JP2000281576A - Proteoglycan production promoter containing imide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject promoter useful in treating and preventing chronic arthrorheumatism, spondylosis deformans, protrusion of intervertebral disc, and the like each caused by cartilage disorder by including a specific imide derivative. SOLUTION: This promoter is obtained by including an imide derivative of formula I [Z is a group of formula II (B is carbonyl or the like; R1 to R4 are each H or a lower alkylene; n is 0 or 1); D is a group of the formula III (A is a hydrocarbon ring which may be crosslinked with a lower alkylene or the like; p and q are each 0-2); G is N, CH or the like; Ar is an aromatic heterocyclic ring or the like] or an acid addition salt thereof. This promoter is pref. a therapeutic agent for cartilage disorders or arthrosis deformans in the form of oral agent or parenteral injection, and, as an oral agent, made into preparations of dosage form such as tablets or granules; in preparation, a stabilizer (e.g. albumin) is preferably added. The daily dose of the imide derivative is pref. 1-100 mg in one to several portions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug useful for the treatment and prevention of cartilage diseases, and more particularly to a proteoglycan production promoter containing imide derivatives, a drug for treating cartilage disorders and a drug for treating osteoarthritis.

[0002]

2. Description of the Related Art Cartilage is connective tissue composed of chondrocytes and a matrix surrounding the chondrocytes, and is present in joints, intervertebral discs of the spinal column, costal cartilage, auricles, external auditory meatus, pubic symphysis, and epiglottis. Cartilage is composed of chondrocytes and cartilage matrix produced by chondrocytes. Depending on the mixing ratio of cartilage matrix components, hyaline cartilage (articular cartilage, costal cartilage, throat cartilage, etc.), fibrocartilage (intervertebral disc cartilage,
Pubic cartilage, meniscus, etc.) and elastic cartilage (auricular cartilage, etc.). The main components of the cartilage matrix are collagen (type II, type IX, etc.) in addition to proteoglycan. It is known that proteoglycans are involved in the swelling characteristic of cartilage tissue (that is, strength against compressive force), and collagen fibers are involved in the rigidity of cartilage against tension and shear force. Aggrecan accounts for 90-95% of the proteoglycans in the cartilage matrix, and glucosaminoglycan chains such as chondroitin sulfate and keratan sulfate chains bind to the core protein cartilage having a molecular weight of about 220,000, resulting in macromolecules (molecular weight of several million). Reach). Many water molecules are hydrated between the glucosaminoglycan chains (in the case of aggrecan, 50 ml / g), which is considered to contribute to the swelling property (The Bone 8, 4). , 1994).
JP-A-5-17440 describes that imide derivatives are useful as psychotropic substances.

[0003]

As described above, cartilage has an important function in maintaining the function of a living body, and various diseases caused by cartilage disorders have been known. Examples include osteoarthritis, chondrodysplasia, osteoarthritic intervertebral disc disease, and incomplete repair / healing of fractures.
Various treatments have been tried in the past to treat cartilage disorders, but they are not aimed at directly eliminating the cause, for example, by administering an anti-inflammatory agent and the like. It is only a symptomatic treatment, such as a method of suppressing a disorder such as pain due to a disease, or a method of injecting a hyaluronic acid preparation or the like into a joint to lubricate the movement of the joint. As described above, no curative treatment for joint disorders has been found, and in particular, osteoarthritis has a large number of patients, and there is an eager need for an effective treatment.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the imide derivative has an action of promoting the production of proteoglycan in chondrocytes, and various factors caused by cartilage disorders have been reported. The present inventors have found that the present invention is effective for treating diseases and completed the present invention.

[0005] That is, the present invention is as follows. [1] Equation 1:

[Formula 9] [Wherein Z is the formula:

[Formula 10] (Wherein, B represents carbonyl or sulfonyl. R
¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom or lower alkyl. However, R ¹ and R ² or R ¹ and R ³ may be combined to form a hydrocarbon ring, or R ¹ and R ³ may be combined to form an aromatic hydrocarbon ring. The hydrocarbon ring may be bridged by a lower alkylene or oxygen atom. The lower alkylene and hydrocarbon ring may be substituted with at least one alkyl. n represents 0 or 1. ). D is the formula:

[Formula 11] (In the formula, A represents a lower alkylene or a hydrocarbon ring which may be bridged with an oxygen atom. The lower alkylene and the hydrocarbon ring may be substituted with at least one alkyl. P and q are each 0 or 1; Or 2).
G represents N, CH or COH, -Ar represents an aromatic heterocyclic group, an aromatic hydrocarbon group, benzoyl, phenoxy or phenylthio, or G represents a carbon atom, -A
r represents biphenylmethylidene. The aromatic heterocyclic group, aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. ] The proteoglycan production promoter containing the imide derivative represented by these, or its acid addition salt.

