KR102144153B1 - Ester and acid anhydride having antipyretic, analgesic and anti-inflammatory activity and preparation method thereof - Google Patents

Abstract

The present invention relates to an ester and an acid anhydride compound having antipyretic, analgesic and anti-inflammatory activity, and a method for preparing the same, wherein the compound represented by Formula 1 or Formula 2 according to the present invention has excellent antipyretic, analgesic and anti-inflammatory activity, and thus related diseases It may be useful for use in preventing, improving and treating.

Description

Ester and acid anhydride having antipyretic, analgesic and anti-inflammatory activity and preparation method thereof having antipyretic, analgesic and anti-inflammatory activity

The present invention relates to esters and acid anhydride compounds having antipyretic, analgesic and anti-inflammatory activities, and a method for preparing the same.

Aspirin is the first in the world to synthesize acetylsalicylic acid, a major component of aspirin, in a pure and stable form by Dr. Felix Hoffmann at Bayer Research Center in Wuppertal, Germany. It is an antipyretic, analgesic, anti-inflammatory drug and cardiovascular disease prevention drug that began to be widely used after success. Acetylsalicylic acid acts on an enzyme called Cyclooxygenase. This enzyme promotes inflammation in the body to make prostaglandin, which causes pain and fever. Acetylsalicylic acid acts on cyclooxygenase to inhibit the production of prostaglandin.

Anti-inflammatory, analgesic, and antipyretic drugs are representative of nonsteroidal antiinflammatory drugs, and drugs include salicylic acid derivatives (aspirin, salicylic acid-like compounds (salicylic acid, ethenzamide)) and aniline derivatives ( Phenacetin, etc.), parizolone derivatives (artipyrine, aminopyrine, sulpyrine), commonly referred to as pyrine analgesics, pyrazolidine derivatives (phenylbutazone, oxy) that have stronger anti-inflammatory, antirheumatism, uric acid excretion than antipyretic analgesic effect. Penbutazone).

These drugs have a strong anti-inflammatory action, analgesic and antipyretic action, but they have a high frequency of causing digestive disorders, liver injury, or systemic side effects due to gastrointestinal absorption. In addition, existing antipyretic and analgesic anti-inflammatory drugs have the disadvantage that the effect is limited to a part, and there is a problem that the effect is low compared to the side effects. Therefore, there is a demand for the development of an alternative agent that exhibits sufficient anti-inflammatory, analgesic, and antipyretic effects while having low side effects.

On the other hand, ester reaction is generally a reaction to obtain a compound formed by desorbing water molecules from an organic acid or inorganic acid and alcohol, and the acid anhydride formation reaction is to obtain an acid anhydride by removing water molecules from two acids. It's a reaction.

Accordingly, the present inventors synthesized 3 types of ester compounds and 5 types of acid anhydride compounds, and confirmed that the 8 types of compounds have excellent antipyretic, analgesic and anti-inflammatory effects, maintain the effect for a long time, and reduce side effects. The present invention has been completed.

Korean Patent Registration No. 10-1150528

An object of the present invention is to provide a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical, health functional food and health food composition for antipyretic, analgesic and anti-inflammatory, including the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical, health functional food and health food composition for antipyretic, analgesic and anti-inflammatory, including a compound represented by Chemical Formula 2, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing a compound represented by Formula 1 or Formula 2.

To achieve the above object,

The present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

이고, R¹은

이다.R is

And R ¹ is

to be.

In addition, the present invention provides a pharmaceutical composition for antipyretic, analgesic, and anti-inflammatory comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

And

It is a substituent selected from the group consisting of.

In addition, the present invention provides a pharmaceutical composition for antipyretic, analgesic and anti-inflammatory comprising a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

Further, the present invention provides a health functional food and a health food composition for antipyretic, analgesic and anti-inflammatory, including a compound represented by the following formula (1) or a food pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

And

It is a substituent selected from the group consisting of.

In addition, the present invention provides a health functional food and health food composition for antipyretic, analgesic, and anti-inflammatory, including a compound represented by the following formula (2) or a food pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

Furthermore, the present invention is as shown in the following Scheme 1,

Adding a compound represented by Formula 3, a compound represented by Formula 4, and a catalyst to an organic solvent, refluxing and then concentrating to obtain a compound represented by Formula 1 (Step 1);

It provides a method for producing a compound represented by the following formula (1) including.

