WO1998033777A1

WO1998033777A1 - Compounds having metalloprotease inhibitory activity

Info

Publication number: WO1998033777A1
Application number: PCT/JP1998/000306
Authority: WO
Inventors: Hiroshige Tsuzuki; Sadao Miyazaki; Tsunetoshi Honma
Original assignee: Shionogi & Co., Ltd.
Priority date: 1997-01-31
Filing date: 1998-01-27
Publication date: 1998-08-06
Also published as: AU5577498A

Abstract

Compounds represented by general formula (I), pharmacologically acceptable salts thereof, or hydrates thereof, and a pharmaceutical composition and a metalloprotease inhibitor each containing the same as the active ingredient.

Description

Description Compound having meta-oral protease inhibitory activity

TECHNICAL FIELD The present invention relates to a compound having a protease inhibitory activity at the mouth and its use. Background art.

The extracellular matrix is composed of collagen, proteodalican, etc., and has a role of maintaining cell functions such as cell growth, differentiation, and adhesion, as well as a tissue support function. The degradation of extracellular matrix involves the protease, which contains a metal ion in the active center, and especially the matrix metaprotease (MMP). Matrix Messenger proteases are currently MMP-1 (type I collagenase; produced by osteoclasts, chondrocytes, tumor cells, fibroblasts, inflammatory cells, etc.), MMP-2, MMP-9 (type IV 18 types are known, including collagenase; produced by tumor cells, fibroblasts, vascular endothelial cells, blood cells, inflammatory cells, epithelial cells, etc.), MMP-3 (stromelysin), etc. In a strategic situation, it is operating due to growth and organizational reform. In various pathologies involving tissue destruction and fibrosis (osteoarthritis, rheumatoid arthritis, corneal ulcer, periodontal disease, metastasis of tumors, invasion, viral infections (eg, HIV infection), etc.) It has been suggested that progress is correlated with increased expression (activity) of the enzyme. At present, not all of the relationships between the above enzymes and disease states have been elucidated, but it is clear that these enzymes are involved in tissue destruction.

Conventionally, as the compound having the meta-oral protease inhibitory action, there are described a phosphoric acid derivative described in JP-A-1-160922 and a peptide derivative described in JP-A-1-16997. Dihydroxamic acid derivative, tribeptide derivative described in EP 12401_A, amide derivative described in JP-A-3-229454, tetracycline derivative described in JP-A 4-178359, JP-A 5-1 0-5693, natural products described in JP-A-5-501864, hydroxyquinoline derivatives described in JP-A-5-97674, hydroxyquinoline derivatives described in JP-A-5-97474, JP-A-8-921 The compound described in 93 is known.

Disclosure of the invention

In view of the above, the present inventors have conducted research to develop compounds having strong meta-oral protease inhibitory activity.

Means for Solving the Problems As a result of intensive studies, the present inventors have found a compound having a strong meta-oral protease inhibitory activity, particularly a strong MMP inhibitory activity.

That is, the present invention provides a compound represented by the following general formula (I):

(I)

[Wherein, X and Y are each independently an oxygen atom or a sulfur atom, Z is one N (R ^A )-(R ^A is a hydrogen atom or lower alkyl), and R ¹ is optionally substituted — Or an optionally substituted heteroaryl, R ² is the same or different and is a hydrogen atom, an optionally substituted lower alkyl, a compound represented by the formula (A):

R ^B 0

Su. Person R ³

(Wherein, R ³ represents alkyl or lower alkyloxy, R ^B represents a hydrogen atom or lower alkyl), a formula (B):

R ^B 0

J

To 0 (CH ₂ ) _M — R ⁴ (Wherein, R ⁴ is an optionally substituted amino, carbonyl, or alkyloxycarbonyl), m is an integer of 1 to 3, R ^B is as defined above, and a group represented by the formula (C):

(Wherein, R ⁵ is a hydrogen atom or Ashiru, n represents an integer of 0 to 3, p is 0 or 1, R ^B are as defined above. However When n = 0, a p = 0.) In A group represented by formula (D):

(Wherein, R ⁵ and R ^B are as defined above, and q is an integer of 1 to 3). The present invention relates to a pharmaceutical composition containing a compound represented by the formula (1) as an active ingredient, and more specifically to the following inventions a) to c).

a) The pharmaceutical composition as described above, which is a female protease inhibitor.

b) The pharmaceutical composition as described above, which is a type I collagenase inhibitor.

c) The pharmaceutical composition as described above, which is a therapeutic or prophylactic agent for rheumatoid arthritis.

Further, the compound of the present invention relates to a compound represented by the following 1) to 6).

1) General formula (I):

[Wherein, X and Y are each independently an oxygen atom or a sulfur atom, Ζ is one N (RA) — (RA is a hydrogen atom or lower alkyl), R ¹ is an optionally substituted aryl or Optionally substituted heteroaryl, wherein R ² is the same or different Elemental atom, optionally substituted lower alkyl, formula (A)

R ^B 0

, 0 with R ³

R ^B 0

J

Ό to (CH ₂ ) _m-

(Wherein, R ⁴ is an optionally substituted amino, carboxy, or alkyloxycarbonyl, m is an integer of 1-3, and RB is as defined above), and a formula (C):

(Wherein, R ⁵ is a hydrogen atom or Ashiru, n represents an integer of from 0 to 3, p is 0 or 1, R ^B are as defined above. However When n = 0, a p = 0.) In A group represented by formula (D):

(Wherein, R ⁵ and R ^B have the same meanings as described above, and q represents an integer of 1 to 3). Provided that R ¹ is not an unsubstituted phenyl, and when R ¹ is p_bromophenyl, R ² is not a hydrogen atom. ] Or a pharmacologically acceptable salt thereof, or a hydrate thereof.

2) General formula (II):

(Wherein, X, Y, Z, and R ² have the same meanings as described above, and R ⁶ and R ⁷ each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, or a substituted Represents amino, nitro, cyano, formyl, carbonyl, lower alkyloxy, lower alkyloxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R ⁶ and R ⁷ are not hydrogen atoms at the same time but R ⁶ and R ⁷ When either one is p-bromo and the other is a hydrogen atom, then R ² is not a hydrogen atom.) Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

3) General formula (I I I):

(In the formula, X, R, and R ² have the same meanings as described above, and R ⁸ and R ⁹ each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, an optionally substituted amino, Represents nitro, cyano, formyl, carboxy, lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R ⁸ is a promoter, R ⁹ is a hydrogen atom, and R ² is not a hydrogen atom And R ⁸ and R ⁹ are not both hydrogen atoms at the same time. Is a pharmacologically acceptable salt or hydrate thereof,

4) General formula (IV):

R 2

(Wherein, R ² has the same meaning as described above, and R ^{1 ()} represents a fluorine atom, a chlorine atom, an iodine atom, an optionally substituted lower alkyl, an optionally substituted amino, nitro, cyano, formyl, carboxy Or a lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio), or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

5) General formula (V):

[Wherein R ¹¹ is the same or differently substituted lower alkyl, and formula (A)

R ^B 0

% 0 'W

(Wherein, R ³ represents alkyl or lower alkyloxy, R ^B represents a hydrogen atom or lower alkyl), a formula (B): R ° O

To 0 (CH ₂ ) _m — R ⁴

(Wherein R ⁴ is an optionally substituted amino, carboxy, or alkyloxycarbonyl, m is an integer of 1-3, and R ^B is as defined above), a formula (C):

(Wherein, R ⁵ and R ^B are as defined above, and Q is an integer of 1 to 3). ] Or a pharmacologically acceptable salt thereof, or a hydrate thereof.

