WO2000058280A1

WO2000058280A1 - Carbocyclic sulfonamide derivatives

Info

Publication number: WO2000058280A1
Application number: PCT/JP2000/001710
Authority: WO
Inventors: Fumihiko Watanabe; Yoshinori Tamura; Yasuhiko Kanda
Original assignee: Shionogi & Co., Ltd.
Priority date: 1999-03-26
Filing date: 2000-03-21
Publication date: 2000-10-05
Also published as: AU3196300A

Abstract

Sulfonamide derivatives having matrix metalloprotease inhibiting effects, which are compounds represented by general formula (I), optical isomers of the same, pharmaceutically acceptable salts of both, or hydrates thereof wherein R1 is hydrogen, optionally substituted lower alkyl, or the like; R2 is a single bond, optionally substituted arylene, or the like; R3 is a single bond, -C C-, or the like; R4 is optionally substituted aryl or the like; M is hydroxyl or the like; and m is 0 or 1.

Description

Specification

Carbocyclic sulfonamide derivative

Technical field

The present invention relates to a sulfonamide derivative having a carbon ring 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 the meta-oral protease, which is a protease containing a metal ion in the active center, and particularly the matrix meta-oral protease (MMP). Many families of MMPs, ranging from MMP-1 (type I collagenase) to ^ 1 syrup-23, have been reported, and under the normal physiological conditions, they are affecting growth and tissue reform. However, the progression of the disease and the enzymes involved in various pathological conditions involving tissue destruction and fibrosis (osteoarthritis, rheumatoid arthritis, corneal ulcers, periodontitis, tumor metastasis or invasion, virus infection (HIV infection)) It has been reported that the increase in the expression (activity) of is correlated. Many MMP inhibitors tend to have an inhibitory action on TNF-α production. MMMM inhibitors having a cyclic structure are described in WO98 / 07677, WO98 / 1655◦6, WO98 / 337768, and the like.

Compounds having a similar side chain and MMP inhibitory activity are described in WO97 / 27174. Disclosure of the invention

If MMP activity can be inhibited as described above, Therefore, development of MMP inhibitors has been desired.

In view of the above points, the present inventors have conducted intensive studies and as a result, have found that a sulfonamide derivative having a certain carbon ring exhibits a strong MMP inhibitory activity.

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

Wherein R ¹ is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl or a substituted A heteroarylalkyl;

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

R ³ is a single bond,-(CH ₂ ) n-,-CH = CH-,-C-C-, CO-,-CO-NH-, N = N-, N (R ^A )-, One Ν — CO— NH—, One NH—CO—, One O—, One S—, One S 0 ₂ —, One S〇. NH—,-SO _z -NH-N = CH

(Wherein, R ^A is hydrogen or lower alkyl, n is 1 or 2); R ⁴ is optionally substituted alkyl, optionally substituted aryl, optionally substituted Heteroaryl, or an optionally substituted non-aromatic complex ring;

M is NHOH, hydroxy, or lower alkyloxy; m is 0 or 1;

However, when R ² and R ³ are both a single bond, R ⁴ is not a substituted aryl, and when R ³ is —0—, M is not NHOH.] Or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

More specifically, it relates to the following I I) to X I V).

II) General formula (II):

[Wherein, I ¹ , Μ, and m are as defined above;

R ⁵ has the formula:

, Or

(Wherein, R ⁶ 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 Heterocyclic, substituted Optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted raid;

R ⁷ is independently optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower anoalkylthio, norogen, nitro, cyano, carboxy, lower alkyl Oxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acryl, acryloxy, optionally substituted aryl, optionally substituted heteroaryl, Optionally substituted non-aromatic heterocyclic ring, optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted ureido; q and r are each independently , 0, 1, 2, or 3;

X is an oxygen or sulfur atom;

Y ¹ is one C≡C—or the formula:

N = N N = N jj π Ν—— Ν ——

Ichi, ~ ~, Ν— ~ ^ ~ ~ 1! ^ ^ ~ ~ ^ ~

, Ν 'Ν, ヽ, ^ S ^, to. ,

Ν— Ο Ο—— Ν

To Ν or Ν ^

Or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

III) General formula (III): (ΠΙ)

[Wherein, R ¹ M and m are as defined above;

R ⁸ is of the formula: ,

Or

(Wherein, R ⁷ and r are as defined above.