[2] -Ar represents a bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy or phenylthio, G represents N, CH or COH, or -Ar represents biphenylmethylidene. And G represents a carbon atom (the bicyclic aromatic heterocyclic group, naphthyl,
Benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. )
A proteoglycan production accelerator containing the imide derivative or the acid addition salt thereof according to [1]. [3] -Ar represents an aromatic heterocyclic group fused with a benzene ring, or naphthyl, benzoyl, phenoxy or phenylthio (the aromatic heterocyclic group fused with the benzene ring, naphthyl, benzoyl, phenoxy and phenylthio are G may represent at least one lower alkyl, lower alkoxy or halogen atom), and G represents N, CH or COH. The proteoglycan production accelerator containing the imide derivative according to [1] or an acid addition salt thereof. .

[4] Z is a formula:

Embedded image (In the formula, -L- represents a single bond or a double bond. E represents a lower alkylene or an oxygen atom which may be substituted with a lower alkyl. R ⁵ represents a hydrogen atom or a lower alkyl. B is a claim. 1, which represents the meaning described in formula (1)) and the formula:

Embedded image (Wherein -L-, E, R ⁵ and B represent the same meaning as above), and the formula:

Embedded image (Wherein, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R
¹² , R ¹³ , R ¹⁴ and R ¹⁵ each represent a hydrogen atom or lower alkyl, or R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R
^{11, R 12, R 13,} R 14, represents a double bond and two adjacent bond in R ^15. B represents the above-mentioned meaning. ),
formula:

Embedded image (Wherein, R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or lower alkyl, or R ¹⁶ and R ¹⁷ together represent a saturated hydrocarbon ring. R ⁵ and B have the same meanings as described above.) .) Or the formula:

Embedded image The proteoglycan production accelerator containing the imide derivative or the acid addition salt thereof according to [1], wherein (B represents the above-mentioned meaning).

[5] [1] to [4] which are therapeutic agents for cartilage disorders
The proteoglycan production promoter according to any one of the above. [6] The proteoglycan production promoter according to any one of [1] to [4], which is a therapeutic agent for osteoarthritis.

[0009] The imide derivative of the formula 1 can be prepared
It is described in JP-A-5-17440.

The lower alkylene in Z and A includes:
For example, groups having 3 or less carbon atoms can be mentioned, and specific examples include methylene, ethylene, trimethylene and the like. Examples of the hydrocarbon ring in Z and A include cycloalkanes and cycloalkenes having 7 or less carbon atoms. Examples of the cycloalkane having 7 or less carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like. Examples of the cycloalkene having 7 or less carbon atoms include cyclopentene, cyclohexene, and cycloheptene.

The hydrocarbon ring bridged by a lower alkylene or oxygen atom in Z and A is, for example, one having 1 carbon atom.
Zero or less rings are mentioned. Specifically, bicyclo [1.
1.1] pentane, bicyclo [2.1.1] hexane,
Bicyclo [2.1.1] hex-2-ene, bicyclo [2.2.1] heptane, bicyclo [2.2.1] hepta-2-ene, bicyclo [2.2.2] octane, bicyclo [ 2.2.2] oct-2-ene, bicyclo [4.
1.1] octane, bicyclo [4.1.1] octa-2
-Ene, bicyclo [4.1.1] oct-3-ene, bicyclo [3.2.1] octane, bicyclo [3.2.
1] oct-2-ene, bicyclo [3.2.1] oct-3-ene, bicyclo [3.2.1] oct-6-ene, bicyclo [3.2.2] nonane, bicyclo [3.
2.2] non-2-ene, bicyclo [3.2.2] non-3-ene, bicyclo [3.2.2] non-6-ene,
2-oxabicyclo [1.1.1] butane, 2-oxabicyclo [2.1.1] pentane, 2-oxabicyclo [2.1.1] penta-4-ene, 7-oxabicyclo [2. 2.1] hexane, 7-oxabicyclo [2.
2.1] Hex-2-ene, 7-oxabicyclo [4.
1.1] heptane, 7-oxabicyclo [4.1.1]
Hept-2-ene, 7-oxabicyclo [4.1.1]
Hept-3-ene, 8-oxabicyclo [3.2.1]
Heptane, 8-oxabicyclo [3.2.1] hepta
2-ene, 8-oxabicyclo [3.2.1] hepta
3-ene, 8-oxabicyclo [3.2.1] hepta
6-ene and the like.