6) In the general formulas described in any of the above, R ² and R ¹¹ are not limited to the above definitions, and are compounds that are groups that are converted to hydrogen atoms in a living body, or pharmacologically acceptable thereof. Salts or hydrates thereof are useful as prodrugs.

Further, the present invention relates to the following A) to D).

A) A pharmaceutical composition comprising the compound according to any one of the above 1) to 6) as an active ingredient.

B) A meta-oral protease inhibitor comprising the compound according to any one of the above 1) to 6) as an active ingredient.

C) A type I composition containing the compound according to any one of 1) to 6) above as an active ingredient. Lagenase inhibitor-D) A therapeutic or prophylactic agent for rheumatoid arthritis, comprising the compound according to any one of the above 1) to 6) as an active ingredient.

The compounds of the present invention all have excellent meta-oral protease activity, and particularly preferred are compounds in which R ² and R ¹¹ are hydrogen atoms and prodrug derivatives which are converted to hydrogen atoms in vivo.

More preferably, in the formula (I), both R ² are a) a hydrogen atom, b) a group represented by the formula (A), c) a group represented by the formula (B), d) a formula (C) Group, e) a group represented by the formula (D), and when the substituent in R ^{1 Q} is f) halogen, g) cyano, h) trioctaalkyl, a compound represented by the following combination is preferable. New ^{^{(R 2, R 1 °)}} = (a, f) (a, g) (a, h) (b, f) (b, g) (b, h) (c, f) (c, g) ( c, h) (d, f) (d, g) (d, h) (e, f) (e, g) (e, h).

Also, R ^B is preferably a hydrogen atom.

In the present specification, “halogen” means fluorine, chlorine, bromine, and iodine. Of these, fluorine, chlorine and bromine are preferred.

As used herein, the term “alkyl” refers to a straight-chain or branched C-〇 ₂ . Means alkyl. For example, methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonanyl, n-decanyl, n-ndenyl, n —Dodeca: ±, n-tridecanyl, n-tetradecanyl, n-pendecanyl, n-hexadenicil, n-heptadecyl, n-octadecanyl, n-nonadenicil, n-icosanil, etc. No. Preferably, methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonanyl, n-decanyl, n-ndene Nil, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pendecanyl, n-hexadenicil, n-hepdecanyl You.

As used herein, “lower alkyl” refers to straight or branched C i Ce alkyl. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl and the like. Preferably, methyl, ethyl, n-propyl, i-propyl are used.

In the present specification, the “optionally substituted lower alkyl” for R ² includes: lower alkyloxy (eg, methyloxy, ethyloxy), hydroxy, mercapto, lower alkylthio (eg, methylthio), carboxy, lower alkyloxy. Carbonyl (methyloxycarbonyl), mono-lower alkyl-substituted amino (for example, N-methylamino), di-lower-alkyl-substituted amino (for example, N, N-dimethylamino), morpholino, halogen (for example, methyl, promo, trifluoro) , Trichloro mouth) and the like, which means the above-mentioned "lower alkyl". Lower alkyl, hydroxy lower alkyl, carboxy lower alkyl and alkyloxycarbonyl lower alkyl are preferred. Particularly, hydroxymethyl, 1-hydroxyl, and 1-hydroxypropyl are preferred.

In the present specification, the “optionally substituted lower alkyl” in R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹ Q includes lower alkyloxy (eg, methyloxy, ethyloxy), hydroxy, mercapto , Lower alkylthio (eg, methylthio), methoxyl, lower alkyloxycarbonyl (methyloxycarbonyl), mono-lower alkyl-substituted amino (eg, N-methyl'amino), di-lower alkyl-substituted amino (eg, N , N-dimethylamino), morpholino, halogen (eg, chloro, promo, trifluoro, trichloro), and the like, which means the above-mentioned "lower alkyl". Lower alkyl, halo lower alkyl and hydroxy lower alkyl are preferred. In particular, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, chloromethyl, chloroethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoro Romethyl, trifluoromethyl and hydroxymethyl are preferred. More preferably, trifluoromethyl is exemplified.

In the present specification, "aryl" means a monocyclic or condensed cyclic aromatic hydrocarbon. For example, phenyl, naphthyl and the like can be mentioned. Phenyl is preferred. As used herein, the term "heteroaryl" means a 5- to 6-membered aromatic ring arbitrarily selected containing one or more oxygen, sulfur, or nitrogen atoms in the ring, which is a carbon ring or a carbon ring. It may be condensed with another heterocycle, and these may be bonded at all substitutable positions. For example, pyrrolyl (eg, 1-pyrrolyl), indolyl (eg, 2-indolyl), carbazolyl (eg, 3-carbazolyl), imidazolyl (eg, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl), benzimidazolyl (Eg, 2-benzimidazolyl), indazolyl (eg, 3-indazolyl), indolizinyl (eg, 6-indolizinyl), pyridyl (eg, 4-pyridyl), quinolyl (eg, 5-quinolyl), isoquinolyl (eg, 3-isoquinolyl), acridyl (eg, 1-acrylidyl), phenanthridinyl (eg, 2-phenanthridinyl), pyridazinyl (eg, 3_pyridazinyl), pyrimidinyl (eg, 4-pyrimidinyl), birazini (For example, 2-pyrazinyl), cinnolinyl (for example, 3-cinolinyl), phthalazinyl (for example, 2-phthalazinyl), quinazolinyl (for example, 2-quinazolinyl), isoxazolyl (for example, 3-isoxazolyl), Benzoisoxazolyl (for example, 3-benzoisoxazolyl), oxazolyl (for example, 2-oxazolyl), benzoxazolyl (for example, 2-benzozoxazolyl), benzoxazodiazolyl (for example, 4-one) Benzoxaziazolyl), isothiazolyl (for example, 3-isothiazolyl), benzoisothiazolyl (for example, 3-benzoisothiazolyl), thiazolyl (for example, 2-thiazolyl), benzothiazolyl (for example, 2-benzothiazolyl) ), Frills (for example, 3-frills), Zofuriru (For example, benzo [b] furan - 3-I le), thienyl (such as 3-thienyl), Benzothenyl (for example, benzo [b] thiophene-2-yl), tetrazolyl and the like. Chenyl, pyridyl and frill are preferred. Particularly, 3-Chenyl and 4-Pyridyl are preferable.