[Scheme 1]

In Scheme 1 above,

이고, R is

ego,

이다.R ¹ is

to be.

In addition, the present invention, as shown in the following scheme 2,

Dissolving the compound represented by Formula 3 and the compound represented by Formula 5 in an organic solvent, refluxing, and stirring to obtain a compound represented by Formula 1 (Step 2);

It provides a method for producing a compound represented by the following formula (1) including.

[Scheme 2]

In Scheme 2 above,

R is C _1-15 straight or branched chain alkyl,

이다.R ¹ is

to be.

In addition, the present invention, as shown in the following Scheme 3,

Dissolving the compound represented by Formula 3 and the compound represented by Formula 6 in an organic solvent, refluxing, and stirring to obtain a compound represented by Formula 2 (Step 3);

It provides a method for producing a compound represented by the following formula (2) including.

[Scheme 3]

In Scheme 3 above,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

Since the compound represented by Formula 1 or Formula 2 according to the present invention has excellent antipyretic, analgesic and anti-inflammatory activities, it may be useful for preventing, improving and treating related diseases.

Hereinafter, the present invention will be described in detail.

Compound or its pharmaceutically Acceptable salt

The present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.

In Formula 1,

이고, R is

ego,

이다.R ¹ is

to be.

Preferred examples of the compound represented by Chemical Formula 1 according to the present invention include the following compounds.

1) 1,1-dioxidobenzo[d]isothiazol-3-yl 2-(4-isobutylphenyl)propanoate.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The expression pharmaceutically acceptable salt is a concentration that is relatively non-toxic and harmless to the patient, and side effects caused by this salt do not degrade the beneficial efficacy of the basic compound of formula (1). It means inorganic addition salt. As these salts, inorganic acids and organic acids can be used as free acids, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, maleic acid, fumarin Acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesol Ponic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, malonic acid, and the like can be used. In addition, these salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.), and the like. For example, as an acid addition salt, acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hybenzate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Isethionate, Lactate, Malate, Mali Eate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccha Rate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, Potassium, sodium, tromethamine, and zinc salts may be included.

The acid addition salt according to the present invention is a precipitate produced by dissolving the compound represented by Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid in a conventional method, for example, May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and then drying or crystallizing in an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Furthermore, the present invention includes not only the compound of Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, isomers, optical isomers, and the like that may be prepared therefrom.

Antipyretic, pain relief and Anti-inflammatory Pharmaceutical composition

The present invention provides a pharmaceutical composition for antipyretic, analgesic, and anti-inflammatory comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다. R ¹ is

And

It is a substituent selected from the group consisting of.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1 may be any one selected from the following compound group.

1) 1,1-dioxidobenzo[d]isothiazol-3-yl 2-(4-isobutylphenyl)propanoate;

2) 4-acetamidophenyl-2-propylpentanoate; And

3) 4-acetamidophenyldodecanoate.

In addition, the present invention provides a pharmaceutical composition for antipyretic, analgesic and anti-inflammatory comprising a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the pharmaceutical composition according to the present invention, the compound represented by Formula 2 may be any one selected from the following compound group.

4) 2-(4-isobutylphenyl)propanoic 2-propylpentanoic anhydride;

5) dodecanoic 2-(4-isobutylphenyl)propanoic anhydride;

6) 2-acetoxybenzoic 2-propylpentanoic anhydride;

7) 2-acetoxybenzoic 2-dodecanoic anhydride; And

8) 2-acetoxybenzoic 2-(4-isobutylphenyl)propanoic anhydride.

The compounds of the present invention can be administered in various oral and parenteral dosage forms at the time of clinical administration, and when formulated, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants are used. Is manufactured.

Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and these solid preparations include at least one excipient, such as starch, calcium carbonate, and water, in one or more compounds of the present invention. It is prepared by mixing sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, or syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives are included. I can.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyloleate may be used as the non-aqueous solvent and the suspension. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease degree, and is generally about 0.001 to 100 mg/kg/day, preferably It is 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07 to 7000 mg/day, preferably 0.7 to 2500 mg/day, and from once a day at regular time intervals according to the judgment of a doctor or pharmacist. It can also be administered in several divided doses.

