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WO2002006227A1 - Inhibiteurs de la metalloprotease matricielle - Google Patents

Inhibiteurs de la metalloprotease matricielle Download PDF

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Publication number
WO2002006227A1
WO2002006227A1 PCT/JP2001/006172 JP0106172W WO0206227A1 WO 2002006227 A1 WO2002006227 A1 WO 2002006227A1 JP 0106172 W JP0106172 W JP 0106172W WO 0206227 A1 WO0206227 A1 WO 0206227A1
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Prior art keywords
group
compound
salt
carbon atoms
linear
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PCT/JP2001/006172
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English (en)
Japanese (ja)
Inventor
Akira Okamachi
Tatsuya Tamura
Yoshiki Hayashi
Teruo Nakamura
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Chugai Seiyaku Kabushiki Kaisha
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Priority to AU2001271068A priority Critical patent/AU2001271068A1/en
Publication of WO2002006227A1 publication Critical patent/WO2002006227A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a compound having a matrix meta-oral protease (hereinafter also referred to as MMP) inhibitory activity. More specifically, the present invention relates to an MMP inhibitory active compound useful for treating osteoarthritis, rheumatoid arthritis, etc., which has a cationic group as a part thereof, and a method for producing the same.
  • MMP matrix meta-oral protease
  • Articular cartilage is composed of about 70% water, chondrocytes and cartilage matrix.
  • the main components of the cartilage matrix are collagen and proteodarican, and a network of collagen having a network structure contains proteodarican having a high water retention ability.
  • the cartilage matrix is highly viscous and plays an important role in reducing the irritating load on cartilage and maintaining the normal shape and function of articular cartilage.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • Matrix destruction in both diseases is triggered by age-related mechanical stress in OA, hyperproliferation of synovial lining cells, pannus formation, and infiltration of inflammatory cells in RA, all of which are induced by protease induction. It is believed to be triggered. Since the cartilage matrix is degraded extracellularly at a neutral pH, matrix meta-oral proteases that optimize the pH in this region are said to be the main players in the degradation [Current Opinion in Ant i-Inf lammatory & I Marauder modulatory Inves tigat ional Drugs, vol. 2, 16-25, (2000)].
  • TIMPs tissue meta-oral protease inhibitors
  • ADAM tissue meta-oral protease inhibitors
  • ADAMTS new MMP-like proteins
  • these enzymes belonging to the MMP family are responsible for various functions such as development, angiogenesis, estrous cycle, bone remodeling, and tissue repair.
  • these functions In order for these functions to be properly expressed, the steps of enzyme production, activation and interaction with the substrate are strictly controlled by in vivo inhibitors such as TIMP.
  • TIMP in vivo inhibitors
  • the destruction of the matrix in the pathological condition is thought to be due to some disruption in the regulatory mechanism of MMPs and excessive production and activation of MMPs.
  • drugs that inhibit MMPs are extremely promising as drugs that suppress the destruction of the cartilage matrix in joint diseases such as OA and RA.
  • Many drugs that inhibit MMP have been reported (Exp. Opin. Ther. Patents (1998) vol. 8, 259-282, J. Enzyme Inhibition (1998) vol. 13, 79-). 101, Drug Discovery Today (1996) vol. 1, 16-26), as a matrix meta-oral protease inhibitor (hereinafter also referred to as MMP I) due to its strong inhibitory activity and high specificity for MMP
  • MMP I matrix meta-oral protease inhibitor
  • MMPI has excellent pharmacological effects, there are still problems to be solved for clinical application as therapeutic agents for chronic diseases such as ⁇ A and RA.
  • hyaluronic acid (hereinafter also referred to as HA) is an in vivo polycarboxylic acid composed of repeating units of N-acetyldarcosamine and glucuronic acid. It plays an important role in maintaining viscoelasticity, load absorption and lubrication. In the cartilage matrix, it binds to cartilage proteodalican to form a polymer called aggrecan, and plays a central role in maintaining water retention and viscoelasticity.
  • HA and its cross-linked product are also collectively referred to as HA preparations. It is widely practiced clinically. Since HA is a constituent of the extracellular matrix, it also has a high affinity for cartilage matrix. In addition, because of its high viscoelasticity, it is characterized by being localized in the joint cavity for a long time after being injected into the joint.
  • MMP I that exhibits high in vivo retention by using it in combination with hyaluronic acid without chemical modification or by administering it alone.
  • An object of the present invention is to provide an MMP inhibitory active compound having an improved local storage property in a living body.
  • Another object of the present invention is to provide a medicament containing the above compound.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the introduction of a thiothion group into MMP I can improve the storage property in a living body. Completed the invention.
  • a cationic MMP inhibitory activity conjugate or a salt thereof is provided.
  • the cationic MMP inhibitory activity conjugate of the present invention or a salt thereof is preferably a hydroxamic acid derivative.
  • the cationic group is preferably bonded to the hydroxamic acid skeleton by a chemical bond.
  • the chemical bond is preferably a covalent bond via a spacer.
  • the cationic group of the catonic MMP inhibitory active compound of the present invention as a part thereof is preferably a polycation group.
  • the catonic MMP-inhibiting compound of the present invention or a salt thereof has the general formula (1):
  • 1 ⁇ is a hydrogen atom, a hydroxyl group, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkoxy group having 1 to 8 carbon atoms, 8 linear or branched alkenyl group, R 5 R 6 N— (CH 2 ) m— (where R 5 and R 6 are each independently a hydrogen atom, a cycloalkyl group, Represents a linear or branched alkyl or acyl group having 1 to 8 carbon atoms which may be substituted with a group or a heterocyclic group, or R 5 and R 6 may form a ring.
  • n represents an integer of 0 to 4.
  • B—SOn— (CH 2 ) m- (where m represents an integer of 0 to 4, and B represents a hydrogen atom, a cycloalkyl group, or aryl.
  • R 4 represents a hydrogen atom or a carbon atom;
  • R 3 may form a ring.
  • R 7 represents a linear or branched alkylene group having 1 to 8 carbon atoms
  • R 8 is substituted with a linear or branched alkyl group having 1 to 4 carbon atoms.
