KR20190134042A - Novel Composition comprising a therapeutic material for treating arthritis of ergostenol glycoside derivatives - Google Patents

Abstract

The present invention relates to an ergostenol glycoside derivative and a composition for preventing and treating arthritis comprising the same. In addition, the ergostenol glycoside derivative is a novel substance which has not existed previously, and there is no research on arthritis activity. In order to prove an effect of the present invention on arthritis alleviation, an expression degree of an arthritis-induced biomarker is compared and analyzed, to prove the activity.

Description

Novel composition comprising a therapeutic material for treating arthritis of ergostenol glycoside derivatives}

The present invention relates to a composition comprising a therapeutic material for arthritis of a novel ergostenol glycoside derivative.

Joints are areas where bones meet, and are composed of cartilage, articular capsules, synovial membranes, ligaments, tendons, and muscles. Arthritis is a joint inflammation caused by a variety of causes, often fever, pain, stiffness and edema occur together, the cause is more than 100 kinds of degenerative changes, immune system abnormalities, infections, trauma, metabolic disorders.

Degenerative arthritis or osteoarthritis of arthritis is a disease caused by damage or degeneration of cartilage that protects joints, and damage to bones and ligaments forming joints, accompanied by inflammation and pain, and stiffness and swelling. The causes are degenerative changes, diseases of the immune system, and the like as the cartilage of the joints wears out, causing pain along with inflammatory reactions.

Major factors associated with the development of degenerative arthritis or osteoarthritis include proteolytic enzymes, nitric oxide (NO), and cytokines.

Cytokine is a water-soluble protein secreted from cells, expressed by a specific signal material, and is influenced by surrounding cells, distinct from enzymes. Among the cytokines, interleukin-1 and IL-1, tumor necrosis factor-α and TNF-α, are known to affect the catabolism of chondrocytes. In addition, cytokines such as Cox-2, inducible nitric oxide (iNOS), and IL-1β, IL-6, TNF-α, are known to be involved in inflammation.

Osteoarthritis, on the other hand, is known to cause excessive production of cytokines such as TNF-α and Cox-2 due to a series of inflammatory reactions caused by macrophages in the joint cavity. It is known to damage the matrix and worsen osteoarthritis.

Since degenerative arthritis is a chronic disease and there is no fundamental treatment, the main purpose of treatment is simply to alleviate pain and prevent cartilage damage.NSAIDs, analgesics, corticosteroids, and injections of hyaluronic acid in the joint cavity are the main therapeutic agents. It is used.

In this regard, corticosteroids are known to relieve inflammation (Peter J. Barnes, Corticosteroids, IgE, and atopy., J Clin Invest. 2001 Feb 1; 107 (3): 265-266). However, due to the side effects of steroid substances, they are not suitable for use as standard therapeutics. In addition, pimecrolimus and tacrolimus have recently attracted attention as immune modulators for the treatment of atopy (Cury Martins J et al, Topical tacrolimus for atopic dermatitis., Cochrane Database Syst Rev. 2015 Jul 1). However, there is a problem that lowers immunity and is susceptible to other diseases.

The present inventors found that the ergostenol glycoside derivatives of the present invention can be usefully used for the prevention, treatment and improvement of arthritis.

One object of the present invention is to provide a composition for preventing or treating arthritis, including ergostenol glycoside and derivatives thereof.

Hereinafter, the present invention will be described in more detail.

Meanwhile, each of the descriptions and the embodiments disclosed herein may be applied to each of the other descriptions and the embodiments. That is, all combinations of the various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific description described below.

In addition, one of ordinary skill in the art can recognize or identify numerous equivalents to certain aspects of the invention described in this application using conventional experiments only. Also, such equivalents are intended to be included in the present invention.

One aspect of the present invention for achieving the object of the present invention provides a novel ergostenol glycoside derivative or a pharmaceutically acceptable salt thereof. The novel ergostenol glycoside derivatives according to the invention may be a compound represented by the following formula (1).

[Formula 1]

Wherein R is a monosaccharide or an amino sugar.

,

,

, 및

의 화학식으로 표시되는 글루코스, 갈락토스, 자일로스, 만노스일 수 있다. 또한, 5탄당으로는,

의 화학식으로 표시되는 것일 수 있다.Monosaccharide (monosaccharide) in the present invention is a unit of carbohydrates having at least two hydroxyl groups and a carbonyl group adjacent thereto, and can be represented by the general formula Cn (H 2 O) n. The monosaccharide may be hexose or pentose. For example, with six sugars

,

,

, And

It may be glucose, galactose, xylose, mannose represented by the formula of. In addition, in five sugars,

It may be represented by the formula of.