Antipyretic, pain relief and Anti-inflammatory Health functional food and health food composition

The present invention provides a health functional food or health food composition for antipyretic, analgesic, and anti-inflammatory comprising a compound represented by the following formula (1) or a food pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ¹ is

And

It is a substituent selected from the group consisting of.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the health functional food composition or health food composition according to the present invention, the compound represented by Formula 1 may be any one selected from the following compound group.

1) 1,1-dioxidobenzo[d]isothiazol-3-yl 2-(4-isobutylphenyl)propanoate;

2) 4-acetamidophenyl-2-propylpentanoate; And

3) 4-acetamidophenyldodecanoate.

In addition, the present invention provides a health functional food or health food composition for antipyretic, analgesic, and anti-inflammatory comprising a compound represented by the following formula (2) or a food pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the health functional food composition or health food composition according to the present invention, the compound represented by Formula 2 may be any one selected from the following compound group.

4) 2-(4-isobutylphenyl)propanoic 2-propylpentanoic anhydride;

5) dodecanoic 2-(4-isobutylphenyl)propanoic anhydride;

6) 2-acetoxybenzoic 2-propylpentanoic anhydride;

7) 2-acetoxybenzoic 2-dodecanoic anhydride; And

8) 2-acetoxybenzoic 2-(4-isobutylphenyl)propanoic anhydride.

The health functional food composition or health food composition according to the present invention is a compound represented by Chemical Formula 1 or Chemical Formula 2 for the purpose of preventing or improving related diseases through antipyretic, analgesic and anti-inflammatory activities, and food acceptable salts thereof , Or its optical isomer may be added to a health functional food or health food such as food and beverage.

There is no particular limitation on the type of food. Examples of foods to which the compound according to the present invention can be added include drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, There are various soups, beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, and include all health foods and functional health foods in the usual sense.

The health food and health functional food composition containing the compound according to the present invention may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the compound according to the present invention may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in health foods and health functional foods may be added in an amount of 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of maintaining health or controlling health, the amount may be less than the above range, and there is no problem in terms of safety, so the active ingredient may be used in an amount above the above range.

The health food and health functional food composition of the present invention is not particularly limited to other ingredients except for containing the compound according to the present invention as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. It can contain as. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the health functional food composition of the present invention.

In addition to the above, the health food and health functional food composition containing the compound according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.) ), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health food and health functional food composition of the present invention may contain flesh for the manufacture of natural fruit juice and fruit juice beverage and vegetable beverage.

These components may be used independently or in combination. Although the proportion of these additives is not so important, it is generally selected from 0.1 to about 20 parts by weight per 100 parts by weight of the health food and health functional food composition containing the active substance of the present invention.

Manufacturing method 1 to 3

The present invention is shown in the following scheme 1,

Adding a compound represented by Formula 3, a compound represented by Formula 4, and a catalyst to an organic solvent, refluxing and then concentrating to obtain a compound represented by Formula 1 (Step 1);

It provides a method for producing a compound represented by the following formula (1) including.

[Scheme 1]

In Scheme 1 above,

이고, R is

ego,

이다.R ¹ is

to be.

In the production method according to the present invention, a preferred example of the compound represented by Formula 1 prepared from Scheme 1 may include the following compounds.

1) 1,1-dioxidobenzo[d]isothiazol-3-yl 2-(4-isobutylphenyl)propanoate.

In addition, the present invention, as shown in the following scheme 2,

Dissolving the compound represented by Formula 3 and the compound represented by Formula 5 in an organic solvent, refluxing, and stirring to obtain a compound represented by Formula 1 (Step 2);

It provides a method for producing a compound represented by the following formula (1) including.

[Scheme 2]

In Scheme 2 above,

R is C _1-15 straight or branched chain alkyl,

이다.R ¹ is

to be.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the production method according to the present invention, preferred examples of the compound represented by Formula 1 prepared from Scheme 2 may include the following compound groups.

2) 4-acetamidophenyl-2-propylpentanoate; And

3) 4-acetamidophenyldodecanoate.

