JP2000281580A - Proteoglycan production-accelerator cont aining phenoxypropylamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject accelerator useful for the treatment and prevention of a disease such as rheumatoid arthritis, spondylosis deformans, disc herniation, etc., caused by a cartilage disturbance by containing a specific phenoxypropylamine derivative. SOLUTION: This objective accelerator is obtained by containing a phenoxypropylamine derivative of formula I [G is O or S; R1, R2 are each H, a halogen or the like; R3 is H, OH, an alkyl or the like; R4 is H or an alkyl; R5 is H or an alkanoyl; R6, R7 are each H, an alkyoxy or the like] or its pharmaceutically permissible salts. The accelerating agent is preferably a treating agent of a cartilage disturbance and osteoarthritis. The accelerator can be prepared as an oral agent, an injection, an inhalation agent and a suppository, and as the oral agent, it is prepared as tablets, granules, fine granules, etc. In preparation, preferably a stabilizing agent (e.g.; albumin, globulin) is added. The administering amount of the compound of the formula is 1-00 mg daily by preferably dividing it one to several times.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament useful for treating and preventing cartilage diseases, and more particularly to a proteoglycan production promoter containing a phenoxypropylamine derivative.
The present invention relates to a therapeutic agent for cartilage disorders and a therapeutic agent for 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).
In JP-A-49-42681, JP-A-49-85074, JP-A-50-14681, JP-A-50-14682, JP-A-50-148362, and JP-A-51-100085, phenoxypropylamine derivatives are mainly used. Nerve action,
It is described that it has an anti-inflammatory effect or a hypotensive effect and is useful as a medicine.

[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 in order to solve the above-mentioned problems, and as a result, a phenoxypropylamine derivative has an action of promoting the production of proteoglycan in chondrocytes, resulting in cartilage damage. The present inventors have found that the present invention is effective for treating various diseases and completed the present invention.

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

[Formula 2] Wherein, G is an oxygen atom, -S -, - S (O ) - or -SO ₂ - represents a. R ¹ and R ² independently represent a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl or nitro. R ³ represents a hydrogen atom, a hydroxyl group, alkyl or alkanoyloxy. R ⁴ represents a hydrogen atom or alkyl. R ⁵ represents a hydrogen atom or alkanoyl. R ⁶ and R ⁷ independently represent a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl or nitro. ] The proteoglycan production promoter containing the phenoxypropylamine derivative represented by these, or its pharmacologically acceptable salt.

[2] The proteoglycan production promoter according to [1], wherein G is an oxygen atom. [3] The proteoglycan production accelerator according to [1] or [2], wherein R ³ is a hydrogen atom or a hydroxyl group, and R ⁵ is a hydrogen atom. [4] R ¹ is a fluorine atom substituted at the p-position, and R ²
Is a hydrogen atom, The proteoglycan production promoter in any one of [1]-[3]. [5] The proteoglycan production promoter according to any one of [1] to [4], wherein R ⁶ is a chlorine atom substituted at the p-position, and R ⁷ is a hydrogen atom. [6] The proteoglycan production promoter according to any one of [1] to [5], which is a therapeutic agent for cartilage disorders. [7] The proteoglycan production promoter according to any one of [1] to [5], which is a therapeutic agent for osteoarthritis.

The alkyl includes, for example, a C ₁ -C ₃ straight-chain or branched-chain alkyl.
Ethyl, propyl, isopropyl and the like can be mentioned. Examples of the alkoxy include C ₁ -C ₃ linear or branched alkoxy, and specific examples include methoxy, ethoxy, propoxy, and isopropoxy. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples include a fluorine atom and a chlorine atom. Examples of the alkanoyl include C ₁ -C ₃ straight-chain or branched-chain alkanoyls, specifically, formyl, acetyl,
Propanoyl and the like. Haloalkyl means alkyl substituted with one or more halogen atoms,
Specifically, trifluoromethyl, fluoromethyl, chloroethyl and the like can be mentioned.

[0008] In the present invention, when an asymmetric carbon is present in the phenoxypropylamine derivative of the formula 1 and a stereoisomer is present, both the racemic form and the optically active form are included. The present invention also includes solvates such as hydrates of the phenoxypropylamine derivative of the formula 1 or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of the phenoxypropylamine derivative of the formula 1 includes, for example, an acid addition salt with an inorganic or organic acid, and specifically, for example, hydrochloric acid, hydrobromic acid, sulfuric acid , Phosphoric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid and the like.

The phenoxypropylamine derivatives of the formula 1 are disclosed in JP-A-49-42681, JP-A-49-85074, JP-A-50-14681, JP-A-50-14682, JP-A-50-148362 and JP-A-50-148362. 51-100085 and the like, and can be easily produced according to the production methods described in these patent publications.

[0011] The therapeutic agent and the promoter of the present invention have an action of promoting the production of proteoglycan in 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

[0012] 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.