  • R 9 represents 1 to 3 oxygen atoms
  • R 10 is an oxygen atom, a sulfur atom, or NR u (where, is a hydrogen atom Or a linear or branched alkyl group having 1 to 4 carbon atoms).
  • catonic MMP inhibitory active compound of the present invention or a salt thereof is represented by the following general formula (3):
  • R 3 is R 12 represents a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted by a cycloalkyl group, an aryl group or a heterocyclic group; R 12 represents one imino group and / or 1 Represents a linear or branched alkylene group having 2 to 23 carbon atoms which may have up to 4 oxygen atoms inserted therein; R 13 is a hydrogen atom or a linear chain having 1 to 4 carbon atoms Or a branched alkyl group; D represents a cationic group) or a salt thereof.
  • D is E x (E is a substituted amino group, a substituted ammonium group, a substituted guanidino group, a substituted amidino group, or a substituted nitrogen-containing heterocyclic ring.
  • E is a substituted amino group, a substituted ammonium group, a substituted guanidino group, a substituted amidino group, or a substituted nitrogen-containing heterocyclic ring.
  • X represents an integer of 1 to 20; and Ex may be a single unit repeating unit or may be composed of two or more units.;) It is preferably a group.
  • a cationic MMP inhibitory activation compound as described above. And a salt thereof, and a hyaluronic acid, a hyaluronic acid derivative or a salt thereof, provided by a non-covalent bond.
  • the non-covalent bond is an ionic bond.
  • a medicament comprising the above-described catonic MMP inhibitory activity conjugate or a salt, mixture or conjugate thereof.
  • a therapeutic agent for joint disease is preferable.
  • the joint disease osteoarthritis, rheumatoid arthritis, or shoulder periarthritis is preferable.
  • catonic MMP inhibitory activity conjugate or a salt, mixture or conjugate thereof may be used for producing a medicament or a pharmaceutical composition such as a therapeutic agent for joint diseases.
  • a method for treating a joint disease using the above-described catonic MMP inhibitory active compound or a salt, mixture or conjugate thereof comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a compound as described above, or a salt, mixture or conjugate thereof.
  • the joint disease is osteoarthritis, 'hidden rheumatoid arthritis, or shoulder periarthritis.
  • FIG. 1 is a graph showing the enzyme inhibitory activities of control compounds 16 (open circles) and 17 (black circles) on gelatinase A.
  • FIG. 2 is a graph showing the enzyme inhibitory activities of control compounds 16 (open circles) and 17 (black circles) on gelatinase B.
  • FIG. 3 is a graph showing the enzyme inhibitory activities of Compounds 7 (closed squares), 11 (open squares with lattices), 15 (open triangles), and 17 (closed circles) on gelatinase A.
  • FIG. 4 is a graph showing the enzyme inhibitory activities of Compounds 7 (closed squares), 11 (open squares with lattices), 15 (open triangles), and 17 (closed circles) on gelatinase B.
  • Figure 5 is a graph showing the enzyme inhibitory activity of compounds 4g (solid circles), 5f (solid triangles), and 6f (solid squares) with control compound 28 (open circles) on gelatinase B. .
  • Figure 6 shows the release of compounds 15 (open triangles) and 16 (open circles) from the solution without hyaluronic acid, and the release of compounds 7 (solid squares), 11 (black inverted triangles), and 15 (black) from the solution with hyaluronic acid. It is a graph which shows the emission of (triangle) and 16 (black circle).
  • Figure 7 shows the release of 4 g (open squares), 5 f (open triangles) and 6 f (closed circles) from the solution without hyaluronic acid, and 4 g (solid squares) from the solution with hyaluronic acid. , 5 f (solid triangles) and 6 f (solid circles).
  • Figure 8 shows compounds 15 (open triangles) and 1 from chondroitin sulfate-free solution.
  • 6 is a graph showing the release of 6 (open circles) and the release of compounds 15 (closed triangles) and 16 (closed circles) from a solution containing chondroitin sulfate.
  • FIG. 9 is a graph showing the effect of control compound 28 on proteodalican rupture in rat knee cartilage. From above, physiological saline + Tris-HCl buffer, physiological saline + stromelysin-1, compound 28 + stromelysin-1, compound 28 / HA mixture + stromelysin-1. ** indicates that it was P ⁇ 0.001 by Turkey's multiple comparison.
  • FIG. 10 is a graph showing the effect of compound 6f on rat prosthesis rupture in cartilage of the knee joint of rats. From the top, physiological saline + Tris-HCl buffer, physiological saline + stromelysin-1, compound 6f + stromelysin-1, compound 6f / HA mixture + stromelysin-11. ** indicates that P ⁇ 0.001 by Turkey's multiple comparison.
  • Japanese Patent Application No. 2000-216 which is the application on which the priority claimed by the present application is based.
  • a catonic MMP inhibitory active compound means a compound structurally having a cationic group as a part thereof and functionally having MMP inhibitory activity. More specifically, the activity of any MMP derived from any living organism (preferably a mammal, particularly preferably a human) is inhibited by, for example, binding thereto. It means any substance that has the property of being able to harm.
  • the catonic MMP inhibitory active compound in the present invention structurally has a cationic group in its molecule, and functionally includes carboxylic acid, phosphoric acid, thiol, hydroxamic acid and the like.
  • a new MMP-like protein with a combination of oral and disintegrin-like domains (a group of proteins belonging to ADAM and ADAMTS, including TNF-converting enzymes and aggrecanases-1, -II) It means a substance having the property of inhibiting the expression of enzyme activity.
  • the activity of the catonic MMP inhibitory activity of the present invention can be determined, for example, by the methods described in Cawston, TE & Barrett, A. J [Anal Biochem., 99, 340-345 (1979)] and Baici, A et al. , 108, 230-232 (1980)], and the inhibitory activity of synthetic substrates described in Masui, Y et al. [Biochem. Med., 17.215-221 (1977)] against degradation by MMPs. Can be measured. Conveniently, the measurement can be similarly performed using a commercially available MMP activity measurement kit developed based on these methods.
  • MMPs which is produced and activated when cells cultured on a film of a substrate such as collagen are stimulated with cytodynamic force
  • cytodynamic force is measured using the release of substrate degradation products in the culture medium as an index.
