KR20130053928A - A pharmaceutical composition for treating or preventing inflammatory ocular diseases comprising caffeoyl derivatives - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing a caffeoyl derivative for preventing or treating inflammatory ocular diseases is provided to effectively suppress expression of inflammatory chemokines. CONSTITUTION: A pharmaceutical composition for preventing or treating inflammatory ocular diseases contains a caffeoyl derivative of chemical formula 1 or a pharmaceutically acceptable salt thereof. The derivative is selected from the group consisting of: (E)-4-(4-hydroxy-3-methoxy butyl)but-3-ene-2-one; (E)-1-(4-hydroxy-3-methoxyphenyl)hep-1-ene-3-one; (E)-3-(4-hydroxy-3-methoxyphenyl)-1-phenylpro-2-ene-1-one; (E)-1-(4-hydroxy-3-methoxyphenyl)-5-phenylpen-1-ene-3-one; (E)-1-(4-hydroxy-3-methoxyphenyl)-6-phenylhex-1-ene-3-one; and (E)-1-(4-hydroxy-3-methoxyphenyl)-7-phenylhep-1-ene-3-one.

Description

A pharmaceutical composition for treating or preventing inflammatory ocular diseases comprising caffeoyl derivatives}

The present invention relates to a caffeoyl derivative compound that can be usefully used for the prevention or treatment of inflammatory eye diseases.

Inflammation is a local or systemic defense against damage or infection of cells and tissues. Inflammation is primarily caused by a cascade of biological reactions that occur by the direct response of numerous humoral mediators that make up the immune system or by stimulating local or systemic effector systems. Mediators involved in the inflammatory response include cytokines and immune cells such as polymorphonuclear leukocytes (PMN), cytotoxic T lymphocytes (CTL), NK cells, and macrophages. Inflammatory diseases are caused by the imbalance of inflammatory cytokines and effector cells, and the main inflammatory diseases include inflammatory eye diseases, inflammatory bowel diseases, autoimmune diseases, and neuropathic joint diseases. .

Major inflammatory cytokines known to date include tumor necrosis factor-α (TNF-α), INF-γ, IL-1, IL-6 and IL-18 produced by macrophages and monocytes. In order to treat inflammatory diseases caused by imbalance of inflammatory cytokines, various studies have been conducted to suppress the inflammatory cytokines and promote the production of anti-inflammatory cytokines.

Grave's ophthalmopathy (thyroid-associated ophthalmopathy), a type of inflammatory eye disease, is a common disease with an incidence of 1/1000 women per year. Individuals with thyroid ophthalmopathy increase the volume of orbital fat and connective tissue and extraocular muscles within the limited orbital space, resulting in morphological changes such as exophthalmos, eyelid retraction, and 3 to 5% of eye movement disorders and diplopia, even He suffers from pain and inflammation accompanied by permanent vision loss.

To date, studies on inflammatory eye disease have focused on the immune response that occurs through activation of autologous T cells and B cells. Inflammation-related cytokines and chemokines such as IL-1, IFN-γ, IL-6, and IP-10 secreted by immune cells have been reported to act as important triggers to produce and secrete large quantities of inflammation-related substances ( khoo, TK; Bahn, RS; Pathogenesis of Graves's ophthalmopathy:.. The role of autoantibodies Thyroid 2007, 17, 1013-8).

In addition, recent studies have shown that both levels of IP-10 and INF-γ in inflammatory chemokines are elevated in the blood of patients with thyroid ophthalmopathy, a type of inflammatory eye disease. In addition, confirming that TNF-α and INF-γ induce mass production of IP-10 in patients with thyroid ophthalmopathy, it has been shown that INF-γ and IP-10 are associated with thyroid ophthalmopathy disease (The Journal of Clinical Endocrinology & Metabolism 91 (2): 614-620).

Thyroid ophthalmopathy progresses from an early acute inflammatory phase to a late chronic fibrosis. In the inflammatory phase, a therapeutic agent targeting an inflammatory site is not used, but an immunosuppressive agent is used as a therapy. Specifically, steroids such as dexamethasone, a non-selective immunosuppressive agent that causes systemic reactions, are most commonly used. However, side effects of high-dose administration are not only problematic, but some patients do not respond to steroid treatment. In the later stages of thyroid ophthalmopathy, fibrosis of the orbital tissue occurs, and irreversible changes that no longer respond to drug treatment progress. Therefore, there is an urgent need for an appropriate therapeutic agent that can alleviate the early inflammatory phase with fewer side effects.

