WO2011097797A1 - Polyphenol acrylic acid derivative, preparation and use in preparing medicine thereof - Google Patents

Abstract

Disclosed are a kind of polyphenol acrylic acid derivative, its preparation, and use in preparing medicine. The compound can be used as an inhibitor of protein kinase or cytokine, tranquilizer, and also can be used to treat eczema, psoriasis, allergy, pruritus, inflammation, asthma, hyperplasia diseases, autoimmune disease, and neoplasm.

Description

 Polyphenol acrylic acid derivative, preparation method thereof and application in preparing medicine

 The present invention relates to a propylene S history compound, and in particular to a polyphenol propylene S history derivative and its use in medicine.

Background technique

 Phenylacrylic acid (cinnamic acid) derivatives are widely distributed in nature in the natural components of plants, and generally have a certain physiological activity. Polyphenolic cinnamic acid, which is known in nature, is known as caffeic acid [(E)-3-(3,4-dihydroxyphenyl)acrylic acid], which is found in many fruits, vegetables and coffee. It is an effective antioxidant in vitro and in vivo [1]. Subcutaneous injection or oral caffeic acid and its derivative phenethyl caffeate can effectively inhibit tumor growth and cancer cell metastasis. The activity of the enzyme MMP-9 is achieved [2]. It has also been found that phenethyl caffeate has physiological activities such as anti-mitosis, anti-inflammatory and immunomodulation [3]. Caffeic acid, caffeic acid phenethyl ester and other polyphenolic cinnamic acid derivatives present in nature, the two phenolic hydroxyl groups are mostly in the 3 and 4 positions on the benzene ring, or 2, 4 positions, and less in the 3, 5 a derivative of the bit. Trans-3-(3,5-dihydroxyphenyl)-2-acrylic acid [4] was extracted only from the flowers of Ipomoea asar ifol ia plants, but there is no literature on physiological activity.

 Derivatives of 1,2-stilbene are abundantly found in plants and microorganisms in nature, among which polyphenols

(Pinosylvin 3, 5-dihydroxystyrene [5-(2-phenylvinyl) _1, 3-benzenediol] has antifungal activity and is an antifungal weapon for trees and other conifers [5]. Several years of research have found that silver pigment also has the activity of preventing leukemia and cancer. [6] Various derivatives of silver pine have various physiological activities, for example, derivatives of silver pine can inhibit the production of prostaglandin E2 [ 7]. A compound very similar to the structure of silver pine is also resveratrol [Resvera trol , 5- [2- (4-hydroxyphenyl) vinyl] -1, 3- Resveratrol], resveratrol was first discovered in red wine [8], it is the most intensive derivative of stilbene, and its various physiological activities are constantly discovered. And use. It can reduce the incidence of cardiovascular system [9], can prolong life [10], prevent tumor formation [11], anti-oxidation [12], anti-inflammatory [1 3]. In addition, resveratrol is used as a dermatological treatment for eczema, psoriasis and acne [14]. Another derivative of stilbene: 5-(2-phenylvinyl)-2-isopropyl-1, 3-benzenediol is isolated from Photobacterium (Photorhabdus), except In addition to its antibacterial activity, it also has good activity in the treatment of inflammation, psoriasis and eczema [15]. The above three derivatives of stilbene have a common feature, that is, two phenolic hydroxyl groups on one benzene ring are in the 1,3 position, such a special molecular structure may be in molecular physiological activity. The aspect plays an important role. In this arrangement and the polyphenolic cinnamic acid derivative molecule mentioned above, the 3, 5 position distribution of the phenolic hydroxyl group is identical.

 Eczema is an inflammation of the skin characterized by redness, itching, and rash, often accompanied by spills, scars, and skin damage. The cause of eczema is related to the history of family hereditary allergy. In many cases, the onset of eczema is induced by environmental factors. Studies have shown that there is a significant association between hereditary allergy and chromosomes. There is no particularly effective drug for this disease. At present, there are obvious side effects on the treatment of this disease, whether it is topical or systemic. Commonly used external medicines are hormone drugs, which cause skin atrophy and depigmentation, and cause side effects due to system absorption. Topical or systemic use of immunosuppressive agents such as cyclosporin, FK-506 or other similar drugs can cause serious side effects. Ultraviolet light irradiation is also a method of treating eczema, but ultraviolet light irradiation has the possibility of skin cancer.