γ 2 is one _C ≡ C—or the formula:

Ν- -Ν

Ό

Ν- -0 0- ■ Ν

もしくは or Ν,

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

IV) R ⁸ is the formula:

(Wherein R ⁷ and r are as defined above). III) The optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

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

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

VIII) A female protease inhibitor comprising as an active ingredient the compound according to any one of I) to VI). IX) A matrix meta-oral protease inhibitor comprising as an active ingredient the compound according to any of I) to VI).

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

XI) A therapeutic or prophylactic agent for nephritis, 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, the term “lower alkyl” used alone or in combination with other terms includes a straight-chain or branched monovalent hydrocarbon group having 1 to ⁸ carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butynole, tert-butyl, n-pentyl, isopentyl, _neo -pentinole, n-hexinole, isohexinole, n-heptinole , N-octynole and the like. Preferably, a C1-C6 alkyl is mentioned. Even more preferred are C1-C3 alkyl.

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, isopentyl, various butyr 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 1 or 2 or more triple bonds. Wrap It may have a double bond. For example, ethynyl, 2-propynyl, 3-prop, tininole, 4-pentinole, 5-hexynole, 6-heptinole, 7-octinole, 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 cycloalkyl having 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclootatyl are exemplified. Preferably a C3-C6 cycloalkyl is mentioned.

As used herein, the term “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 (for example, 2-phenylethyl), phenylpropyl (for example, 3-phenylpropyl), naphthylmethyl (for example, 1-naphthylmethyl, 2-naphthylmethyl), and anthrylmethyl (for example, 9) —Anthrylmethyl, etc.). Preferably, benzyl and phenylethyl are exemplified.

In the present specification, “heteroaryl J” used alone or in combination with other terms is a 5- to 6-membered arbitrarily selected member containing one or more oxygen, sulfur or nitrogen atoms in a ring. Which may be fused to a cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions, eg, pyrrolyl (For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (for example, 2-furyl, 3-furyl), chenyl (for example, 2-phenyl, 3-phenyl), imidazolyl ( For example, 2-imidazolyl, 4-imidazolyl), virazolyl (for example, 1-virazolyl, 3-virazolyl), isothiazolyl (for example, 3-isothiazolyl), isoxazolyl ( example For example, 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-pyridazinyl), tetrazolyl (eg, 1H-tetrazolyl), oxazidazolyl (eg, 1,3,4) —Oxaziaziryl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), indridinyl (eg, 2-indridinyl, 6-indolizinyl), isoindolyl (eg, 2-isoindolyl), indolyl (eg, 1—indolyl, 2—In drill, 3—In drill), Danzolyl (eg, 3-indazolyl), purinyl (eg, 8-purinyl), quinolizinyl (eg, 2-quinolinidinyl), isoquinolyl (eg, 3-isoquinolyl), quinolyl (eg, 2 — Quinolyl, 5-quinolinyl), phthalazinyl (eg, 1-phthalazinyl), naphthyridinyl (eg, 2-naphthyridinyl), quinolanyl (eg, 2-quinolanyl), quinazolinyl (eg, 2-quinazolinyl), cinnolinyl ( For example, 3-cinnolinyl), pteridinyl (for example, 2-pteridinyl), carbazolyl (for example, 2-force rubazolyl, 3-force rubazolyl), phenanthinidinyl (for example, 2-pentanidinyl, 3-phenylenidinyl) Acridinil (for example, 1 , 2-acridinyl), dibenzofuranyl (eg, 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (eg, 2-benzoimidazolyl), benzoisoxazolyl (eg, 3-benzoisoxyl) Zolyl), benzoxazolyl (for example, 2-benzoxazolyl), benzoxodiazolyl (for example, 4-benzobenzodiazolyl), benzoisothiazolyl (for example, 3-benzozo) Isothiazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzofuryl (for example, 3-benzofuryl), and benzothenyl (for example, 2-benzozoenyl). As the “heteroaryl” for R ⁴ , phenyl, pyridyl, dibenzofuranyl, 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-thiazolylmethyl), thiazolylethyl (for example, 5-thiazolyl-2-ethyl), benzothiazolylmethyl (for example, (benzothiazoyl-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), benzotriazolylmethyl (Eg, 1-benzotriazolylmethyl), benzoquinolylmethyl (eg, 2-benzoquinolylmethyl), benzimidazolylmethyl (eg, 2-benzoimidazolylmethyl), pyridylmethyl (eg, 4-pyridyl) Methyl), and the like.