Under these circumstances, the present inventors have made intensive efforts to develop a therapeutic agent that can alleviate the early inflammatory phase of inflammatory eye disease. As a result, the caffe oil derivative compound according to the present invention effectively inhibits the expression of inflammatory chemokine (IP-10). It was confirmed that the present invention can be usefully used for the prevention or treatment of eye diseases, and completed the present invention.

The present invention is to provide a pharmaceutical composition comprising a caffeoyl derivative compound or a pharmaceutically acceptable salt thereof that can prevent or treat inflammatory eye disease.

As one embodiment for solving the above problems, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory eye disease comprising a caffeoyl derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

R ₁ is C ₁ -C ₄ alkyl,

R ₂ is C ₁ -C ₆ alkyl, phenyl or C ₁ -C ₆ phenylalkyl.

As used herein, the term 'alkyl' means a straight or branched chain saturated hydrocarbon radical having 1 to 4 or 1 to 6 carbon atoms.

As used herein, the term 'phenylalkyl' refers to a straight or branched chain saturated hydrocarbon radical having 1 to 6 carbon atoms linked to a phenyl group, and includes, for example, phenylethyl, phenylpropyl, phenylbutyl and the like.

In a preferred embodiment of the invention, it is preferred that R ₁ is methyl and R ₂ is methyl, butyl, phenyl, phenylethyl, phenylpropyl or phenylbutyl.

Representative examples of the caffeoyl derivative represented by Formula 1 are as follows:

1) (E) -4- (4-hydroxy-3-methoxyphenyl) but-3-en-2-one,

2) (E) -1- (4-hydroxy-3-methoxyphenyl) hep-1-en-3-one,

3) (E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylpro-2-en-1-one,

4) (E) -1- (4-hydroxy-3-methoxyphenyl) -5-phenylphen-1-en-3-one,

5) (E) -1- (4-hydroxy-3-methoxyphenyl) -6-phenylhex-1-en-3-one, and

6) (E) -1- (4-hydroxy-3-methoxyphenyl) -7-phenylhep-1-en-3-one.

The caffeoyl derivative represented by Formula 1 of the present invention may be separated from a natural source, obtained from a natural source, prepared by chemical modification, chemically synthesized, or a commercially prepared product. An exemplary method for preparing the compound represented by Formula 1 according to the present invention is as follows:

[Reaction Scheme 1]

A compound represented by the formula (II), which is readily available commercially, is reacted with tert-butyldimethylsilyl trifluoromethansulfonate (TBSOTf) to form a protecting group to obtain a compound represented by the formula (III). The compound represented by the above formula (III) is subjected to Grignard reaction with a magnesium bromide reagent having a desired substituent to obtain a racemic secondary alcohol compound represented by the formula (IV). After oxidizing the alcohol compound with an oxidizing agent, the caffeoyl derivative compound represented by Formula (I) may be prepared by deprotection in a tetrahydrofuran solvent.

Caffeoyl derivative compounds of the present invention can be used in the form of pharmaceutically acceptable salts. The compounds of the present invention may also be used alone or in combination with other pharmaceutically active compounds or as a set.

As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium.

As used herein, the term 'inflammatory eye disease' refers to all inflammatory diseases in the eye, intraocular, orbital, eye, periorbital, posterior, or cone, accompanied by or induced by the inflammatory response.

The inflammatory eye disease may preferably be any one of thyroid ophthalmopathy, uveitis, scleritis and idiopathic orbital inflammation, and more preferably thyroid ophthalmopathy.

Caffeoyl derivative compounds or pharmaceutically acceptable salts thereof according to the present invention can inhibit the expression of inflammatory chemokines and thus can be usefully used for the prevention or treatment of inflammatory eye diseases.

Preferably, the composition of the present invention can inhibit the expression of Interferon-γ inducible protein-10 (IP-10). In particular, the compound of the present invention can directly inhibit the expression of the IP-10 by targeting IP-10, which is a major chemokine of the inflammatory eye disease inflammatory site, the conventional steroid preparations that do not directly target the inflammatory site Side effects of indirect treatment used, such as systemic reactions, problems that cannot be treated with steroids in some patients, can be addressed.

