WO2001083461A1

WO2001083461A1 - Thiazole and oxazole derivatives

Info

Publication number: WO2001083461A1
Application number: PCT/JP2001/003437
Authority: WO
Inventors: Shingo Furue; Fumihiko Watanabe; Yoshinori Tamura
Original assignee: Shionogi & Co., Ltd.
Priority date: 2000-04-28
Filing date: 2001-04-23
Publication date: 2001-11-08
Also published as: AU2001248820A1

Abstract

Compounds of the general formula (I), optical isomers or prodrugs of the same, pharmaceutically acceptable salts of them, or solvates thereof: (I) wherein R1 is hydroxyl or the like; R2 is optionally substituted lower alkyl or the like; R3 is hydrogen or the like; R4 is optionally substituted arylene or the like; R5 is a group of formula (i), (ii), (iii), or (iv): (i) (ii) (iii) (iv) and R6 is optionally substituted aryl or the like.

Description

Description Thiazole and oxazole derivatives

The present invention relates to thiazole and oxazole derivatives and meta-oral protease inhibitors containing them, particularly matrix metalloprotease-12 selective inhibitors. Background art

The extracellular matrix is composed of collagen, fibronectin, laminin, proteoglycan, etc., and plays a role in tissue support, cell proliferation, differentiation, adhesion and the like. Degradation of extracellular matrix involves meta-oral proteases that contain metal ions in the active center, particularly matrix meta-oral proteases (MMPs). Many families of MMPs, ranging from MMP-1 (type I collagenase) to MMP-23, have been reported to affect growth and tissue reform under the original physiological conditions. However, the progression of the disease and the above-mentioned enzymes in various disease states accompanied by tissue destruction and fibrosis (osteoarthritis, rheumatoid arthritis, corneal ulcer, periodontal disease, metastasis or invasion of tumor, virus infection (HIV infection)) It has been reported that the increase in the expression (activity) of is correlated.

Matrix meta-oral protease_12 (MMP-12) is expressed in macrophages and has a characteristic that is unique to other MMPs in that it degrades elastin. It is also known to cleave type I collagen, type IV collagen, fibronectin, laminin and the like. SCIENCE 1997, 277 (26), 2002-2004 and Exp. Opin. Ther. Patents (1999)

9 (7), 851-895, etc. Therefore, MMP-1 for chronic obstructive pulmonary disease (COPD), a disease characterized by airway obstruction due to emphysema or chronic bronchitis. 2 involvement is possible. Also, Exp. Opin. Ther. Patents (1999) 9 (7), 851-895, etc. suggested that MMP-12 is involved in diseases such as metastatic cancer and atherosclerosis. Have been.

Sulfonamide derivatives having oxazole are described in WO 99/0480.

Sulfonamide derivatives having an MMP inhibitory action are described in WO97 / 27174.

No compound having an MMP-12 inhibitory action is known.

Disclosure of the invention

If the activity of MMP-12 can be inhibited as described above, it is considered that it will greatly contribute to amelioration of the above-mentioned pathology caused by or related to the activity or prevention of progression. Is desired.

The present inventors have conducted intensive studies in view of the above points, and as a result, have found that certain novel sulfonamide derivatives having an oxazole ring or a thiazole ring exhibit selective MMP-12 inhibitory activity. Was.

That is, the present invention provides 1) a general formula (I):

R ²

R ⁶ — R ⁵ -R -S0 _2- , COR ¹ (I)

R ³

[Wherein, R ¹ is NHOH, hydroxy, or lower alkyloxy;

R ² is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted Teroarylalkyl;

R ³ is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted Teroarylalkyl; R ⁴ is optionally substituted arylene, or optionally substituted heteroarylene;

R ⁵ has the formula:

Or

A group represented by;

R ⁶ is an aryl which may be substituted, a heteroaryl which may be substituted, or a non-aromatic heterocyclic group which may be substituted], an optically active form thereof, a prodrug thereof, Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

More specifically, the present invention relates to the following 2) to 18).

2) R ⁶ is the formula:

(In the formula, each R ⁷ is independently a hydrogen atom, halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyl-oxy, lower alkylthio, halo-lower alkyl, hydroxy, carboxy, lower An alkyloxycarbonyl, an aminocarbonyl, an acyl, a nitro, a cyano, or an optionally substituted amino; m is a group represented by 0, 1, 2, or 3). The compound according to 1), an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

In the above formula, the bond to R ⁵ is bonded to a substitutable portion of the ring, and R 7 can be substituted at any substitutable position. For example,

The group represented by

And the like.

3) The compound according to 1) or 2), wherein R ¹ is hydroxy, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

4) R ² is hydrogen, lower alkyl optionally substituted with aminocarbonyl or lower alkylthio, aryl which may be substituted with hydroxy, aralkyl optionally substituted with hydroxy, or hydroxy. Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a compound thereof according to any one of 1) to 3), which is heteroarylalkyl optionally substituted with Solvates thereof.

5) R ² is a hydrogen atom, methyl, isopropyl, isobutyl, benzyl, indole — 3-ylmethinole, 4-hydroxybenzinole, or (5-hydroxy-indone-l-3-inole) methyl 1) ~ 4) The compound according to any one of the above, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6) The compound according to any one of 1) to 5), wherein R ³ is a hydrogen atom, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof. Japanese food. .

7) The compound according to any one of 1) to 6), wherein R ⁴ is 1,4-phenylene or 2,5-thiofendyl, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof. Salts or solvates thereof.

8) R ⁵ has the formula:

Or

The compound according to any one of 1) to 7), which is a group represented by the formula: an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

9) R ⁶ is the formula:

The compound according to any one of 1) to 8), which is a group represented by the formula: an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

10) General formula (II):

(Π)

[Wherein, R ⁸ is a hydrogen atom, methyl, isopropyl, isoptyl, benzinole, 4-hydroxybenzyl, indole-3-ylmethyl, or (5-hydroxyindole-3-yl) methyl;

R ⁹ is 1,4-phenylene or 2,5-thiofendyl;

R ¹ ° is the formula:

A group represented by;

R ¹¹ is each independently a hydrogen atom, halogen, lower alkyl, lower alkyloxy, halo-lower alkyl, acyl, nitro, cyano, optionally substituted amino, or hydroxy;

m is 0, 1, 2, or 3], an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

11) A pharmaceutical composition comprising the compound according to any one of 1) to 10) as an active ingredient.

1 2) A meta-oral protease inhibitor comprising as an active ingredient the compound according to any one of 1) to 10).

(13) A matrix meta-oral protease inhibitor comprising the compound according to any of (1) to (10) as an active ingredient.

14) A matrix meta-oral protease 12 inhibitor comprising the compound according to any one of 1) to 10) as an active ingredient.

15) An agent for treating or preventing chronic obstructive pulmonary disease, comprising the compound according to any one of 1) to 10) as an active ingredient.

16) Use of the compound according to any one of 1) 10) for the manufacture of a medicament for treating chronic obstructive pulmonary disease.

(17) A method for treating chronic obstructive pulmonary disease in a mammal, comprising administering a therapeutically effective amount of the compound according to any of (1) to (10) to a mammal, including a human.

18) A method for inhibiting MMP-12, comprising contacting the compound according to any one of 1) 10) with MMP-12.

In the present specification, the term “lower alkyl” used alone or in combination with other terms includes a linear or branched monovalent hydrocarbon group having 18 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptinole, sec-butynole, tert-butynole, n-pentynole, isopentinole, neopentyl, n-xynole, isohexynole, n-heptyl, n- Occtinole And the like. Preferably, a C1-C6 alkyl is mentioned. Even more preferred are C1-C3 alkyl.