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 (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolidinyl (eg, 3-pyrrolinyl), imidazolidinyl (eg, 2-imidazolidinyl), imidazolinyl (eg, imidazolinyl), pyrazolidinyl (eg, 1 -Birazolidinyl, 2-birazolidinyl), pyrazolinyl (for example, birazolinyl), piperidyl (for example, piperidino, 2-piperidyl), piperazinyl (for example, 1-piperazur), indolinyl (for example, 1-indolinil), a Soindolinyl (for example, isoindolinyl), morpholinyl (for example, mo ^ <holino, 3-morpholinyl) and the like can be mentioned.

Examples of the “non-aromatic heterocycle” for R ⁴ include bilazolidinyl, piperidyl, Linyl, morpholinyl 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. Preferably, 1,4-phenylene is used.

In the present specification, “heteroarylene” means the divalent group of the above “heteroaryl”. For example, thiofenzil, flangyl, pyridingil and the like can be mentioned. In more detail, 2,5-chofenzir, 2,5 frangyl 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 the aryl moiety is the above "aryl". Arylcarbonyl. 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. Preferably, fluorine, chlorine, and bromine are used.

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 “quaternary alkyloxycarbonyl” includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl and the like. In the present specification, the term `` halo lower alkyl '' used alone or in combination with other terms refers to the above `` lower alkyl '' substituted at 1 to 8, preferably 1 to 5 positions with the halogen. Include. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluorethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferably, trifluoromethyl is used. In the present specification, examples of the “halo lower alkyloxy” include 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.

In the present specification, the term “substituted amino” used alone or in combination with other terms refers to 1 or 2 in the above “lower alkyl”, the above “aralkyl”, the above “heteroarylalkyl”, or the above “acyl”. Includes 2-substituted amino. For example, methylamino, dimethylamino, ethylmethylamino, acetylamino, 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 exemplified. In the present specification, examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, and nitrogen. , Cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acysiloxy, may be substituted And non-aromatic heterocycles, aryloxy (eg, phenyloxy), aralkyloxy (eg, 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” for R ^1, an aminocarbonyl or an optionally substituted non-aromatic heterocyclic ring is preferable.

As the substituent for the “optionally substituted lower alkyl” in R ⁶ and R ⁷ , 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 "A substituent may be substituted. Examples of the substituent in the raid j include an optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, and di. Toro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyl Xy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle And optionally substituted aralkyl, lower alkylsulfonyl, guanidino, azo group, or optionally substituted ureide, etc. These may be substituted one or more times in all possible positions.

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

R ⁴ "optionally substituted cycloalkyl", "optionally substituted O 1

Examples of the substituents of the “good aryl”, the “optionally substituted heteroaryl”, and the “optionally substituted non-aromatic heterocycle” include lower alkyl, hydroxy lower alkyl, hydroxy, lower alkyloxy, Preferred are lower alkylthio, halogen, nitro, carboxy, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, heteroaryl, non-aromatic heterocycle, and the like.

Substitution of “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, and “optionally substituted heteroarylalkyl” in R ¹ Examples of the group include an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, nodogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo. Preferred are lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, aryl, heteroaryl, non-aromatic heterocycle, aralkyl and the like.

As the “optionally substituted aryl” in R ⁷ , an unsubstituted aryl is preferable. Examples of the substituent include optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, and halo-lower alkyl. And halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, and acyloxy.