In addition, the present invention, as shown in the following Scheme 3,

Dissolving the compound represented by Formula 3 and the compound represented by Formula 6 in an organic solvent, refluxing, and stirring to obtain a compound represented by Formula 2 (Step 3);

It provides a method for producing a compound represented by the following formula (2) including.

[Scheme 3]

In Scheme 3 above,

로 이루어지는 군으로부터 선택되는 치환기이고,R is C _1-15 straight or branched chain alkyl and

It is a substituent selected from the group consisting of,

및

로 이루어지는 군으로부터 선택되는 치환기이다.R ² is

And

It is a substituent selected from the group consisting of.

또는

일 수 있다.Preferably, the straight chain or branched chain alkyl of C _1-15 is

or

Can be

In the production method according to the present invention, preferred examples of the compound represented by Formula 2 prepared from Scheme 3 may include the following compound groups.

4) 2-(4-isobutylphenyl)propanoic 2-propylpentanoic anhydride;

5) dodecanoic 2-(4-isobutylphenyl)propanoic anhydride;

6) 2-acetoxybenzoic 2-propylpentanoic anhydride;

7) 2-acetoxybenzoic 2-dodecanoic anhydride; And

8) 2-acetoxybenzoic 2-(4-isobutylphenyl)propanoic anhydride.

In the production method according to the present invention, the organic solvent is ethanol, tetrahydrofuran (THF), benzene, KOH/MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), diisopropyl ether , Diethyl ether, dioxane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetone, chlorobenzene, etc. may be used alone or in combination. Preferably, tetrahydrofuran (THF) may be used as the organic solvent in Step 1 or Step 2.

Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Ester and Acid anhydride Preparation of compound

< Example 1> Preparation of Ester Compound 1

The method for synthesizing the ester compound of Example 1 is as shown in Scheme 1 below.

Specifically, the compound represented by formula 4 (3-chloro-1,2-benzisothiazole-1,1-dioxide (3-chloro-1,2-) in a 100 mL one necked round-bottomed flask sufficiently dried at room temperature. benzisothiazole-1,1-dioxide; BID-Cl), 1g, 5mmol) and molecular sieve were added, followed by stirring at room temperature with 20 mL of tetrahydrofuran (THF) as a solvent, and then in 20 mL of THF as Formula 3 A solution of the indicated compound (2-(4-isobutylphenyl)propanoic acid (2-4(isobutylphenyl)propanoic acid), 1.02g, 5mmol) was slowly added dropwise, and then triethylamine (TEA) as a catalyst 2 mL was added and refluxed for 48 hours. After checking the degree and completion of the reaction by TLC at room temperature, the residue obtained by completely removing the solvent with a vacuum rotary evaporator was flash column chromatography to prepare the compound of Example 1 represented by Chemical Formula 1.

[Scheme 1]

Example 1: 1 ,One- Dioxidobenzo[d]isothiazole -3-yl 2-(4- Isobutylphenyl ) Propanoate (1,1- Dioxidobenzo[d]isothiazol -3- yl 2-(4-isobutylphenyl)propanoate)

The properties of the compound of Example 1 (1.20g, yield 65%) as a white solid obtained through the above method are as follows.

mp: 285°C;

R _f : 0.7 (TLC eluent; EA:n-Hexane = 2:1 v/v);

MASS (70eV), m/z (rel. intensity %): 137(100), 121(21.6), 373.11(4.5);

¹ H NMR (MeOD, 400MHz): δ 0.902 (d, CH ₃ , 6H), 1.421 (d, CH ₃ , 3H), 1.840 (m, CH, 1H), 2.439 (d, CH ₂ , 2H), 3.675 (f, CH, 1H), 7.084 (d, CH, 2H), 7.104 (d, CH, 2H), 7.940 (d, CH, 2H), 8.069 (d, CH, 2H);

¹³ C NMR (MeOD, 100 MHz): δ 19.1, 22.7, 31.4, 46.0, 46.3, 122.1, 125.99, 128.2, 128.6, 130.2, 135.8, 136.3, 139.2, 139.8, 141.8;

Anal. calc. for C ₂₀ H ₂₁ NO ₄ S: C 64.66, H 5.70, N 3.78, O 17.21, S 8.63.