Accordingly, as another aspect, the present invention provides a method for the prevention or treatment of inflammatory eye disease, comprising administering to a subject having or probable inflammatory eye disease a pharmaceutically effective amount of a composition of the present invention. .

According to a specific embodiment, the caffe oil derivative compound of the present invention inhibited the expression of IP-10 induced by interferon gamma of inflammatory orbital fibroblasts in a concentration dependent manner (FIGS. 1 and 2). That is, by inhibiting the inflammatory response induced by inflammatory chemokine at the site of inflammation, it was confirmed that the effective preventive and therapeutic effects on inflammatory eye disease without side effects due to systemic action.

As used herein, the term 'prevention' means all actions of inhibiting or delaying inflammatory eye disease by administration of a composition comprising the caffeoyl derivative compound or a pharmaceutically acceptable salt thereof. In addition, the term 'treatment' as used in the present invention means any action that improves or advantageously changes the condition of the disease by administration of the composition comprising the caffeoyl derivative compound or a pharmaceutically acceptable salt thereof.

The term 'individual' as used in the present invention means all animals including humans who have already developed or may develop an inflammatory eye disease, and by administering the composition of the present invention to an individual, the disease can be effectively prevented and treated.

The composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term 'pharmaceutically effective amount' refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to the medical treatment in a medical treatment, and an effective dose level may refer to an individual type and severity, age, Sex, type of inflammatory eye disease, activity of drug, sensitivity to drug, time of administration, route of administration and rate of release, duration of treatment, factors including concomitant drug use and other factors well known in the medical arts. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

The composition for preventing or treating inflammatory eye disease of the present invention may include a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described active ingredient. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

Compositions for the prophylaxis or treatment of inflammatory eye diseases of the present invention are in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. Can be formulated and used. In detail, when formulating, it can be prepared by using diluents or excipients such as fillers, weighing agents, binders, humectants, disintegrants, surfactants and the like which are generally used. Solid formulations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. Examples of the suppository base include withexol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

Compositions for the prophylaxis or treatment of inflammatory eye diseases of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, the dosage of Depending on the condition and weight, extent of disease, drug form, route of administration, and time, it may be appropriately selected by those skilled in the art.

As another aspect, the present invention provides a composition for inhibiting the expression of IP-10 comprising a caffeoyl derivative compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

In a specific embodiment, when the caffeyl oil derivative compound of the present invention to the inflammatory fibro orbital cells induced inflammatory response with interferon gamma, it was confirmed that significantly inhibit the expression of IP-10 compared to the control (Control) (FIG. 2). Therefore, the composition for inhibiting IP-10 expression of the present invention can be usefully used for the prevention and treatment of diseases mediated by IP-10, including inflammatory eye diseases.

Caffe oil derivatives according to the present invention not only do not have systemic side effects of steroidal drugs that are conventionally used as a therapeutic agent for inflammatory eye diseases, but also effectively inhibit the expression of inflammatory chemokines (IP-10) at the site of inflammation, It can be usefully used for the prevention or treatment of eye diseases.

Figure 1 shows the effect of inhibiting the expression of IP-10 in inflammatory orbital fibroblasts by the compounds synthesized in Preparation Examples 1 to 6 of the present invention according to one embodiment of the present invention (Control: untreated group, INF-γ: interferon gamma treatment group, JC 1 to JC 6: interferon gamma + compound treatment group according to Preparation Examples 1 to 6 of the present invention).
Figure 2 shows the effect of inhibiting the expression of IP-10 of non-inflammatory orbital fibroblasts and inflammatory orbital fibroblasts by the compound synthesized in Preparation Example 3 of the present invention according to an embodiment of the present invention (Normal: non-inflammatory Orbital fibroblasts, TAO: Inflammatory orbital fibroblasts, Control: untreated group, INF-γ: interferon gamma treated group, 5μM to 20μM: Compound 5μM to 20μM treatment group according to Preparation Example 3 of the present invention).

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention more specifically, but the scope of the present invention is not limited by these examples.

Manufacturing example  1: (E) -4- (4- Hydroxy -3- Methoxyphenyl Synthesis of but-3-en-2-one.

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Thereafter, 15.0 mmol of methylmagnesium bromide was reacted with Grignard to obtain a racemic secondary alcohol compound. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was separated and purified through column chromatography to obtain (E) -4- (4-hydroxy-3-methoxyphenyl) but-3-en-2-one.