의 화학식으로 표시되는 N-아세틸글루코사민(N-acetylglucosamine)일 수 있다.In the present invention, an amino sugar is a compound in which a part of a hydroxy group (OH) (for example, one hydroxy group) is substituted with an amino group in a monosaccharide. Specifically, the amino sugar may be glucosamine or galactosamine. For example, the amino group of the amino sugar may be acetylated. Specifically,

It may be N-acetylglucosamine represented by the formula of (N-acetylglucosamine).

The ergostenol of the present invention may have a unique conformation unlike a general steroid compound by having a position of a double bond between carbon 8 and carbon 14. Specifically, ergostenol and its glycoside derivatives may have a three-dimensional conformation shown in FIG. 1.

The present invention includes all pharmaceutically acceptable salt forms of the compound represented by the formula (1).

For example, inorganic salts made with calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, and other inorganic salts, acetic acid, trifluoroacetic acid, citric acid , Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbon Organic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, Amino acid salts and trimethylamine, triethylamine, ammonia, pyridine, sulfonates, glycine, arginine, lysine, etc., prepared with camphorsulfonic acid or naphthalenesulfonic acid; Although there are amine salts made of picoline and the like, the salts used in the present invention are not limited by these salts.

For example, the pharmaceutically acceptable salt may be hydrochloric acid as inorganic acid, methanesulfonic acid as organic acid.

Another aspect provides a pharmaceutical composition for the prevention or treatment of arthritis, including ergostenol, its glycoside derivatives or pharmaceutically acceptable salts thereof.

Arthritis of the present invention may be a degenerative arthritis, specifically, may be any one selected from the group consisting of psoriatic arthritis, osteoarthritis, rheumatoid arthritis, and periarthritis. The composition of the present invention may promote cartilage regeneration or prevent breakage of cartilage.

In the present invention, the pharmaceutical composition may be a formulation selected from the group consisting of ointments, gels, creams, patches and sprays. In addition, the pharmaceutical composition may be an oral or injectable preparation. The oral preparations are powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, suspensions, solutions, emulsions or syrups, and the injectable preparations may be in the form of sterile injectables.

The pharmaceutical composition of the present invention may be formulated by adding a pharmaceutically acceptable carrier, and the formulation may be referred to Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA. The pharmaceutically acceptable carrier refers to those commonly used in preparing pharmaceutical compositions to those skilled in the art. For example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl Pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Pharmaceutically acceptable carriers also include diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like. For example, oral solid preparations include tablets, pills, powders, granules, capsules, and the like, including at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin. And the like, and may include a lubricant such as magnesium stearate, talc and the like. Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include water, diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, and the like. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspending agents, emulsions, and lyophilized preparations. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil and ethyl oleate. Injectable esters such as the like and the like. However, the present invention is not limited to the above-listed pharmaceutically acceptable carriers and the like, and these are merely exemplary. The carrier may include a non-naturally occuring carrier.

In addition, the pharmaceutical composition of the present invention may further contain one or more active ingredients indicating improvement, alleviation, treatment or prevention of arthritis in addition to ergostenol and its glycoside derivatives.

In addition, the pharmaceutical composition of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug treatment and biological response modifiers for the improvement, alleviation, treatment or prevention of arthritis.

Another embodiment provides a cosmetic composition for improving or alleviating arthritis, including ergostenol or glycoside derivatives thereof. The arthritis is as described above.

In the present invention, the cosmetic composition is supple cosmetics, astringent cosmetics, nourishing cosmetics, nutrition cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, It may be a formulation selected from the group consisting of body oils, body essences, makeup bases, foundations, hair dyes, shampoos, rinses and body cleansers.

The cosmetic composition of the present invention may be prepared in various forms according to a conventional cosmetic preparation method using the ergostenol or its glycoside derivatives, stabilizers, solubilizers, vitamins, Conventional adjuvants such as pigments, and perfumes.

In addition, when the cosmetic composition is prepared in the form of a cosmetic product containing the ergostenol or its glycoside derivatives, shampoo, hair lotion, hair cream, hair gel and the like, it is diluted with a conventional cleansing liquid, astringent liquid and moisturizing liquid Can be used.

The cosmetic composition of the present invention may contain 0.001% to 20% by weight of the ergostenol or its glycoside derivatives based on the total weight of the composition.

The present invention seeks to provide a method for the prevention or treatment of arthritis comprising the administration of a therapeutically effective amount of ergostenol or its glycoside derivatives.