< Example 2-3> Preparation of ester compound 2

The method for synthesizing the ester compounds of Examples 2 and 3 is as shown in Scheme 2 below.

Specifically, a compound represented by Formula 3 (Compound 3) and a compound represented by Formula 5 (Compound 5) were added to a 250 mL one necked round-bottomed flask sufficiently dried at room temperature using a Deanstark apparatus, and tetrahydrofuran; THF) 20 mL was used as a solvent to reflux. After stirring for 24 hours, the water removed by deanstark was checked, and the degree and completion of the reaction were confirmed by TLC. The obtained sticky oil or solid reactant was subjected to flash column chromatography to prepare the compounds of Examples 2 and 3 represented by Chemical Formula 1. The compound 3 and compound 5 used in the preparation of the compound are as shown in Table 1 below.

[Scheme 2]

Compound 3 Compound 5 RCOOH Added amount R ¹ OH Added amount Example 2 2-propylpentanoic acid
(2-propylpentanoic acid) 1.58mL, 0.01mol N- (4-hydroxyphenyl)acetamide ( N- 4-hydorxyphenyl)acetamide) 1.51g, 0.01mol Example 3 Dodecanoic acid
(dodecanoic acid) 2.00g, 0.01mol N- (4-hydroxyphenyl)acetamide ( N- 4-hydorxyphenyl)acetamide) 1.51g, 0.01mol

Example 2: 4 - Acetamidophenyl -2- Propylpentanoate (4- Acetamidophenyl -2-propylpentanoate)

The properties of the compound of Example 2 (1.664g, yield 57.1%) as a light brown solid obtained through the above method are as follows.

mp: 229 to 230°C;

R _f : 0.5 (TLC eluent; EA:n-Hexane = 5:5 v/v);

MASS (70 eV), m/z (rel. intensity %): 277.2 (100), 278.2 (17.3), 279.2 (1.4);

¹ H NMR (CDCl ₃ , 400MHz): δ 0.89(t,6H), 1.56(dd,8H), 2.00(s,3H), 2.61(s,1H), 6.99(s,2H), 7.48(s, 2H), 7.87 (s, 1H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 175.673 (1C), 168.718 (1C), 146.797 (1C), 135.527 (1C), 121.861 (2C), 120.920 (2C), 45.337 (1C), 34.652 (2C) , 22.755 (1C), 20.705 (2C), 14.023 (2C);

Anal. calc. for C ₁₆ H ₂₃ NO ₃ : C 69.23, H 8.36, N 5.05, O 17.30;

Found: C 69.24, H 8.35, N 5.06, O 17.31.

Example 3: 4 - Acetamidophenyldodecanoate (4-Acetamidophenyldodecanoate)

The properties of the compound of Example 3 (0.35g, yield 10.5%) as a white solid obtained through the above method are as follows.

mp: 289 to 290°C;

R _f : 0.3 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 332.2(100), 334.2(21.6), 335.2(2.2);

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.81 (s, 3H), 1.12 (m, 24H), 1.69 (d, 2H), 2.05 (s, 3H), 2.47 (d, 2H), 6.92 (s, 2H), 7.38 (s, 2H), 7.59 (s, 1H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 172.770 (1C), 168.559 (1C), 146.797 (1C), 135.441 (1C), 121.899 (2C), 120.824 (2C), 34.350 (1C), 31.895 (1C) , 29.590 (6C), 24.913 (1C) 24.311 (1C), 22.677 (1C), 14.119 (1C);

Anal. calc. for C ₂₀ H ₃₁ NO ₃ : C 72.04, H 9.37, N 4.20, O 14.39;

Found: C 72.02, H 9.35, N 4.21, O 14.38.

< Example 4-8> Acid anhydride Preparation of compounds 1

The method of synthesizing the acid anhydride compounds of Examples 4 to 8 is as shown in Scheme 3 below.

Specifically, prepared by performing substantially the same method as in Example 2-3, but using the compound represented by Formula 6 (Compound 6) instead of the compound represented by Formula 5 (Compound 5), Example represented by Formula 2 Compounds of 4 to 8 were prepared. Compound 3 and compound 6 used to prepare the compound are as shown in Table 1 below.