  • Experimental system [Gavrilovic ,; et al., Cited in Cell. Biol. Int. Reports, 9, 1097-1107 (1985): Br. J. Pharmacol., 100, 631-635 (1990)]
  • An experimental system that evaluates the release of TNFa from the cell membrane surface induced by stimulating peripheral leukocytes with lipopolysaccharide or the like as the activity of TNF ⁇ -converting enzyme [DiMartino et al .: Inflam.
  • the inhibitory active compounds of the present invention include, in at least one of these assay systems, compounds that exhibit 45% or more, particularly 50% or more inhibition at any concentration of 1 OmgZm 1 or less. It is.
  • hydroxamic acid derivative having a cationic group as a part thereof is preferable.
  • the “hydroxamic acid derivative” in the present invention includes a substance having a cationic group and a hydroxamic acid skeleton (N-hydroxyamide). Specifically, for example, a substance having a cationic group, And a compound having a partial structure represented by the aforementioned general formula (1), a compound represented by the aforementioned general formula (3), and the like.
  • the cationic group means a group having a positive charge, and includes a monocation group and a polycation group.
  • E is a substituted amino group, a substituted ammonium group, a substituted guanidino group, a substituted amidino group, or a substituted nitrogen-containing heterocyclic ring.
  • X is an integer of 1 to 20; E includes a case where a single unit is formed, a case where two or more units are formed, and the like.
  • the monocation group is, for example, a case where X is 1 in the definition of Ex in the general formula (3).
  • the polycation group includes, for example, a group in which X is an integer of 2 or more in the definition of Ex, more specifically, a group in which X is an integer of 2 to 20.
  • the cationic MMP-inhibiting active compound of the present invention preferably has a thione group capable of chemically bonding in its molecule.
  • the chemical bond may be a bond via a spacer or a bond not via a spacer.
  • the bonding mode of the spacer includes a covalent bond, and when not via a spacer, an amide bond, an ether bond, or the like can be used, but the covalent bond via the spacer is required. Is preferred. Regardless of whether the cation group is bonded via a spacer or not, it is preferable that the cation group be bonded to a site that does not impair the desired MMP inhibitory activity.
  • one cationic MMP inhibitory compound molecule may have a plurality of cationic groups (in which case, the cationic groups are the same). May be different from each other).
  • the bonding mode of these cationic groups may be, independently of each other, a bond via a spacer or a bond without a spacer. Further, when a plurality of spacers are present in one cationic MMP inhibitory active compound molecule, they may or may not be the same.
  • Examples of the linear or branched alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, an isobutyl group, t-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like.
  • linear or branched alkoxy group having 1 to 8 carbon atoms examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, Hexoxy, heptyloxy, octyloxy, isopentyloxy and the like.
  • Examples of the linear or branched alkenyl group having 2 to 8 carbon atoms include a vinyl group, an aryl group, an n-butenyl group, an i-butenyl group, a sec-butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, And an octenyl group.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms, and specific examples thereof include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Is raised.
  • aryl group examples include an aryl group having 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms which may have a substituent such as a hydroxyl group and a methoxy group, and specifically, a phenyl group, Examples thereof include a p-hydroxyphenyl group, a p-methoxyphenyl group, and a naphthyl group.
  • heterocyclic group one or more, preferably one to three, particularly preferably one hetero atom selected from a nitrogen atom, a sulfur atom, and an oxygen atom selected from the group consisting of 5 atoms To 20, preferably 5 to 10, particularly preferably 5, 6, 9 or 10 saturated or unsaturated heterocycles.
  • heterocyclic group one or more, preferably one to three, particularly preferably one hetero atom selected from a nitrogen atom, a sulfur atom, and an oxygen atom selected from the group consisting of 5 atoms To 20, preferably 5 to 10, particularly preferably 5, 6, 9 or 10 saturated or unsaturated heterocycles.
  • examples thereof include a lysyl group, a quinolyl group, an imidazolyl group, and an indolyl group.
  • the number of carbon atoms which may be substituted by a cycloalkyl group, an aryl group or a heterocyclic group
  • Non-limiting specific examples of the acyl group component of the straight-chain or branched-chain acyl group of the following are formyl group, acetyl group, propionyl group, butyryl group, isoptyryl group, valeryl group, isovaleryl group, piperoyl group, oxalyl Group, malonyl group, succinyl group, daltanyl group and the like.
  • linear or branched alkyl group having 1 to 4 carbon atoms examples include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, sec-butyl group, isobutyl group, t-butyl group.
  • alkyl of a linear or branched alkyl group having 1 to 8 carbon atoms which may be substituted with a cycloalkyl group, an aryl group or a heterocyclic group.
  • a methyl group, an isobutyl group, and a t-butyl group are preferable.
  • the heterocyclic group here preferably includes an indolyl group.
  • Non-limiting specific examples of R 5 R 6 N— (CH 2 ) m— in the general formula (1) include an amino group, a methylamino group, a dimethylamino group, an aminomethyl group, a phenacylaminoethyl group, and the like. And preferably an amino group and an aminomethyl group.
  • non-limiting specific examples of the case where R 5 and R 6 form a ring include the following groups.
  • Non-limiting specific examples of I and L include methylene, ethylene, trimethylene, and tetramethylene, preferably, I includes, for example, trimethylene, and L includes, for example, methylene.
  • K is absent or represents an aromatic ring which may have a substituent, wherein the aromatic ring is phenyl, tolyl, xylyl, naphthyl, biphenyl, anthryl, phenanthryl, pyridyl, indolyl, quinolyl And imidazolyl, and preferably phenyl.
  • I—J—K—L— is, for example, an alcohol derivative or a phenol derivative in which the residue from the R side has a halogenated alkyl group, preferably a propylpromide group, and the residue from the R 3 side has a hydroxyl group. Is obtained by condensing a compound that is a parahydroxybenzyl group.
  • I—J—K—L— is the general formula (4):
  • 1 ⁇ is preferably a hydrogen atom, a 7-acid group, a methoxy group or an aryl group.
  • R 2 is preferably an isobutyl group
  • R 3 is preferably a t-butyl group or a 3 -indolylmethyl group.
