WO2015010666A2 - Phenol derivative and use thereof - Google Patents

Abstract

A phenol derivative and a use thereof are disclosed. The phenol derivative comprises a compound as represented by structural formulas (I), (II) or (III) or a pharmaceutically acceptable salt, ester and amide thereof. In structural formulas (I), (II) or (III), R¹ is selected from an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, halogen or an acyl group; R² and R³ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group or an acyl group; and R⁴, R⁵, R⁶ and R⁷ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group. Also disclosed is the use of the compound or the pharmaceutically acceptable salt, ester and amide thereof in the preparation of drugs used for treating immune disease, inflammation or autoimmune disease.

Description

Phenol derivative and application thereof Technical field

The invention belongs to the technical field of medicine, and particularly relates to a phenol derivative and its application in preparing a medicament for treating an immune disease, inflammation or autoimmune disease.

Background technique

Dihydroxybenzoic acid, dihydroxyphenylacetic acid, and dihydroxyphenylpropionic acid derivatives are a well-known class of compounds having various activities, which are widely distributed in nature. Related alkylated dihydroxy products are found in wheat, barley, rye, and ginkgo (Suzuki, Y. Phytochemistry, 1999. 52(2): 281–201 Zhou Houde, Liu Yuhuan, Li Ruiqi, Han Dongping, Qian Fei, Jiao Shuai, Sheng Sheng, Food Science, 2008, 29 (08): 680-684), their metabolites in humans and animals are mainly the corresponding dihydroxybenzoic acid and dihydroxyphenylpropionic acid derivatives (Ross, AB;

P; Kamal-Eldin, A. 2004. Journal of Chromatography B, 809(1): 125–130). 2-n-hexane-5-n-propane-1,3 benzenediol is a kind of Pseudomonas sp. Antibiotics (Kanda, N.; Ishizaki, N.; Inoue, N.; Oshima, M. and Handa, A. The Journal of antibiotics, 1975. 28(12): 935-942).

Since natural derivatives and synthetic derivatives of such derivatives exhibit a range of physiological activities, they are increasingly stimulating interest in it. The physiological activities of dihydroxybenzoic acid, dihydroxyphenylacetic acid and dihydroxyphenylpropionic acid derivatives include antioxidant, antibacterial, cholesterol lowering, antifungal, antiviral, analgesic, anticancer, anti-inflammatory, etc. (J. Li, D. Zhang, X. Zhu, Z. He, S. Liu, M. Li, J. Pang, and Y. Lin, 2011, Mar Drugs. 9(10): 1887–1901; SMFiuza, C. Gomes, LJ Teixeira, MT

Da Cruz, MNDS Cordeiro, N. Milhazes, F. Borges, MPM Marques, 2004, Bioorganic & Medicinal Chemistry, 12(13): 3581-3589).

Dihydroxybenzoic acid and dihydroxyphenylacetic acid derivatives can be conveniently produced by chemical reaction from substituted benzene as a raw material, and dihydroxyphenylpropionic acid can be prepared by hydrogenation reduction of the corresponding cinnamic acid. In the basic structure of dihydroxybenzoic acid, dihydroxyphenylacetic acid and dihydroxyphenylpropionic acid derivatives, the substitution of a benzene ring results in a large number of different derivatives (P. Sharma, J. Chem. Pharm. Res., 2011, 3(2): 403-423). From the perspective of biotransformation, such compounds can be converted from the corresponding alkyl or aromatic ring groups. In the basic structure of the cinnamic acid derivative, the substitution of the benzene ring results in a large number of different derivatives (P. Sharma, J. Chem. Pharm. Res., 2011, 3(2): 403-423). From the perspective of biosynthetic routes, cinnamic acid derivatives are associated with anthraquinone derivatives (Austin MB, Noel JP, Nat. Prod. Rep., 2003, 20: 79-110).

The corresponding unsaturated derivative of the dihydroxyphenylpropionic acid derivative is a cinnamic acid derivative, also called a benzoic acid derivative. The cinnamic acid derivative is also a well-known compound having various activities, which is widely distributed in nature (P. Sharma, J. Chem. Pharm. Res., 2011, 3(2): 403-423). In recent years, since natural derivatives and synthetic derivatives of cinnamic acid derivatives have exhibited a series of physiological activities, they have increasingly attracted interest in it. Physiological activities of cinnamic acid derivatives include anti-tuberculosis, anti-diabetes, anti-oxidation, anti-bacterial, liver protection, central nervous system inhibition, cholesterol lowering, anti-fungal, blood sugar lowering, anti-malarial, anti-viral, analgesic, cytotoxic, anti-inflammatory, etc. . At the same time, cinnamic acid derivatives are widely used as cosmetics as ultraviolet absorbers and aroma substances.