In the present specification, “optionally substituted aryl” refers to hydroxy, lower alkyloxy (eg, methyloxy, ethyloxy), mercapto, lower alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclopropyl, Croptyl, cyclopentyl), halogen (eg, fluorine, chlorine, bromine, iodine), carboxy, lower alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxycarbonyl), nitro, cyano, aryloxy (eg, phenyloxy), Optionally substituted amino (eg, amino, methylamino, dimethylamino, acetylamino, benzylideneamino, acetylamino), guanidino, optionally substituted lower alkyl (eg, , Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, trifluoromethyl, Hydroxymethyl, chloromethyl), alkenyl (eg, vinyl, probenyl), alkynyl (eg, ethynyl, phenylethyl), alkanoyl (eg, formyl, acetyl, propionyl), and acyloxy (eg, acetyloxy) , Alkylsulfonyl (eg, methylsulfonyl), benzyl, azo group (eg, phenylazo), optionally substituted heteroaryl (eg, 3-pyridyl), optionally substituted ureide (eg, urey 1 or 2 or more It means “aryl”, which may be substituted. Among the substituents mentioned above, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, carboxy, lower alkyloxycarbonyl, nitro, cyano, optionally substituted amino, optionally substituted lower alkyl Alkanoyl is preferred. In particular, hydroxy, methyloxy, fluoro, black, promo, carboxy, methyloxycarbonyl, Cyano, amino, dimethylamino, acetylamino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl and trifluoromethyl are preferred. More preferred are hydroxy, alkyloxy, cyano, methyloxycarbonyl, and trifluoromethyl.

As used herein, “optionally substituted heteroaryl” refers to hydroxy, lower alkyloxy (eg, methyloxy, ethyloxy), mercapto, lower alkylthio (eg, methylthio), cycloalkyl (eg, cyclopropyl, cyclobutyl, etc.). , Cyclopentyl), halogen (eg, fluorine, chlorine, bromine, iodine), carboxy, lower alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxyl ponyl), nitro, cyano, aryloxy (eg, phenyloxy), substituted Optionally amino (eg, amino, methylamino, dimethylamino, getylamino, benzylideneamino, acetylamino), guanidino, optionally substituted lower alkyl For example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, trifluoro Methyl, hydroxymethyl, chloromethyl), alkenyl (for example, vinyl, probenyl), alkynyl (for example, ethynyl, phenyluethynyl), alkanoyl (for example, formyl, acetyl, propionyl), acylooxy (for example, acetyloxy), Alkylsulfonyl (eg, methylsulfonyl), benzyl, azo group (eg, phenylazo), optionally substituted heteroaryl (eg, 3_pyridyl), optionally substituted ureido (eg, ureido) , Phenylureido) etc. or 1 The above "heteroaryl" which may be substituted by 2 or more is meant. Among the substituents mentioned above, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, carboxyl, lower alkyloxycarbonyl, cyano, optionally substituted amino, Lower alkyl, which may be substituted, is preferred. In particular, hydroxy, methyloxyfluor, black mouth, bromo, propyloxy, methyloxycarbonyl, cyano, amino, dimethylamino, acetylamino, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, Preferred are sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, and trifluoromethyl.

As used herein, the term “lower alkyloxy” means a lower alkyloxy in which the alkyl moiety is a straight-chain or branched C ₆ alkyl. For example, methyloxy, ethyloxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, tert-butyloxy and the like can be mentioned. Methyloxy, ethyloxy and n-propyloxy are preferred. In the present specification, “alkyloxycarbonyl” means an alkyloxycarbonyl in which the alkyl portion is the above-mentioned “alkyl” having a straight or branched chain. For example, methyloxypropylonyl, ethyloxycarbonyl, n-propyloxypropylonyl, n-butyloxypropylonyl, n—pentyloxycarbonyl, n_hexyloxycarbonyl, n—heptyloxycarbonyl, n— Octyloxycarbonyl, n-nonanyoxycarbonyl, n-decanyloxycarbonyl, n-endyloxycarbonyl, n-dodecanyloxycarbonyl, n-tridecanyloxycarbonyl, n-tetradeca Niloxycarbonyl, n — pentadecanyloxycarbonyl, n _ hexadecanyloxycarbonyl, n — heptadecanyloxycarponyl, n — octadecanyloxycarponyl, n — nonadecanyoxy Carbonyl, n-icosanilooxycarbonyl and the like. Preferably, methyloxycarbonyl, ethyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, n-nonanyloxycarbonyl, n-decanyloxycarbonyl, n-ndenylinyl N-dodecanyloxycarbonyl, n-tridecanyloxycarbonyl, n-tetra Decanyloxycarbonyl, n-pentyl decanyloxycarbonyl, n-hexa-decanyloxycarbonyl, and n-heptadecanyloxycarbonyl. Preferably, methyloxycarbonyl, ethyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, n-nonanyloxycarbonyl, n-decanyloxycarbonyl, n-ndeca Niloxycarbonyl, n — dodecanyloxycarbonyl, n — tridecanyloxycarbonyl, n-tetradecanioxycarbonyl, n-pentadecanyloxycarbonyl, n-hexadecanyloxycarbonyl, n —Heptane decanyloxycarbonyl, n-octane decanyloxycarbonyl, n—nonadecanyloxycarbonyl, n—icosanyloxycarbonyl and the like. Preferably, methyloxycarbonyl, ethyloxycarbonyl, η-heptyloxycarbonyl, η-octyloxycarbonyl, η-nonanyloxycarbonyl, η-decanyloxycarbonyl, η-indenyloxycarbonyloxy, η-dodecanyloxycarbonyl, η-tridecanyloxycarbonyl, η-tetradecanyloxycarbonyl, η-pentyl decanyloxycarbonyl, η-hexadecanyloxycarbonyl, η-heppu Decanyloxycarponyl

In the present specification, “lower alkyloxycarbonyl” means an alkyloxycarbonyl in which the alkyl moiety is the above “lower alkyl”. For example, methyloxycarbonyl, ethyloxycarbonyl, η-propyloxycarbonyl, i-propyloxycarbonyl, n_butyloxycarbonyl and the like can be mentioned. Methyloxycarbonyl and ethyloxycarbonyl are preferred.

In the present specification, “acyl” means an alkylcarbonyl in which the alkyl portion is the above “alkyl”. For example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl, n-nonanylcarbonyl, n-deca Nilcarponyl, n — ndecanylcarbonyl, n — Dodecylcarbonyl, n — tridecanylcarbonyl, n-tetradecanylcarbonyl, n —pendecanylcarbonyl, n —hexadecanylcarbonyl, n-heptadecanylcarbonyl, n —octadecanyl Carbonyl, n-nonadenylcarbonyl, n-icosanylcarbonyl and the like. Preferably, methyl carbonyl, ethyl carbyl, n-heptyl carbonyl, n-octyl carbonyl, n-nonanyl carbonyl, n-decanyl carbonyl, n-ndyl carbonyl, n-dodecanyl carbonyl, n-toridecan Nylcarbonyl, n-tetradecalcarbonyl, n-pentadecanylcarbonyl, n-hexadelicylcarbonyl, and n-hepdecanecarbonyl.