• As used herein, “lower alkenyl” used alone or in combination with other terms refers to a straight chain having 2 to 8 carbon atoms and having one or more double bonds. Includes branched or branched monovalent hydrocarbon radicals. For example, vinyl, aryl, propenyl, crotonyl ', isopentyl, various butenyl derivatives', and living organisms. Preferably, a C2-C6 alkenyl is mentioned. More preferably, a C2-C4 alkenyl is mentioned.

As used herein, the term "lower alkyl" refers to a linear or branched monovalent carbon having 2 to 8 carbon atoms and having one or more triple bonds. It may contain a hydrogen group and have a double bond. For example, ethynyl, 2-propynyl, 3-butyninole, 4-pentininole, 5-hexyninole, 6-heptininole, 7-octininole and the like can be mentioned. Preferably, a C2-C6 alkynyl is mentioned. Still more preferably, C2-C4 alkynyl is mentioned.

In the present specification, “cycloalkyl” includes cycloanolequinole having 3 to 8 carbon atoms. For example, cyclopropyl, cyclopentyl, cyclopentyl, cyclohexyl, cycloheptyl, 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.

Phenyl is preferred as the "Ariru" in R ^2.

As “aryl” for R ^3, phenyl is preferred.

Phenyl as "Ariru" in R ^6, 1 one-naphthyl, 2-naphthyl is good better record,.

In the present specification, the “aralkyl” refers to the above “lower alkyl” substituted by one or more “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), anthrylmethyl (eg, For example, 91-tolylmethyl and the like). 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 (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (for example, 2-furyl, 3-furyl), cheninore (for example, 2-phenyl, 3-phenyl), Imidazolyl (eg, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-birazolyl), isothiazolyl (eg, 3-isothiazolyl), isoxazolyl (eg, 3-isoxazolyl), oxazolyl ( For example, 2-oxazolyl), thiazolyl (for example, 2_thiazolyl), pyridyl (for example, 2-pyridyl, 3-pyridyl, 4-pyridyl), birazinyl (for example, 2-pyragel), pyrimidinil (for example, 2_pyrimidinyl, 4_pyrimidinyl), pyridazyl (eg, 3-pyridazinyl) , Tetrazolyl (for example, 1H-tetrazolyl), oxadizazolyl (for example, 1,3,4-oxadiazolyl), thiadiazolyl (for example, 1,3,4-thiadiazolyl), indolizyl (for example, 2-indolizinyl, 6- Indolidinyl), isoindolyl (for example, 2-isoindolyl), indolyl (for example, 1-indolyl, 2_indolyl, 3—indolyl), indazolyl (for example, 3-indazolyl), prill (for example, 8— Purinyl), quinolizinyl (for example, 2-quinolinyl), isoquinolyl (for example, 3-isoquinolyl), quinolyl (for example, 2_quinolyl, 5-quinolinyl), phthaladur (for example, 1-phthalazinyl), naphthyridinyl (eg, 2-naphthyridinyl), Quinolanyl (for example, 2-quinolinyl), quinazolinyl (for example, 2-quinazolinyl), cinnoyl (for example, 3_cinnolinyl), pteridinyl (for example, 2-pteridinyl), carbazolyl (for example, 2-carbazolyl, 3 —Force rubazolyl), phenanthridinyl (eg, 2—phenanthridinyl, 3—phenanthridinyl), ataridyl (eg, 1—atalinidyl, 2-attaridisil), dibenzofuranyl (eg, 1 —Dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxazolyl), benzoxoxazolyl (eg, 2-benzo) Benzoxazolyl), benzoxoxadiazolyl (eg, 4-benzoxazidi) Azolyl), benzoisothiazolyl (for example, 3-benzoisothiazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzofuryl (for example, 3-benzofuryl), benzocenyl (for example, 2-benzozoenyl), etc. Are mentioned.

As the "Heteroariru" in R ^2, arbitrariness indolyl, imidazolyl, etc. are preferred.

As the “heteroaryl” for R ³ , pyridyl, chenyl, furinole, imidazolyl and the like are preferable. '

“Heteroaryl” for R ⁶ includes quinolyl (eg, 2-quinolyl), pyridyl (eg, 3-pyridyl), benzofuranyl (eg, 2-benzofuryl), benzothenyl (eg, 2-benzozoenyl), dibenzo Furanyl, isoquinolyl (for example, 3-isoquinolyl), cherry (for example, 2-phenyl), furyl (for example, 2-furyl) and the like are preferable.

In the present specification, the term "heteroarylalkyl" means one or more of the above "lower alkyl" substituted by the above "heteroaryl", and these may be substituted at all possible positions. . For example, thiazolylmethyl (for example, 4-thiazolylmethyl), thiazolylethyl (for example, 5-thiazolyl-2-ethyl), benzothiazolylmethyl (for example, (benzothiazolyl-2-yl) methyl), Methyl (eg, (indole-3-yl) methyl), imidazolylmethyl (eg, 4-imidazolylmethyl), benzothiazolylmethyl (eg, 2-benzothiazolylmethyl), indazolylmethyl (Eg, 1-indazolylmethyl), benzotriazolylmethyl (eg, 1-benzotriazolylmethyl), benzoquinolylmethyl (eg, 2-benzoquinolylmethyl), benzoimidazolylmethyl (eg, 2-benzoimidazolyl) Methyl), pyridylmethyl (for example, 4-pyridylmethyl) and the like.

As the “heteroarylalkyl” for R ² , indolylmethyl (eg, indole-3-ylmethyl), imidazolylmethyl (eg, imidazole-5-ylmethyl) and the like can be mentioned.

In the present specification, the term “non-aromatic complex ring” used alone or in combination with other terms refers to an arbitrarily selected non-aromatic complex ring containing one or more oxygen, sulfur or nitrogen atoms in the ring. Includes aromatic 5- to 7-membered rings or rings obtained by condensing two or more of them. For example, pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (for example, 3-pyrrolidinyl), imidazolidinyl (for example, 2-imidazolidinyl), imidazolinyl, virazolidinyl (for example, 1-virazolidinyl, 2-virazolidinyl) , Pyrazolinyl, piperidyl (eg, piperidino, ₂ -piperidyl), piperazil (eg, 1-piperazinyl), indolinyl

(For example, 1-indolinyl), isoindolinyl, morpholinyl (for example, monoreolino, 3-monoreforinyl), 4H— [1,2,4] oxadiazolyl 5-one, 1,2,3,4-tetrahydron [1,8] naphthyridine, 1,3-benzodioxolyl and the like.

As the “non-aromatic heterocycle” for R ⁶ , birazolidinyl, piperidyl, pyrrolinyl, morpholinyl, 1,3-benzodioxolyl and the like are preferable.

In the present specification, “arylene” means a divalent group derived from 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. Good Preferable is 1,4-phenylene.

In the present specification, “heteroarylene” means a divalent group derived from the above “heteroaryl”. For example, thiofenzil, frangyl, pyridzinyl and the like can be mentioned. More specifically, 2,5-thiofenzil, 2,5-furandyl 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. For example, acetyl, propionyl, benzoyl and the like can be mentioned. “Lower alkyl” and “aryl” may be substituted by the respective substituents described below. In the present specification, "halogen" means fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine.

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

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

In the present specification, examples of the “lower alkenyloxy” include bieroxy, aryloxy, probenyloxy, crotonyloxy, isopentenyloxy and the like.

In the present specification, examples of the “lower alkyloxycarbonyl” include methyloxycarbonyl, ethynoleoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like.