As used herein, the term "therapeutically effective amount" refers to an amount of ergostenol or its glycoside derivatives effective for the prevention or treatment of arthritis.

The method of preventing or treating arthritis of the present invention includes not only treating the disease itself but also inhibiting or avoiding the manifestation thereof by administering the ergostenol or its glycoside derivatives. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Its dose and frequency of dose will vary depending on the age, weight and response of the individual patient and a suitable dosage regimen can be readily selected by one of ordinary skill in the art that naturally considers these factors.

In addition, the method of preventing or treating arthritis of the present invention may further comprise administering a therapeutically effective amount of an additional active agent to help treat the disease in combination with the ergostenol or its glycoside derivatives, and further active agents May exhibit a synergistic or auxiliary effect with the ergostenol or its glycoside derivatives.

The present invention is to provide the use of ergostenol or its glycoside derivatives for the manufacture of a medicament for the prevention or treatment of arthritis. The ergostenol or its glycoside derivatives for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier and the like, and may be prepared as a complex formulation with other active agents to have a synergistic action of the active ingredients.

The matters mentioned in the uses, compositions and methods of treatment of the invention apply equally unless they contradict each other.

Another embodiment provides an efficient method for preparing the ergostenol and its glycoside derivatives.

First, the preparation of ergostenol may be provided by using ergosterol, which is commonly present in nature, as a starting material. Specifically, the step of reacting ergosterol with a Pd / C catalyst in an alcohol solvent and a chlorine-based organic solvent to obtain ergostenol.

The chlorine-based organic solvent may be selected from the group consisting of methylene chloride, chloroform, 1,2-dichloroethane, and the alcohol solvent may be methanol, ethanol or propanol.

After filling the hydrogen in the above step and stirred at room temperature for a long time, it can be concentrated under reduced pressure by filtration with Cetlite, recrystallized by using methanol in the concentrated solid can be filtered to obtain ergostenol.

The obtained ergostenol may be mixed with an OH group protected sugar and a chlorine-based organic solvent, followed by stirring in the presence of an acid catalyst, thereby preparing a glycoside derivative of ergostenol.

The OH group of the sugar in which the OH group is protected may be protected by a tetrabenzoyl group. The OH group in which the glucosylation reaction will occur may be in the form of pyranosylation and combined with trichloroacetimidate. The chlorine-based organic solvent may be selected from the group consisting of methylene chloride, chloroform, 1,2-dichloroethane.

The acid catalyst may be selected from the group consisting of TMSOTf, BF ₃ OEt ₂ , Cu (OTf) ₂ , Sc (OTf) ₃ , SiO ₂ —H ₂ SO ₄ , and cellulose-HClO ₄ . In this step, the stirring may be performed at room temperature, and the organic base (eg, TEA) may be added to the reaction solution, neutralized, and then filtered and concentrated under reduced pressure.

Through the above step, the OH group of the sugar can be obtained ergostenol glycoside derivatives, through deprotection can finally obtain the ergostenol glycoside derivatives of the present invention. Specifically, the OH group-protected ergostenol glycoside derivatives can be obtained by adding NaOMe or K ₂ CO ₃ under a chlorine-based organic solvent and an alcohol solvent and stirring at room temperature.

As another aspect, the present invention provides a health functional food composition for preventing or improving inflammation including the ergostenol derivative.

The novel ergostenol derivatives of the present invention can be usefully used as a pharmaceutical material for the treatment of degenerative arthritis and rheumatoid arthritis because it inhibits the production of arthritis-induced biomarker collagenase and promotes collagen protein production.

1 is a diagram showing a three-dimensional form of ergostenol and its glycoside derivatives of the present invention.
FIG. 2 is a diagram illustrating evaluation results of arthritis activity in four substances of FIG. 1.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

Production Example  One. Ergostenol  Produce

Dissolve ergosterol (3 g) with methylene chloride (30 ml) and methanol (70 ml) and add Palladium carbon (0.3 g). After filling with hydrogen and stirred at room temperature for 20 hours. After filtration through Celite and concentrated under reduced pressure immediately. The concentrated solid was recrystallized with methanol and filtered to give the product as a white solid in 99% (3 g) yield.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.62 (brs, 1H), 2.39-2.35 (m, 1H), 2.20-2.17 (m, 2H), 1.95-1.91 (m, 1H), 1.83- 1.80 (m, 2H), 1.17-1.54 (m, 7H), 1.45-1.30 (m, 7H), 1.27-1.25 (m, 5H), 1.10-1.06 (m, 5H), 1.01-0.97 (m, 1H ), 0.97-0.91 (m, 3H) 0.85 (d, 6H, J = 7.9 Hz), 0.78 (d, 6H, J = 6.6 Hz), 0.69 (s, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ (ppm): 142.7, 126.3, 71.3, 56.7, 49.3, 44.3, 42.7, 39.1, 38.3, 37.3, 36.8, 36.5, 34.8, 33.5, 31.6, 31.5, 30.4, 29.6, 28.9, 27.0, 25.8, 20.5, 20.0, 19.3, 18.2, 17.6, 15.4, 12.8