As used herein, the term "lower alkylthio", the alkyl moiety means a lower alkylthio is linear or branched C i to C ₆ alkyl. For example, methylthio, ethylthio and the like can be mentioned.

In the present specification, the “optionally substituted amino” refers to an amino in which a nitrogen atom may be substituted by one or two of the above “lower alkyl” or lower alkanol, that is, unsubstituted amino, monosubstituted Means amino or disubstituted amino. For example, methylamino, dimethylamino, ethylamino, getylamino, methylethylamino, propylamino, N-methylpropylamino, ethylpropylamino, dipropylamino, dibutylamino, acetylamino and the like can be mentioned. Particularly, amino, methylamino, dimethylamino, and acetylamino are preferable. BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention can be synthesized, for example, by the method shown by the following formula. However, these are merely examples of the method for producing the compound represented by the general formula (I), and compounds produced by other methods are also included in the scope of the present invention.

0, ノノ. ⁰ ,? ¹ ί, ο

_Η Η π - ^ - j-

R- ^N _Y ^N _L ² ΗΟ ^ Ν 丫_{γ γ} Ν_ΟΗ

Ο R ^A R ^A Ο Ο R ^A R ^A O

(XI) (X)

(Wherein, R ¹ and R ^A are as defined above)

This production method is a general method for synthesizing a dimer of a 2,4-imidazolidinedione derivative. That is, as a starting material, a benzaldehyde derivative represented by the general formula (VI) (otherwise, 3-thiophencarbaldehyde, 4-pyridinecarbaldehyde, etc.) or an amino acid derivative represented by the general formula (VII) is used. This is a method for producing the desired compounds represented by the general formulas (IX), (X) and (XI). In the first step, a benzaldehyde derivative (VI) is used as a starting material, and in the first step, an amino acid derivative is used as a starting material, and the step is performed to convert to a 2,4_imidazolidinedione derivative represented by the general formula (VIII). (Advances in Heterocyclic chemistry, 38, 177-228, 1985, HT Bucherer, HT Fishbeck, J. Pract. Chem., 140, 69, 1934, HT Bucherer, W. Steiner, J. Praact. Chem., 140 , 291, 1934, New Experimental Chemistry, Vol. 14, Method of Organic Compound Reaction (III), 1647, etc.). The second step is a step of converting the compound represented by the general formula (VIII) into a dimer represented by the general formula (IX). In the third step, the 3-position nitrogen atom is In this step, the compound is converted into a compound represented by the general formula (X) by chilling (an alkylation or the like can be similarly performed). The fourth step is a step in which various side chains are further introduced by using hydroxymethyl at the 3-position as a foothold, thereby leading to a target compound represented by the general formula (XI). However, if the starting compound has a substituent that hinders the reaction in each step, the starting compound should be protected in advance by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. To remove the protecting group. The details of each step are as follows.

1st step

This step is performed using a Bucherer-Bergs reaction. The benzaldehyde derivative represented by the general formula (VI), which is a starting material, is dissolved in an alcohol solvent such as ethanol and propanol. To this solution is added an aqueous solution of a cyanating agent such as sodium cyanide and cyanogen amide at room temperature under ice-cooling to room temperature, and the mixture is stirred for 3 to 30 minutes, preferably 5 to 10 minutes. Further, an aqueous solution of ammonium carbonate is added, and after 10 to 40 minutes, preferably 20 to 30 minutes, the reaction temperature is raised to 50 to 80 ° (preferably 60 to 70 ° C). After cooling, the insoluble portion is removed by filtration, and an acid such as concentrated hydrochloric acid is added to the filtrate so that the pH becomes about 2 to 3. The mixture is stirred at 90 to 120, preferably at 95 to 110 ° C., for 15 minutes to 1 hour, preferably 30 minutes to 1 hour. It can be converted to a 2,4-imidazolidinedione derivative represented by the general formula (VIII).

1st process

This step can be performed by using a modification of the first step. An aqueous solution of a cyanating agent such as sodium cyanate and potassium cyanate is added to an aqueous solution of the amino acid derivative represented by the general formula (VII), which is a starting material, at 90 to 100 ° C, preferably 94 to 100 ° C. Stir at 98 ° C for 1-3 hours, preferably 1.5-2 hours. reaction After adding an acid such as concentrated hydrochloric acid to the liquid under ice cooling, the mixture is stirred at 90 to 100 ° C, preferably 94 to 98 ° C for 1 to 3 hours, preferably 1.5 to 2 hours. I do. By performing ordinary post-treatment, it can be converted to the desired 2,4-imidazolidinedione derivative represented by the general formula (VIII).

Second step

In this step, the 2,4-imidazolidinedione derivative (VIII) obtained in the previous step is converted to a dimer. For example, it can be produced by the following two methods, Method a and Method b (Kenneth H. Dudley and Daniel L. Bius., The Journal of Organic Chemistry, 34, (4), 1133-1136 (1969) ), Karl E. Schulte, Volker von Weissenborn and Soon K. Kwon., Arch. Pharm., 309, 1066-1019 (1976)).

(Method a)

The compound represented by the general formula (VIII) obtained in the first step is suspended in water, and dissolved by adding an aqueous sodium hydroxide solution (preferably 1 to 2N). After stirring for 3 to 10 hours, preferably 5 to 8 hours while passing air under ice-cooling to 50 ° C, preferably 15 to 30 ° C, 3 to 20 hours, preferably 8 to 10 hours Leave for 15 hours. By performing ordinary post-treatment, a dimer represented by the general formula (IX) can be obtained.

(Method b)

Glacial acetic acid is added to the compound represented by the general formula (VIII) obtained in the first step, and the mixture is dissolved by heating to 80 to 110 ° C, preferably 90 to 100 ° C. A solution of bromine in glacial acetic acid is added and the mixture is stirred with 80-: L10 :, preferably SOIOOO, for 30 minutes to 3 hours, preferably 1-2 hours. By performing ordinary post-treatment, a dimer represented by the general formula (IX) can be obtained.

In addition, as a method of performing the second step continuously from the first step, after filtering off the insoluble portion in the first step, the filtrate is cooled with ice to 50 t: preferably 15 to 30 ° C. Through the air While stirring for 3 to 10 hours, preferably for 5 to 8 hours, and after leaving for 3 to 20 hours, preferably for 8 to 15 hours, the pH of the reaction solution is adjusted to 3 to 3 by adding an acid such as concentrated hydrochloric acid. 4, and normal post-processing can be performed.