  • R 4 represents a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, an isobutyl group, although a t-butyl group is exemplified, a methyl group, a hydrogen atom, and more preferably a hydrogen atom are preferred.
  • R 3 is a 3-indolylmethyl group or a t-butyl group
  • R 4 is a hydrogen atom
  • a compound represented by the general formula (3) is preferable.
  • Cationic MMP inhibitory compounds having a partial structure represented by the general formula (1), wherein the partial structure represented by the general formula (1) is covalently bonded to a cation group via a spacer. Is preferably a compound represented by the general formula (3).
  • the structure represented by the general formula (1) contains one or more asymmetric carbon centers, and the present invention includes any asymmetric carbon center having an absolute configuration of either R configuration or S configuration. .
  • the type of spacer is not particularly limited as long as it does not significantly affect MMP inhibitory activity.
  • the HA or HA derivative or its derivative is used.
  • the type of spacer is not particularly limited as long as the activity of these salts as a component of synovial fluid, that is, viscoelasticity is not significantly affected.
  • Non-limiting specific examples include, for example, spacers represented by the aforementioned general formula (2).
  • the spacer represented by the general formula (2) binds to the hydroxamic acid skeleton at the R 7 -terminal and binds to a cation group at the R 10 -terminal.
  • examples of the linear or branched alkyl group having 1 to 8 carbon atoms in R 7 include a methylene group, an ethane-1,2-diyl group, a propane-1,1,3-diyl group, and a butane.
  • 1,4-diyl group pentane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, octane-1,8-diyl group, 2- Methylpentane-1,3-diyl group, 2-methylbutane1-1,4-diyl group, 3-methylbutane-1,4-diyl group, 3-methylpentane1-1,5-diyl group, 3-ethylethylpentane-1, 5-diyl group, 3-methylhexane-1,6-diyl group, 4-methylhexane-1,6-diyl group, 4-methylheptane 1, 7—diyl group and the like.
  • R 7 is preferably a ethane-1,2-diyl group, a propane-1,3-diyl group, or a butan-1,4-diyl group.
  • a linear or branched C 1 to C 4 methylene group or imino group of R 8 which may be substituted with a linear or branched alkyl group having 1 to 4 carbon atoms.
  • the chain alkyl group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, and a t-butyl group.
  • R 8 is preferably a methylene group which may be substituted with a linear or branched alkyl group having 1 to 3 carbon atoms, and an oxygen atom, and methylene group, and Oxygen atoms are particularly preferred.
  • non-limiting specific examples of a linear or branched alkylene group having 1 to 10 carbon atoms, in which 1 to 3 oxygen atoms may be inserted, in R 9 include: Methylene group, ethane-1,2-diyl group, propane-1,3-diyl group, butane-1,4-diyl group, pentane-1,5-diyl group, hexane-1,6-diyl group, Heptane-1,7-diyl group, octane-1,8-diyl group, nonane_1,9-diyl group, octane-11,10-diyl group, 2-methylpentane-1,1,3-diyl group, 2-Methylbutane-1,4-diyl group, 3-methylbutane-1,4-diyl group, 3-methylpentane-1,5-diyl group, 3-ethylpentane
  • R 9 is preferably a 1,2-diyl group, a propane-1,3-diyl group, a 1,4-dibutane group, a 1,1-diyl 3,6-dioxanone group, or the like. No.
  • Non-limiting specific examples of NRu in the above include imino group, methylimino group, ethylimino group, n-propylimino group, i-propylimino group, n-butylimino group, sec-butylimino group, isobutylimino group, t-butylimino group Groups.
  • R 10 is preferably an imino group or a methylimino group, and particularly preferably an imino group.
  • spacer one represented by the general formula (2), one (CH 2) 4 one NH - one (CH 2) 5 -NH- one (CH 2) 6 - NH-, One (CH 2 ) 7- NH-,-(CH 2 ) 8 -NH-,-(CH 2 ) 9 -NH-,-(CH 2 ) 10 -NH-, one (CH 2 ) u-NH-, one NH-, - - (CH 2) 12 (CH 2) 2 - ⁇ - (CH 2) 2 - NH-, - (CH 2) 3-0- (CH 2) "- one (CH 2) 4 - 0- (CH 2 ) 4 — NH—,-(CH 2 ) 3-O- (CH 2 ) 2 — ⁇ (CH 2 ) 2 _0— (CH 2 ) 3 — NH—, etc. But - (CH 2) 3-O- (CH 2) 2 - ⁇ one (CH 2) 2 - ⁇ - (CH 2) 3 - NH- are preferred.
  • the spacer represented by the general formula (2) may have an asymmetric carbon atom, and there may be a stereoisomer whose absolute configuration is R configuration or S configuration. Or any of the structural units in any proportion thereof are encompassed by the present invention.
  • 1 ⁇ is preferably a hydrogen atom, a hydroxyl group, a methoxy group or an aryl group. More preferably, it is a hydroxyl group.
  • R 3 is preferably a t-butyl group or a 3-indolylmethyl group, and more preferably a t-butyl group.
  • one imino group and / or a linear or branched alkylene group having 2 to 23 carbon atoms which may have 1 to 4 oxygen atoms in R 12 may be 1,2-diyl group, propane-1,3-diyl group, butane-1,4-diyl group, pentane-1,5-diyl group, hexane-1,1,6-diyl group, heptane-1 1 , 7-diyl group, octane-1,8-diyl group, nonane-1,1,1-diyl group, decane-1,10-diyl group, pendecane-1,11 Giyile group, dodecane-1,12-diyl group, 2-methylpentane-1,1,3-diyl group, 2-methylbutane-1,1,4-diyl group, 3-methylbutane-1,1,4-diyl group 1,3-methylpentane-1,
  • R 12 is preferably butane-1,4-diyl group, pentane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, octane-1,8 —Diyl group, nonane-1,9-diyl group, decane-1,10-diyle group, didecane-1,11-diyl group, dodecane-1,12-diyl group, 1 (CH 2 ) 2 — ⁇ 1 ( (CH 2 ) 2 —, one (CH 2 ) 3-0- (CH 2 ) 3 —,-(CH 2 ) 4 _ ⁇ one (CH 2 ) 4 —,-(CH 2 ) “0-(CH 2 ) 2 - O- (CH 2) 2 - 0- (CH 2) 3 -. and the like, especially preferably, a (CH 2) 3-0- (CH 2 ) 2 _ ⁇ one (CH 2)
  • R 13 preferably includes a hydrogen atom, a methyl group, and the like, and particularly preferably a hydrogen atom.