[Scheme 3]

Compound 3 Compound 6 RCOOH Added amount R ² COOH Added amount Example 4 2-propylpentanoic acid
(2-propylpentanoic acid) 1.58mL, 0.01mol 2-(4-isobutylphenyl)propanoic acid (2-4(isobutylphenyl)propanoic acid) 2.06g, 0.01mol Example 5 Dodecanoic acid
(dodecanoic acid) 2.00g, 0.01mol 2-(4-isobutylphenyl)propanoic acid (2-4(isobutylphenyl)propanoic acid) 2.06g, 0.01mol Example 6 2-propylpentanoic acid
(2-propylpentanoic acid) 1.58mL, 0.01mol 2-acetoxybenzoic acid
(2-acetoxybenzoic acid) 1.80g, 0.01mol Example 7 Dodecanoic acid
(dodecanoic acid) 2.00g, 0.01mol 2-acetoxybenzoic acid
(2-acetoxybenzoic acid) 1.80g, 0.01mol Example 8 2-(4-isobutylphenyl)propanoic acid (2-4(isobutylphenyl)propanoic acid) 2.06g, 0.01mol 2-acetoxybenzoic acid
(2-acetoxybenzoic acid) 1.80g, 0.01mol

Example 4: 2 -(4- Isobutylphenyl ) Propanoic 2- Propylpentanoic Anhydride (2-(4-Isobutylphenyl)propanoic 2- propylpentanoic anhydride)

The properties of the compound of Example 4 (0.89g, yield 26.8%) as a lemon-colored liquid obtained through the above method are as follows.

mp: sticky oil;

R _f : 0.5 (TLC eluent; EA:n-Hexane = 1:9 v/v);

MASS (70 eV), m/z (rel. intensity %): 332.2 (100), 333.2 (22.7), 334.2 (2.5);

¹ H NMR (MeOD, 400MHz): δ 0.96 (t, 9H), 1.38 (dd, 6H), 1.78 (m, 2H), 1.89 (m, 2H), 2.47 (s, 3H), 3.77 (t, 1H) ), 7.11 (t, 2H) 7.13 (t, 2H);

¹³ C NMR (MeOD, 100 MHz): δ 176.254 (1C), 174.466 (1C), 140.168 (1C), 138.032 (1C), 129.045 (2C), 126.946 (2C), 63.750 (1C), 44.783 (1C), 34.598 (1C), 30.098 (2C), 24.868 (1C), 21.713 (2C), 20.440 (2C), 17.866 (2C), 13.347 (1C);

Anal. calc. for C ₂₁ H ₃₂ O ₃ : C 75.86, H 9.70, O 14.44;

Found: C 75.84, H 9.72, O 14.42.

Example 5: Dodecanoic 2-(4- Isobutylphenyl ) Propanoic Anhydride (Dodecanoic 2-(4- isobutylphenyl ) propanoic anhydride)

The properties of the compound of Example 5 (1.16g, yield 29.9%) as a brown solid obtained through the above method are as follows.

mp: 218 to 219°C;

R _f : 0.8 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 388.3(100), 389.3(27.0), 390.3(2.7);

¹ H NMR (MeOD, 400MHz): δ 0.87 (t, 9H), 1.28 (s, 16H), 1.59 (dd, 6H), 2.26 (m, 2H), 2.42 (t, 2H), 4.08 (d, 1H) ), 7.08 (d, 2H), 7.16 (d, 2H);

¹³ C NMR (MeOD, 100 MHz): δ 175.145 (1C), 173.952 (1C), 137.977 (1C), 128.980 (1C), 126.815 (4C), 44.663 (1C), 33.695 (1C), 31.716 (1C), 29.393 (1C), 25.845 (1C), 24.728 (1C), 21.415 (3C), 17.423 (1C), 13.164 (1C);

Anal. calc. for C ₂₅ H ₄₀ O ₃ : C 77.27, H 10.38, O 12.35;

Found: C 77.28, H 10.37, O 12.35.