3rd step

In this step, the dimer represented by the general formula (IX) is converted into an N-hydroxymethyl derivative. The reaction can be carried out under the conditions of N-hydroxymethylation which is usually carried out, for example, by the following method (SA Varia, S. Schuller, KB Sloan, and VJ Stella, Journal of Pharmaceutical Sciences, 78, (8), 1068-1073 (1984))

An aqueous formalin solution and a base such as potassium carbonate or sodium carbonate (or an aqueous solution thereof) are added to the compound represented by the general formula (IX) obtained in the second step to form a suspension, which is then cooled to −60 ° C under ice-cooling. Stir at preferably 20 to 40 ° C for 5 to 50 hours, preferably 10 to 30 hours. After usual post-treatment, the compound can be converted into the desired compound represented by the general formula (X).

Also for the introduction of certain R ² side chain in a solvent such as dimethyl formamidine de, potassium carbonate, base is added such as sodium carbonate, a halide such substituents to be introduced to react under the same conditions as above Can be performed.

4th step

Esterification reaction of the compound represented by the general formula (X) obtained in the third step (a method using a dehydrating condensing agent such as N, N-dicyclohexylcarpoimide (DCC), an azide method) , An acid chloride method, an acid anhydride method, an active ester method, etc.) to obtain a compound represented by the general formula (II) having a side chain R ² . Here, by using the esterification method described in the example, a compound having a target side chain R ² can be obtained in this step (Jounal of Pharmaceutical Sciences Vol. 72, No. 4, 1983, 400-405). , Jounal of Pharmaceutical Sciences Vol. 73, No. 8, 1984, 1068-1073, Jounal of Pharmaceutical Sciences Vol. 84, No. 3, J. Pharm. Pharmacol. 47, 1995, 197-203, 1995, 300-302, Arch. Pharm. (Weinheim) 326, 1993, 477-481), and a method using DCC as a condensing agent will be described below. The compound represented by the general formula (X) is dissolved in a solvent such as dichloromethane, tetrahydrofuran or toluene, and a base such as 4-dimethylaminopyridine, triethylamine or pyridine is added. By adding DCC at a temperature of 20 to 90 ° C, preferably 0 to 50 ° C, stirring for 1 to 40 hours, preferably 5 to 30 hours, and performing a usual post-treatment, The desired compound represented by the general formula (XI) can be obtained. Further, a base such as pyridine can also be used as the solvent.

The term "the compound of the present invention" also includes pharmacologically acceptable salts or hydrates 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.). 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, racemates, and meso isomers. Particularly, a meso form is preferable.

The compound of the present invention exhibits excellent meta-oral protease inhibitory activity, especially MMP inhibitory activity, and inhibits matrix degradation, as described in Experimental Examples described later. Therefore, the compound of the present invention is effective for diseases caused by MMP and its related enzyme, TNF-a convertase.

Specifically, osteoarthritis, rheumatoid arthritis, corneal ulcers, periodontal disease, tumor metastasis or invasion, progression of viral infections (eg, HIV infection), atherosclerosis obliterans, atherosclerosis Aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, abnormal angiogenesis, scleritis, multiple sclerosis, open-angle glaucoma, retinopathy, proliferative network Membranosis, neovascular glaucoma, pterygium, keratitis, bullous epidermis, psoriasis, diabetes, nephritis, neurological disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumors, hemangiofibromas, hemangiomas, It can be used as a prophylactic or therapeutic agent for fever, bleeding, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn's disease, meningitis, and gastrointestinal ulcer.

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

Dosage will also vary depending on the condition of the disease, the route of administration, the age or weight of the patient, and will ultimately be at the discretion of a physician, but for oral administration to adults, 0.1 to 100 mgZkg Daily, preferably 1 to 20 mgZkgZ days, when administered parenterally, usually 0.01 to; L 0 mgZkgZ days, preferably 0.1 to 1 mgZkg / day. This may be administered once or in several divided doses.

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

Example

Example 1 '

(XI-2)

1st step

Synthesis of 5- (4-chlorophenyl) -imidazolidine-2,4-dione (VIII-1)

P—Black mouth Benzaldehyde (VI-1) (21.05 g, 0.15 mo1) Stir the ethanol (3 15 ml) solution and add sodium cyanide (14.7 g, 0

A 3mo1) aqueous solution (157ml) was added. Five minutes later, an aqueous solution of ammonium carbonate (57.65 g, 0.6 mol) (158 ml) was added, and after another 20 minutes, the temperature was raised to 60 ° C, followed by stirring for 4 hours. After removing the insoluble portion by filtration, the filtrate was acidified (pH 2-3) with concentrated hydrochloric acid, and heated and stirred at 97 ° C for 30 minutes. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude crystals obtained by collecting the precipitated crystals by filtration were dissolved in methanol (200 ml), treated with activated carbon (6 g), recrystallized, and then recrystallized to obtain the compound (VIII-1) (18.47 g,

5 8%).

Melting point: 190-191 ° C

IR (Nujol): 3298, 3180, 3030, 1770, 1724, 1597 cm— ¹

NMR (de-DMSO) (ppm): 5.21 (s, IH), 7.36 and 7.48 (each d, J = 8.2 Hz, each 2H), 8.43 (s, IH), 10.84 (s, IH).

1st process

Synthesis of 5- (4-chlorophenyl) -imidazolidin-1,2,4-dione (VI I 1-1)

To an aqueous solution (9 ml) of DL-2-(4-chlorophenyl) glycine (VII-1) (928 mg, 5 mmo1) was added potassium cyanate (1.22 g, 15 mmo1). ) And stirred at 95-97 ° C. for 1.5 hours. Concentrated hydrochloric acid (4.75 ml) was added to the reaction mixture under ice-cooling, and the mixture was stirred at 97 ° C for 2 hours. After cooling with ice, the precipitated crystals were collected by filtration, washed with water, and dried to obtain a compound (VIII-1) (86 Omg, 82%). Melting point: 19 1 ~ 192 ° C

IR (Nujol): 3298, 3180 , 3030, 1770, 1724, 1597 cm one ¹

_{NMR (d 6 -DMSO) (ppm} ): 5.21 (s, IH), 7.36 and 7.48 (each d, J = 8.2 Hz, each 2H), 8.43 (s, IH), 10.84 (s, IH).

Second step

4,4'-bis- (4-chlorophenyl) — [4,4 '] biimidazolidinyl Synthesis of 2,2 ', 5,5'-tetraone (IX-1)-Add glacial acetic acid (51 ml) to compound (VIII-1) (12.64 g, 60 mmo1), and add 90 ° C To dissolve. A glacial acetic acid solution of bromine (3.78 mmol / m 1) (7.94 ml, 30 mmol) was added, and the mixture was stirred at 97 ° C for 1 hour. The reaction solution was cooled, and the precipitated crystals were collected by filtration. After washing with glacial acetic acid, water and methanol in that order, and drying, compound (IX-1) (12.08 g, 96%) was obtained.