Psoriasis is also often manifested as an inflammatory disease, hyperproliferation of the skin, and scale-like scarring, so it is also known as ichthyosis. People with this disease account for about 3% of the total population. The cause of psoriasis is not fully understood. It is generally thought to be related to the abnormalization of keratinocyte function, but also to inflammation or immune system. Related to the disorder. There are also different types of psoriasis, and the severity and location of the disease will vary. The treatment of psoriasis also has two methods of topical and systemic treatment, however, no matter which method has significant side effects. Commonly used external medicines include coal tar, vitamin D3, vitamin A and hormonal drugs, but these treatments are not ideal and have obvious side effects. Drugs used as systemic drugs include methotrexate, cyclosporine and other immunosuppressive agents, as well as palladium, red peony and anti-proliferative drugs, all of which have non-negligible side effects.

Summary of the invention

 The invention draws on the structural characteristics and physiological activity of polyphenol cinnamic acid and polyphenol stilbene, and provides a new class of polyphenol acrylic acid derivatives (polyphenol cinnamic acid derivatives), and also provides such new The preparation of the compounds and their use in medicines have significant anti-eczema, anti-psoriatic, anti-allergic and anti-itch activity.

 The compound of formula I according to the invention and its pharmaceutically acceptable salts:

 I

Its towel:

 Selected from a) H, b) alkyl, alkenyl, alkynyl, cycloalkyl or aralkyl, c) halogen;

R ₂ and R ₃ are each independently selected from the group consisting of:

 a) H, b) alkyl, cycloalkyl or aralkyl, c) acyl;

 X is selected from the group below:

a) R ₆ , b) 0R ₇ , c) NR ₈ R ₉ ;

R ₆ , R ₇ , 1 ₈ and 1 _{9 are} independently selected from the group consisting of: a) H, b) alkyl, cycloalkyl or aralkyl; c) aryl.

 The compounds of the formula I according to the invention have the trans- and cis-configurations of the double bond structure Z or E isomers, and the invention includes all isomers of the compounds;

Preferred compounds are those wherein R ₂ and R ₃ are hydrogen, fluorenyl and acetyl. Particularly preferred compounds are among them hydrogen and alkyl.

 Examples of preferred compounds are the following compounds:

 3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid;

 3-(3,5-dihydroxy-4-isopropylphenyl) decyl acrylate;

 Benzyl-3-(3,5-dihydroxy-4-isopropylphenyl)acrylamide;

 3-(3,5-Dihydroxy-4-isopropylphenyl)acrylic acid 2-phenylethyl ester.

 The compounds of formula I of the present invention may form salts, including those formed by pharmaceutically acceptable organic or inorganic S-bases.

 The preparation method of the compound of the formula I according to the present invention is as described in the following synthetic route diagram.

The reaction conditions for each step of the chemical reaction in the above synthetic route are as follows: a) Solvent: acetone; reagent: dinonyl sulphate, potassium carbonate; reaction conditions: heating under reflux for 24 hours,

 b) Solvent: nitrodecane; reagent: aluminum trichloride, halogenated alkane; reaction conditions: 60 ° C, 24 small c) Solvent: anhydrous diethyl ether; reagent: lithium tetrahydrogenate; reaction conditions: 0 ° C, 2 hour.

 d) Solvent: Dichlorodecane; Reagent: Pyridinium chromate anhydride; Reaction conditions: Normal temperature, 2 hours. e) Solvent: pyridine; reagent: malonic acid; reaction conditions: 70 ° C, 7 hours.

 f) Solvent: Reagent: thionyl chloride. After the first step of acid chlorination, add alcohol or amine to obtain the desired product.

 g) Solvent: Dichlorodecane; Reagent: Boron tribromide; Reaction conditions: 0 ° C, 24 hours.

 The methods used in this roadmap are classical methods in organic chemical reactions, and an experienced technician can synthesize a compound of formula I as described in the course of the synthetic route.

 The compound of the formula I according to the invention is useful as a medicament for the treatment of diseases associated with immunity, autoimmunity and hyperplasia, such as eczema, psoriasis, allergies, itching and inflammation, or a combination thereof.

 The compounds of formula I according to the invention are useful for the inclusion of specific immunological, autoimmune and inflammatory compounds of the invention for use in the treatment (including the amelioration, reduction, elimination or cure of a source or symptom) and/or prevention (including substantial A drug that is or completely limits, prevents or avoids a condition associated with the above activities. Such applications are illustrated by the following examples, but are not limited to the treatment and/or prevention of conditions in the following ranges.