Recently, a uniquely substituted anthracene derivative has been reported in the literature. In this group of derivatives, two hydroxyl groups are at the 3 and 5 positions, and there is also a substituent at the 4 position between the two hydroxyl groups. These special compounds have inhibitory activity against kinases, anti-infective activity, affect T lymphocytes, macrophages, neutrophils and mast cells, and can regulate a variety of immune and inflammatory activities (US Patent 7,868,047) And US Patent 7,321,050). We have recently discovered that in addition to this unique substituted form of anthracene derivatives on a benzene ring, dihydroxybenzoic acid, dihydroxyphenylacetic acid and dihydroxyphenylpropionic acid derivatives also have potent biological activity. At the same time, the development of the convenient preparation of these phenol derivatives of the present invention can be made into different preparations and can be targeted to different diseases. The present invention relates to structures, synthetic methods, pharmaceutical combinations thereof, and the like of these novel dihydroxybenzoic acid, dihydroxyphenylacetic acid, and dihydroxyphenylpropionic acid derivatives, and their use in the treatment of diseases.

Summary of the invention

Disclosed herein are compounds having structural formula I, II or III and pharmaceutically acceptable salts, esters or amides thereof, and effective amounts of these compounds (including compounds of structural formula I, II or III and Pharmaceutically acceptable salts, esters or amides for use as immunomodulatory agents and for the use of these compounds in the manufacture of a medicament for the treatment of immunological, inflammatory or autoimmune diseases.

In one aspect, the present invention provides a phenol derivative comprising a compound of the formula I, II or III or a pharmaceutically acceptable salt, ester or amide thereof, the specific structural formula of which is as follows:

Structural Formula I:

Structural Formula II:

Structural Formula III:

Wherein, in Formula I, R ^{l is} selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; and R ² and R ³ are each independently selected from hydrogen, alkyl. , cycloalkyl, aryl, aralkyl or acyl, etc.; but when R ^l is isopropyl or bromo, R ² and R ³ cannot be methyl at the same time.

In Formula II, R ^{l is} selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; and R ² and R ³ are each independently selected from hydrogen, alkyl, and ring. An alkyl group, an aryl group, an arylalkyl group or an acyl group; and R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.

In Formula III, R ^{l is} selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; and R ² and R ³ are each independently selected from hydrogen, alkyl, and ring. An alkyl group, an aryl group, an arylalkyl group or an acyl group; and R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group.

In the formulae I, II and III, the alkyl group may be an alkyl group of 1 to 18 carbons, such as an alkyl group of 1 to 6 carbons, such as an ethyl group, an isopropyl group or a butyl group; the cycloalkyl group may be 3 a -6 carbon ring; the alkenyl group may be an alkenyl group of 2 to 18 carbons, such as an alkenyl group of 2 to 6 carbons, such as a vinyl group, an isopropenyl group, etc.; an alkynyl group may be an alkyne of 2 to 18 carbons a group such as an alkynyl group of 2 to 6 carbons, such as an ethynyl group, a propynyl group or the like; the aryl group may be an aryl group of 6 to 18 carbons, such as an aryl group of 6 to 10 carbons, such as a phenyl group, a naphthyl group. , p-methylbenzene, etc.; the aralkyl group may be an aralkyl group of 7 to 18 carbons, wherein the carbon number of the alkyl group is the same as defined above, and the carbon number of the aryl group is also the same as defined above, and examples are, for example, a benzyl group. 2-phenethyl, 3-phenylpropyl, etc.; halogen is F, Cl, Br or I; acyl is a saturated or unsaturated acyl group of 1-18 carbons (eg 2-6 carbons), such as acetyl .

In some embodiments, in Formula I, R ^{l is} selected from ethyl, isopropyl or butyl, and R ² and R ³ are each independently selected from hydrogen, methyl or acetyl.

Preferably, the phenol derivative of the invention is selected from the group consisting of:

3,5-dihydroxy-4-ethylbenzoic acid,

3,5-dihydroxy-4-isopropylbenzoic acid,

3,5-dihydroxy-4-butylbenzoic acid,

3,5-dimethoxy-4-ethylbenzoic acid,

3,5-dimethoxy-4-butylbenzoic acid,

3,5-diacetoxy-4-ethylbenzoic acid,

3,5-diacetoxy-4-isopropylbenzoic acid,

3,5-Diacetoxy-4-butylbenzoic acid.

In some embodiments, in Formula II, R ^{l is} selected from methyl, ethyl, isopropyl or butyl, and R ² and R ³ are each independently selected from hydrogen or methyl, and R ⁴ and R ⁵ are each independently The ground is selected from hydrogen or methyl.

Preferably, the phenol derivative of the invention is selected from the group consisting of:

3,5-dihydroxy-4-ethylphenylacetic acid,

3,5-dihydroxy-4-isopropylphenylacetic acid,

3,5-dihydroxy-4-butylphenylacetic acid,

3,5-dihydroxy-4-ethyl-α-methylphenylacetic acid,

3,5-dihydroxy-4-isopropyl-α-methylphenylacetic acid,

3,5-dihydroxy-4-butyl-α-methylphenylacetic acid,

3,5-dimethoxy-4-ethylphenylacetic acid,

3,5-dimethoxy-4-isopropylphenylacetic acid,

3,5-dimethoxy-4-butylphenylacetic acid,

3,5-dimethoxy-4-ethyl-α-methylphenylacetic acid,

3,5-dimethoxy-4-isopropyl-α-methylphenylacetic acid,

3,5-Dimethoxy-4-butyl-α-methylphenylacetic acid.