Melting point:> 300 ° C

IR (Nujol): 3292, 3212, 3330, 1787, 1768, 1697 cm- ¹

NMR (d ₆ -DMSO) (ppm): 7.41 (s, 8H), 9.14 (s, 2H), 11.03 (s, 2H).

It can also be performed as a continuous step from the first step.

Sodium cyanide (11.76 g, 0.24 mo 1) while stirring a solution of p-clonal benzaldehyde (VI-1) (16.87 g, 0.12 mol) in ethanol (240 ml) at room temperature An aqueous solution (120 ml) was added. Five minutes later, an aqueous solution of ammonium carbonate (28.83 g, 0.30 mO 1) (120 ml) was added, and after another 20 minutes, the temperature was raised to 60 ° C and the mixture was stirred for 4 hours. Thereafter, the insoluble portion was removed by filtration, and the filtrate was allowed to stand overnight at room temperature with stirring and air for 4.5 hours. While stirring the reaction mixture under ice cooling, concentrated hydrochloric acid was added to make the mixture acidic (pH 3 to 4), and the precipitated crystals were collected by filtration. Washing was sequentially performed with 50% ethanol and water, and after drying, crude crystals (9.84 g) were obtained. Methanol (200 ml, twice 540 ml) was added to the crude crystals, and the mixture was stirred and refluxed to remove impurities soluble in methanol, thereby obtaining the compound (IX-1) (8.09 g). Recrystallization from aqueous dimethyl sulfoxide gave compound (IX-1) (7.44 g, 29.6%).

3rd step

4,4'-Bis- (4-chlorophenyl)-1,1'-bis-hydroxymethyl- [4,4 '] biimidazolidinyl-2,2', 5,5'-tetraone (X-1) Synthesis of Compound (IX—1) (6.09 g, 14.5 3 mmo 1) with 37% formalin (3-2.5 ml, 0.4 mo 1) and potassium carbonate (35 1 mg, 2.5 4 mmo 1) An aqueous solution (252 ml) was added to form a suspension mixture, and the mixture was stirred at room temperature for 40 hours. The precipitated crystals were collected by filtration, washed with 3% formalin, and dried to obtain compound (X-1) (6.69 g, 96%).

Melting point:> 300 ° C

IR (Nujol): 3424, 3300, 1703, 1771, 1595 cm- ¹

NMR (de-DMSO) (ppm): 4.50-4.80 (m, 4H), 7.40 (s, 8H), 9.54 (s, 2H).

Step 4 Step A

Dimethylaminoacetic acid [4,4'-bis- (4-chlorophenyl) 1-1'-dimethylaminoacetoxymethyl-1,2,2 ', 5,5'-tetraoxo [4,4'] biimidazolidinyl-1-1 Synthesis of [Methylmethyl] Ester (XI-1)

Compound (X-1) (4.79 g, 1 Ommo 1) in dry pyridine (144 ml) solution, N, N-dimethyldaricin hydrochloride (4.19 g, 30 mmo 1), dicyclohexyl Carpomidide (DCC) (6.19 g, 30 mmo 1) was added, and the mixture was stirred at room temperature for 25 hours. The precipitated crystals were collected by filtration, and the obtained crystals were washed with ethyl acetate and dried to obtain a mixed crystal (14.5 g).

Then, water (160 ml) was added to make a suspension, and under ice-cooling, 1 N hydrochloric acid (40 ml, 4 Ommo 1) was added, and the mixture was stirred and the insoluble portion was removed by filtration. The filtrate was treated with activated carbon and distilled off under reduced pressure to obtain a crude hydrochloride of the compound (XI-1). This was treated with sodium hydrogen carbonate to obtain compound (XI-1) (4.74 g, 73%).

To the compound (XI — 1) (7.0 6 g, 10.87 mmo 1) was added water (212 ml), and under ice-cooling, 1N-hydrochloric acid (21 ml, 21 mm 01) was added, followed by room temperature For 1 hour to dissolve. This solution was treated with activated carbon (2.0 g), concentrated under reduced pressure, and lyophilized to obtain the hydrochloride of compound (XI-1) (7.37 g, 94%). IR (KBr): 3422, 3097, 2982, 2797, 2681, 2462, 1766, 1728, 1636, 1595 cm- ¹ -NMR (de-DMSO) (ppm): 2.78-2.88 (m, 12H), 4.17 (s , 4H), 5.43 and 5.52 (each d, J = 10.8 Hz, each 2H), 7.35-7.46 (each d, J = 9 Hz, each 4H), 9.99 (s, 2H).

Step 4 B

Mono succinate [1 '-(3-carboxypropionyloxymethyl)-4,4'-bis-(4-chloro-phenyl)-1, 2 ', 5, 5'-tetraoxo [4, 4 '] Synthesis of imidazolidinyl-1-ylmethyl] ester (XI-1) In a nitrogen gas stream, a solution of compound (X-1) (4.65 g, 9.7 mmo1) in dry pyridine (46.5 ml) was added with anhydrous succinate. Acid (5.824 g, 58.2 mmo1) was added and left for 2 days. A cold 2% aqueous solution of sodium carbonate (500 ml) was stirred and a pale yellow reaction solution was injected. After washing three times with chloroform (200 ml), the aqueous layer (alkali layer) was made acidic (pH 2-3) by adding concentrated hydrochloric acid under ice-cooling. The precipitated crystals were collected by filtration to give crude crystals (6.30 g). This was washed by heating with methanol (63 ml) to remove methanol-soluble impurities to obtain compound (XI-1) (5.98 g, 90%).

Melting point: 242-244 ° C (decomposition)

IR (Nojol): 3152, 3064 , 2718, 2614, 1781, 1743, 1717, 1685, 1592 cm- 1 NMR (d 6 -DMSO) (ppm): 2.44 (s, 8H), 5.19 and 5,30 (each d, J = 15.6 Hz, each 2H), 7.47 (m, 8H).

<Preparation of Compound (XI-1) Sodium Salt> '

To a compound (XI-1) (6.57 g, 9.67 mmo1), add water (131 ml), and under ice-cooling, add 1 N sodium hydroxide (18.4 ml, 18.4 mmo1). Was added dropwise, and the mixture was stirred at room temperature for 1 hour. The insoluble portion was removed by filtration, and the filtrate was concentrated under reduced pressure and freeze-dried to obtain a sodium salt of compound (XI-1).

IR (KBr): 3112, 3076, 3028, 3011, 2952, 2901, 2848, 1929, 1799, 1714, 1606, lo65 cm— ¹ _{NMR (D 2 0) (ppm} ): 2.44-2.52 (m, 8H), 5.17 and 5.36 (each d, J = 10.8 Hz, each 2H) ^ 7.53 and 7.71 (each d, J = 8.7 Hz, each 4H) .