Example 6: 2 - Acetoxybenzoic 2- Propylpentanoic Anhydride (2-Acetoxybenzoic 2- propylpentanoic anhydride)

The properties of the compound of Example 6 (1.38g, yield 45.1%) as a dark brown liquid obtained through the above method are as follows.

mp: sticky oil;

R _f : 0.6 (TLC eluent; EA:n-Hexane = 1:9 v/v);

MASS (70 eV), m/z (rel. intensity %): 306.1 (100), 307.2 (18.4), 308.2 (1.6);

¹ H NMR (MeOD, 400MHz): δ 0.91 (t, 6H), 1.37 (m, 8H), 1.58 (t, 1H), 1.99 (s, 3H), 6.77 (t, 2H), 7.17 (t, 2H) );

¹³ C NMR (MeOD, 100 MHz): δ 179.279 (1C), 171.787 (1C), 156.879 (1C), 129.048 (1C), 119.205 (4C), 114.877 (1C), 45.225 (1C), 34.525 (2C), 20.341 (2C), 13.114 (2C);

Anal. calc. for C ₁₇ H ₂₂ O ₅ : C 66.65, H 7.24, O 26.11;

Found: C 66.64, H 7.22, O 26.12.

Example 7: 2 - Acetoxybenzoic 2- Dodecanoic Anhydride (2- Acetoxybenzoic 2-dodecanoic anhydride)

The properties of the compound of Example 7 (2.31g, yield 47.0%) as a white solid obtained through the above method are as follows.

mp: 218 to 219°C;

R _f : 0.5 (TLC eluent; EA:n-Hexane = 5:5 v/v);

MASS (70 eV), m/z (rel. intensity %): 362.2 (100), 363.2 (22.7), 364.2 (2.5);

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.92 (t, 3H), 1.26 (m, 16H), 1.57 (t, 2H), 2.15 (s, 3H), 2.57 (t, 2H), 7.31 (d , 2H), 7.84 (d, 2H);

¹³ C NMR (CDCl ₃ , 100 MHz): δ 175.521 (2C), 151.101 (1C), 150.897 (1C), 134.732 (1C), 132.553 (1C), 126.004 (1C), 124.136 (1C), 123.809 (1C) ), 31.920 (1C), 34.141 (1C), 29.655 (14C), 24.491 (1C), 22.698 (1C), 14.139 (1C);

Anal. calc. for C ₂₀ H ₃₈ O ₃ : C 73.57, H 11.73, O 14.70;

Found: C 73.58, H 11.72, O 14.72.

Example 8: 2 - Acetoxybenzoic 2-(4- Isobutylphenyl ) Propanoic Anhydride (2-Acetoxybenzoic 2-(4- isobutylphenyl ) propanoic anhydride)

The properties of the compound of Example 8 (1.10g, yield 29.9%) as a dark brown liquid obtained through the above method are as follows.

mp: sticky oil;

R _f : 0.6 (TLC eluent; EA:n-Hexane = 3:7 v/v);

MASS (70eV), m/z (rel. intensity %); 368.2 (100), 369.2 (23.8), 370.0 (2.7);

¹ H NMR (MeOD, 400 MHz): δ 0.87 (t, 3H), 1.18 (s, 6H), 1.45 (t, 1H), 2.28 (s, 3H), 2.42 (t, 1H) 2.60 (d, 2H) ) 7.08 (m, 8H);

¹³ C NMR (MeOD, 100 MHz): δ 201.134 (1C), 178.582 (1C), 167.057 (1C), 150.412 (1C), 140.322 (1C), 135.352 (1C), 134.061 (1C), 130.366 (1C) , 129.050(1C), 126.932(1C), 126.133(1C), 123.474(1C), 119.136(1C), 116.747(1C), 44.543(1C), 38.913(1C), 29.906(1C), 21.518(2C) , 20.090 (1C), 17.040 (1C);

Anal. calc. for C ₂₂ H ₂₄ O ₅ : C 71.72, H 6.57, O 21.71;

Found: C 71.72, H 6.57, O 21.75.

< Formulation example 1> Preparation of pharmaceutical formulation

<1-1> Preparation of powder

2 g of a compound of Formula 1 or Formula 2

1 g lactose

After mixing the above ingredients, the powder was prepared by filling the airtight cloth.

<1-2> Preparation of tablets

100 mg of a compound of Formula 1 or Formula 2

Corn starch 100 mg

100 mg lactose

Magnesium stearate 2 mg

After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.