  • R 3 is a t-butyl group
  • R 12 is — (CH 2 ) 3 — ⁇ (CH 2 ) 2 -0- (CH 2 ) 2 — ⁇ — (CH 2 ) 3 — and R 13 are preferably hydrogen atoms.
  • D is preferably a cationic group represented by Ex.
  • E include a unit containing a substituted amino group, a substituted ammonium group, a substituted guanidino group, a substituted amidino group, or a substituted nitrogen-containing heterocyclic ring in the structure, and preferably a substituted amino group. It is a unit containing a substitutable ammonium group and a substitutable guanidino group in its structure, and particularly preferably a unit containing a substitutable guanidino group in its structure.
  • substituted amino group, substituted ammonium group, substituted guanidino group, or substituted amidino group in E means an amino group, an ammonium group which may be substituted with one or more groups.
  • a substituent such as a hydrogen atom, an amino group, a hydroxyl group, an alkyl group, an alkoxy group, an alkenyl group, an aryl group, and the like. Preferred are a hydrogen atom, an alkyl group and the like.
  • the substituted nitrogen-containing heterocyclic ring in E represents a heterocyclic group containing one or more nitrogen atoms, which may be substituted with one or more groups.
  • the substituent include a hydrogen atom, an amino group, a hydroxyl group, an alkyl group, an alkoxy group, an alkenyl group, an aryl group and the like, and preferably a hydrogen atom, an amino group, a hydroxyl group and an alkyl group.
  • X is preferably an integer of 1 to 20, more preferably 2 or more, even more preferably 4 or more.
  • Ex may be a single unit repetition or may be composed of two or more units.
  • E is a basic amino acid such as arginine (Ar g), lysine (Lys), histidine (His), orditin ( ⁇ rn), etc.
  • a liponucleoside such as adenosine, guanosine, cytidine, or lysine, in which a plurality of these units form a polypeptide or a polynucleotide by means of a peptide bond or a nucleotide bond. included.
  • Ex consists of a single unit includes a group represented by the following formula.
  • the structure represented by the general formula (3) may contain one or more asymmetric carbon centers, and each of the asymmetric carbon centers has an absolute configuration of either R configuration or S configuration. All mixtures in any proportion of are also included in the present invention.
  • hyaluronic acid refers to a disaccharide polymer comprising glucuronic acid and N-acetyldarcosamine having a weight-average molecular weight of 50,000 to 10,000,000, and And mixtures thereof.
  • HA is preferably hyaluronic acid having a weight average molecular weight of 700,000 to 10,000,000, and HA having a weight average molecular weight of 1,000,000 to 100,000,000,000 is preferable. Particularly preferred.
  • hyaluronic acid derivative means any substance having a hyaluronic acid skeleton derived from hyaluronic acid.
  • Non-limiting specific examples of hyaluronic acid derivatives include;
  • a hyaluronic acid derivative in which one or more carboxyl groups in HA are esterified for example, benzyl esterified HA (Hyaff, registered trademark, Fidia Advanced Biopolymers)
  • a polymer obtained by crosslinking a disaccharide polymer consisting of glucuronic acid having a weight average molecular weight of 50,000 to 10,000,000,000,000 and N-acetyltilcosamine with formaldehyde to further polymerize for example, , Synvisc (registered trademark, Biomatrix)
  • acetylated H in which at least one hydroxyl group in HA is acetylated A, or one or more active ingredients of HA or the above-mentioned HA derivative, for example, an anticancer agent (for example, an alkylating agent, an antimetabolite, an alkaloid, etc.), an immunosuppressant, an anti-inflammatory agent (steroid, non-steroid)
  • an anticancer agent for example, an alkylating agent, an antimetabolite, an alkaloid, etc.
  • an immunosuppressant for example, an anticancer agent (for example, an alkylating agent, an antimetabolite, an alkaloid, etc.), an immunosuppressant, an anti-inflammatory agent (steroid, non-steroid)
  • Anti-rheumatic drugs, anti-rheumatic drugs, antibacterial drugs (3-lactam antibiotics, aminoglycoside antibiotics, macrolide antibiotics, tetracycline antibiotics, new quinolone antibiotics
  • Non-limiting specific examples of the salt of HA or HA derivative include sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt and the like.
  • HA origin of HA is not particularly limited.
  • HA derived from bacteria such as actinomycetes, humans, pigs, and chickens can be used.
  • Non-limiting specific examples of HA and their salts include, for example, Squel (registered trademark, Nippon Russel), Alz (registered trademark, Kaken Pharmaceutical), Opegan (registered trademark, Santen Pharmaceutical), Hyalgan (registered trademark) , Fidea), Ortobisque (registered trademark, Anika Therapeutics), Hyalon (registered trademark, Pharmacia & Upjohn), etc., and various reagent manufacturers such as Wako Pure Chemical Industries, Ltd. HA and the salts thereof described in "Kiguchi” can also be mentioned.
  • the catonic MMP inhibitory active compound of the present invention that binds to HA or an HA derivative or a salt thereof by non-covalent bond does not need to be one kind, and may be two or more different compounds.
  • the total number of positive charges of the cationic group possessed by the catonic MMP-inhibiting compound of the present invention is preferably smaller than the number of dalcuronic acid residues of HA or a salt thereof mixed or non-covalently bound, and hyaluronic acid or a hyaluronic acid or a salt thereof is preferred. Any amount that does not precipitate the salt can be used. Preferably, it is 0.1 to 80%, more preferably 1 to 30%, based on the number of dalcuronic acid residues of hyaluronic acid or a salt thereof.
  • the catonic MMP-inhibiting activating compound or a salt, mixture or conjugate thereof is pharmaceutically acceptable. It may be used after being formulated together with an acceptable excipient or stabilizer.
