example 4

A tablet is prepared containing the following ingredients:

 Ingredient 10 mg of the compound represented by the formula (I)

 Lactose 90 mg Microcrystalline cellulose 30 mg CM C-Na 15 mg Magnesium stearate _ 5 mg

 150 mg of the compound represented by the formula (I), lactose, microcrystalline cellulose, and CM C—Na (carboxymethylcellulose sodium salt) are passed through a 60-mesh sieve and mixed. The mixed powder is mixed with magnesium stearate to obtain a mixed powder for tablet making. The mixed powder is directly hit to obtain tablets of 150 mg. Industrial applicability

 It has been found that the sulfonamide derivative according to the present invention has a meta-oral protease inhibitory activity and can effectively function as a therapeutic or preventive agent for cancer, nephritis, osteoarthritis, heart failure, rheumatoid arthritis and the like.

Claims

 The scope of the claims -General formula (I)

 Wherein ring A is

(Wherein, R ⁵ is a hydrogen atom, hydroxy, one Z—R ⁶ (where Z is one 0—, one S—, or one N (R ^A ) —; R ⁶ may be substituted) Aryl; R ^A is a hydrogen atom, lower alkyl, aralkyl, or acyl); R ¹ is NHOH, hydroxy, or lower alkyloxy; R ² is a single bond, an optionally substituted arylene, or an optionally substituted heteroarylene; R ³ is a single bond, — (CH ₂ ) p—, — CH = CH—, one C≡ C—, — CO—, one CO—NH—, one N = N—, one N (R ^B ) —, One NH—CO—NH—, One NH—CO—, One S—, — S 0 _2— , One S 0 ₂ NH—, One S 0 ₂ — NH—N = CH—, or Formula:

N—— O O—— N  Or Wherein R ^B is hydrogen or lower alkyl, p is 1 or 2; R ⁴ is cycloalkyl which may be substituted, aryl which may be substituted, aryl which may be substituted Heteroaryl, or an optionally substituted non-aromatic compound; However, when R ² and R ³ are both a single bond, R ⁴ may be substituted but not aryl.], An optically active form thereof, or a pharmaceutically acceptable salt thereof. , Or their hydrates. 2. General formula (II):

Wherein the A ring and R ¹ are as defined above. R ⁷ has the formula:

, Or (In the formula, R ⁸ is independently optionally substituted lower alkyl, cycloalkyl Alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, non-substituted or substituted amino , Unsubstituted or substituted aminocarbonyl, acyl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle, optionally substituted aralkyl, lower alkylsulfonyl, guanidino An azo group, or an optionally substituted urea; R ⁹ is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkylo. Xoxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acryl, acryloxy, optionally substituted aryl, optionally substituted heteroaryl An optionally substituted non-aromatic heterocyclic ring, an optionally substituted aralkyl, a lower alkylsulfonyl, a guanidino, an azo group, or an optionally substituted ureide; q and r are each independently And 0, 1, 2, or 3; X is an oxygen or sulfur atom; Υ 1 is one C≡≡ C one or formula:  N:: N N:: N N- -N N—— N  ― N, J ~ ~~, Ν— ',,

, S ', <y N—— O O—— N  If <ha ~ ^ A group represented by;  X is an oxygen atom or a sulfur atom)], an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 3. General formula (III):

[Wherein, A ring and R ¹ are as defined above; R ^{1 Q} is the formula:

, Or (Wherein R ⁹ and r are as defined above;  Y 2 is one c≡C one or formula:  N  ― N

Ν- -Ο Ο- -Ν  も し く は or Ν, Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 4. R ¹ ° is the formula:

(Wherein R ⁹ and r are as defined above), the optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 5. Ring A has the formula:

(Wherein, R ⁵ has the same meaning as described above), the compound according to any one of claims 1 to 4, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 6. The compound according to claim ^1, wherein R ¹ is hydroxy, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 as an active ingredient.  8. A metabolic protease inhibitor comprising the compound according to any one of claims 1 to 6 as an active ingredient. 9. A matrix meta-oral protease inhibitor comprising the compound according to any one of claims 1 to 6 as an active ingredient.  10. A therapeutic or prophylactic agent for cancer comprising the compound according to any one of claims 1 to 6 as an active ingredient.  11. An agent for treating or preventing nephritis, comprising the compound according to any one of claims 1 to 6 as an active ingredient.  12. An agent for treating or preventing osteoarthritis, comprising the compound according to any one of claims 1 to 6 as an active ingredient.  13. An agent for treating or preventing heart failure, comprising the compound according to any one of claims 1 to 6 as an active ingredient.  14. An agent for treating or preventing rheumatoid arthritis, comprising the compound according to any one of claims 1 to 6 as an active ingredient.