[0013] The therapeutic agent and accelerator of the present invention can take various formulations (for example, liquids, solids, capsules, etc.), but generally only the phenoxypropylamine derivative as an active ingredient or a conventional phenoxypropylamine derivative. Oral preparations, injections, inhalants, or suppositories together with carriers. Oral drugs include, for example, tablets, granules, fine granules, powders, soft or hard capsules, solutions, emulsions, suspensions, syrups, and the like. It can be prepared according to a conventional method. Injectables can be prepared by a conventional method. For example, a phenoxypropylamine derivative is dissolved in a suitable solvent (eg, sterilized water, buffer, physiological saline, etc.).
, And then sterilized by filtration with a filter or the like, and then filled in a sterile container to prepare the product. Suppositories can be prepared by a conventional method using a conventional base (for example, cacao butter, laurin butter, glycerogelatin, macrogol, witepsol, etc.). Inhalants can be prepared according to conventional methods for preparation. The content of the phenoxypropylamine derivative in the preparation can be appropriately adjusted according to the dosage form, the 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.

[0015] The therapeutic agent and 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 phenoxypropylamine derivative is appropriately adjusted depending on the condition, age, body weight, etc. of the patient, but is usually 0.05 mg to 500 mg, preferably 1 mg to 100 mg.
It is appropriate to administer this once or several times a day.

[0016]

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.

JP-A-49-42681, JP-A-49-85074, JP-A-50-1
4681, JP-A-50-14682, JP-A-50-148362, JP-A-51-10
The following compounds 1 and 2 which can be produced in the same manner as in the production method described in [0085] were tested for the following proteoglycan production promoting action.

Embedded image

[0018]

[Formula 4]

Materials and Methods Cells and cultured cell chondrocytes were obtained by substituting the growth plate chondrocytes from the costal cartilage of a 3 week old Japanese white rabbit by slightly modifying the method described in the literature (Calcif. Tissue Res. 19 , 1975). Released. The chondrocytes isolated in this way were 10% FBS, penicillin 50 U / m
L, DMEM / F-1 containing 50 μg / mL streptomycin
2 geometric mixed medium (hereinafter, referred to as medium A) at 37 ℃, 5% CO ₂ /
Maintained under 95% air.

Measurement of Proteoglycan Synthesis Chondrocytes were seeded at a density of 2 × 10 ⁴ cells per 6 mm well (collagen-coated 96-well plate) and maintained in 0.15 mL of medium A. The next day, the medium was replaced with 0.15 mL of medium A containing 0.3% BSA, 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. 5 μl of 100 μCi / mL [ ³⁵ S] -sulfuric acid was added 20 hours before the end of the incubation. After incubation, 10 μL per well of a 96-well plate with cell culture
Aqueous solution (0.2 mg / mL chondroitin sulfate, 25 mM MgSO ₄
And 15 μL of a 33% aqueous sodium acetate solution were added and stirred. 8 per well from a 96-well plate after stirring
0 μL was transferred to another assay plate, 140 μL of 99.5% ethanol was added, and the mixture was stirred and allowed to stand at −20 ° C. for 30 minutes. The suspension in the assay plate is filtered using a micro-cell harvester (SKATRON) with a glass fiber filter (WAL).
LAC) and infiltrated the cocktail for liquid scintillation, and counted using a 1205 beta plate (WALLAC) (Biochimica et Biophysica Acta, 96
9 , 1988). ED ₅₀ is, 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).

[0021]

[Table 1] Compound ED ₅₀ ――――――――――― Compound 1 3.77 Compound 2 6.60

[0022]

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 (7)

[Claims] [Claim 1] Formula: Wherein, G is an oxygen atom, -S -, - S (O ) - or -SO ₂ - represents a. R ¹ and R ² independently represent a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl or nitro. R ³ represents a hydrogen atom, a hydroxyl group, alkyl or alkanoyloxy. R ⁴ represents a hydrogen atom or alkyl. R ⁵ represents a hydrogen atom or alkanoyl. R ⁶ and R ⁷ independently represent a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl or nitro. ] The proteoglycan production promoter containing the phenoxypropylamine derivative represented by these, or its pharmacologically acceptable salt. 2. The proteoglycan production promoter according to claim 1, wherein G is an oxygen atom. Wherein R ³ is a hydrogen atom or a hydroxyl group, R ⁵
3. The proteoglycan production promoter according to claim 1, wherein is a hydrogen atom. 4. The proteoglycan production promoter according to claim 1, wherein R ¹ is a fluorine atom substituted at the p-position, and R ² is a hydrogen atom. 5. R ⁶ is a chlorine atom substituted at the p-position,
The proteoglycan production promoter according to claim 1, wherein R ⁷ is a hydrogen atom. 6. The proteoglycan production promoter according to claim 1, which is a therapeutic agent for cartilage disorders. 7. The method according to claim 1, which is a therapeutic agent for osteoarthritis.
The proteoglycan production promoter according to any one of the above.