Example 2

Synthesis of 4,4'-bis- (4-chlorophenyl) 1-1,1'-dimethyl- [4,4 '] biimidazolidinyl_2,2', 5,5'-tetraone (IX-2) Compound (IX-1) (4 19 mg, 1 mmo 1) was suspended in methanol (3 ml), and sodium methyloxide / methanol solution (2.3 m 1, 2.3 mm o 1) Methyl (1.08 g, 7.63 mmo 1) was added, and the mixture was stirred at room temperature for 3 hours. Water (12 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration to obtain a mixed crystal of the compound (IX-1) and the compound (IX-2). To this, IN-sodium hydroxide (2 ml) was added and stirred to obtain a sodium hydroxide-insoluble compound (IX-2) (114 mg, 26%).

Melting point: 272-275 ° C (decomposition)

IR (Nojol): 3308, 1773, 1697, 1598 cm— ¹

NMR (de-DMSO) (ppm): 2.74 (s, 6H), 7.40 (s, 8H), 9.52 (s, 2H).

Example 3

[4,4'-bis- (4-chlorophenyl) 1-1,1'-methyloxycarbonylmethyl-2,2 ', 5,5'-tetraoxo [4,4'] biimidazolidinyl — 1 — Synthesis of methyl monoacetate (IX-3)

To a suspension of the compound (IX-1) (4 19 mg, 1 mmo 1) in anhydrous dimethylformamide (13 ml) was added potassium carbonate (414 mg, 3 mmo 1), methyl bromoacetate ( 459 mg, 3 mmo 1) was added, and the mixture was stirred at room temperature for 22 hours. The organic matter was removed by filtration, evaporated under reduced pressure, and recrystallized from chloroform-methanol.

(IX-3) (120 mg, 21%) was obtained.

Melting point: 247-248 ° C

IR (Nujol): 3356, 1784, 1755, 1703 cm— ¹ NMR (d _e -DMSO) (ppm): 3.57 (s, 6H), 4.12 (s, 4H), 7.35-7.45 (m, 8H), 9.71 (s, 2H), compound (IX—4 ) ~ Compound (IX-24) was synthesized. Tables 1 to 3 show the results. In addition, the compounds (IX-25) to compounds (IX-196) shown in Tables 3 to 8 can be synthesized by using the same method.

6Z

/ 86dT / X3d οε

90 £ 00 / 86df / X3d LLL ££ IS6 OAV ιε

90 £ 00 / 86dT / I3J

Table 5

Table 6

CO

Example 19 7, 1 98

Synthesis of 4,4'-dithiophene-3-yl- [4,4 '] piimidazolidinyl-1,2,5,2', 5'-tetraone (XI-1)

Using 3-thiophenecarbaldehyde as a starting material, a compound (XII-1) was synthesized in the same manner as in the above example. Table 4 shows the physical constants.

Compound (XI 1-2) was synthesized in the same manner. Table 4 shows the results. In addition, by using the same method, compounds (XI1-3) to compound (XI1-6) can be synthesized.

88

6 Halla £ 00 / 86dT / X3J LLL £ £ IS6 O. Test examples of the compound of the present invention are shown below. The test compounds correspond to those used in the examples and tables. Test example 1

Type I collagenase inhibitor atsey method

Type I collagenase (MMP-1) was purchased and used from Kagai Co., Ltd. (8, Tomijindai, Yamagata Prefecture). The activity of type I collagenase (MMP-1) against type I collagen, which is a natural substrate, was measured using type I collagenase atskit, sold by Yagai Co., Ltd. (8 Tomijindai, Yamagata City, Yamagata Prefecture). .

The effect of type I collagenase (MMP-1) on synthetic substrates was measured by the method of Harold Weingarten et al. (Analytical Biochemistry, 147, 437-440 (1985)). That is, HS-Leu produced by the action of type I collagenase (MMP-1) using Ac-Pro-Leu-Gly- (2-mercapto-4-methyl-pentanoyl) -Leu-Gly-OEt as a substrate -Leu-Gly-OEt was labeled with ABD-F (7-Fluoro-4-sulfanyl-2, l, 3-benzoxadiazole) and the fluorescence intensity was measured. Assays for inhibitors perform the following four assays for one compound (inhibitor).

(A) substrate (type I collagen or synthetic substrate), enzyme (type I collagenase (MM P-1)), inhibitor

(B) Substrate (type I collagen or synthetic substrate) ', inhibitor

(C) Substrate (type I collagen or synthetic substrate), enzyme (type I collagenase (MMP-1))

(D) Substrate (type I collagen or synthetic substrate)

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

Inhibition (%) = {1-(A- B) / (C-D)} X 100

I. Indicates the concentration of the inhibitor at which the inhibition (%) becomes 50%. Inhibition activity was measured As a result, the same tendency was observed when the substrate was measured using either type I collagen or a synthetic substrate. Table 5 shows the results of inhibition using synthetic substrates. Table 5

Test example 2

(1) Isolation and purification of MMP-9 (92 kDa Gelatinase B)

With reference to the following literature, type IV collagenase (MMP-9) was purified.

a) Scott M. Wilhelm et al, J. Biol. Chem., 264, 17213-17221, (1989) SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages ( Human lung fibroblasts transformed with SV40 secrete the same 92-kDa type IV collagenase as secreted by normal human macrophages.)

b) Yasunori Okada et al, J. Biol. Chem., 267, 21712-21719, (1992) Matrix Metalloproteinase 9 (92-kDa Gelatinase / TypelV Collagenase) from HT 1080 Human Fibrosarcoma Cells (human fibroblast of HT 1080 strain) Matrix meta-oral protease 9 from sarcoma cells (92k-Da gelatinase / type IV collagenase)) c) Robin V. Ward et al'Biochem. J., (1991) 278, 179-187 The purification of tissue inhibitor of metalloproteinase-2 from its 72kDa progelatinase complex Made)

MMP_9 is secreted into the culture medium by stimulating human fibroblast sarcoma ATCCHT180 strain with 12-tetradecanoylphorpol-13-acetate (TPA). MMP was prepared by gelatin-zymography (HidekazuTanaka et al, (1993) Biochem. Biophys. Res. Commun., 190, 732-740, molecular cloning and expression of mouse 105-kDa gelatinase cDNA). — 9 was produced. The culture supernatant of the HT180 strain was concentrated and purified with Gelatin Sepharose 4B, Concanavalin A Sepharose and Cefacryl S-200. This purified pro-MMP-9 (92 kDa, gelatinase B) showed a single active band by gelatin zymography. Then, activation with trypsin was performed to obtain activated MMP-9.

(2) IV type collagenase inhibitor

Collagenase uses the above-mentioned MMP-9, the substrate and the measurement kit use the type IV collagenase activity measurement kit of Yagai Co., Ltd. (Yamagata 8 Tomijindai, Yamagata Prefecture). Yagai Co., Ltd. (Yamagata 巿 8, Fujindai, Yamagata Prefecture). The following four assays are performed for one compound (inhibitor).