Production Example  2. Ergostenol - Glucose  Produce

2-1. 2,3,4,6- Tetrabenzoyl Glucose - Ergostenol  Produce

Ergostenol (0.1 g) and 2,3,4,6-tetra-O-benzoyl-aD-glucopyranosyl trichloroacetimimidate (0.37 g) are dissolved in methylene chloride (2.5 ml) and then 4A molecules Rush was added and stirred at room temperature. TMSOTf (4.5 μl) was added and stirred at room temperature for 2.5 hours. TEA (1 ml) was added to the reaction solution, neutralized, and the filtrate was concentrated under reduced pressure. The concentrate was purified via column chromatography to give the product in 90% yield.

2-2. Ergostenol - Glucose  Produce

2,3,4,6-tetrabenzoyl glucose-ergostenol (0.46 g) obtained in Preparation Example 2-1 was dissolved in methylene chloride (5 ml) and methanol (5 ml), followed by 0.5 M NaOMe (5.6 ml). ) Was added and stirred at room temperature for 1.5 hours. After neutralizing with Dowex Mac-3, the filtrate was concentrated under reduced pressure. Purification by column chromatography gave the product in 71% yield.

¹ H NMR (300 MHz, Pyridine-d ⁵ ) δ (ppm): 5.11 (d, 1H, J = 7.7 Hz), 4.65-4.68 (m, 1H), 4.44-4.50 (m, 1H), 4.28-4.39 ( m, 2H), 4.03-4.12 (m, 3H), 2.36 (d, 1H, J = 14.5 Hz), 2.25-2.28 (m, 2H), 2.06 (m, 1H), 1.83-1.96 (m, 4H) , 1.32-1.61 (m, 11H), 1.06-1.21 (m, 8H), 0.99-1.01 (m, 4H), 0.88-0.90 (m, 6H), 0.81-0.85 (m, 6H), 0.63 (s, 3H)

¹³ C NMR (75 MHz, Pyridine-d ⁵ ) δ (ppm): 142.61, 126.85, 102.10, 78.69, 78.62, 76.94, 75.41, 71.84, 62.99, 57.01, 49.56, 44.06, 42.97, 39.37, 37.57, 37.15, 36.75 , 35.08, 34.87, 33.81, 31.77, 30.72, 30.09, 29.91, 29.26, 27.37, 26.13, 20.68, 20.23, 19.50, 18.51, 17.77, 15.63, 12.83

Production Example  3. Ergostenol - Galactose  Produce

3-1. 2,3,4,6- Tetrabenzoyl Galactose - Ergostenol  Produce

Ergostenol (0.136 g) and 2,3,4,6-tetra-O-benzoyl-aD-galactopyranosyl trichloroacetimidadate (0.5 g) are dissolved in methylene chloride (10 ml) and then 4A mole. The cylindrical was added and stirred at room temperature. Cellulose-HClO ₄ (0.17 mmol / g, 60 mg) was added thereto and stirred at room temperature for one day. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified via column chromatography to give the product in 79% yield.

3-2. Ergostenol - Galactose  Produce

2,3,4,6-tetrabenzoyl galactose-ergostenol (0.39 g) obtained in Preparation Example 3-1 was dissolved in methylene chloride (4 ml) and methanol (4 ml), followed by 0.5M NaOMe (4.8). ml) was added and stirred at room temperature for 2 hours. After neutralizing with Dowex Mac-3, the filtrate was concentrated under reduced pressure. Purification by column chromatography gave the product in 80% yield.