In the present specification, the term “halo lower alkyl” used alone or in combination with another term means 1 to 8, preferably 1 to 5, Substituted "lower alkyl". For example, trifluoromethyl, trichloromethylinole, diphneoleolochinole, triflinoleolotine, dichloroethynole, trichloroethyl, and the like can be mentioned. Preferably, trifluoromethyl is used. In the present specification, the “halo lower alkyloxy” includes trifluoromethyloxy and the like.

In the present specification, examples of the “lower alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like. Preferably, methylsulfonyl is used.

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

In the present specification, the “optionally substituted amino” refers to an amino or one or two substituted with the above “lower alkyl”, “aralkyl”, “heteroarylalkyl”, or the above “acyl”. Amino. For example, amino, methylinoamino, dimethylamino, ethylinomethylamino, getylamino, benzinoamino, acetylamino, benzoylamino and the like can be mentioned. Preferably, amino, methylamino, dimethylamino, ethylmethylamino, acetylamino, acetylamino are exemplified.

In the present specification, examples of the “optionally substituted aminocarbonyl” include aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, ethylaminocarbonyl, and the like. Preferably, aminocarbonyl and dimethylaminocarbonyl are mentioned.

In the present specification, examples of the substituent in the “optionally substituted lower alkyl” include cycloalkynole, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbo. Binore, halo-lower-alkyl, halo-lower-alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryloxy (for example, F-niloxy), aral kiloxy (eg, benzyloxy), lower alkylsulfonyl, guanidino, Examples thereof include an azo group and an optionally substituted urea. These may be substituted one or more times in all possible positions.

As the substituent for the “optionally substituted lower alkyl” for R ² , hydroxy and lower alkyloxy are preferable.

The substituent of the “optionally substituted lower alkyl” for R ³ is preferably a hydroxy, a lower alkyloxy, or an optionally substituted non-aromatic heterocyclic group. In the present specification, “optionally substituted arylene”, “optionally substituted heteroarylene”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “substituted” Substituents in the "optionally substituted non-aromatic heterocyclic group", "optionally substituted aralkyl", "optionally substituted heteroarylalkyl", and "optionally substituted ureido" May be substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, haguchi Lower alkyl, halo-lower alkyloxy, optionally substituted amino, substituted Optionally substituted aminocarbonyl, acyl, asinoleoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle, optionally substituted aralkyl, Examples thereof include lower alkylsulfonyl, guanidino, azo group, and optionally substituted ureido. These may be substituted one or more times in all possible positions.

As the substituents of the “optionally substituted arylene” and the “optionally substituted heteroarylene” for R ⁴ , among the above substituents, halogen, nitro, cyano, lower alkyloxy and the like are particularly preferable. As the “optionally substituted arylene” and “optionally substituted heteroarylene”, unsubstituted “arylene” and “heteroarylene” are preferable.

Examples of the substituent of “optionally substituted aryl” in R ² include lower alkyl, lower alkenyl and lower alkyl which may be particularly substituted among the above substituents. Nil, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, optionally substituted amino, optionally substituted Aminocarbyl, acryl, acryloxy and the like are preferred. As the “aryl which may be substituted”, an aryl which may be substituted with hydroxy is preferable.

Examples of the substituent of “optionally substituted aryl” in R ³ include lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto and lower alkylthio which may be particularly substituted among the above substituents. , Halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, optionally substituted aminocarbyl, acyl, and acyloxy. As the “optionally substituted aryl”, an aryl which may be substituted with hydroxy, lower alkyloxy, halogen, or halo-lower alkyl is preferable.

Examples of the substituent of the “optionally substituted aryl” in R ⁶ include lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, and lower alkyl which may be particularly substituted among the above substituents. Alkoxy-, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower anoreoxy carbonyl, halo-lower alkyl, halo-lower alkynoleoxy, optionally substituted amino, optionally substituted aminocarbo- , Acryl, acryloxy and the like are preferred. More preferred substituents include halogen, lower alkyl, cycloanoleyl, lower alkenyl, lower alkynyl, lower α / lex / reoxy, lower alkenyloxy, lower alkylthio, halo-lower alkyl, hydroxy, carboxy, lower alkyloxy. Examples include carbonyl, aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino. The “optionally substituted aryl” includes lower alkyl, lower alkyloxy, halogen, lower alkylthio, and optionally substituted amino. Are preferred.

Examples of the substituent of the “optionally substituted heteroaryl” for R ² include lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, and lower alkylthio which may be particularly substituted among the above substituents. Preferred are halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, and acyloxy. As the “optionally substituted heteroaryl”, a heteroaryl optionally substituted with hydroxy or halogen is preferable.

Examples of the substituent of the “optionally substituted heteroaryl” for R ³ include lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, and lower alkylthio which may be particularly substituted among the above substituents. And nitrogen, nitrogen, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl and acyloxy. As the “optionally substituted heteroaryl”, a heteroaryl which may be substituted with hydroxy, lower alkyloxy, halogen, or halo-lower alkyl is preferable.

Examples of the substituent of the “optionally substituted heteroaryl” for R ⁶ include lower alkyl, cycloalkyl, lower alkenyl, lower alkyl, hydroxy, lower alkyloxy which may be particularly substituted among the above substituents. , Lower alkenyloxy, menolecapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower anorex / reoxycarbonyl, halo-lower alkyl, halo-lower alkynoleoxy, optionally substituted amino, optionally substituted amino Preference is given to carbonyl, acyl, acyloxy and the like. More preferred substituents include halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyl / reoxy, lower alkylthio, halo-lower alkyl, and hydride. Examples include mouth xy, carboxy, lower anoalkyloxycarbonyl, aminoamino, acyl, nitro, cyano, or optionally substituted amino. As the “optionally substituted heteroaryl”, a lower alkyl, a lower alkyloxy, a halogen, a lower alkylthio, and a heteroaryl which may be substituted by an optionally substituted amino are preferable.

Examples of the substituent of the `` aralkyl which may be substituted '' in R ² include a lower alkyl, a lower alkenyl, a lower alkynyl, a hydroxy, a lower alkyloxy, a mercapto, which may be particularly substituted among the above substituents. Preferred are lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxy phenol, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, asyl, and acyloxy. "As the optionally substituted aralkyl J, an aralkyl group optionally substituted with hydroxy is preferable.

Examples of the substituent of the `` aralkyl which may be substituted '' in R ³ include a lower alkyl, a lower alkenyl, a lower alkynyl, a hydroxy, a lower alkyloxy, a mercapto, which may be particularly substituted among the above substituents. Lower alkylthio, nitrogen, nitro, cyano, carboxy, lower alkyloxycanolevonyl, lower alkyl lower alkyl, halo lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, acyloxy Are preferred. “As the optionally substituted aralkyl J, an aralkyl optionally substituted with hydroxy, lower alkyloxy, halogen, or halo-lower alkyl is preferable.

Examples of the substituent of the “optionally substituted heteroarylalkyl” for R ² include lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, and mercapto which may be particularly substituted among the above substituents. , Lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, and acyloxy Is preferred Les ,. As the “optionally substituted heteroarylalkyl”, a heteroarylalkyl optionally substituted with halogen or hydroxy is preferable.

Examples of the substituent of the “optionally substituted heteroarylalkyl” for R ³ include lower alkyl, lower alkenyl, lower anohexyl, hydroxy, and the like which may be particularly substituted among the above substituents. Lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, optionally substituted aminocarbonyl, Preferred are acyl and acyloxy. As the “optionally substituted heteroarylalkyl”, a heteroarylalkyl optionally substituted with hydroxy, lower alkynoleoxy, halogen or halo-lower alkyl is preferable.