<1-3> Preparation of capsules

100 mg of a compound of Formula 1 or Formula 2

Corn starch 100 mg

100 mg lactose

Magnesium stearate 2 mg

After mixing the above ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule formulation.

<1-4> Preparation of injection solution

Compound of Formula 1 or Formula 2 10 ㎍/㎖

Dilute hydrochloric acid BP until pH 3.5

Sodium chloride BP for injection up to 1 ml

Dissolve the compound of Formula 1 or Formula 2 according to the present invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with diluted hydrochloric acid BP, and adjust the volume with sodium chloride BP for injection. Adjust and mix thoroughly. The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120° C. for 15 minutes or longer to prepare an injection solution.

< Formulation example 2> Manufacture of health functional food and health food

<2-1> Manufacture of health functional food

100 mg of a compound of Formula 1 or Formula 2

Vitamin mixture right amount

Vitamin A acetate 70 μg

1.0 mg of vitamin E

Vitamin B1 0.13 mg

Vitamin B2 0.15 mg

0.5 mg of vitamin B6

Vitamin B12 0.2 μg

10 mg of vitamin C

Biotin 10 μg

1.7 mg of nicotinic acid amide

50 μg folic acid

0.5 mg of calcium pantothenate

Suitable amount of inorganic mixture

1.75 mg ferrous sulfate

Zinc oxide 0.82 mg

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Dicalcium phosphate 55 mg

90 mg of potassium citrate

100 mg of calcium carbonate

Magnesium chloride 24.8 mg

The composition ratio of the vitamin and mineral mixture is a mixture of ingredients suitable for a health functional food in a preferred embodiment, but the mixing ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health functional food manufacturing method. Then, the granules are prepared, and can be used to prepare a health functional food composition according to a conventional method.

<2-2> Production of health functional beverages

100 mg of a compound of Formula 1 or Formula 2

100 mg citric acid

100 mg oligosaccharide

Plum Concentrate 2 mg

100 mg taurine

Total 500 mL with purified water

After mixing the above ingredients according to a normal health drink manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in one sterilized container, sealed and sterilized, and then stored in a refrigerator. It is used in the manufacture of health drink composition. The composition ratio is composed of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the blending ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the intended use.

<2-3> Manufacture of dairy products

0.01-1 parts by weight of the ester of Formula 1 or the acid anhydride compound of Formula 2 of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

<2-4> Linear Produce

Brown rice, barley, glutinous rice, and adlay were gelatinized and dried by a known method, and then roasted and prepared into a powder having a particle size of 60 mesh with a grinder. Black soybeans, black sesame seeds, and perilla seeds were also steamed and dried by a known method, and then roasted, and then prepared into a powder having a particle size of 60 mesh with a grinder. It was prepared by mixing the dry powder of the grains and seeds prepared above and the ester of Formula 1 or the acid anhydride compound of Formula 2 in the following ratio.

Grains (34 parts by weight of brown rice, 19 parts by weight of barley, 20 parts by weight of barley),

Seeds (perilla 7 parts by weight, black soybean 8 parts by weight, black sesame 7 parts by weight),

A compound of formula 1 (2 parts by weight),

Ganoderma lucidum (1.5 parts by weight), and

Rehmannia (1.5 parts by weight).

Claims (16)

A compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the above formula 1,
R is

ego,
R ¹ is

to be).
delete delete delete delete delete delete delete delete delete delete delete As shown in Scheme 1 below,
Adding a compound represented by Formula 3, a compound represented by Formula 4, and a catalyst to an organic solvent, refluxing and then concentrating to obtain a compound represented by Formula 1 (Step 1);
A method for preparing a compound represented by the following formula 1, including:
[Scheme 1]

(In Scheme 1 above,
R is

ego,
R ¹ is

to be).
delete delete The method of claim 13,
The organic solvent is ethanol, tetrahydrofuran (THF), benzene, KOH/MeOH, MeOH, toluene, CH ₂ Cl ₂ , hexane, dimethylformamide (DMF), diisopropyl ether, diethyl ether, dioxane, dimethyl A method of manufacturing, characterized in that it is at least one selected from the group consisting of acetamide (DMA), dimethyl sulfoxide (DMSO), acetone and chlorobenzene.