R _f = 0.3 (30% ethyl acetate / hexanes); mp 126 [deg.] C; IR (neat, NaCl) 3408, 2975, 1730, 1665, 1481, 1248, 1080 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.46 (d, J = 12.0 Hz, 1H), 7.07 (t, J = 4.8 Hz, 2H), 6.93 (d, J = 5.4 Hz, 1H), 6.59 (d, J = 12.0 Hz, 1H), 5.71 (brs, 1H), 3.92 (s, 3H), 2.37 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) 198.9, 148.8, 147.4, 144.2, 127.2, 125.3, 123.9, 115.3, 109.9, 56.3, 27.6; HRMS calcd. for C ₁₁ H ₁₃ O ₃ : 193.0865 [M + H] ⁺ , found: 193.0878.

Manufacturing example  2: (E) -1- (4- Hydroxy -3- Methoxyphenyl Synthesis of Hep-1-en-3-one

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Thereafter, a racemic secondary alcohol compound was obtained by performing Grignard reaction with 15.0 mmol of butylmagnesium bromide. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was separated and purified through column chromatography to obtain (E) -1- (4-hydroxy-3-methoxyphenyl) hep-1-en-3-one.

R _f = 0.4 (20% ethyl acetate / hexanes); Semisolid; IR (neat, NaCl) 3090, 2985, 2875, 1732, 1473, 1254, 1089 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.50 (d, J = 16.0 Hz, 1H), 7.12-7.04 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 5.43 (brs, 1H), 3.93 (s, 3H), 2.66 (t, J = 7.5 Hz, 2H), 1.70-1.64 (m, 2H), 1.42-1.36 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) 200.4, 148.1, 146.8, 142.6, 126.9, 123.9, 123.3, 114.9, 109.5, 56.2, 40.7, 27.0, 22.6, 14.3; HRMS calcd. for C ₁₄ H ₁₉ O ₃ : 235.1334 [M + H] ⁺ , found: 235.1351.

Manufacturing example  3: (E) -3- (4- Hydroxy -3- Methoxyphenyl )-One- Phenylprop 2-en-1-one

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Then, a racemic secondary alcohol compound was obtained by carrying out Grignard reaction with 15.0 mmol of phenylmagnesium bromide. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography to obtain (E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylpro-2-en-1-one. .

R _f = 0.4 (20% ethyl acetate / hexanes); mp 86-87 ° C .; IR (neat, NaCl) 3321, 3001, 2960, 1739, 1656, 1420, 1285, 1038 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 8.02 (d, J = 5.4 Hz, 2H), 7.76 (d, J = 11.7 Hz, 1H), 7.58 (t, J = 5.1 Hz, 1H), 7.50 (t, J = 5.4 Hz, 2H), 7.38 (d, J = 11.7 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 7.14 (s, 1H), 6.96 (d, J = 6.0 Hz, 1H) , 5.66 (brs, 1 H), 3.95 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) 191.1, 149.0, 147.4, 145.7, 138.9, 132.9, 128.9, 128.8, 127.8, 123.8, 120.1, 115.4, 110.6, 56.4; HRMS calcd. for C ₁₆ H ₁₅ O ₃ : 255.1051 [M + H] ⁺ , found: 255.1038.

Manufacturing example  4: (E) -1- (4- Hydroxy -3- Methoxyphenyl ) -5- Phenylphene Synthesis of -1-en-3-one

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Then, racemic secondary alcohol compound was obtained by performing Grignard reaction with 15.0 mmol of phenylethylmagnesium bromide. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was separated and purified through column chromatography to obtain (E) -1- (4-hydroxy-3-methoxyphenyl) -5-phenylphen-1-en-3-one. .

R _f = 0.3 (20% ethyl acetate / hexanes); IR (neat, NaCl) 3365, 2957, 2868, 1733, 1665, 1471, 1254, 1092 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.48 (d, J = 16.1 Hz, 1H), 7.32-7.15 (m, 5H), 7.04 (t, J = 5.7 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.51 (d, J = 16.1 Hz, 1H), 5.36 (brs, 1H), 3.89 (s, 3H), 2.99 (s, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) 199.9, 149.0, 147.6, 143.6, 141.7, 128.9, 128.8, 127.2, 126.5, 124.2, 123.9, 115.5, 110.1, 56.3, 42.6, 30.7; HRMS calcd. for C ₁₈ H ₁₉ O ₃ : 283.2334 [M + H] ⁺ , found: 283.2355.