Examples of the substituent of the “optionally substituted non-aromatic heterocyclic group” for R ⁶ include lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, and lower alkyl which may be particularly substituted among the above substituents. Droxy, lower alkyloxy, lower alkenyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, cyanocarbonyl, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, optionally substituted amino, substituted Preferred are aminocarbonyl, acyl, and acyloxy. More preferred substituents include halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo-lower alkyl, hydroxy, canoleboxyl, lower alkyloxycarbonyl, Examples include aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino. As the "optionally substituted non-aromatic heterocyclic group", a lower alkyl, a lower alkyloxy, a halogen, a lower alkylthio, a non-aromatic heterocyclic group which may be substituted with an optionally substituted amino or the like. preferable. BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention can be synthesized using the starting materials shown below according to the method described in WO97 / 271714 WO99 / 0480, etc. explain.

Method A

General formula (I I I): Kon

H

(III)

(Wherein, R ³ , R ² , R ³ , R ⁴ , and R ⁶ are as defined above)

Can be synthesized, for example, as follows.

HCI

H ₂ N

Second step

O- O 4th process

R ° —R ⁴ —one ヽ COOR ¹²

, N

(X)

(R ² , R ⁴ , and R ⁶ are as defined above, R ¹² is a carboxyl-protecting group, and H a 1 is independently halogen.)

(First step)

It can be synthesized in the same manner as in the first step of Method A described in WO97 / 27174. Wear.

(2nd step)

Compound (VI) is dissolved in a solvent such as methylene chloride, tetrahydrofuran, toluene, or a mixed solvent such as methylene chloride-methanol. Sulfuryl chloride or the like is added to the solution at a temperature of 20 ° C to 30 ° C, preferably 0 ° C to 20 ° C, and 30 ° C to 100 ° C, preferably 50 ° C (~ 7 ° C). The reaction is carried out for 2 hours to 24 hours, preferably 2 hours to 5 hours at 0 ° C. Compound (VII) can be obtained by performing ordinary post-treatment (third step).

The mixture of compound (VII) and compound (VIII) is reacted at 100 ° C. to 180 ° C., preferably at 130 ° C. to 150 ° C., for 2 hours to 10 hours, preferably for 4 hours. Then, the compound (IX) can be obtained by ordinary post-treatment. This reaction may be performed in a solvent such as dimethylformamide.

(4th step)

It can be synthesized in the same manner as in the first step of Method A described in WO97 / 27174.

Further, the obtained compound (X) can be converted into a compound which has been subjected to open mouth xam oxidation by the method described in WO97 / 27174.

B method

General formula (X I):

(XI)

(Wherein, RR ² , R ³ , R ⁴ , and R ⁶ are as defined above)

The compound represented by, for example, can be synthesized as follows, Hal

(XII) (XIII) Step 2 N-

R. R ⁴ — S0 ₂ Hal

, 0

(XIV)

(IV) (XV)

4th step

(XVI)

(First step)

The compound (XIII) can be synthesized using the compound (XII) as a starting material in the same manner as described in J. Heterocyclic Chem., 29, 1245 (1992).

(2nd step)

Using compound (XIII) as a starting material, compound (XIV) can be synthesized by a method similar to the method described in WO98 / 43032.

(3rd step)

The compound (XV) can be synthesized using the compound (XIV) as a main raw material in the same manner as in the first step of Method A described in WO97 / 27174.

(4th step)

Using compound (XV) as a starting material, compound (XVI) can be synthesized in the same manner as in method A, step 1 described in W097Z27174. C method

General formula (XX):

(XX)

'

(Wherein, R ¹ R ² , R ³ , R ⁴ , and R ⁶ are as defined above)

The compound represented by, for example, can be synthesized as follows,

R

HCI Step 1 0

H ₂ N 'OOR ¹² _NC _ _R _{4_ S02Ha |} NC-R ⁴ -SN ^ COOR ¹²

(IV) (XXI) (XXII)

(XXIV)

(XXV)

(First step)

(2nd step) ''

Compound (XXII) and thioacetamide were converted into saturated dimethylformamide hydrochloride, The suspension is suspended in methanol, ethanol or the like, and reacted at 60 ° C. to 140 ° C., preferably 80 ° C. to 100 ° C. for 2 hours to 10 hours, preferably 2 hours to 3 hours. Compound (XXIII) can be obtained by ordinary post-treatment.

(3rd step)

Compound (XXIII) and compound (XIV) are dissolved in dimethylformamide, methanol, ethanol, etc., at 50 ° C to 120 ° C, preferably at 60 ° C to 80 ° C for 1 hour. The reaction is carried out for up to 8 hours, preferably for 2 hours to 3 hours. Compound (XXIV) can be obtained by ordinary post-treatment.

(4th step)

The compound can be synthesized in the same manner as in the first step of Method A described in WO97 / 27174.

D method

General formula (XXV I):

(Wherein, R ¹ R ² , R ³ , R ⁴ , and R ⁶ are as defined above)

The compound represented by, for example, can be synthesized as follows,

Stage 1 Stage 2 King

R ⁶ — CN. -► R ⁶ — CSNH ₂

(XXX)

(First step)

It can be carried out in the same manner as in the second step of Method C.

(2nd step)

The compound (XXVIII) and the compound (VII) are dissolved in dimethylformamide, methanol, ethanol, etc., and dissolved at 50 ° (: up to 120 ° C, preferably at The reaction is carried out for a period of from 8 hours to 8 hours, preferably from 2 hours to 3 hours.

(3rd step)

References to "the compound of the present invention" also include pharmaceutically acceptable salts or solvates thereof. For example, alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (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, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and solvates with a suitable solvent. These salts and solvates can be formed by conventional methods. Hydrates are preferred as solvates. When forming a hydrate, it may be coordinated with any number of water molecules.

The present invention also includes a prodrug of the compound of the present invention. A prodrug is a derivative of a compound of the present invention that has a chemically or metabolically degradable group and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. . A method for selecting an appropriate prodrug derivative and a method for producing it are described in, for example, Design of Prodrugs, Elsevier, and Amsterdam 1985. When the compound of the present invention has a carboxyl group, an ester derivative produced by reacting the base acidic compound with a suitable alcohol, particularly an optionally substituted alkyloxycarbonyl or base acid Examples thereof include amide derivatives produced by reacting a compound with an appropriate amine, especially prodrugs such as optionally substituted alkylaminocarbonyl. Particularly preferred esters as prodrugs include methinoles estenole, ethynole esters, n-propyl estenoles, isopropinoles estenoles, n- petitnolestenores, isobutinoestenoles, tert- Butylacenole, morpholinoethyl ester, and N-getyldalicholamide ester. When the compound of the present invention has a hydroxyl group, for example, a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified. It is. Particularly preferred acyloxy as prodrugs include ococ ₂

H _5, one 〇_CO (t - B u), one OC_〇_C _{₁ 5} H ₃ _1, one OCO (m-COON a - P h), one _{_{O CO CH 2 CH 2 COON a}} , one O COCH (NH ₂ ) CH ₃ , _〇CO CH ₂ N (CH ₃ ) _{2 and the} like. When the compound of the present invention has an amino group, the compound having an amino group is combined with a suitable acid halide or a suitable mixed acid anhydride. Prodrugs such as amide derivatives produced by the reaction are exemplified. Particularly preferred amides as prodrugs include mono-NHCO (CH ₂ ) ₂₀ CH ₃ , mono-NHCO CH (NH ₂ ) CH _{3 and the} like.