For example: transplant rejection; myocardial infarction during organ transplantation; protection against ischemic or reperfusion injury caused by stroke or other causes; induction of transplantation tolerance; arthritis; inflammatory bowel disease; contact allergic reaction; Psoriasis; eczema; contact dermatitis; conjunctivitis; allergic Diseases such as respiratory allergy (asthma, hay fever, allergic rhinitis) or skin allergies; acute inflammatory reactions (eg acute dyspnea syndrome and ischemia/reperfusion injury); dermatomyositis; localized baldness; chronic Actinic dermatitis; systemic sclerosis; restenosis; surgical adhesions; calming; tuberculosis and chronic inflammatory lung disease (eg, asthma, pneumoconiosis, chronic obstructive pulmonary disease, etc.).

 The invention further provides a medicament of the compound of formula I for use in the treatment and prevention of a condition as described above, such as a specific condition.

 The invention also provides the use of the compounds of formula I in combination with other therapeutic agents. Other therapeutic agents known to those skilled in the art, such as cyclosporin A, vitamin A, vitamin D3, FK506 and rapamycin, etc., can be used in the present invention together with the compounds of the present invention. In the practice of the present invention, such other therapeutic agents may be used prior to, or concurrent with, administration of the compound of the present invention, or may be combined with the compounds of the present invention in a combined preparation.

 The invention further provides a pharmaceutical composition comprising at least one compound of formula I which is effective to treat the above conditions and a pharmaceutically acceptable carrier or diluent. By using a conventional solid or liquid carrier or diluent, and a class of pharmaceutical additives (eg, excipients, binders, preservatives, stabilizers, flavoring agents, etc.) suitable for the desired mode of administration, depending on the drug Formulation is well known in the art of formulation.

 The pharmaceutical combination containing the compound of the present invention may be in a form suitable for systemic, oral and/or topical use. For example, the pharmaceutical composition may be in the form of a "sterile aqueous injectable solution" or "oleoemulsified emulsion" which may be suitably pharmaceutically acceptable dispersing agents and/or surface according to known techniques. Preparation of the active agent. Among the acceptable vehicles and solutions that may be employed are water, green solution and isotonic sodium chloride solution.

For administration to the rectum, the compound of formula I can also be formulated in the form of a "suppository". These compositions can be prepared by admixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature, so that the drug is released in the rectum so that the drug is released The materials are cocoa butter and polyethylene glycol.

 The preparation for oral administration may be a tablet, a lozenge, a lozenge, an aqueous solution or an oil solution, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup. Compositions for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions. The tablet contains a mixture of the active ingredient and a non-toxic pharmaceutically acceptable excipient which is suitable for the manufacture of a tablet, such as an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or Sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gel or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

 The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsifier. The oil phase may be a plant oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture of these. Suitable emulsifiers may be naturally occurring phospholipids such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides. These preparations may also contain sustained release agents, preservatives, flavoring agents and coloring agents.

 For topical use, creams, ointments, gels, solutions or suspensions containing the compound of formula I, and the like can be used. The preparation of such topical formulations has been a very mature technology in the field of pharmaceutical formulations. For topical administration, these compounds can also be formulated as powders or sprays.

The metering level is about 0.01 to 200 mg/kg body weight per day, and can be effectively used to treat the above-mentioned conditions, or each patient can be dosed from about 0.5 mg to about 10 g per day. The particular level of measurement for a particular patient will depend on a number of factors, including age, health status, gender, diet, time of administration, route of administration, rate of excretion, combination of drugs, and the particular condition and severity being treated. DETAILED DESCRIPTION OF THE INVENTION The process for the preparation of the compounds of formula I is carried out by the methods described in the following synthetic scheme:

 The reaction conditions for each step of the chemical reaction in the above synthetic route are as follows:

 a) Solvent: acetone; reagent: dinonyl succinic acid, potassium carbonate; reaction conditions: heating under reflux for 24 hours.

 b) Solvent: nitrodecane; Reagents: aluminum trichloride, alkyl halide; reaction conditions: 60 ° C, 24 hours.

 c) Solvent: anhydrous diethyl ether; reagent: lithium tetrahydrogenate; reaction conditions: 0 ° C, 2 hours.

 d) Solvent: Dichlorodecane; Reagent: Pyridinium chromate anhydride; Reaction conditions: Normal temperature, 2 hours. e) Solvent: pyridine; reagent: malonic acid; reaction conditions: 70 ° C, 7 hours.

f) Solvent: Reagent: thionyl chloride, after the first step of acid chloride is added, the alcohol or amine is added to obtain the desired product. g) Solvent: Dichlorodecane; Reagent: Boron tribromide; Reaction conditions: 0 ° C, 24 hours.