  • the mixture or conjugate of the catonic MMP-inhibiting compound of the present invention or a salt thereof and HA, an HA derivative or a salt thereof can be obtained, for example, by mixing both in a suitable solvent and stirring.
  • a suitable solvent include water, a buffer and the like, and a phosphate buffer PBS is preferably used.
  • the pH during mixing and stirring is 2.0 to 12.0, preferably 4.0 to 10.0, and more preferably 6.0 to 8.0.
  • a commercially available HA preparation it is preferable to mix and stir the mixture at the preparation standard pH.
  • a predetermined amount of the cationic MMP inhibitory active compound of the present invention or a salt thereof may be directly mixed into the HA preparation.
  • the temperature during mixing and stirring is about 4 to 60 ° C, preferably about 4 to 30 ° C.
  • the catonic MMP inhibitory activity conjugate of the present invention or a salt thereof may be used alone, or simultaneously with an HA preparation containing HA, an HA derivative or a salt thereof, or immediately after administration of the HA preparation, in vivo. It may be administered.
  • the catonic MMP-inhibiting active compound of the present invention is mixed with or simultaneously administered with an HA preparation, the electrostatic binding of these compounds causes the HA-dependent cationic MMP-inhibiting compound to be retained in the joint cavity. Therefore, not only is it possible to improve the efficacy of HA preparations as a therapeutic agent for joint diseases, but also to reduce the general systemic side effects of substances having MMP inhibitory activity.
  • the electrostatic binding by the cationic group may be caused by the in vivo HA, chondroitin sulfate or chondroitin sulfate constituting cartilage proteodarican even after the administration and after the dissociation of the catonic MMP inhibitory activity of the present invention from the HA preparation. Since it can also occur between polyadiones such as keratan sulfate, MMP inhibitory activity can be expected to be maintained for a longer period in the joint cavity or on articular cartilage or synovial tissue.
  • the administration form of the medicament containing the MMP-inhibiting compound of the present invention or a salt, conjugate or mixture thereof of the present invention is not particularly limited, and may be oral administration, parenteral administration, systemic administration, or local administration.
  • the medicament of the present invention is administered parenterally. It is preferably administered topically, for example, it can be administered intra-articularly, intravenously, intramuscularly or subcutaneously as an injection, or transdermally as a spray, topical cream, lotion or ointment Can be administered.
  • the dose of the medicament of the present invention can be appropriately selected according to the patient's condition, age, sex, etc., but when used as an injection, it is generally determined as the amount of the conjugate or mixture as an active ingredient.
  • 0.0 l mgZ body weight kg / day to 10 O mgZ body weight kg / day preferably 0.1 mgZ body weight kg / day to 10 mg / kg body weight / day.
  • the daily dose of the medicament may be administered in divided doses several times a day, or once a day. Alternatively, it may be administered once every 2 to 28 days.
  • the method for producing the catonic MMP inhibitory active compound of the present invention is not particularly limited.
  • the compound can be produced by the following method or by applying the method:
  • a known MMP I described in the literature can be described in the literature. (Provided that the functional group is protected with a suitable protecting group widely used in organic synthesis), the spacer portion is bound, the cation group is bound, and all the protecting groups are bound.
  • Removal method The known MMP I described in the literature, with a part of the spacer previously bonded thereto, is subjected to the method described in the literature (provided that the functional group is an appropriate protecting group widely used in organic synthesis).
  • 4,7,10-Trioxa-1,13-tridecandamine (16.25 g, 74 mmo 1) was dissolved in methanol (750 ml), and the mixture was stirred at room temperature and stirred at room temperature.
  • a solution of lg, 74mmo 1) in methanol (75 Oml) was added dropwise over 1 hour. After the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour, and after the reaction, the solvent was distilled off in an evaporator. The residue obtained by concentration was purified by silica gel column chromatography using chloroform-methanol as eluent to give 10.7 g (yield 45%) of the title compound as an oil.
  • reaction solution was washed with 100 ml of water, and the solvent was distilled off in an evaporator.
  • the residue obtained by concentration was purified by silica gel column chromatography using chloroform-methanol as eluent to give 9.65 g (yield 80%) of the title compound as an oil.
  • N-t-butoxycarbone 4,7,10-trioxa-1,13-tridecandiamine (0.64 g, 2.Ommo 1) was dissolved in dimethylformamide (DMF) (5 ml) and stirred at room temperature.
  • DMF dimethylformamide
  • N-benzyloxycarbonyl-L-t bite isine (0.58 g, 2.2 mmo 1) in DMF (5 ml) and disopropylethylamine (0.52 ml, 3. Ommo 1). Then, under ice-cooling and stirring, ⁇ — (7-azabenzotriazolyl-1-yl) -11,1,1,3,3-tetramethylperonium hexafluorophosphate (HATU) (0.
  • the organic layer was dried over anhydrous magnesium sulfate, the anhydrous magnesium sulfate was filtered off, and the solvent was distilled off using an evaporator.
  • the obtained concentrate was dissolved in DMF (8 ml) and N- ⁇ -N- D-lysine (0.63 g, 1.83 mmo 1) in DMF (5 ml) and 1-hydroxybenzotriazole monohydrate (HOBT) (0.28 g, 1.83 mmo) 1) was added under stirring at room temperature, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (0.35 g, 1.83 mmol 1) was added under ice-cooling stirring.
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • the reaction mixture was concentrated under reduced pressure, and the obtained liquid substance was washed with n-hexane and further concentrated under reduced pressure.
  • the concentrate was dissolved in DMF (20 ml) under ice cooling, and diisopropylethylamine (1.76 ml, 10.
  • N 2 (t-butoxycarbonyl) 1 N 5 — (imino ⁇ [(2,2,5,7,8-pentamethyl-3,4-dihydro-1 2H-chromen-1 6-yl) sulfonyl] Amino ⁇ methyl) —D—Ornithyl-N 6 — CN 2 — (t-Butoxycarponyl) -N 5 — (Imino ⁇ C (2,2,5,7,8-pentamethyl-3,4—dihydro-2H—chromene-6— Yl) sulfonyl] amino ⁇ methyl) 1 D—Ordityl] 1 N 1 — ⁇ 3- C2-(2- ⁇ 3- [(N— ⁇ (2R) — 2—
  • the reaction mixture was concentrated under reduced pressure, and then dissolved in ethyl acetate.