Examples of the aromatic hydrocarbon ring for Z include groups having 10 or less carbon atoms, and specific examples include a phenyl ring and a naphthyl ring. As the bonding position of the hydrocarbon ring in A, for example, -1,1-, -1,2-,-
1,3-, -1,4- and the like. Examples of the aromatic hydrocarbon group in -Ar include groups having 10 or less carbon atoms, and specific examples include phenyl and naphthyl. Examples of the aromatic heterocyclic group in -Ar include a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.

The monocyclic aromatic heterocyclic group is, for example, a group having 6 carbon atoms.
Or less, as hetero atoms, groups containing 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, the same or different, and specifically, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furyl , Imidazolyl and the like. As the bicyclic aromatic heterocyclic group, for example, a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom having 10 or less carbon atoms is 1 to 5
Groups which are the same or different from each other, and specifically include benzolog fused rings such as benzisothiazolyl, benzisoxazolyl, benzfuryl, quinolyl, isoquinolyl, indolyl, indazolyl, benzimidazolyl, and benzoxazolyl. , Naphthyridinyl, pteridinyl, thienofuranyl, imidazothiophen-yl, imidazofuranyl and the like.

The alkyl includes, for example, a group having 6 or less carbon atoms, preferably a lower alkyl having 4 or less carbon atoms, specifically, methyl, ethyl, propyl, 2-
Propyl, butyl and the like. Examples of the lower alkyl include groups having 4 or less carbon atoms, and specific examples include methyl, ethyl, propyl, 2-propyl, and butyl. Examples of lower alkoxy include groups having 4 or less carbon atoms, and specific examples include methoxy, ethoxy, propoxy, 2-propoxy, and butoxy.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The acid addition salts include pharmaceutically acceptable addition salts with inorganic and organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like.
Examples of the organic acid include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, and the like. The imide derivative of Formula 1 has stereoisomers and / or optical isomers. The present invention includes a mixture of these isomers and an isolated isomer.

The preferred group represented by -Ar is a bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy or phenylthio (where G is N, CH
Alternatively, it represents COH. ) Or biphenylmethylidene (where G represents a carbon atom) (wherein the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene are at least one lower alkyl, lower alkoxy or May be substituted with a halogen atom).

More preferred groups represented by -Ar include a benzolog fused ring, naphthyl, benzoyl, phenoxy or phenyl (the benzolog fused ring, naphthyl, benzoyl, phenoxy and phenylthio are at least one lower alkyl, lower alkoxy or halogen atom May be substituted.). In this case, G represents N, CH or COH. More preferred groups represented by -Ar include, specifically, benzisothiazolyl,
Benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl or indolyl (where the benzisothiazolyl, benzisoxazolyl, isoquinolyl, benzfuranyl, indazolyl and indolyl are substituted with at least one lower alkyl, lower alkoxy or halogen atom) Good). At this time, G
Represents N, CH or COH.

The saturated hydrocarbon ring formed by R ¹⁶ and R ¹⁷ together includes, for example, cycloalkanes having 7 or less carbon atoms, and specifically, cyclopropane, cyclobutane, cyclopentane, cyclohexane And cycloheptane.

More preferred groups represented by Z include the following:

Embedded image (In the formula, -L'- represents a single bond. E represents a lower alkylene or an oxygen atom which may be substituted with a lower alkyl.
R ⁵ represents a hydrogen atom or lower alkyl. B represents carbonyl or sulfonyl. ),formula:

Embedded image (Wherein -L′-, E, R ⁵ and B represent the above-mentioned meanings), a formula:

Embedded image (Wherein, R ⁶ ′, R ⁷ ′, R ⁸ ′, R ⁹ ′, R ¹⁰ ′, R ¹¹ ′,
^{R 12 ', R 13',} R 14 ', R 15' each represents a hydrogen atom or a lower alkyl. B represents the above-mentioned meaning. ),formula:

Embedded image (Wherein, R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or a lower alkyl group, or R ¹⁶ and R ¹⁷ together represent a saturated hydrocarbon ring. R ⁴ represents a hydrogen atom or a lower alkyl group. B represents the above-mentioned meaning.), And a formula:

Embedded image (B represents the above-mentioned meaning.).