 Synthesis Example 1: 3,5-Dimethoxyoxybenzoate

Into 300 ml of acetone, 15.4 g of 3,5-dihydroxybenzoic acid having a concentration of 0.1 mol, 38 g of diamyl sulfate having a concentration of 0.3 mol, and 70 g of potassium carbonate having a concentration of 0.5 mol were added, and the resulting system was The mixture was heated to reflux for 15 hours under good stirring. After the heating was stopped, the solid was removed by filtration, and the filtrate was evaporated to remove acetone. The residue was crystallised from ethyl acetate: petroleum ether to give the product 3, 5-dimethoxy phthalic acid decyl ester 18 g, yield 94 %. 1HNMR ( CDC13, pm ) 54.2 ( s, 6H ) , 4.6 (s, 3H) , 6. 3 ", 1H, J = 2.2Hz ) , 1. 2 (d, 2H, J = 2.2Hz) ₀ MS: 197 (M+l).

 Synthesis Example 2: 3,5-dimethoxyoxy-4-ylisopropylbenzoate

 Add 20 g of anhydrous aluminum trichloride to a solution of 20 g of 3,5-dimethoxyoxybenzoate and a solution of 0.1 g of dibromopropane in a concentration of 0.1 mol of nitrodecane dissolved in 0.1 mol. The resulting solution was heated and stirred at 80 ° C for 24 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed three times with 500 ml of water. The solvent was evaporated, and the residue was purifiedjjjjjjjjjjjjjjjjjjjj , Yield: 65%. 1 draw R (CDC13, ppm) δΐ.61 ( d, 6H, J = 7.1Hz ), 3.66 ( hept, 1H, J = 7.1Hz ), 3.88 ( s, 6H), 3.94 ( s, 3H), 7.25 ( s, 2H). MS: 239 (M+l).

 Synthesis Example 3: 3,5-dimethoxyoxy-4-isopropylbenzyl alcohol

2.26 g (0.07 mol) of lithium tetrahydroaluminum was suspended in 500 ml of anhydrous diethyl ether, and 3,5-dimethoxyoxy-4-iso was added dropwise to the suspension at 0 ° C under good agitation. A solution of 24 g (0.1 mol) of propyl benzoquinoneate in 100 ml of diethyl ether. After the addition was completed, the system was naturally warmed to room temperature, and stirring was continued for 30 minutes, and then excess lithium tetrahydrogenate was quenched by adding 5 ml of saturated brine. Filter After removing the solid, the solvent was evaporated under reduced pressure and the residue was crystallised from EtOAc-EtOAc (EtOAc (EtOAc) 86%. 1HNMR (CDC13, m) δΐ.33 (d, 6H, J=7.1Hz), 3.65 (hept, 1H, J=7.1Hz), 3.86 (s, 6H), 4.70(s, 1H), 6.62 (s, 2H), MS: 211 (M+l).

 Synthesis Example 4: 3, 5-Dimethoxyoxy-4-isopropylphenylfurfural

 To a system in which 42 g (0.2 mol) of pyridine chromic anhydride was suspended in 200 ml of dichloromethane, 2,5-dimethoxy-4-isopropylbenzyl alcohol (21 mol) was added in 50 ml of dichloro The solution in decane was stirred for 1 hour, and then 600 ml of diethyl ether was added, and then the reaction solution was passed through a magnesium silicate column to obtain a pale yellow liquid. After evaporation of the solvent under reduced pressure, the residue was obtained from ethyl acetate. Crystallization from the ether system gave 17 g of 3,5-dimethoxyoxy-4-isopropylphenylfurfural in a yield of 82%. 1H匪R (CDC13, ppm) 51.32 ( d, 6H, J=7.2Hz ) , 3.68 (hept, 1H, J=7.2Hz) , 3.92 (s, 6H), 7.12 (s, 2H ), 9.96 ( s, 1H). MS: 209 (M+l).