  • the organic layer was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • D-arginyl _N 6 D-arginyl— N 1 — ⁇ 3-[2-(2— ⁇ 3- [(N- ⁇ (2R) -2-[(IS) —1-hydroxy-2 -— (hydroxy Synthesis of (Cyamino) 12-year-old oxoethyl] 1-4-Methylpentanoyl ⁇ —3-Methyl-L-valyl) Amino] Propoxy ⁇ Ethoxy) Ethoxy] Propyl ⁇ 1-D-Lysine Amide (Compound 4g)
  • the resulting concentrate is dissolved in DMF (6 ml) under ice-cooling, and the mixture is stirred under ice-cooling for diisopropylethylamine. (4 ml, 22.6 mmol), N- ⁇ -N- ⁇ -bis-butoxycarbonyl-D-lysine (2.61 g, 7.53 mmol) in DMF (6 ml) and HATU (2.86) g, 7.53 mmo 1) were added sequentially. After stirring for 30 minutes under ice cooling, the mixture was stirred at room temperature for 16 hours. After the reaction, the solvent was distilled off under reduced pressure using an evaporator.
  • Compound 5b Compound 5a (200 mg, 0.16 mmo 1) was dissolved in dichloromethane (0.8 ml), TFA (0.3 ml) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes under ice cooling and then at room temperature for 1 hour. did. After the reaction, the solvent was distilled off under reduced pressure overnight, and n-hexane was added to the obtained concentrate under ice cooling, and the supernatant was removed. After this operation was repeated five more times, the residue was concentrated under reduced pressure using an evaporator.
  • the resulting concentrate is dissolved in DMF (1.6 ml) under ice cooling, and stirred under ice cooling with diisopropylethylamine (0.5 ml, 2.88 mmol), N-at-butoxycarboneol.
  • N — ⁇ (2,2,5,7,8-pentanomethylchroman-6-sulfonyl) -D-arginine (519mg, 0.96mmo1), DMF (1.6ml), HAT U (365mg, 0. 96mmo 1) was added sequentially.
  • the resulting mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 17 hours. After the reaction, the solvent was distilled off under reduced pressure overnight.
  • the obtained concentrate is dissolved in DMF (8 ml) under ice-cooling, and stirred under ice-cooling, diisopropylethylamine (5 ml, 28.6 mmol), ⁇ - ⁇ - ⁇ - ⁇ -bis-butoxycarpineol
  • diisopropylethylamine 5 ml, 28.6 mmol
  • ⁇ - ⁇ - ⁇ - ⁇ -bis-butoxycarpineol A solution of D-lysine (3.30 g, 9.53 mmol) in DMF (8 ml) and HATU (3.62 g, 9.53 mmol) were sequentially added. After stirring for 30 minutes under ice cooling, the mixture was stirred at room temperature for 15 hours. After the reaction, the solvent was distilled off under reduced pressure using an evaporator.
  • Ethyl acetate was added to the concentrate, which was washed sequentially with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. After washing, the organic layer was dried over anhydrous magnesium sulfate, the anhydrous magnesium sulfate was filtered off, and the solvent was distilled off with an evaporator. The obtained concentrated residue was purified by silica gel column chromatography using methanol-dichloromethane as an eluent to obtain 3.16 g (yield 92%) of the title compound 6a as a colorless amorphous solid. .
  • the obtained concentrate is dissolved in DMF (20 ml) under ice-cooling, and stirred under ice-cooling, diisopropylethylamine (6 ml, 34.2 mmo1), N-Q! —T-butoxycarbone II- ⁇ (2,2,5,7,8_pentamethylchroman-1-6-sulfonyl) -D-arginine (6.17 g, 11.4 mmo 1) and HATU (4.34 g, 11.4 mmo 1) were added sequentially. . After stirring for 30 minutes under ice cooling, the mixture was stirred at room temperature for 20 hours. After the reaction, the solvent was distilled off under reduced pressure in an evaporator.
  • the enzyme inhibitory activity of the catonic MMP inhibitory activity compound of the present invention on gelatinase A and gelatinase B was measured.
  • the inhibitory activities for these enzymes were determined using a kit for measuring the activity of gelatinase manufactured by Roche Diagnostics. According to the attached protocol, L2U gelatinase A and 0.5 mU gelatinase B manufactured by the company were activated, and the enzyme reaction was measured at 37 ° C. for 1 hour.
  • test substances 4 g, 5 f and 6 f of the compounds synthesized in the above synthesis examples were used.
  • compound 28 having no cationic group shown in the following formula
  • Test conjugates were used as test conjugates. Each test compound was dissolved in a pH 7.5, 4.6 mM phosphate buffer containing 150 mM NaCl. Each of the test compound solutions obtained is mixed at room temperature such that the number of moles of the test substance is about 10 to 15% and the final HA concentration is 0.5% with respect to the number of disaccharide repeat units of HA. , HA formulation (Svenel; Roussel Morishita Co., Ltd., Denki Kagaku Kogyo Co., Ltd., Chugai Pharmaceutical Co., Ltd.), and agitating and mixing using a Portex mixer to confirm that the whole became uniform. Verification did.
  • test substance-HA mixed solution 1.5 mL was added to one of the two-chamber cells separated by a membrane filter (manufactured by MILLIPORE) having a pore size of 0.025 ⁇ , and the other part was the aforementioned phosphate buffer solution. Only 8 mL was added. A 0.1 mL sample was sampled over time from the cell containing only the phosphate buffer, and the released test substance was quantified (quantified by absorbance at 284 nm). As a control, a similar test was performed for a system containing no HA preparation. Fig. 6 shows the results.
  • the MMP-inhibiting active compound of the present invention in which a D-Arg residue is introduced as a cationic group is administered into a joint cavity by mixing with an HA preparation, the MMP-inhibiting active compound of the present invention is interacted with HA. Is expected to be sustained release.