"Teroari Ichiru to which may be substituted" in R ⁶ and R ^7, "optionally substituted non-aromatic heterocyclic ring", "optionally substituted Ararukiru", and "substituted As the “good raid”, an unsubstituted one is preferable. Examples of the substituent include an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, and halogeno. Nitro, cyano, carboxy, lower alkyloxycarbonyl, halo-lower alkyl, halo-lower alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy and the like. BEST MODE FOR CARRYING OUT THE INVENTION

The compound (I) of the present invention can be obtained from WO97 / 27 by starting from 1-amino-1-cyclopentanecarboxylic acid or 1-amino-cyclohexanecarboxylic acid, an ester thereof, or a salt thereof. It can be produced according to the method described in 174 (Methods A to F). An example is shown below.

(IV) (V)

(VI)

(Wherein, R ² , R ³ , R ⁴ and m are as defined above, R ^{1 ()} is lower alkyl, and Ha 1 is halogen)

(First step)

In this step, the compound (IV) having an amino group is converted to a sulfonamide derivative (V). The method can be carried out in the same manner as described in W097 / 271774 (Method A-first step).

(3rd step)

Deprotection of the carboxyl group of compound (V) to obtain compound (VI) can be carried out according to the method described in Protective uroups 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 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, lithium Acid, sulfuric acid, etc.) and salts with organic acids (acetic acid, citric 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 the experimental examples described below.

Specifically, osteoarthritis, rheumatoid arthritis, corneal ulcer, periodontitis, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerotic aneurysms, atherosclerosis , Restenosis, sepsis, septic shock, coronary thrombosis, abnormal neovascularization, scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, Vesicular epidermis, psoriasis, diabetes, nephritis, neurological disease, inflammation, osteoporosis, bone resorption, gingivitis, tumor growth, tumor angiogenesis, eye tumor, angiofibromas, hemangiomas, fever, bleeding, coagulation, bad Can be used as a therapeutic agent for fluid, anorexia, acute infection, shock, autoimmune disease, malaria, 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 injection Is sterilized with an appropriate carrier to give a preparation.

Dosage will vary depending on disease state, route of administration, age or weight of patient, but for oral administration to adults, is usually 0.1 to 100 mg / kg / day, and is preferred. Or 1 to 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)

Et ₃ N

COOMe CI0 ₂ S 飞 COOMe

NH ₂ HCI 1st process NHSO

( ^H0 ) 2 ^B "S '" _ ^ ^Me COOMe

Step 2 NHSO, / ^Me

3rd step

(First step)

Dissolve 500 mg (2.79 mmol) of the compound (1) in 10 ml of dry dichloromethane, and cool under ice-cooling. To the mixture were added 1.2 ml (8.73 mmol) of trietinoreamin and 930 mg (3.07 mmol) of 4-odobenzenesulfonylk mouth light. After stirring at room temperature overnight, the reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from getyl ether / n-hexane to obtain 890 mg of compound (2). Yield 75%. 139-140 ° C. IR V max (cm- ¹ ) (KBr): 3433, 3255, 2935, 1720, 1567, 1435, 1334, 1276, 1164, 1151.

_{iH NMR (CDC1 3, δ ppm} ) 1.17-1.53 (m, 6H), 1.80-1.89 (m, 4H), 4.79 (s, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H).

Elemental analysis value (%) C14H18NIO4S

Calculated values: C; 39.73, H; 4.29, N; 3.31, I; 29.98, S; 7.58.

Obtained: C; 39.57, H; 4.24, N; 3.37, I; 30.22, S; 7.62.

(2nd step)

400 mg (0.945 mmol) of the compound (2) was dissolved in 8.0 ml of tetrahydrofuran, and 268 mg (1.23 mmol) of 5-tolyl-2-thiopheneboic acid, 392 mg of lithium carbonate (2.84 mmol) ) And 163 mg (0.142 mmol) of tetraxtriphenylphosphine palladium were added, and the mixture was stirred under reflux for 2 days under an argon atmosphere. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran / n-hexane and tetrahydrofuran / ethyl acetate to obtain 256 mg of compound (3). Yield 58%. 223-225 ° C.