(E) Substrate (type IV collagen), enzyme (MMP-9), inhibitor

(F) Substrate (type IV collagen), inhibitor

(G) Substrate (type IV collagen), enzyme (MMP-9)

(H) Substrate (type IV collagen) ·

In each case, the fluorescence intensity was measured in accordance with the Atsusei method of Kagay Co., Ltd. (Yamagata, No. 8 Tomijindai, Yamagata Prefecture), and the inhibition (%) was determined by the following equation.

Inhibition (%) = {1-(E-F) / (G-H)} X 100

IC _5. Indicates the concentration of the inhibitor at which the inhibition (%) becomes 50%.

As a result, IC _{5 of} compound (IX-1) against MMP-9. Is 0.2 M and 1 B As described above, the compounds of the present invention exhibited strong MMP inhibitory activity, formulation examples

Formulation Example 1

A granule containing the following ingredients is produced.

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

Lactose 700 mg

Corn starch 274 mg

HPC-L 16 mg

1000 mg

The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed with a V-type mixer. An aqueous solution of HP C-L (low viscosity hydroxypropyl cell mouth) is added to the mixed powder, kneaded, granulated (extrusion granulated with a pore size of 0.5 to 1 mm), and dried. The obtained dried granules are combed through a vibrating sieve (12 to 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

Cornstarch10 mg

Magnesium stearate 1 mg

100 mg

The lactose 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 the No. 5 hard gelatin capsules with 10 times powder. Formulation Example 3

Manufacture granules for capsule filling containing the following ingredients

Ingredient 15 mg of the compound represented by the formula (I)

Lactose 90 mg

Corn starch 42 mg

HPC-L 3 mg

150 mg

Pass lactose, a compound represented by formula (I), through a 60-mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and an HP C-L solution is added to the mixed powder, followed by kneading, granulation, and drying. After sizing the obtained dried granules, 150 mg of the dried granules is filled into a No. 4 hard gelatin capsule.

Formulation Example 4

A tablet is prepared containing the following ingredients:

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

Lactose 90 mg

Microcrystalline cellulose 30 mg

CMC-Na 15 mg

Magnesium stearate 5 mg

150 mg

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 hit directly to obtain 15 Omg tablets. Industrial applicability

The compound of the present invention has excellent meta-oral protease inhibitory activity, especially MMP inhibitory activity Inhibits matrix degradation. Therefore, the compound of the present invention is effective for diseases caused by MMP and its related enzyme TNF-α convertase and the like.

Claims

The scope of the claims

1. General formula (I):

Wherein, X and Y are each independently oxygen atom or a sulfur atom, Z is one N (RA) - (R ^A is a hydrogen atom or a lower alkyl), R ¹ good § Li Lumpur substituted Or an optionally substituted heteroaryl, R ² is the same or different and is a hydrogen atom, an optionally substituted lower alkyl, a formula (A):

R ^B O

, 0 with R ³

(Wherein, R ⁴ is an optionally substituted amino, carbonyl, or alkyloxycarbonyl, m is an integer of 1 to 3, R ^B is as defined above), a formula (C):

(Wherein, R ⁵ and R ^B have the same meanings as described above, and q represents an integer of 1 to 3). ] The pharmaceutical composition containing the compound represented by these as an active ingredient.

2. The pharmaceutical composition according to claim 1, which is a meta-oral protease inhibitor.

3. The pharmaceutical composition according to claim 1, which is a type I collagenase inhibitor.

4. The pharmaceutical composition according to claim 1, which is an agent for treating or preventing rheumatoid arthritis.

5. General formula (I):

XR ¹ R ¹ X

R 2-1 NN, _R 2 (I)

丫 Y 'Ύ

Y

R ^B 0

H * ((CCHH ² )) _mm —— f FT

(Wherein, R ⁴ is an optionally substituted amino, carboxy, or alkyloxycarbonyl, m is an integer of 1 to 3, and R ^B is as defined above), a formula (C):

Shown (wherein, R ⁵ and R ^B are as defined above, q is an integer of 1 to 3) a group represented by the. However, R ¹ is not an unsubstituted phenyl, and when R ¹ is p-bromophenyl, R ² is not a hydrogen atom. ] Or a pharmacologically acceptable salt thereof, or a hydrate thereof.

6. General formula (II):

r

(Wherein, X, Y, Ζ, and R ² have the same meanings as described above, and R ⁶ and R ⁷ each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, or an optionally substituted Amino, nitro, cyano, formyl, carboxy, lower alkyloxy, represents luponyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R ⁶ and R ⁷ are not both hydrogen atoms and either R ⁶ or R ⁷ When one is p-promo and the other is a hydrogen atom, R ² is not a hydrogen atom.) Or a pharmacologically acceptable salt thereof, or a water thereof. Japanese food.

7. General formula (I I I):

(In the formula, X, R, and R ² have the same meanings as described above, and R ⁸ and R ⁹ each independently represent a hydrogen atom, an optionally substituted lower alkyl, a halogen, an optionally substituted amino, Represents nitro, cyano, formyl, carboxy, lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio, provided that R ⁸ is bromo, R ⁹ is hydrogen, and R ² is not hydrogen And R ⁸ and R ⁹ are not hydrogen atoms at the same time.) Or a pharmacologically acceptable salt thereof, or a hydrate thereof.

8. General formula (IV):

R

(Wherein, R ² is as defined above, R ^{1 Q} is a fluorine atom, a chlorine atom, an iodine atom, an optionally substituted lower alkyl, an optionally substituted amino, nitro, cyano, formyl, carboxy, A lower alkyloxycarbonyl, hydroxy, lower alkyloxy, mercapto, or lower alkylthio) compound; Or a pharmacologically acceptable salt thereof, or a hydrate thereof,

9. General formula (V):

R ^c 0

0 with R ³

R ^B 0

J

◦ ', (CH ₂ ) _m — R ⁴

(Wherein R ⁴ is an optionally substituted amino, carboxy, or alkyloxycarbonyl, m is an integer of 13 and R ^B is as defined above), a formula (C):

(Wherein, R ⁵ is a hydrogen atom or Ashiru, n represents an integer of from 0 to 3, p is 0 or 1 R ^B are as defined above. However, when n = 0, p = 0.) Represented by Group, or formula (D):

10. A compound according to any one of claims 5 to 9, wherein R ² and R ¹¹ are groups that are converted to a hydrogen atom in a living body, or a pharmaceutically acceptable salt thereof, Or their hydrates.

11. A pharmaceutical composition comprising the compound according to any one of claims 5 to 10 as an active ingredient.

12. A meta-proteinase inhibitor comprising the compound according to any one of claims 5 to 10 as an active ingredient.

13. A type I collagenase inhibitor comprising the compound according to any one of claims 5 to 10 as an active ingredient.

14. An agent for treating or preventing rheumatoid arthritis, comprising the compound according to any one of claims 5 to 10 as an active ingredient.