[0020] The therapeutic agent and the promoter of the present invention have an action of promoting the production of proteoglycan by chondrocytes. Therefore, the therapeutic agent and the promoting agent of the present invention are effective in treating and preventing various diseases caused by cartilage disorders, and include, for example, the following diseases. Osteoarthritis Rheumatoid arthritis Osteoarthritis Intervertebral disc herniation Chondrodysplasia Healing and repair of fractures Repair of articular cartilage and articular disc by trauma Acute suppurative arthritis Tuberculous arthritis Syphilitic arthritis Rheumatic fever, Systemic lupus erythematosus Bone transplant Repair by

The therapeutic agent and promoter of the present invention are applicable to the treatment and prevention of various diseases caused by cartilage disorders in mammals (eg, cows, horses, pigs, sheep, dogs, cats, etc.) in addition to humans. Is done.

[0022] The therapeutic agent and accelerator of the present invention can take various preparation forms (for example, liquid preparation, solid preparation, capsule preparation, etc.). In general, only the imide derivative as an active ingredient or a conventional carrier together with the imide derivative is used. Oral, injection, inhalant, or suppository. Oral drugs include, for example, tablets, granules, fine granules, powders, soft or hard capsules, solutions, emulsions,
They are formulated into dosage forms such as suspensions and syrups, and these formulations can be prepared according to the usual methods of formulation. Injectables can be prepared by a conventional method. For example, after dissolving an imide derivative in an appropriate solvent (eg, sterilized water, buffer, physiological saline, etc.), the solution is sterilized by filtration through a filter or the like. And then filling into sterile containers. Suppositories are prepared using conventional bases (eg,
Cacao butter, laurin butter, glycerogelatin, macrogol, witepsol). Inhalants can be prepared according to conventional methods for preparation. The content of the imide derivative in the preparation can be appropriately adjusted according to the dosage form, applicable disease and the like.

At the time of formulation, a stabilizer is preferably added. Examples of the stabilizer include albumin, globulin, gelatin, glycine, mannitol, glucose, and the like.
Dextran, sorbitol, ethylene glycol and the like can be mentioned. Further, the preparation of the present invention may contain additives necessary for preparation, for example, excipients, solubilizing agents, antioxidants, soothing agents, isotonic agents and the like. In the case of a liquid preparation, it is desirable to preserve by freezing or freeze-drying to remove water. The lyophilized preparation is used after reconstitution by adding distilled water for injection or the like at the time of use.

[0024] The therapeutic agent and the accelerator of the present invention can be administered by an appropriate administration route depending on the form of the preparation. For example, it can be administered in the form of an injection to vein, artery, subcutaneous, intramuscular, and the like. The dose of the imide derivative is appropriately adjusted depending on the patient's condition, age, weight, etc.
mg to 500 mg, preferably 1 mg to 100 mg, which is suitably administered once or several times a day.

[0025]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The materials and methods used in the following experiments are as follows.

[0026] The three compounds of Examples 128, 131 and 155 described in JP-A-5-17440 were tested for the following proteoglycan production promoting action.

Embedded image

Embedded image

Embedded image

Materials and methodsCells and cell culture  Chondrocytes are described in the literature (Calcif.Tissue Res.19, 1975)
The method described above was changed slightly, and the ribs of a 3-week-old Japanese white rabbit were
Growth plate chondrocytes were isolated from cartilage. In this way,
The released chondrocytes were 10% FBS, penicillin 50 U / m
L, DMEM / F-1 containing 50 μg / mL streptomycin
37 ° C, 5% CO2 in a bi-equivalent mixed medium (hereinafter referred to as medium A)_Two/
Maintained under 95% air.