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

The compounds of the present invention exhibit excellent MMP-12 selective inhibitory activity as described in the experimental examples described below.

Specifically, chronic obstructive pulmonary disease, osteoarthritis, rheumatoid arthritis, corneal ulcer, periodontitis, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, arteriosclerosis Aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative retinopathy, angiogenesis Glaucoma, pterygium, keratitis, bullous epidermis, psoriasis, diabetes, nephritis, neurological disease, inflammation, osteoporosis, bone resorption, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, hemangiofibromas, hemangiomas For fever, bleeding, bleeding, coagulation, cachexia, anorexia, acute infections, shock, autoimmunity, malaria, Crohn's disease, meningitis, heart failure, asthmatic airway inflammation, arteriosclerosis, and gastrointestinal ulcers Use as a therapeutic Can be. In particular, it can be used as a therapeutic agent for chronic obstructive pulmonary disease.

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, It can be administered parenterally as a transdermal absorbent, an 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, the product should be sterilized with a suitable carrier.

The dosage varies depending on the disease state, the route of administration, the age of the patient, or the weight of the patient.When administered orally to an adult, it is usually 0.1 to 100 mg / _kg / day, preferably It is 1-20 mg / kg / day.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. Is not limited by these

In the examples, the following abbreviations are used.

M e: Mechinore

E t: ethyl

n-Pr: n—propyl

i-Pr: Isopropyl

n—Bu: n—Buchinore

i-Bu: Isobutyl

t—B u: t e r t—butinore

P h: phenyl

B n: benzyl

DM S O: dimethyl sulfoxide

Example

Example 1 Preparation of Compound (A-1) e

6

gH ₃

S-N to COOH

K (First step)

To a suspension of D-alanine methyl ester hydrochloride (1) (2.30 g, 16.5 mmol) and 4-acetylbenzenesulfoninolechloride (2) (3.28 g, 15 mmol) in methylene chloride (10 ml) was added: N-Methylmorpholine (4.41 ml, 37.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. The reaction solution was poured into ice_2mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane Z ethyl acetate = 1 Z 1 was collected and crystallized with hexane to give the desired product having a melting point of 109-li C (3) (3.44 g, yield 80.3%).

IR (KBr, V max cm " 1) 3282, 1735, 1687, 1340, 1307, 1228, 1168, 1139, 1095 Ή NMR (CDC1 3, δ ppm): 1.41 (d, J = 7.2 Hz, 3H), 2.65 (s, 3H), 3.56 (s, 3H), 4.05 (m, 1H), 5.34 (d, J = 8.7 Hz, 1H), 7.92-7.98 (m, 2H), 8.04-8.09 (m, 2H)

[a] _D + 25.2 ± 1.3 (c = 0.509, DMSO, 24.C)

As elemental analysis _{_{_{(C 12 H 15 N0 5 S}}} ).

Calculated values: C; 50.52, H; 5.30, N; 4.91, S; 11.24

Experimental value: C; 50.43, H; 5.23, N; 4.97, S; 11.28

(2nd step)

To a mixed solution of compound (3) (5.84 g, 20.5 mmol) in methylene chloride (50 ml) and methanol (4.97 ml) was added sulfuryl chloride (4.93 ml, 61.4 mmol) under ice cooling, and the mixture was heated at 50 ° C for 3 hours. Stirred. The reaction solution was poured forever, and extracted with black-mouthed form. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 1 Z1 was collected and crystallized from acetone hexane to give a melting point of 118-120 ° C. The desired product (4) (4.99 g, yield 76.2%) was obtained.

IE (KBr, V max cm " ¹ ) 3266, 1741, 1704, 1436, 1402, 1346, 1326, 1211, 1184, 1164, 1143, 1089, 707 Ή NMR (CDClg, δ ppm): 1.42 (d, J = 7.0 Hz, 3H), 3.57 (s, 3H), 4.06 (m, 1H), 4.70 (s, 2H), 5.35 (d, J = 8.2 Hz , 1H), 7.94-8.02 (m, 2H), 8.05-8.12 (m, 2H) [a] _D + 22.1 + 1.2 (c = 0.507, DMSO, 24 ° C)

Elemental analysis (C ₁₂ H ₁₄ CIN 0 ₅ S)

Calculated value: C; 45.07, H; 4.41, Cl; 11.09, Ν; 4 · 38, S; 10.03

Experimental value: C; 45.12, H; 4.30, Cl; 11.01, N; 4.45, S; 10.07

(3rd step)

A mixture of the yidani (4) (480 mg, 1.5 mmol) and 2-naphthamide (516 mg, 3 mmol) was stirred at 140 ° C for 24 hours. The reaction solution was poured with ice-cold 2 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with octamethylforminoacetate = 81 was collected and crystallized with acetone Z hexane to obtain the target substance with a melting point of 157-159 ° C. 5) (242 mg, yield 37.0%) was obtained.

IR (KBr, v max cm ¹ ) 3299, 1737, 1342, 1213, 1166, 1141, 1093, 757

NMR (CDClg, δ ppm): 1.42 (d, J = 7.2 Hz, 3H), 3.56 (s, 3H), 4.04 (m, 1H), 5.27 (d, J = 8.4 Hz, 1H), 7.52-7.61 ( m, 2H), 7.87-8.03 (m, 7H), 8.13 (s, 1H), 8.21 (dd, J = 1.8, 8.7 Hz, 1H), 8.62 (d, J = 1.2 Hz, 1H)

[a] _D + 17.5 ± 1.1 (c = 0.514, DMSO, 24 ° C)

Elemental analysis as _{_{_{(C 23 H 20 N 2 O}}} 5 S)

Calculated value: C; 63.29, H; 4.62, N; 6.42, S; 7.35

Experimental value: C; 63.11, H; 4.57, N; 6.47, S; 7.28

(4th step)

To a solution of (5) (200 mg, 0.458 mmol) in dimethyl sulfoxide. (5.5 ml) was added lmol / L sodium hydroxide aqueous solution (1.37 ml) at room temperature, and the mixture was stirred for 6 hours. The precipitated sodium salt was collected by filtration, poured into ice-cold 2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure. The residue was crystallized from acetone / hexane to give a melting point of 211-.

The desired product (6) (173 mg, yield 89.4%) at 213 ° C was obtained.

IR (KBr, V max cm- ¹ ) 3288, 1751, 1608, 1328, 1164, 1124, 1091, 755

Ή NMR (DMSO-d ₆₎ δ ppm): 1.19 (d, J = 7.2 Hz, 3H), 3.84 (m, IH), 7.59-7.69 (m,

2H), 7.90 (d, J = 8.7 Hz, 2H), 7.98-8.25 (m, 7H), 8.68 (s, IH), 8.97 (s, 1H), 12.67

(br s, IH)

[a] _D -1.6 + 0.8 (c = 0.506, DMSO, 24 ° C)

Elemental analysis as _{_{_{(C 22 H 18 N 2 O}}} 5 S.0.2H 2 O)

Calculated values: C; 62.02, H; 4.35, N; 6.57, S; 7.53

Experimental values: C; 61.95, H; 4.15, N; 6.64, S; 7.49

Compounds (A-2) to (A-8) were synthesized in the same manner as in Example 1.

οε

.Cl7C0 / l0df / X3d I9W8 / I0 OAV Example 9

10 11 4th process

To COOH

B-l

(First step)

Compound (8) was obtained according to the method described in J. Heterocyclic Chem., 29, 1245 (1992), using 4′-two-way phenacyl bromide (7) as a starting material. 187-189 ° C.