IR (KBr, v max cm-i) 3465, 3267, 2925, 1741, 1591, 1452, 1315, 1236, 1163, 1149.iH NMR (CDCls, δ ppm): 1.20-1.52 (m, 6H), 1.82- 1.92 (m, 4H), 2.39 (s, 3H), 3.54 (s, 3H), 7.22 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 4.2 Hz, IH), 7.53 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H).

Elemental analysis value (%) C25H27N04S2 O.2H2O Calculated values: C; 63.45, H; 5.84, N; 2.96, S; 13.55.

Found: C; 63.30, H; 5.70, N; 3.10, S; 13.80.

(3rd step)

0.87 ml of a 1N aqueous solution of sodium hydroxide was added to 2.7 ml of dimethyl sulfoxide of 135 mg (0.287 mmol) of the compound (3), and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was acidified with 1N hydrochloric acid, and extracted with a mixed solvent of tetrahydrofuran monoethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetone / n-hexane to obtain 116 mg of the compound (A-1). Yield 89%. 259-261 ° C.

IR (KBr, v max cm 3440, 3251, 2918, 1724, 1591, 1490, 1454, 1326, 1164, 1153.iH NMR (DMSO-de, δ ppm): 1.12- 1.39 (m, 6H), 1.60-1.87 (m, 4H), 7.27 (d, J = 8.1

Hz, 2H), 7.55 (d, J = 3.6 Hz, IH), 7.61 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 4.2 Hz, IH),

7.79 (d, J = 9.0 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.89 (s, IH), 12.40 (brs, IH).

Elemental analysis value (%) C24H25NO4S2

Calculated values: C; 63.27, H; 5.53, N; 3.07, S; 14.08

Obtained: C; 63.01, H; 5.40, N; 3.14, S; 14.13

Compounds (A-2) to (A-3) were synthesized in the same manner as in Example 1.

Example 4

A-4

(First step) Compound (1) was reacted with a sulfonyl chloride compound by a method similar to the method described in the first step of Example 1 to obtain compound (4).

(2nd step)

Compound (5) was obtained by a method similar to the method described in Tamura, Y. et al., M.J. Med. Chem. 1998, 41, 640.

(3rd step)

Compound (A-4) was obtained according to a method similar to the method described in the third step of Example 1. Compounds (A-5) to (A-7) were synthesized by carrying out a reaction similar to the above.

Table 1 shows the physical constants.

l 挲

OI O / OOdiY ェ :) d 08Z8S / 00 OAV By using the same method, a compound represented by the following combination of substituents in the general formula shown below can be synthesized.

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

N:: N = N jj—— ji N- -N

Ql = Q2 = Q4 =

SS

(R ² , R ³ , R ⁴ ) = (1, 4-phenylene, -CH2-, Ph), (1, 4-phenylene, -CH2-, 4-Me-Ph), (1,4-phenylene, -CH2-, 4-Et-P), (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, -CHs-, 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, -CH2 -, 4-CF3-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, -CH2-, 4-NMeEt-Ph), (1, 4-phenylene, -CH = CH-, Ph), (1,4- -'-HNOO "' sua uaqd-n)

'"HNOO"' θΠθΐΑπθηά-^ 'χ)' (qj-lO 'ΉΝΟΟ "' auatAueqd-^ 'i)' (qj-d ^ '" HNOO 9Z-' euaiAuaqd-f. '!)' (Qd-QHS -i ⁷ '"HNOO"

'(q <J 30'"HNOO-

'"HNOO-' (q <I- ^J ii '' HNOO-

'(qj-ig-' -ΗΝΟΟ "'traqWi)' (qj-epM-l ^ '" HNOO "' U9qd- 'i)' (qd '" HNOO "' uaqd QZ -V'l) '(qd- 139 N '〇D〇 D-' eueiAueqd-^ 'T)'(qd'iaHN'3≡〇''a ^ a ^ naqd f'l)