In some embodiments, in Formula III, R ^{l is} selected from ethyl, isopropyl or butyl, and R ² and R ³ are each independently selected from hydrogen or methyl, R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen or methyl.

Preferably, the phenol derivative in the examples of the present invention is selected from the group consisting of:

3,5-dihydroxy-4-ethyl phenylpropionic acid,

3,5-dihydroxy-4-isopropylbenzenepropionic acid,

3,5-dihydroxy-4-butyl phenylpropionic acid,

3,5-dimethoxy-4-ethyl phenylpropionic acid,

3,5-dimethoxy-4-isopropylbenzenepropionic acid,

3,5-Dimethoxy-4-butyl phenylpropionic acid.

Particularly preferably, the phenol derivative in the examples of the invention is selected from the group consisting of:

3,5-dihydroxy-4-ethylbenzoic acid,

3,5-dihydroxy-4-isopropylbenzoic acid,

3,5-dihydroxy-4-ethylphenylacetic acid,

3,5-dihydroxy-4-isopropylphenylacetic acid,

3,5-dihydroxy-4-ethyl-α-methylphenylacetic acid,

3,5-dihydroxy-4-isopropyl-α-methylphenylacetic acid,

3,5-dihydroxy-4-ethyl phenylpropionic acid,

3,5-Dihydroxy-4-isopropylbenzenepropionic acid.

In another aspect, the present invention also provides a method for preparing the phenol derivative, which is prepared as follows:

The compound of the formula III provided by the invention can be prepared by reduction of the corresponding cinnamic acid, and the reduction reaction:

The aforementioned cinnamic acid can be synthesized from the intermediate benzaldehyde derivative by the following method. The intermediate benzaldehyde derivative itself can be synthesized by a literature method (Chinese Patent: Publication No. 1688535, 2005).

Synthesis of cinnamic acid precursor 1. Perkin reaction:

Route 2. Knoevenagel condensation reaction:

Route 3. Claisen–Schmidt condensation reaction:

Route 4. Heck reaction:

Some of the other compounds of the present invention (Formula I and II) may be hydrolyzed by the corresponding esters, and these esters may be synthesized from the intermediate benzaldehyde derivatives and the chloromethane derivatives by the following methods or other known methods. The intermediate benzaldehyde derivative and the chloromethane derivative itself can be synthesized by a literature method (Chinese Patent: Publication No. 1688535A, 2005).

Reaction Scheme 1. Hydrolysis reaction (Me may also be other esters or other derivatives):

Reaction route 2. Deprotection reaction:

The deprotection reaction can simultaneously hydrolyze the ester to the corresponding acid.

Reaction route 3. Multi-step synthesis:

There are other methods in the literature that can also be used in the synthesis of the compounds of the present invention, which are not described in detail in the examples of the present invention.

Among them, the pharmaceutically acceptable salts of the present invention can also be prepared because the compounds of the present invention have the ability to form salts. The pharmaceutically acceptable salt may be formed by combining the compound with an inorganic acid and/or an organic acid, an inorganic base and/or an organic base, and suitable acids include hydrochloric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, and Malay. Acids, tartaric acid, etc., are all pharmaceutically acceptable. At the same time, other uses of these salts, for example for the production of these compounds or non-pharmaceutical purposes The use of the invention is also within the scope of the invention. Commonly used pharmaceutically acceptable esters include methyl esters, ethyl esters, propyl esters (including isopropyl esters), long chain fatty alcohol esters, benzyl alcohol esters or phenylpropanol esters. Pharmaceutically used amides include unsubstituted amides, formamides, acetamides or diacetamides, and the like. The preparation of pharmaceutically acceptable salts, esters, and amides of these compounds is a common technique in the art, and thus the detailed description of the embodiments of the present invention is omitted.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a phenol derivative of the present invention and a pharmaceutically acceptable diluent and/or carrier, the phenol derivative having the formula I, a compound of II or III or a salt, ester, amide or the like thereof. For details, refer to the foregoing description of the phenol derivative, which will not be described in detail in the embodiments of the present invention. Among them, pharmaceutically acceptable diluents and/or carriers including pharmaceutically acceptable excipients are readily apparent to those skilled in the art.

Specifically, examples of the pharmaceutical composition of the present invention are various solid forms (tablets, pills, capsules, small particles, powders, suppositories, etc.) and liquid forms (solutions, suspensions, emulsions), which can be used for oral or topical use. , injection and rectal and other forms of medication. These compositions may contain only the pure compounds of the invention, or they may be combined with carriers or with other active ingredients. These combinations are sterilizable when used as an injection. For external use, it is preferred to prepare a cream, ointment, gel, solution or suspension containing the phenol derivative (for the purpose of external use, a mouthwash or an elixir should be included).

Wherein, the phenol derivative of the active ingredient of the pharmaceutical composition of the present invention may be combined with a carrier to produce a single dose, and the content of the active ingredient in the single dose may vary depending on the subject to be treated and the manner of administration, for example, For oral formulations, the active ingredient may be from 0.5 mg to 5 g, and the carrier may be present in an amount of from 5% to 95% of the total. Each dosage unit will generally contain from about 1 mg to about 500 mg of the active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

In another aspect, the present invention provides the use of the aforementioned phenol derivative for the preparation of a medicament for treating an immune disease, inflammation or autoimmune disease.