IR (KBr, v max cm " ¹ ) 3435,1603,1520,1335

Ή NMR (DMSO-d ₆ , δ ppm): 7.58-7.60 (m, 3H), 8.10-8.16 (m, 5H), 8.35 (d, J = 8.7 Hz, 2H)

(2nd step)

Using compound (8) as a starting substance, compound (9) was obtained by the method described in WO98 / 40332. 138-140 ° C

IR (KBr, v max cm " ¹ ) 3431,2594,1716,1599,1373,1163

_{NMR (CDC1 3, δ ppm)} : 7.51-7.54 (m, 3H), 7.70 (s, 1H), 7.93 (d, J = 9.0Hz, 2H), 8.10-8.16 (m, 4H)

(3rd step) To a suspension of 277 mg (10) of D-valine methyl ester hydrochloride in 5 ml of methylene chloride were added 0.41 ml of N-methylmorpholine and 480 mg of the compound (9), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic solvent layer to 2 mol / L-hydrochloric acid and washed sequentially with 5% -NaHC0 ₃ solution, water. After drying over Na ₂ SO _{4, the} mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel. The fraction eluted with chloroform / ethyl acetate = 2.5 / 1 was collected and recrystallized from acetone / n-hexane to give 304 mg of the target product (11) having a melting point of 138-140 ° C. . Yield 48.9%.

IE (KBr, V max cm ' ¹ ) 3450, 3278, 1739, 1603, 1333, 1167, 1140

_{Ή ΝΜΕ (CDC1 3, δ ppm} ): 0.89 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 2.06 (m, IH), 3.47 (s, 3H), 3.79 ( dd, J = 9.9, 4.8 Hz, IH), 5.17 (d, J = 9.9 Hz, IH), 7.50-7.52 (m, 3H), 7.60 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H ), 7.90 (d, J = 8.7 Hz, 2H), 8.11-8.15 (m, 2H)

[a] _D + 6.3 ± 0.9 (c = 0.505, DMSO, 24.5 ° C)

Elemental analysis as _{_{_{(C 21 H 22 N 2 0}}} 5 S)

Calculated values: C; 60.85, H; 5.35, N; 6.76, S; 7.74

Experimental value: C; 61.15, H; 5.13, N; 6.72, S; 8.08

(4th step)

1.88 ml of Imol / L-NaOH solution was added to a solution of 260 mg of dimethyl sulfoxide in 7.5 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature overnight. The reaction solution was acidified with 2 mol / L-hydrochloric acid and extracted with ethyl acetate. The organic solvent layer is washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue is recrystallized from acetone / n-hexane to give the target compound having a melting point of 220-221 ° C (B- 1 173 mg) was obtained. Yield 68.9%.

IR (KBr, V max cm " ¹ ) 2300-3600 br, 3442, 3271, 1693, 1450, 1342, 1335, 1268, 1169, 1146

Ή NMR (DMSO-d ₆ , δ ppm): 0.81 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H), 1.96 (m, 1H), 3.57 (dd, J = 6.0 , 8.7 Hz, 1H), 7.53-7.65 (m, 3H), 7.88 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 8.04 (s, IH), 8.09-8.19 (m, 3H), 12.62 (br s, IH) [a] _D + 12.2+ 1.0 (c = 0.509, DMSO, 24 ° C)

Elemental analysis as _{_{_{(C 20 H 20 N 2 O}}} 5 S)

Calculated value: C; 59.99, H; 5.03, N; 7.00, S; 8.01

Experimental value: C; 59.84, H; 4.99, N; 6.99, S; 7.97

Compound (B-2) to compound (B-6) were synthesized in the same manner as in Example 9. Table 2 shows the results.

s 挲

Litio odriijd Example 15

C-1

(First step) ''

Suspension of D-valin methyl ester hydrochloride (14) (2.20 g, 13.1 mmol) and 4-cyanobenzensulfonyl chloride (15) (2.40 g, 11.9 mmol) in tetrahydrofuran (40 ml) To the mixture was added N-methylmorpholine (3.90 ml, 35.5 mnol) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice—2 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale brown oil (3.89 _g ). Crystallization from ether / hexane gave the desired product (16) (3.12 g, yield 88.0%) having a melting point of 54-57 ° C.

IR (KBr, V max cm " ¹ ) 3292, 2974, 2231, 1732, 1709, 1348, 1173

_{Ή NMR (CD C1 3, δ} pp m): 0.87 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 2.09 (m, 1H), 3.51 (s, 3H), 3.80 (dd, J = 4.9, 10.2 Hz, IH), 5.25 (d, J = 10.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H)

[a] _D + 4.7 + 0.9 (c = 0.506, DMSO, 23 ° C)

Elemental analysis as _{_{_{(C 13 H 16 N 2 0}}} 4 S)

Calculated values: C; 52.69 _; H; 5.44, N; 9.45, S; 10.82

Experimental value: C; 52.80, H; 5.34, N; 9.52, S; 10.55

(2nd step)

The compound (16) (5.93 g, 20 mmol) and thioacetamide (1.80 g, 24 mmol) were suspended in a saturated solution of dimethylformamide hydrochloride (30 ml) and stirred at 100 ° C for 2.5 hours. Was. The reaction solution was poured on ice and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane Z ethyl acetate = 1/2 was collected and crystallized from acetone / hexane to give the desired product having a melting point of 166-167 ° C ( 17) (3.73 g, 56.4% yield).

IR (KBr, V max cm " ¹ ) 3446, 3336, 3322, 2964, 1725, 1621, 1411, 1348, 1328, 1297, 1213, 1174, 848, 638

Ή NMR (DMSO-d ₆ , δ ppm): 0.80 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 7.8 Hz, 3H), 1.92 (m, 1H), 3.35 (s, 3H), 3.59 (dd, J = 7.2, 8.1 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 8.1 Hz, 2H), 8.39 (d, J = 8.1 Hz, 1H), 9.70 (br s, 1H), 10.10 (br s, 1H)

_{[a] 365 - 5.0 ± 0.9} (c = 0.505, DMSO, 24 ° C)

_{HR-FABMS m / z C 13} H 19 N 2 0 4 S 2 [M + H] + and to

Calculated value: 331.0786

Experimental value: 331.0779

(3rd step)

A solution of compound (17) (330 mg, 1 mmol) and 2-bromoacetylnaphthalene (10) (249 mg, 1 mmol) in dimethylformamide (4 ml) was stirred at 80 ° C for 2 hours. The reaction solution was poured into ice_2mol / L hydrochloric acid and extracted with ethyl acetate. Organic layer is saturated bicarbonate

O 〇

Elemental analysis (C ₂₄ H ₂₂ N ₂ O ₄ S ₂ -0.3H ₂ O)

Calculated value: C; 61.07, Η; 4.83, Ν; 5.94, S; 13.59

Experimental value: C; 61.05, H; 4.77, N; 6.17, S; 13.65

Compounds (C-2) to (C-7) were synthesized in the same manner as in Example 15. Table 3 shows the results.

6S

ε 輋

Z. £ £ 0 / T0df / X3d Example 22

3rd step

(First step)

2-Naphthonitrile (19) (4.60 g, 3 mmol) and thioacetamide (4.51 g, 60 mmol) were suspended in a saturated solution of dimethylformamide hydrochloride (36 ml). Stirred for hours. The reaction solution was poured on ice and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane to give the desired product (20) (3.82 g, yield 68.0%) having a melting point of 139-140 ° C.