'(qj-θΙΑΙΗΝ-ΐ' 0 0 · 'θΠ9 [Απθη (ί-' ϋ '(q <I- ^z HN-' Ό ≡ 0- 'ana ^ naqci-^' T) '(qj- ^ O- t ''"D ≡ 0"'snsiinaqd

91

• ⁹ WS '-0≡0-' lAnaqd i) '(qj 30-'"0≡0"'I"' (qj-eWO -f 00- 'ana naqd-n)' (qj-ng ^- ^ 'Cho Q-' snaiAnaqd- 'i)' (qd-ngu- ^

(0-'sua uaqd-t'i)

'-〇≡〇-

'(rfd' Ό≡Q- '9ΠΘΙ naqd

'ΐ)' (qd '-Ο≡0-' eueiAuaqd-^ 'x)' (qj ^ ga N-t '' -ΗΟ = ΗΟ "'sua uaqd- i) Οΐ

'-ΗΟ = ΗΟ-' au τΐθη ( ϊ- 'τ)' (qj-w顧- 'ΉΟ ^ ΗΟ "' - 'τ)

■ f'l) '^ d- ^z OK-' · ΗΟ = ΗΟ "'an u _T )' (qj-e ^ O- ^ '-ΗΟ = ΗΟ ·'

■ f'l)

'ans tisqd-^' ΐ) '(qd-i-' -ΗΟ = ΗΟ- U3qd- 'i)' (qd-ejAIS- ^ '-ΗΟ = ΗΟ "' snaiAna dg-'ΐ)' (¾ ^ 30 -^ '-ΗΟ = ΗΟ ·' auai aaqd-^ 'T)' ^ ά ^ ΜΟ '' ΗΟΗΟ = ΗΟ'anei ^ uaqd -f'l) '^ d- ⁿ -f' -HO = HO- 'euaiAueqd-^' T) '(qj-ngu- ^' -ΗΟ = ΗΟ "'

-'ΐ)' (qj-Jdi- '-ΗΟ = ΗΟ-' euei ueqd-^ 'T)' (qj-aju- ^ '' ΗΟ = Η〇_ 'anaiAueqd-' ΐ)

O IO / OOdf / XDd 08Z8S / 00O Cn 〇

0

p), e NHCOHCOillnvl NN 4NM .--- yp), e NHCOm TlinlNh 4-- y py f)) en3〇2hlC〇e NCphHCph-llnlHO NN 4F ---

¾y py) ell! Lle! L §00lienl NCOclphH 4-- y py) enllCephHOhnl NHCOF N-- py, e in one ---

ο Ο

y plienl nBu

py py) elinletphlinlE-- y: py pNHEelienl 4ll; nl-i y ppy) py) e-llnl22e〇eNH:? hlinl N:? h! l! ll ----- ¾y), le3llll CFBr: ph - bt

e o py) thi 4OE

lp-,-

Q), eilnl640Etph ---

Q) eeJinnl64 JBUPJ1:-nehlleln

4ellnl 4ell! Ll-- jpy Q), 4NEeet! Nlnt54eEpN! H ---- jpy ¾y Nilelinelhtnl

¾y) yyJeln2 4N〇h:? E lienn NHl lil-- y: pyQ) ¾) enlellrl 43ΓeeC hlnl: a 4FphI --- bo

〇 o (, (pyp ,,, 4N pth25tCCplihioedl 4NHE2 tohhniiii-≡-- -----

Ω

III

〇〇

Ω

t

00

py) s (y ,, CONHohd liiti d ni HilCOHlN--ppyy (,, oo5thiied liilid:? h2lni ni C〇Hll --- b