Each compound of the present invention exhibits varying degrees of immunomodulatory activity, as will be illustrated by subsequent examples. Those compounds known in the literature that have immunomodulatory activity, as disclosed herein, are useful as active ingredients in pharmaceuticals for the treatment of various diseases, such as clinical transplant rejection (including organ transplantation, Acute transplantation, allogeneic transplantation and allogeneic transplantation, such as in the treatment of burns, to avoid ischemic or reperfusion injury, such as ischemic and multiple perfusion injuries caused by organ transplantation, can also treat acute heart infarction, Stroke or other diseases; induce transplant tolerance, treat arthritis (such as rheumatoid arthritis, psoriatic arthritis, bone joints); multiple sclerosis, inflammatory bowel disease, including ulcerative colitis and Crohn's disease; Lupus (systemic lupus erythematosus); graft versus host disease; T cell hypersensitivity, including contact hypersensitivity, delayed hypersensitivity, gluten allergic bowel disease (gluten allergy), psoriasis, contact Dermatitis (including caused by poison ivy), Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, such as Grave's disease, Addison's disease, Adrenal autoimmune disease, polygland autoimmune syndrome, immune alopecia, pernicious anemia, vitiligo, immune hypopituitarism, Guillain-Barré syndrome, and other immune diseases such as glomeruli Nephritis, serum disease, urticaria, and allergic diseases such as respiratory allergic diseases (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome) Symptoms and ischemia-reperfusion injury; dermatomyositis; alopecia areata; chronic actinic dermatitis, eczema, Behcet's disease, palmew impetigo, gangrenous pyoderma, Sezary's sydrome , atopic dermatitis, scleroderma.

The present invention also provides a method for treating and preventing the above diseases comprising an agent comprising the phenol derivative, comprising the step of administering an effective amount of at least one compound having the formula I, II or III and the compound to the individual in need of treatment. A pharmaceutically acceptable salt, ester or amide. It can also be administered concurrently with other agents, such as those well known to the expert, including pharmaceutically acceptable diluents and/or carriers. In the methods of the invention, these other agents may be administered before or after administration of the compounds of the invention.

Specifically, examples of the pharmaceutical combination for treating the aforementioned diseases are various solid forms (tablets, pills, capsules, small particles, powders, suppositories, etc.) and liquid forms (solutions, suspensions, emulsions) in oral, topical, injection, and A suitable pharmaceutical combination of rectal and other forms of administration. These formulations may contain only the pure compound of the invention, or it may be combined with a carrier or with other active compounds. These combinations may require sterilization when used as an injectable solution. For external use, it is preferred to prepare a cream, ointment, gel, solution or suspension containing Compound I or V (for the purpose of external use, mouthwash and gargle should be included).

Specifically, the pharmaceutical composition for treating the aforementioned diseases may be administered by a method in which about 0.01-140 mg of the compound of the present invention per kg of body weight per day is a useful dosage level for treating the aforementioned various diseases, and the other The choice is about 0.5 mg to 7 grams per patient per day. For example, the anti-inflammatory dose is about 0.01-50 mg per kg of body weight per day, or 0.5 mg to 3.5 g per patient per day, preferably 2.5 mg to 1 g per day. A single dose of the active ingredient in the medicament may be combined with the carrier. The amount of the active ingredient in this single dose may vary depending on the subject being treated and the mode of administration. For example, an oral formulation may have an active ingredient content of 0.5. From milligrams to 5 grams, the amount of carrier compatible with it may range from 5% to 95% of the total content. Each dosage unit will generally contain from about 1 mg to about 500 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

However, it will be understood that the specific dosage to a particular person varies with a number of factors including age, weight, health status, gender, diet, time of administration, route of administration, rate of excretion, combination of drugs, and The severity of the disease being treated. The invention will now be described in greater detail by the following non-limiting examples.

detailed description

Example 1: phenylpropionic acid derivatives

Synthesis of 3,5-dimethoxy-4-isopropylcinnamic acid

a) 3,5-Dimethoxy-4-isopropylbenzaldehyde is produced by literature method (Chinese Patent: 1688535A, 2005)

b) Synthesis of 3,5-dimethoxy-4-isopropylcinnamic acid

Agitated magnetons, 15 g of malonic acid and 1.20 g of β-alanine were added to a 100 mL round bottom flask, followed by 30 mL of pyridine and 13 g of 3,5-dimethoxy-4-isopropylbenzaldehyde. Heat the reactants to around 130 °C. After the reaction was substantially complete (greater than 1.5 hours), the reaction was cooled to room temperature and then poured into 120-150 mL of ice water. The reaction mixture was slowly neutralized with about 50 mL of hydrochloric acid (6 N) until the pH was acidic and the precipitate did not increase. Filtered, washed repeatedly with water, and dried to obtain 3,5-dimethoxy-4-isopropylcinnamic acid. The 3,5-dimethoxy-4-isopropylcinnamic acid was directly reacted as follows. .