  • Test compounds 4 g, 5 f and 6 f were used as test compounds. Each test compound was dissolved in lOmM phosphate buffer containing NaCl at pH 7.4, 150 ⁇ . Each of the obtained test compound solutions was subjected to HA at room temperature so that the number of moles of the test substance was about 1% based on the number of disaccharide repeating units of HA and the final HA concentration was 0.5%. In addition to the formulation (Svenile; Roussel Morishita, Inc., Denki Kagaku Kogyo, Chugai Pharmaceutical Co., Ltd.), the mixture was stirred and mixed using a Portex mixer, and the mixture was stirred at room temperature on a shaker. The mixture was shaken for 1 hour to confirm that the whole was uniform.
  • test substance-HA mixed solution obtained in this way 1.5 mL was added to one of the two champer cells separated by a membrane filter (manufactured by MILLIPORE) with a pore size of 0.025 ⁇ , and the other was only the above-mentioned phosphate buffer.
  • 0.1 mL samples were taken over time from the cell containing only the phosphate buffer, and the released test substance was quantified by the TNBS (trinitrbenzensulfonic acid) method.
  • TNBS trinitrbenzensulfonic acid
  • Solution C 0. 1M NaOH solution 0. 1M Na 2 B 4 0 7
  • Solution D Mix 0.4 mL of Solution A and 26.3 mL of Solution B
  • the compound for inhibiting MMP inhibition of the present invention in which a D-Arg residue is introduced as a cationic group, is mixed with HA and administered into a joint cavity, the compound for inhibiting MMP inhibition of the present invention interacts with HA. It is expected that the compound will be sustained release.
  • Compounds 15 and 16 were used as test substances, and chondroitin sulfate (Sanadium (CS-C) manufactured by Wako Pure Chemical Industries, Ltd.) was used as chondroitin sulfate.
  • Compounds 15 and 16 were replaced with CS-C 2 Mix each with 0.5% CS-C solution (pH 7.4, 20 mM phosphate buffer containing 150 mM NaCl) at room temperature so that the number of moles of the test substance is 10% based on the number of sugar repeating units.
  • Compound 15 into which D-Arg residue has been introduced is expected to increase retention by interacting with chondroitin sulfate, which is an extracellular matrix component in the joint cavity.
  • group I received 50 ⁇ of Tris-HCl buffer (50 t / l Tris-HC1, 0.15 mol / L NaCl, 10 mmol / L CaCl 2l pH 7.5) and the other groups (1 In groups 1, III, and IV), 5 ( ⁇ L each) of activated human recombinant stromelysin-1 (Nature 389, 77-81, 1997) prepared in Tris-HCl buffer to a final concentration of 160 ⁇ was used. Two hours later, the rats were euthanized by cervical dislocation and injected into the knee joint cavity.
  • the joint lavage fluid was collected.
  • the left and right joint fluids of each individual were combined into one specimen.
  • Synovial fluid at a final concentration of 10 TRU Chondroitin sulfate C (Wako Boshin) after digestion with Dase (actinomycetes, Amano Pharmaceutical) at 60 ° C overnight, and then with papain (Sigma) at a final concentration of 0.5mg / mL for 5 hours at 65 ° C.
  • the amount of proteodalican was measured by a colorimetric method using dimethyl methylene blue using (manufactured by Kogyo Co., Ltd.) as a standard product.
  • mice Male SD rats weighing about 200 g were divided into four groups, I to IV, and the following aqueous solutions were prepared. For each group, 5 (L) was injected into the knee joint cavity of both feet.
  • Group I received 50 ⁇ ⁇ ⁇ of Tris-HCl buffer, and groups II, III and IV received 50 ⁇ of stromelysin-11 at a final concentration of 160 g / mL. It was injected into the knee joint cavity. Two hours later, the rats were euthanized by cervical dislocation, 100 saline was injected into each joint cavity, and the joint lavage fluid was collected. The left and right joint fluids of each individual were combined into one specimen.
  • the catonic MMP-inhibiting compound of the present invention when administered alone, for example, can be electrostatically bound to cartilage tissue proteodalican and the like, and can be expected to be stored on cartilage tissue.
  • cartilage tissue proteodalican and the like when administered together with an HA preparation, it exhibits excellent joint cavity retention due to electrostatic binding with the HA preparation, and even after dissociation from HA, as described above, proteodalican, a cartilage tissue Since it can be electrostatically coupled with, further storage properties can be expected. Therefore, the MMP inhibitory effect can be localized, prolonged, and the number of administrations can be reduced, and this can be a therapeutic agent for joint diseases excellent in joint rupture suppression effect and the like.
  • pharmaceutical utility based on the cationic properties of the cationic active compound of the present invention can be expected.

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Abstract

L'invention concerne des inhibiteurs de la métalloprotéase matricielle (MMP) dont la rétention dans la partie de l'organisme à traiter est améliorée. L'invention concerne plus spécifiquement des inhibiteurs de métalloprotéase matricielle cationiques, dont la molécule contient des groupes cationiques, ou des sels de ceux-ci.
PCT/JP2001/006172 2000-07-18 2001-07-17 Inhibiteurs de la metalloprotease matricielle WO2002006227A1 (fr)

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JP2019514957A (ja) * 2016-05-06 2019-06-06 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 軟骨へのカプセル化薬剤の制御送達のための二成分型自己集合ゲル
US11672864B2 (en) 2010-09-24 2023-06-13 The Brigham And Women's Hospital, Inc. Nanostructured gels capable of controlled release of encapsulated agents
US11839605B2 (en) 2018-10-11 2023-12-12 Alivio Therapeutics, Inc. Non-injectable hydrogel formulations for smart release

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US11672864B2 (en) 2010-09-24 2023-06-13 The Brigham And Women's Hospital, Inc. Nanostructured gels capable of controlled release of encapsulated agents
JP2019514957A (ja) * 2016-05-06 2019-06-06 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． 軟骨へのカプセル化薬剤の制御送達のための二成分型自己集合ゲル
JP7169880B2 (ja) 2016-05-06 2022-11-11 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッド 軟骨へのカプセル化薬剤の制御送達のための二成分型自己集合ゲル
US11839605B2 (en) 2018-10-11 2023-12-12 Alivio Therapeutics, Inc. Non-injectable hydrogel formulations for smart release

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