[0028]Measurement of proteoglycan synthesis  For chondrocytes, use 6mm wells (collagen-coated 96-well plate)
G) 2 × 10^FourSeeded at a density of 0.15 ml and maintained in 0.15 mL of medium A.
I carried it. The next day, in 0.15 mL of Medium A containing 0.3% BSA
Replaced and pre-incubated for 24 hours. afterwards,
0.3% BSA and the above compound (concentration in culture solution is 1, 3, 1
0, 30 μM) for 24 hours in 0.1 mL of Medium A
I did. 5 μl of 100 μCi / mL [³⁵S] -sulfuric acid
20 hours before the end of the reaction. End of incubation
After that, 10 μL per well of a 96-well plate where cell culture was performed
Aqueous solution (0.2mg / mL chondroitin sulfate, 25mM MgSO_Four 
And 15 μL of 33% aqueous sodium acetate solution
And stirred. 8 per well from a 96-well plate after stirring
Transfer 0 μL to another assay plate and add 140 μL of 99.5%
Add ethanol, stir and leave at -20 ° C for 30 minutes.
Was. Transfer the suspension in the assay plate to the microcell harvester.
Glass fiber filter (WAL) with Star (SKATRON)
LAC) and trap it for liquid scintillation.
After infiltration into the cowl using a 1205 beta plate (WALLAC)
(Biochimica et Biophysica Acta,96
9, 1988). ED₅₀Is the TGF-β of each plate
(1ng / mL) count is 100%, count of no additive group is 0%
The dose of the sample corresponding to 50% (molarity: μ
M).

[0029]

[Table 1] Compound ED₅₀  ――――――――――― Compound 1 10.3 Compound 2 10.2 Compound 3 18.7

[0030]

Industrial Applicability According to the present invention, it is possible to provide a proteoglycan production promoting agent, a therapeutic agent for cartilage disorders and a therapeutic agent for osteoarthritis.

Claims (6)

[Claims] [Claim 1] Formula: [Wherein Z is the formula: (Wherein, B represents carbonyl or sulfonyl. R
¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom or lower alkyl. However, R ¹ and R ² or R ¹ and R ³ may be combined to form a hydrocarbon ring, or R ¹ and R ³ may be combined to form an aromatic hydrocarbon ring. The hydrocarbon ring may be bridged by a lower alkylene or oxygen atom. The lower alkylene and hydrocarbon ring may be substituted with at least one alkyl. n represents 0 or 1. ). D is the formula: (In the formula, A represents a lower alkylene or a hydrocarbon ring which may be bridged with an oxygen atom. The lower alkylene and the hydrocarbon ring may be substituted with at least one alkyl. P and q are each 0 or 1; Or 2).
G represents N, CH or COH, -Ar represents an aromatic heterocyclic group, an aromatic hydrocarbon group, benzoyl, phenoxy or phenylthio, or G represents a carbon atom, -A
r represents biphenylmethylidene. The aromatic heterocyclic group, aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom. ] The proteoglycan production promoter containing the imide derivative represented by these, or its acid addition salt. 2. Ar represents a bicyclic aromatic heterocyclic group, represents naphthyl, benzoyl, phenoxy or phenylthio, G represents N, CH or COH, or -Ar represents biphenylmethylidene. , G represents a carbon atom (the bicyclic aromatic heterocyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene may be substituted with at least one lower alkyl, lower alkoxy or halogen atom). A proteoglycan production promoter comprising the imide derivative according to claim 1 or an acid addition salt thereof. 3. Ar represents an aromatic heterocyclic group condensed with a benzene ring or naphthyl, benzoyl, phenoxy or phenylthio (an aromatic heterocyclic group condensed with the benzene ring, naphthyl, benzoyl, phenoxy and Phenylthio may be substituted by at least one lower alkyl, lower alkoxy or halogen atom), and G represents N, CH or COH. 2. Proteoglycan containing an imide derivative or an acid addition salt thereof according to claim 1. Accelerator. 4. Z is a formula: (In the formula, -L- represents a single bond or a double bond. E represents a lower alkylene or an oxygen atom which may be substituted with a lower alkyl. R ⁵ represents a hydrogen atom or a lower alkyl. B is a claim. 1)), a formula: (Wherein -L-, E, R ⁵ and B represent the above-mentioned meanings), and the formula: (Wherein, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R
¹² , R ¹³ , R ¹⁴ and R ¹⁵ each represent a hydrogen atom or lower alkyl, or R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R
^{11, R 12, R 13,} R 14, represents a double bond and two adjacent bond in R ^15. B represents the above-mentioned meaning. ),
Formula: (Wherein, R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or lower alkyl, or R ¹⁶ and R ¹⁷ together represent a saturated hydrocarbon ring. R ⁵ and B have the same meanings as described above.) )) Or the formula: The proteoglycan production accelerator containing the imide derivative or an acid addition salt thereof according to claim 1, wherein (B represents the above-mentioned meaning). 5. The proteoglycan production promoter according to claim 1, which is a therapeutic agent for cartilage disorders. 6. The pharmaceutical composition according to claim 1, which is a therapeutic agent for osteoarthritis.
The proteoglycan production promoter according to any one of the above.