Synthesis of 3,5-dihydroxy-4-isopropylcinnamic acid

A mixture of 3,5-dimethoxy-4-isopropylcinnamic acid (2.5 g) and pyridine hydrochloride (6.7 g) was heated at 200 ° C under a nitrogen stream for 2 hours. After the reaction mixture was cooled to room temperature, 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added, and the organic phase and the aqueous phase were separated, the aqueous phase was extracted three times with 150 ml of ethyl acetate, and the mixture was combined and washed with saturated brine. Dry with sodium sulfate. After evaporating the ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate/hexane/acetic acid (50/50/1, volume ratio) to give 3,5-dihydroxy-4-isopropyl Cinnamic acid.

Synthesis of 3,5-dimethoxy-4-butylcinnamic acid

In a 100 mL three-necked flask, 3.8 mL of N,N-dimethylacetamide and 7 mL of benzene were added. Then, hydrogen chloride gas was introduced thereto for about one hour until N,N-dimethylacetamide precipitated as a hydrochloride. 2 g of 3,5-dimethoxy-4-butylbenzaldehyde was added to the reaction solution, heated to 190-200 ° C, and the distilled benzene was recovered, and the reaction was continued until completion. It was then cooled, 60 mL of water was added, and the pH was adjusted to 9-10 with a 20 wt% NaOH solution, and distilled until the distillate was clear. Further, 15 mL of 20 wt% NaOH was added and refluxed for 5-6 hours until no precipitate was observed in the reaction solution, and the reaction mixture was filtered. The filtrate was slowly neutralized with hydrochloric acid (6N) until the pH was strongly acidic and the precipitate did not increase. Filtration, repeated washing with water, and drying to obtain the synthesis of 3,5-dimethoxy-4-butylcinnamic acid, the synthesis of the 3,5-dimethoxy-4-butylcinnamic acid is directly Reaction.

Synthesis of 3,5-dihydroxy-4-butylcinnamic acid

a mixture of 3,5-dimethoxy-4-butylcinnamic acid (2.5 g) and pyridine hydrochloride (6.7 g) at 200 ° C with a nitrogen stream Heat under protected conditions for 2 hours. After the reaction mixture was cooled to room temperature, 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added, and the organic phase and the aqueous phase were separated, the aqueous phase was extracted three times with 150 ml of ethyl acetate, and the mixture was combined and washed with saturated brine. Dry with sodium sulfate. After evaporating the ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate/hexane/acetic acid (50/50/1, volume ratio) to give 3,5-dihydroxy-4-butyl acid.

c) Synthesis of 3,5-dihydroxy-4-isopropylbenzenepropionic acid

The 3,5-dihydroxy-4-isopropylcinnamic acid (0.25 g) prepared above was dissolved in 50 ml of ethanol, and Pd/C (25 mg, 10% W/W) was added. Hydrogen gas (with a balloon) was introduced into the reaction solution under normal pressure at room temperature, and the reaction was followed. After completion of the reaction, the reaction solution was filtered through Celite (Celite), evaporated to dryness, and purified by silica gel column with MeOH / CH ₂ Cl _2: the eluent to give 3,5-di (V / V = 1 4) Synthesis of hydroxy-4-isopropylbenzenepropionic acid. MS: 225 (M+1), 224.

d) Synthesis of 3,5-dimethoxy-4-isopropylbenzenepropionic acid

The 3,5-dimethoxy-4-isopropylcinnamic acid (0.25 g) prepared above was dissolved in 50 ml of ethanol, and Pd/C (25 mg, 10% W/W) was added. Hydrogen gas (with a balloon) was introduced into the reaction solution under normal pressure at room temperature, and the reaction was followed. After completion of the reaction, the reaction solution was filtered through Celite (Celite), evaporated to dryness, and purified by silica gel column with MeOH / CH ₂ Cl _2: the eluent to give 3,5-di (V / V = 1 4) Methoxy-4-isopropylbenzenepropionic acid.

e) Synthesis of 3,5-dihydroxy-4-isopropylbenzenepropionic acid

A mixture of 3,5-dimethoxy-4-isopropylbenzenepropionic acid (2.5 g) and pyridine hydrochloride (6.7 g) was heated at 200 ° C under a nitrogen stream for 2 hours. After the reaction mixture was cooled to room temperature, 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added, and the organic phase and the aqueous phase were separated, the aqueous phase was extracted three times with 150 ml of ethyl acetate, and the mixture was combined and washed with saturated brine. Dry with sodium sulfate. After evaporating the ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate/hexane/acetic acid (50/50/1, volume ratio) to give 3,5-dihydroxy-4-isopropyl Phenylpropionic acid.

f) Synthesis of 3,5-dihydroxy-4-isopropylbenzenepropionic acid

Dissolve 3,5-dimethoxy-4-isopropylbenzenepropionic acid (15 g) in dry dichloromethane (100 ml), freeze at -78 ° C, add tribromide under nitrogen. Boron (5.7 ml, 60 mmol). This reaction was stirred at -78 ° C for 1 hour, then allowed to warm to room temperature, and the reaction was further stirred under nitrogen for 2 days. The reaction was stopped by the addition of water, followed by the addition of 20 wt% NaOH to adjust the pH to greater than 12. The organic phase was removed, the aqueous phase was washed twice with 100 mL hexanes, then the pH was adjusted to 1 with 6N hydrochloric acid, then extracted three times with 200 ml of ethyl acetate, and the combined organic phase was combined with 50 ml brine. Wash twice, It was dried over anhydrous sodium sulfate. After evaporating the solvent, the crude product was purified by silica gel column chromatography to afford 3,5-dihydroxy-4-isopropylbenzenepropionic acid.