〇 ο

D

b

o

ts ti ti y

&

^ ^ ^

〇

JO

), (P, e 4l:? H25t0EMii 4 ---- thiophen-diyl, -Q6-, 4- CFs-Ph), (2,5-thiophen-diyl, -Q6-, 4-N0 2 -Ph), (2,5- thiophen-diyl, -Q6-, 4 -NH2-Ph), (2,5-thiophen-diyl, -Q6-, 4-NHMe-Ph), (2,5-thiophen-diyl, -Q6-, 4-NMe ₂ -Ph), (2, 5-thiophen-diyl, -Q6-, 4-NHEt-Ph), (2,5-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-Ph ), (2,5-thiophen-diyl, -Q7-, 4-NHMe-Ph), (2,5-thiophen-diyl, -Q7-, 4-NMe ₂ -P), (2,5-thiophen- diyl, -Q7-, 4-NHEt-Ph), (2,5-thiophen-diyl, -Q7-, 4-NMeEt-Ph)

Test example

Test Example 1 Isolation and purification of MMP-2

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

Test Example 2 Method for measuring enzyme inhibitory activity of MM P-2

MMP-2 enzyme activity measurement method is described in C. Graham Knight, Frances Willenbrock and Gillian Murphy: A novel co marin-labelled peptide for sensitive continuous assays of the matrix metalloproteinases: FEBS LETT., 296, (1992), 263-266 Method. Substrate: MOCAc-Pro-Leu-Gly-Leu-A ₂ Pr (DNP) -Ala-Arg-NH ₂ was from Peptide Institute, Inc. Osaka, 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 formula, inhibition (%) = {1- (A-B) / (C-D)} × 100

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

IC _5. The values are shown in Table 2. Table 2

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

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 the cone through a 120 mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HPC-L (low viscosity hydroxypropylcellulose) is added to the mixed powder, and the mixture is kneaded, granulated (extrusion granulated with a pore size of 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 Cornstarch 10 mg Magnesium stearate---1 mg

100 mg Lactose, a compound represented by the formula (I), is passed through a 60-mesh sieve. Cone: Put it 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 Compound of formula U) 15 mg 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 cornstarch through a sieve of 120 mesh. These are mixed, and an HP C-L solution is added to the mixed powder, followed by kneading, granulation, and drying. 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)

? Sucrose 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 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 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

1. General formula (I):

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

R ³ is a single bond, — (CH ₂ ) n—, CH = CH, one C≡C one, CO—, —CO—NH—, one N = N, one N ( ^RA ) one, NH—CO NH, one NH- CO, one O, one S, one S 0 ₂ -, one S_〇 _{_{2 NH-, - S 0 2 -NH}} -N = CH -, or / this »A:

—— OO——

， Or N |

Wherein R ^A is hydrogen or lower alkyl, n 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 complex ring;

M is NHOH, hydroxy, or lower alkyloxy;

m is 0 or 1;

However, when both R ² and R ³ are a single bond, R ⁴ may be substituted. M is not NH 0 H, if R ³ is — 0—, not a aryl, a compound thereof, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydration thereof object.

2. General formula (II):

[Wherein, R M and m are as defined above;

R ⁵ has the formula:

, Or

(Wherein R ⁶ 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-anoreoxy, halo-lower-anoreoxy, 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 perrad;

R ⁷ is independently optionally substituted lower alkyl, cycloalkyl, Lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, logen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo lower alkyl, halo lower alkyloxy, unsubstituted or substituted amino, unsubstituted Or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocycle, optionally substituted aralkyl, lower alkyl A sulfonyl, guanidino, azo group, or an optionally substituted ureid; q and r are each independently 0, 1, 2, or 3;

X is an oxygen or sulfur atom;

Υ 1 is one C≡ C one or formula:

—

N O O—— N

Or "^

3. General formula (I I I):

(ΠΙ)

[Wherein, II ¹ , M, and m are as defined above;

R ⁸ is of the formula: ,

Or

(Wherein, R ⁷ and r are as defined above.

Y ² is one C≡C—or the formula:

N

― N

N- -0 0- ■ N

N or ~ ^ N ^ ""

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

4. R ⁸ has the formula:

(Wherein R ⁷ and Γ are as defined above), an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

5. The compound according to any one of claims 1 to 4, wherein R ¹ is a hydrogen atom, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

6. The compound according to any one of claims 1 to 5, wherein Μ 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 metallobutanidase 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 preventive 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.