¹ H NMR (300 MHz, Pyridine-d ⁵ ) δ (ppm): 5.02 (d, 1H, J = 7.5 Hz), 4.63 (s, 1H), 4.48-4.54 (m, 3H), 4.20-4.28 (m, 2H), 4.04 (m, 1H), 2.37 (d, 1H, J = 14.5 Hz), 2.25 (m, 2H), 2.09 (m, 1H), 1.83-1.93 (m, 4H), 1.34-1.61 (m , 11H), 1.06-1.19 (m, 8H), 0.99-1.01 (m, 4H), 0.88-0.90 (m, 6H), 0.82-0.85 (m, 6H), 0.62 (s, 3H)

¹³ C NMR (75 MHz, Pyridine-d ⁵ ) δ (ppm): 142.60, 126.86, 102.69, 77.11, 76.80, 75.48, 72.76, 70.45, 62.70, 57.01, 49.56, 44.08, 42.97, 39.37, 37.57, 37.14, 36.77 , 35.08, 34.89, 33.81, 31.76, 30.72, 30.11, 29.92, 29.27, 27.36, 26.12, 20.67, 20.22, 19.49, 18.50, 17.76, 15.63, 12.81

Production Example  4. Ergostenol - Xylose  Produce

4-1. 2,3,4- Tribenzoyl Xylose - Ergostenol  Produce

Ergostenol (0.5 g) and 2,3,4-tri-O-benzoyl-aD-xylopyranosyl trichloroacetimimidate (1.5 g) are dissolved in methylene chloride (30 ml) and then 4A molecular weight. The broth was added and stirred at room temperature. Cellulose-HClO ₄ (0.17 mmol / g, 0.22 g) was added thereto and stirred at room temperature for one day. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The concentrate was purified via column chromatography to give the product in 82% yield.

4-2. Ergostenol - Xylose  Produce

2,3,4-tribenzoyl xylose-ergostenol (0.86 g) obtained in Preparation Example 4-1 was dissolved in methylene chloride (10 ml) and methanol (10 ml), followed by 0.5 M NaOMe (12 ml). Was added and stirred at room temperature for 2 hours. After neutralizing with Dowex Mac-3, the filtrate was concentrated under reduced pressure. Purification by column chromatography gave the product in 70% yield.

¹ H NMR (300 MHz, Pyridine-d ⁵ ) δ (ppm): 4.95 (d, 1H, J = 7.5 Hz), 4.42-4.48 (m, 1H), 4.22-4.35 (2H, m), 4.05 (t, 1H, J = 8.0 Hz), 3.96 (m, 1H), 3.83 (t, 1H, J = 10.3 Hz), 2.37 (d, 1H, J = 12.6 Hz), 2.25-2.28 (m, 2H), 2.11 ( m, 1H), 1.84-1.97 (m, 4H), 1.36-1.65 (m, 11H), 1.04-1.32 (m, 9H), 1.00 (d, 3H, J = 6.4 Hz), 0.88-0.90 (m, 6H), 0.81-0.85 (m, 6H), 0.64 (s, 3H)

¹³ C NMR (75 MHz, Pyridine-d ⁵ ) δ (ppm): 142.65, 126.84, 103.04, 78.59, 77.31, 75.16, 71.28, 67.23, 57.03, 49.57, 44.23, 42.99, 39.38, 37.58, 37.17, 36.85, 35.09 , 34.94, 33.81, 31.76, 30.73, 30.22, 29.92, 29.27, 27.38, 26.13, 20.68, 20.25, 19.51, 18.51, 17.77, 15.63, 12.84

Example  One. Ergostenol  And collagen producing activity of glycoside derivatives thereof

In the present invention, the following experiment was performed to evaluate the arthritis activity of ergostenol, β-glucosyl ergostenol, β-galactosyl ergostenol, and β-xyloxy ergostenol.

Human chondrocytes were used to compare the expression level of MMP (collagenase), a biomarker that causes cartilage tissue damage.

As a result, it was confirmed that the tumor necrosis factor (TNF-a) inhibits the expression of MMP-1 and MMP-13.

In addition, collagen (COL2A1) production activity was verified. As a result, it was confirmed that there is activity to increase collagen expression damaged by tumor necrosis factor.

This experiment compares the gene expression levels of collagenase 1,3,13 and collagen, biomarkers used in the activity verification for arthritis, and cultured human chondrocytes. And the synthetic compound was treated at this concentration for 24 hours. Then, RT-PCR test was performed using specific primers of each gene. The gene amplification conditions were performed 25 ~ 30 cycles at 62 ^o C and observed after EtBR staining after electrophoresis using 1% agarose gel.

From the above results, it can be seen that ergostenol and its glycoside derivatives inhibit the expression of MMP-1 and MMP-13, promote collagen production, and alleviate arthritis.

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (2)

A pharmaceutical composition for preventing or treating arthritis, comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]

Wherein R is hydrogen, acetyl,

,

,

,

,

, And

It is selected from the group consisting of.
The pharmaceutical composition of claim 1, wherein the arthritis is degenerative arthritis.

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