Example 2: Synthesis of 3,5-dimethoxy-4-ethylbenzenepropionic acid and 3,5-dihydroxy-4-ethylbenzenepropionic acid

This embodiment is basically the same as the synthesis method used in Example 1, except that 3,5-dimethoxy-4-ethylcinnamic acid (0.25 g) is used as a raw material, and the corresponding product is obtained by the above method. . 3,5-Dihydroxy-4-ethylbenzenepropionic acid, MS: 211 (M+1), 210).

The same method can also be prepared:

3,5-Dihydroxy-4-butylbenzenepropionic acid (MS: 239 (M+1), 238); 3,5-dimethoxy-4-butylbenzenepropionic acid.

Example 3: Synthesis of benzoic acid derivatives

Synthesis of 3,5-dihydroxy-4-isopropylbenzoic acid

a). Methyl 3,5-dimethoxy-4-isopropylbenzoate is produced by literature method (Chinese Patent: 1688535A, 2005)

b) Synthesis of 3,5-dihydroxy-4-isopropylbenzoic acid

Methyl 3,5-dimethoxy-4-isopropylbenzoate (10 g) was dissolved in dry dichloromethane (100 ml), chilled at -78 ° C, and added dropwise under nitrogen. Boron bromide (5.5 ml). This reaction was stirred at -78 ° C for 1 hour, then allowed to warm to room temperature, and the reaction was further stirred under nitrogen for 2 days. The reaction was stopped by the addition of water, followed by the addition of 20 wt% NaOH to adjust the pH to greater than 12. The organic phase was removed, the aqueous phase was washed twice with 100 mL hexanes, then the pH was adjusted to 1 with 6N hydrochloric acid, then extracted three times with 200 ml of ethyl acetate, and the combined organic phase was combined with 50 ml brine. It was washed twice and dried over anhydrous sodium sulfate. After evaporating the solvent, the crude product was purified by silica gel column chromatography to afford 3,5-dihydroxy-4-isopropylbenzoic acid. MS: 197 (M + 1), 196.

The same method can be prepared:

3,5-dihydroxy-4-ethylbenzoic acid (MS: 183 (M+1), 182), 3,5-dihydroxy-4-butylbenzoic acid (MS: 211 (M+1), 210 ,3,5-dimethoxy-4-ethylbenzoic acid, 3,5-dimethoxy-4-butylbenzoic acid, 3,5-diacetoxy-4-ethylbenzoic acid, 3,5-Diacetoxy-4-isopropylbenzoic acid, 3,5-diacetoxy-4-butylbenzoic acid.

Example 4: Preparation of phenylacetic acid derivatives

Synthesis of 3,5-dimethoxy-4-isopropylphenylacetic acid

a. In a 100 mL round bottom flask equipped with a cooling tube and a loading funnel, 10 g of small particles of sodium cyanide (98%) and 20 mL of water were placed. The mixture was heated with a water bath and stirred to dissolve most of the sodium cyanide. Then 20g of 3,5-dimethoxy-4-isopropyl A solution of benzyl chloride dissolved in 25 g of ethanol was slowly added dropwise over one hour through an addition funnel. The reaction was refluxed until the reaction was completed (about 5 hours). After cooling, filtration, and washing the solid with a small amount of ethanol, the filtrate was concentrated to give 3,5-dimethoxy-4-isopropylbenzenecyanide.

b. In a 250 mL round bottom flask, a sulfuric acid solution of 42 mL of concentrated sulfuric acid and 28 mL of water was added, and the cyanide obtained above was added. The reaction was refluxed for three hours, cooled, poured into 100 mL of ice water, and filtered to give a preliminary product. First product by silica gel column eluting with _{MeOH / CH 2 Cl 2 (V} / V = 1: 4) as eluent afforded 3,5-dimethoxy-4-isopropyl-phenylacetic acid.

Example 5: Synthesis of 3,5-dihydroxy-4-isopropylphenylacetic acid

A mixture of 3,5-dimethoxy-4-isopropylphenylacetic acid (2.5 g) and pyridine hydrochloride (7 g) was heated at 200 ° C under a nitrogen stream for 2 hours. After the reaction mixture was cooled to room temperature, 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added, and the organic phase and the aqueous phase were separated, the aqueous phase was extracted three times with 150 ml of ethyl acetate, and the mixture was combined and washed with saturated brine. Dry with sodium sulfate. After evaporating the ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate/hexane/acetic acid (50/50/1, volume ratio) to give 3,5-dihydroxy-4-isopropyl Phenylacetic acid. MS: 211 (M+1), 210.

The same method can be prepared:

3,5-dihydroxy-4-ethylphenylacetic acid (MS: 197 (M+1), 196); 3,5-dihydroxy-4-butylphenylacetic acid (MS: 225 (M+1), 224 3,5-dimethoxy-4-ethylphenylacetic acid, 3,5-dimethoxy-4-butylphenylacetic acid.