IR (KBr, V max cm " ¹ ) 3370, 3280, 3178, 1619, 1388, 1282, 908, 813

Ή NMR (DMSO- d ₆ , δ ppm): 7.55-7.65 (m, 2H), 7.91-8.06 (m, 4H), 8.44 (d, J = 1.2 Hz, 1H), 9.67 (s, 1H), 9.99 (s, 1H)

As elemental analysis (CnH ₉ NS)

Calculated: C; 70.55, H; 4.84, N; 7.48, S; 17.12

Experimental values: C; 70.28, H; 4.88, N; 7.48, S; 16.89

(2nd step)

A solution of compound (4) (320 mg, lmmol) and compound (20) (187 mg, lmmol) in dimethylformamide (5 ml) was stirred at 80 ° C for 24 hours. The reaction solution is ice--2mol / L salt Poured into the acid and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and the fraction eluted with hexane / ethyl acetate = 3/2 was collected and crystallized with acetone / hexane to obtain the target substance with a melting point of 163-165 ° C. (21) (386 mg, yield 85.3%) was obtained.

IR (KBr, V max cm " ¹ ) 3442, 3280, 1735, 1434, 1336, 1218, 1160, 1132, 1093, 754 Ή NMR (CDC13 _; δ ppm): 1.42 (d, J = 7.5 Hz, 3H) , 3.56 (s, 3H), 4.05 (m, 1H), 5.29 (d, J = 8.7 Hz, 1H), 7.52-7.59 (m, 2H), 7.67 (s, 1H), 7.85-8.00 (m, 5H ), 8.14-8.21 (m, 3H), 8.51 (s, 1H)

[a] _D + 16.5 + 1.1 (c = 0.510, DMSO, 26 ° C)

Elemental analysis as _{_{_{(C 23 H 20 N 2 O}}} 4 S 2)

Calculated values: C; 61.04, Η; 4.45, Ν; 6 · 19, S; 14.17

Experimental values: C; 60.98, Η; 4 · 38, Ν; 6 · 22, S; 14.02

(3rd step)

To a solution of the aldehyde compound (21) (340 mg, 0.751 mmol) in dimethyl sulfoxide (9.0 ml) was added lmol / L aqueous sodium hydroxide solution (2.25 ml) at room temperature, and the mixture was stirred for 3 hours. The precipitated sodium salt was collected by filtration, poured into ice-cold 2 mol / L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from acetone / hexane to give the desired product (D-1) (309 mg, yield 93.8%) having a melting point of 197-199 ° C.

IR (KBr, V max cm ' ¹ ) 3239, 1724, 1700, 1315, 1301, 1147, 1126, 1091, 740 Ή NMR (DMSO-d ₆₎ δ ppm): 1.19 (d, J = 7.2 Hz, 3H) , 3.84 (m, 1H), 7.59-7.65 (m, 2H), 7.91 (d, J = 8.4 Hz, 2H), 8.01 (m, 1H), 8.07-8.16 (m, 2H), 8.18-8.32 (m , 4H), 8.45 (s, 1H), 8.65 (s, 1H), 12.67 (br s, 1H)

[a] _D + 2.2 ± 0.8 (c = 0.509, DMSO, 26 ° C)

Elemental analysis as _{_{_{(C 22 H 18 N 2 O}}} 4 S 2 .0.3H 2 O)

Calculated value: C; 59.52, H; 4.22, N; 6.31, S; 14.45 Experimental values: C; 59.49, H; 4.19, N; 6.40, S; 14.61

Compounds (D-2) to (D-38) were synthesized in the same manner as in Example 22. The results are shown in Tables 4 to 8.

Table 4

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I hear odf / e :) d I9W8 / 10 OAV f

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19 10 OAV 9f

I9W8 / I0 OAV Lf

8 Halla Test Example 1 Isolation and purification of MMP

MMP-1 was purchased from Kagay Co., Ltd.

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

MMP-8 was synthesized by PCR using commercially available Human Bone Marrow cDNA.

Catalytic domain ( ⁹⁹ Phe ~ ²⁶² Gly) was amplified. This was cloned into the Escherichia coli expression vector pTrc99A into which the His tag and enterokinase cleavage site were introduced, and the IPTG

(Isopropyl-?-D-thiogalactopyranoside) induced expression in the insoluble fraction (Thau F. Ho, M. Walid Qoronfleh, Robert C. Wahl Trica A. Pulvino, Karen J. Vavra, Joe Falvo, Tracey M. Banks, Patricia G. Brake and Richard B. Giccarelli: Gene expression, purification and characterization of recombinant human neutrophil collagenase. Gene 146, (1994) 297-301, prepared with slight modification of this sample). MMP-8 was isolated from the insoluble fraction by metal chelate chromatography after dissolving in a denaturing agent (6M urea) by a conventional method. Next, the denaturing agent (6 M urea) was removed by dialysis, and the enzyme was refolded at the same time to obtain an active form of MMP-8.

MMP-9 is based on Y. Okada et al. (Yas nori Okada, Yukio Gonoji, Katsumi

Naka, Katsuro Tomita'Isao Nakanisni, Kazushi Iwata, Kyoko Yamashita, and Taro Hayakawa.Matrix metalloproteinase 9 (92-kDa gelatinase / type IV collagenase) from HT 1080 human nbrosarcoma cells.Purification and activation of the precursor and enzymic properties J.Bioi .Chem

1992, 267, 21712-21719) and other methods (l) Yasunori Okada, Tatsuhisa Morodomi, Jan J. Enghild, ko Suzuki, Atsushi Yasui, Isao Nakanishi Guy salvesen and Hideaki Nagase Matrix metalloproteinase 2 from human rhumatoid synovial fibroblasts. activation of the precursor and enzymic properties.Eur.J.biochem. 1990, 194, 721-730, 2) Robin V. Ward,

Rosalind M. Hembry, John J. Reynolds and Gillian Murphy The purification of tissue inhibitor of metalloproteinase-2 from its 72kDa progelatinase complex. Biochem. J 1991, 278, 179-187]. That is, Human fibrosarcoma ATCC HT1080 contains 10% Fatal calf serum (FCS)

37 at Dulbecco's ModifiedMedium (DMEM). C. Culturing was performed for 48 hrs (5%) to make it Confluent. Confluent Cells were further cultured in DMEM without FCS (2nd). During this culture, to obtain MMP-9, 50 ng / ml Phorbol-12-myristate-13-acetate (TPA) was added to DMEM. The culture solution treated with TPA was centrifuged (3000 rpm, 15 min), and the supernatant was concentrated to about 450 ml by ultrafiltration (UP-20, Toyo). This concentrate is then extracted with Gelatin-Sepharose and Concanavalin A-Sepharose.The MMP-9 fraction is then dialyzed, concentrated by ultrafiltration (UP-20, Toyo), and adsorbed on Sephacryl S-200 and Green A matrix. And separation. Procollagenase was then activated with TPCK-Trypsin (Final cone. 3 / g / 50 React. Mix).

MMP- 12 amplified the Human Placenta Total Catalytic from ENA by ^{RT-PCR d (Hnain (1} () (r Plie~ 263 Gly). This His tag, the E. coli expression vector pTi'c99AHE introducing the Enterokinaze cleavage site After cloning, expression was induced by IPTG (Isopropyl-β-D-thiogalactopyranoside) and expressed in the insoluble fraction.MMP-12 was isolated from the insoluble fraction by dissolving in a denaturant (6M urea) by a conventional method. The denatured agent (6M urea) was removed by dialysis and the enzyme was refolded at the same time to obtain active MMP-12.