Manufacturing example  5: (E) -1- (4- Hydroxy -3- Methoxyphenyl ) -6- Phenylhex Synthesis of -1-en-3-one

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Thereafter, 15.0 mmol of phenylpropylmagnesium bromide was reacted with Grignard to obtain a racemic secondary alcohol compound. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was separated and purified by column chromatography to obtain (E) -1- (4-hydroxy-3-methoxyphenyl) -6-phenylhex-1-en-3-one. .

R _f = 0.3 (20% ethyl acetate / hexanes); IR (neat, NaCl) 3354, 3007, 2956, 1739, 1649, 1460, 1266, 1048 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.44 (d, J = 16.1 Hz, 1H), 7.28 (t, J = 6.6 Hz, 2H), 7.19 (t, J = 6.9 Hz, 3H), 7.04 (t, J = 5.0 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 16.1 Hz, 1H), 5.39 (brs, 1H), 3.90 (s, 3H), 2.67 (q, J = 7.6 Hz, 3H), 2.05-1.96 (m, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) 200.7, 148.9, 147.4, 143.3, 142.1, 128.9, 128.8, 127.3, 126.3, 124.3, 123.8, 115.4, 110.0, 56.3, 40.1, 35.6, 26.3; HRMS calcd. for C ₁₉ H ₂₁ O ₃ : 297.1491 [M + H] ⁺ , found: 297.1479.

Manufacturing example  6: (E) -1- (4- Hydroxy -3- Methoxyphenyl ) -7- Phenylhep Synthesis of -1-en-3-one

(E) -3- (4-hydroxy-3-methoxyphenyl) acrylaldehyde was reacted with 11.0 mmol of tert-butyldimethylsilyl trifluoromethanesulfonate to form a protecting group with a tert-butyldimethylsiloxy group. Thereafter, 15.0 mmol of phenylbutylmagnesium bromide was reacted with Grignard to obtain a racemic secondary alcohol compound. The alcohol compound was oxidized using an oxidizing agent to obtain a ketone compound, which was dissolved in 80 mL of tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF, 10.0 mmol, 1 M solution in THF) was added thereto at room temperature for 10 minutes. Stirred. The reaction solution was diluted with 30 mL of ethyl acetate, washed with 70 mL of saturated brine, and the organic layer was separated. The water layer was extracted twice with 30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of saturated brine, separated, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was separated and purified through column chromatography to obtain (E) -1- (4-hydroxy-3-methoxyphenyl) -7-phenylhep-1-en-3-one. .

R _f = 0.3 (20% ethyl acetate / hexanes); mp 74-75 ° C .; IR (neat, NaCl) 3043, 3002, 2975, 1731, 1667, 1458, 1292, 1086 cm ⁻¹ ; ¹ H NMR (400 MHz, CDCl ₃ ) 7.47 (d, J = 16.1 Hz, 1H), 7.26 (t, J = 6.8 Hz, 2H), 7.16 (t, J = 7.2 Hz, 3H), 7.06 (t, J = 6.1 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 16.1 Hz, 1H), 5.48 (brs, 1H), 3.90 (s, 3H), 2.65 (q, J = 4.9 Hz, 3H), 1.77-1.55 (m, 3H), 1.27 (t, J = 6.3 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) 200.8, 148.9, 147.5, 143.2, 142.7, 128.8, 128.7, 127.3, 126.1, 124.3, 123.8, 115.4, 110.0, 56.3, 40.9, 36.2, 31.5, 24.6; HRMS calcd. for C ₂₀ H ₂₃ O ₃ : 311.1647 [M + H] ⁺ , found: 311.1662.

Example  One: Manufacturing example  Inflammation of compounds synthesized from 1 to 6 IP -10 expression inhibition effect test

 Orbital adipose tissue was obtained from a patient with thyroid ophthalmopathy.² Inflammatory orbital fibroblasts were inoculated into T-flasks and cultured in a cell culture using DMEM culture medium containing 10% fetal bovine serum and antibiotics.