Example 6: Synthesis of 3,5-dimethoxy-4-isopropyl-α-methylphenylacetic acid

a. Synthesis of 3,5-dimethoxy-4-isopropylbenzenecyanate as in Example 4a. The crude product was purified by silica gel column eluting with ethyl acetate / n-hexane (V/V = 1:2) to give pure 3,5-dimethoxy-4-isopropyl phenylacetonitrile.

In a 250 mL round bottom flask, add 55 mL of 50 wt% aqueous sodium hydroxide solution, 35 g (0.2 moles) of 3,5-dimethoxy-4-isopropylbenzenecyanate and 0.5 g (0.022 mole) of triethylbenzene. Methyl ammonium chloride salt. With stirring, 31 g (0.22 moles) of methyl iodide (about 1 to 1.5 hours) was slowly added at 25 - 35 ° C, and then the reaction was continued for 2 to 3 hours, followed by TLC. After completion of the reaction, 75 ml of water and 20 ml of ethyl acetate were added, the organic phase was separated, and the aqueous phase was extracted twice with 20 ml of ethyl acetate. The organic phase was washed with 20 mL of water and 20 mL of diluted hydrochloric acid (1 N), washed with water, dried over anhydrous magnesium sulfate and evaporated. The first product was purified by silica gel column eluting with n-hexane (V/V = 1:3) to give 3,5-dimethoxy-4-isopropyl-[alpha]-methylphenylacetonitrile.

b. In a 250 mL round bottom flask, a sulfuric acid solution of 65 mL of concentrated sulfuric acid and 40 mL of water was added, and the cyanide obtained above was added. The reaction was refluxed for three hours, cooled, poured into 100 mL of ice water, and filtered to give a preliminary product. First product by silica gel column eluting with _{MeOH / CH 2 Cl 2 (V} / V = 1: 4) as eluent afforded 3,5-dimethoxy-4-isopropyl-phenylacetic acid -α-.

Example 6: Synthesis of 3,5-dihydroxy-4-isopropyl-α-methylphenylacetic acid

A mixture of 3,5-dimethoxy-4-isopropyl-α-methylphenylacetic acid (2.5 g) and pyridine hydrochloride (7 g) was heated at 200 ° C under a nitrogen stream protection. hour. After the reaction mixture was cooled to room temperature, 100 ml of 2N hydrochloric acid and 300 ml of ethyl acetate were added, and the organic phase and the aqueous phase were separated, the aqueous phase was extracted three times with 150 ml of ethyl acetate, and the mixture was combined and washed with saturated brine. Dry with sodium sulfate. After evaporating the ethyl acetate, the residue was purified by column chromatography eluting with ethyl acetate/hexane/acetic acid (50/50/1, volume ratio) to give 3,5-dihydroxy-4-isopropyl -α-methylphenylacetic acid.

The same method can be synthesized:

3,5-dihydroxy-4-ethyl-α-methylphenylacetic acid, 3,5-dihydroxy-4-butyl-α-methylphenylacetic acid, 3,5-dimethoxy-4-ethyl Base-α-methylphenylacetic acid, 3,5-dimethoxy-4-butyl-α-methylphenylacetic acid.

Example 7: Preparation of a pharmaceutical composition:

3,5-Dihydroxy-4-isopropylbenzoic acid is formulated into a cream according to the following formula:

Example 7: Preparation of a pharmaceutical composition

3,5-Dihydroxy-4-isopropylphenylacetic acid is formulated into a cream according to the following formula:

Example 9: Testing of the pharmacodynamic activity of the compounds of the invention

Effectiveness of edema induced by TPA

Female mice (Balb/c) of 10-12 weeks, phenenimod 0.5% was used as a positive control, and phorbol-12-myristate-13-acetate (TPA) was used as an edema inducer. Both the TPA and the test compound were dissolved in 100% ethanol, and 20 μl was applied to the right ear of the mouse, and a group of six mice. The concentration of TPA was 0.01% (w/v). The thickness of the mouse ears was measured after 6 hours of TPA treatment to determine whether the edema was alleviated. In each experiment, TPA-treated parallel mice were treated with 3,5-dihydroxy-4-isopropylbenzoic acid, 3,5-dihydroxy-4-isopropylphenylacetic acid, 3,5-dihydroxyl, respectively. The level of inhibition of edema can be obtained by measuring the thickness of the ear, and the percentage of the thickness of the ear after ethanol treatment is expressed as a percentage by treatment with -4-isopropyl phenylpropionic acid, phenenyl or only ethanol.

The results showed that 3,5-dihydroxy-4-isopropylbenzoic acid, 3,5-dihydroxy-4-isopropylphenylacetic acid, 3,5-dihydroxy-4-isopropylbenzenepropionic acid and benzene The enemore can significantly reduce edema, and these show that the compounds of the present invention can be used in the treatment of immunological diseases, inflammation or autoimmune diseases.