MMP-13 prepared mRNA from human cartilage-derived cancer cell SW1353 stimulated with IL-1 and TNF. Catalytic domain ( ¹⁰⁴ Tyr to ²⁶⁷ Gly) was amplified by RT-PCR. This was cloned into an Escherichia coli expression vector pTrc99AHE into which a His tag and an enterokinase cleavage site had been introduced, and induced by IPTG (Isopropyl-β-D-thiogalactopyranoside) to express it in the insoluble fraction. MMP-13 was isolated from the insoluble fraction by dissolving it in a denaturing agent (6M urea) by a conventional method, and then by metal chelate chromatography (NiCelating Sepharose). Next, the denaturant (6M urea) was removed by dialysis, and at the same time, the enzyme was refolded to obtain active MMP-13. Test Example 2 Method for measuring 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 coumarin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases: FEBS LETT., 296, (1992), 263-266. According to. Substrate: MOCAc-Pro-Leu-Gly -Leu-A 2 Pr (DNP) -Ala-Ai'g-NH 2 was used Peptide Institute, Inc. Osaka, the Japan. The following four assays were performed for one 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) / (C—D)} X100

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

Table 9 shows the inhibitory activities measured by the above method.

≠ 6

90

Test example 3

Male Sprague-Dawley rats (weighing 390-430 g at the start of the experiment) were systemically exposed to 30 cigarettes a day for 5-8 days per week for 7-8 weeks using a commercially available tobacco filter. Compound (D-26) was suspended in 0.5% methylcellulose and orally administered at 30 mg / kg twice a day. The vehicle group was orally administered 2 ml / kg of 0.5% meth / recellulose. 16 to 24 hours after the last cigarette smoke exposure, the animals were anesthetized by intraperitoneal administration of 40 mg / kg sodium pentobarbital. Immediately after spontaneous respiration was stopped by intravenous administration of a muscle relaxant pancuronium bromide (0.3 mg / rat), the patient was placed under artificial respiration using a pressure-controlled ventilator to evaluate pulmonary compliance. After exsanguination lethal, connected by tubes Note morphism tube made of airway and glass, after injection of air to transpulmonary pressure is 30 cm H ₂ 0, evacuated until after lung pressure becomes 0 cm H ₂ 0, further through lung pressure was pull to become one 20 cmH ₂ O. Changes in transpulmonary pressure and lung volume upon deflation were observed and recorded as a pressure-volume curve. The slope of the pressure capacity curve was evaluated as static lung compliance. Transpulmonary pressure was evaluated as the maximum intake amount changes in lung volume from the total lung volume position until transpulmonary pressure 0 cm H functional residual capacity position showing the ₂ 0 indicating a 25 cm H ₂ 0.

Data are shown as standard error of the mean. The statistical test was performed by Student's t-test, and when P <0.05, it was determined that there was a significant difference.

The results are shown in Table 10.

Table 10

Ρ <0.05 vs air exposure group *; Ρ <0.05 vs tobacco smoke exposure group

As shown in Table 10, compound D-26 significantly inhibited the increase in pulmonary lung compliance, static lung compliance, and maximum inspiratory volume due to tobacco smoke exposure in rats. Formulation example

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 HPC-L 16 m¾

Pass lactose (1000 mg) with lactose 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 pore diameter: 0.5 to lmm), and dried. The obtained dried granules are passed through a vibrating sieve (12/60 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 No. 10 hard gelatin capsule into No. 5 hard gelatin capsule. Formulation Example 3

Manufacture granules for capsule filling containing the following ingredients

Ingredients Compound of formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg

150 mg Lactose, a compound represented by the formula (I), is passed through a 60-mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HP C-L solution is added to the mixed powder, kneaded, granulated, and dried. After sizing the obtained dried granules, 150 mg thereof 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

CMC-Na 15 mg Magnesium stearate 5 mg

150 mg of the compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-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 a tablet of 150 mg. Industrial applicability

The sulfonamide derivative according to the present invention has a meta-oral protease inhibitory action, It has been found that it has a MP-12 selective inhibitory effect and can function effectively as a therapeutic or preventive agent for chronic obstructive pulmonary disease and the like.

Claims

The scope of the claims

1. General formula (I):

R ⁶ — R ⁵ -R ⁴ -S0 ₂ -COR ¹ (I)

R ³

[Wherein, R ¹ is NHOH, hydroxy, or lower alkyloxy;

R ³ is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or an optionally substituted Teraryl alkyl;

R ⁴ is optionally substituted arylene, or optionally substituted heteroarylene;

R ⁵ has the formula:

,,, Or

A group represented by;

2. R ⁶ has the formula:

(In the formula, each R ⁷ is independently a hydrogen atom, halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio, halo-lower alkyl, hydroxy, carboxy, lower alkylo Xycarbonyl, aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino;

2. The compound according to claim 1, wherein m is a group represented by 0, 1, 2, or 3), an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The compound according to claim ^1, wherein R ¹ is hydroxy, an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. R ² is a hydrogen atom, § amino carbonyl or lower alkyl which may be substituted with lower alkylthio, optionally substituted arsenide Dorokishi Ariru, optionally substituted arsenide Doroki shea Ararukiru or human Dorokishi, The compound according to any one of claims 1 to 3, which is a heteroarylalkyl optionally substituted with, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof. Japanese food.

5. The method of claim 1, wherein R ² is hydrogen, methyl, isopropyl, isobutyl, benzyl, indole-3-ylmethinole, 4-hydroxypentzino !, or (5-hydroxyindo-1-ru-3-yl) methyl. 5. The compound according to any one of to 4 above, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. The compound according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom, an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

. 7 R ⁴ is 1, 4-Hue - Ren or 2, 5-A compound according to any one of the which claims 1-6 Chiofenjiiru, an optically active form thereof, a prodrug or its those pharmaceutically, acceptable Salts or solvates thereof.

. 8 R ⁵ has the formula:

Or

The compound according to any one of claims 1 to 7, which is a group represented by the formula: an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

9. R ⁶ has the formula:

(R ⁷ and m are as defined above)

The compound according to any one of claims 1 to 8, which is a group represented by the formula: an optically active form thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. General formula (II): (II)

[Wherein, R ⁸ is a hydrogen atom, methyl, isopropyl, isobutyl, benzyl, 4-hydroxybenzyl, indone-l 3-y ^ -methyl, or (5-hydroxyl-dole-l3-inole ) Methyl;

R ⁹ is 1,4-phenylene or 2,5-thiofendyl;

R ^1. Is the formula: A s—— J π_ _ π-"" ^s

A group represented by N or NT ";

R ¹¹ is each independently a hydrogen atom, a halogen, a lower alkyl, a lower alkyloxy, a halo-lower alkyl, an acyl, a nitro, a cyano, an optionally substituted amino, or a hydroxy;

m is 0, 1, 2, or 3], an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. · 11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 as an active ingredient.

12. A meta-protease inhibitor comprising the compound according to any one of claims 1 to 10 as an active ingredient.

13. A matrix meta-oral protease inhibitor comprising the compound according to any one of claims 1 to 10 as an active ingredient.

14. A matrix meta-oral protease 112 inhibitor comprising the compound according to any one of claims 1 to 10 as an active ingredient.

15. An agent for treating or preventing chronic obstructive pulmonary disease, comprising the compound according to any one of claims 1 to 10 as an active ingredient.

16. Claims 1 to 10 for producing a medicament for treating chronic obstructive pulmonary disease. Use of the compound according to any one of the above.

17. A method for treating chronic obstructive pulmonary disease in a mammal, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 10 to the mammal, including a human. .

18. A method for inhibiting Matrix Metaoral Protease 112, comprising contacting Matrix Metaoral Protease 12 with the compound according to any one of claims 1 to 10.