After 30 minutes pretreatment with 10 uM of the sample compound synthesized according to Preparation Examples 1 to 6 of the present invention, the cultured inflammatory orbital fibroblasts were treated with 10 ng / ml of interferon gamma (IFN-γ). Was collected. Thereafter, an enzymelinked immumosorbent assay was performed to increase the expression of IP-10 induced by interferon gamma in inflammatory orbital fibroblasts and to express the sample compound (compound synthesized in Preparation Examples 1 to 6). Inhibitory effect was quantified. All experiments were repeated three or more times, each of which was analyzed for significance using the student's t-test and the results are shown in FIG.

As a result, as shown in Figure 1, when only interferon gamma treatment in inflammatory orbital fibroblasts significantly increased the expression of IP-10. However, when interferon gamma and the sample compound were administered, expression of IP-10 was significantly inhibited. In particular, the compound synthesized in Preparation Example 3 (JC 3), it was confirmed that inhibiting the expression of IP-10 to a level similar to the normal control (control).

Example  2: Manufacturing example  In the inflammatory response of the compound synthesized IP -10 expression inhibition effect test

Orbital adipose tissue was obtained from patients who underwent orbital or bleeding surgery for non-inflammatory diseases to primarily culture normal orbital fibroblasts (Normal, n = 2), and orbital adipose tissue from patients with thyroid ophthalmopathy for comparative analysis. Was obtained (TAO, n = 2). All orbital fat tissues obtained were treated with collagenase to obtain 75 cm ² Cells were obtained by inoculating a T-flask and cultured in a cell culture using DMEM culture medium containing 10% fetal bovine serum and antibiotics. Inflammatory orbital fibroblasts from normal and thyroid ophthalmopathy patients from four patients were used for the test.

Non-inflammatory orbital fibroblasts and inflammatory orbital fibroblasts from patients with thyroid ophthalmopathy were cultured in DMEM medium and pretreated with sample compounds synthesized according to Preparation Example 3 at 5-20 uM per ml for 30 minutes, followed by interferon gamma (IFN -γ, 10 ng / ml) was added to the culture. Negative control (Control) was not treated anything, after 24 hours the expression of IP-10 in the cells was quantified by the enzyme-linked immumosorbent assay (enzymelinked immumosorbent assay) and the results are shown in FIG.

As a result, as shown in FIG. 2, the expression of IP-10 was significantly increased by the treatment with interferon gamma alone, but the concentration of IP-10 was increased depending on the concentration of the sample compound synthesized according to Preparation Example 3 of the present invention. It was confirmed that the inhibition. These results indicate that the compounds of the present invention can significantly inhibit the expression of major chemokine IP-10 in inflammatory eye diseases, and thus can be usefully used for the prevention and treatment of inflammatory eye diseases.

Claims (5)

A pharmaceutical composition for preventing or treating an inflammatory eye disease including a caffeoyl derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
R ₁ is C ₁ -C ₄ alkyl,
R ₂ is C ₁ -C ₆ alkyl, phenyl or C ₁ -C ₆ phenylalkyl.
According to claim 1, wherein the cafe oil derivative represented by Formula 1
1) (E) -4- (4-hydroxy-3-methoxyphenyl) but-3-en-2-one,
2) (E) -1- (4-hydroxy-3-methoxyphenyl) hep-1-en-3-one,
3) (E) -3- (4-hydroxy-3-methoxyphenyl) -1-phenylpro-2-en-1-one,
4) (E) -1- (4-hydroxy-3-methoxyphenyl) -5-phenylphen-1-en-3-one,
5) (E) -1- (4-hydroxy-3-methoxyphenyl) -6-phenylhex-1-en-3-one, and
6) (E) -1- (4-hydroxy-3-methoxyphenyl) -7-phenylhep-1-en-3-one
Pharmaceutical composition for the prevention or treatment of inflammatory eye disease, characterized in that selected from the group consisting of.
The pharmaceutical composition for preventing or treating inflammatory eye disease according to claim 1, wherein the inflammatory eye disease is thyroid ophthalmopathy, uveitis, scleritis or idiopathic orbital inflammation.
According to claim 1, wherein the composition is a pharmaceutical composition for the prevention or treatment of inflammatory eye disease, characterized in that to suppress the expression of Interferon-γ inducible protein-10 (IP-10).
A composition for inhibiting expression of IP-10 comprising a caffeoyl derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
R ₁ is C ₁ -C ₄ alkyl,
R ₂ is C ₁ -C ₆ alkyl, phenyl or C ₁ -C ₆ phenylalkyl.

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