Table 1

Medication	Edema inhibition rate (%)
		TPA (0.01%) + phenene mound (0.5%)	12
TPA (0.0l%) + 3,5-dihydroxy-4-isopropylbenzoic acid (0.5%)	9
		TPA (0.0l%) + 3,5-dihydroxy-4-isopropylphenylacetic acid (0.5%)	9
TPA (0.0l%) + 3,5-dihydroxy-4-isopropylbenzenepropionic acid (0.5%)	11

Table 1 shows the anti-inflammatory activity of the dermal administration of a compound of the present invention having a structure I, II, III or phenenimod on a TPA-induced ear edema model.

The above are only the embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalents, improvements, etc., which are within the spirit and scope of the present invention, should be included in the scope of the present invention. Inside.

Claims (10)

1. A phenol derivative characterized by comprising a compound of the formula (I), (II) or (III) or a pharmaceutically acceptable salt, ester or amide thereof:

   Structural Formula I:

   

   Structural Formula II:

   

   Structural Formula III:

   

   among them,

   In the formula (I), R ^{l is} selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; and R ² and R ³ are each independently selected from hydrogen, alkyl, and ring. An alkyl group, an aryl group, an arylalkyl group or an acyl group; but when R ^l is isopropyl or bromo, R ² and R ^{3 may} not be a methyl group at the same time;

   In formula (II), R ^{l is} selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; R ² and R ³ are each independently selected from hydrogen, alkyl, and ring. An alkyl group, an aryl group, an arylalkyl group or an acyl group; R ⁴ and R ⁵ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl;

   In the formula (III), R ^{l is} selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, halogen or acyl; and R ² and R ³ are each independently selected from hydrogen, alkyl, and ring. Alkyl, aryl, aralkyl or acyl; R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl.
2. The phenol derivative according to claim 1, wherein

   In the formulae (I), (II) and (III), the alkyl group is an alkyl group of 1 to 18 carbons, the cycloalkyl group is a ring of 3 to 6 carbons, and the alkenyl group is 2 An 18-carbon alkenyl group, said alkynyl group being an alkynyl group of 2 to 18 carbons, said aryl group being an aryl group of 6 to 18 carbons, said aralkyl group being an aralkyl group of 7 to 18 carbons The acyl group is a saturated or unsaturated acyl group of 1 to 18 carbons.
3. The phenol derivative according to claim 1, wherein

   In formula (I), R ^{l is} selected from ethyl, isopropyl or butyl, and R ² and R ³ are each independently selected from hydrogen, methyl or acetyl.
4. The phenol derivative according to claim 1 or 3, wherein the phenol derivative is selected from the group consisting of:

   3,5-dihydroxy-4-ethylbenzoic acid,

   3,5-dihydroxy-4-isopropylbenzoic acid,

   3,5-dihydroxy-4-butylbenzoic acid,

   3,5-dimethoxy-4-ethylbenzoic acid,

   3,5-dimethoxy-4-butylbenzoic acid,

   3,5-diacetoxy-4-ethylbenzoic acid,

   3,5-diacetoxy-4-isopropylbenzoic acid,

   3,5-Diacetoxy-4-butylbenzoic acid.
5. The phenol derivative according to claim 1, wherein

   In formula (II), R ^{l is} selected from methyl, ethyl, isopropyl or butyl, R ² and R ³ are each independently selected from hydrogen or methyl, and R ⁴ and R ⁵ are each independently selected from hydrogen. Or methyl.
6. The phenol derivative according to claim 1 or 5, wherein the phenol derivative is selected from the group consisting of:

   3,5-dihydroxy-4-ethylphenylacetic acid,

   3,5-dihydroxy-4-isopropylphenylacetic acid,

   3,5-dihydroxy-4-butylphenylacetic acid,

   3,5-dihydroxy-4-ethyl-α-methylphenylacetic acid,

   3,5-dihydroxy-4-isopropyl-α-methylphenylacetic acid,

   3,5-dihydroxy-4-butyl-α-methylphenylacetic acid,

   3,5-dimethoxy-4-ethylphenylacetic acid,

   3,5-dimethoxy-4-isopropylphenylacetic acid,

   3,5-dimethoxy-4-butylphenylacetic acid,

   3,5-dimethoxy-4-ethyl-α-methylphenylacetic acid,

   3,5-dimethoxy-4-isopropyl-α-methylphenylacetic acid,

   3,5-Dimethoxy-4-butyl-α-methylphenylacetic acid.
7. The phenol derivative according to claim 1, wherein

   In formula (III), R ^{l is} selected from ethyl, isopropyl or butyl, R ² and R ³ are each independently selected from hydrogen or methyl, and R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently Selected from hydrogen or methyl.
8. The phenol derivative according to claim 1 or 7, wherein the phenol derivative is selected from the group consisting of:

   3,5-dihydroxy-4-ethyl phenylpropionic acid,

   3,5-dihydroxy-4-isopropylbenzenepropionic acid,

   3,5-dihydroxy-4-butyl phenylpropionic acid,

   3,5-dimethoxy-4-ethyl phenylpropionic acid,

   3,5-dimethoxy-4-isopropylbenzenepropionic acid,

   3,5-Dimethoxy-4-butyl phenylpropionic acid.
9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, amide thereof, and a pharmaceutically acceptable diluent or/and carrier.
10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester or amide thereof, for the manufacture of a medicament for the treatment of an immune disease, inflammation or autoimmune disease.