 Synthesis Example 5·· 3-(3,5-Dimethoxyoxy_4-isopropylphenyl)acrylic acid

 21 g (0.1 mol) of 3,5-dimethoxy-4-phenylbenzofural, 21 g of malonic acid (0.11 mol) and 2 ml of piperidine were dissolved in 200 ml of pyridine. After heating at 70 ° C, stirring for 8 hours, after the reaction system was cooled to room temperature, 500 ml of 6N hydrochloric acid was slowly added, and the product was extracted by adding 500 ml of ethyl acetate. The organic phase was washed twice with 6 N hydrochloric acid 500 ml, water 500 ml. After washing once, drying over anhydrous sodium S-sodium, the solvent is evaporated under reduced pressure, and the residue is crystallized from a mixture of methanol and water (8: 2) to give 3-(3,5-dimethoxy- 23 g of propyl phenyl)acrylic acid, yield 93%. 1 draw R (CDC13, ppm) 51.23 (d, 6H), 3.60 (hept, 1H), 3.82 (s, 6H), 6.4 (d, 1H), 6.71 (s, 2H), 7.75 (d, 1H). MS: 251 (M+l).

 Synthesis Example 6: 3-(3,5-Dimethoxyoxy-4-isopropylphenyl)acryloyl chloride

Dissolve 3-(3,5-dioxaoxy-4-isopropylphenyl)acrylic acid in 100 ml of thionyl chloride Gram (0.1 mole), the resulting solution was heated to reflux for 2 hours. After the completion of the heating, the succinyl chloride was distilled off, 50 ml of dry benzene was added, and the benzene was distilled off under pressure to carry out the remaining succinyl chloride. The residue was 3-(3,5-dimethoxy-4-phenylphenyl)acryloyl chloride without further purification.

 Synthesis Example 7: Oxyl 3-(3,5-dimethoxyoxy-4-isopropylphenyl)acrylate

2 g of the acid chloride (7.5 mmol) obtained in Synthesis Example 6 was dissolved in 100 ml of anhydrous tetrahydrofuran, and 2 ml of anhydrous decyl alcohol was added to the solution, and the reaction system was heated under reflux for 1 hour, and the solvent was evaporated. The material was purified by silica gel column chromatography eluting with ethyl acetate- petroleum ether (1: 20) to give ethyl 3-(3,5-dimethoxyoxy-4-isopropylphenyl) acrylate. , the yield is 65%. 1HNMR (CDC13, m) δΐ.24 (d, 6H), 3.61 (hept, 1Η), 3.80(s, 3H), 3.83 (s, 6H), 6.36 (d, 1H), 6.64 (s, 2H), 7.70 (d, 1H). MS: 265 (M+l) ₀

Synthesis Example 8: 2-(3,5-Dimethoxyoxy-4-ylisopropylphenyl)acrylic acid-2-phenylethyl ester was dissolved in 100 ml of anhydrous tetrahydrofuran, 2 g, obtained in Synthesis Example 6. To the solution, 1 g of 2-phenylethanol (16 mmol) was added, and the reaction mixture was stirred and heated to reflux for 1 hr. Ethyl acetate- petroleum ether (1:20) system gave 1.7 g of 3-(3,5-dimethoxyoxy-4-isopropylphenyl)acrylic acid-2-phenylethyl ester, yield 52%. 1HNMR (CDC13, m) δΐ.22 (d, 6H), 3.03 (t, 2Η), 3.62 (hept, 1H), 3.83 ( s, 6H ), 4.38 (t, 2H) , 6.34 (d, 1H), 6.62 (s, 2H), 7.26 (m, 5H), 7.68 (d, 1H). MS: 355 (M+l) ₀

 Synthesis Example 9: Nitro-benzyl-3-(3,5-dioxaoxy-4-isopropylphenyl)acrylamide was dissolved in 100 ml of anhydrous tetrahydrofuran (1 g) obtained in Synthesis Example 6. To the solution was added 1 g of benzylamine (1,7 mmol), and the reaction system was stirred and heated to reflux.

After 1 hour, the solvent was evaporated.

15) system, obtaining 3-(3,5-dimethoxy-4-phenylphenyl)acrylic acid benzylamine 1.6 g, yield 62%. 1HNMR (CDC13, m) 51.23 (d, 6H), 3.62 (hept, 1H), 3.83 (s, 6H), 4.41 (d, 2H), 5.86 (br s, 1H), 6.38 (d, 1H), 6.65 (s, 2H), 7.71 (d, 1H). MS: 340 (M+l).

 Synthesis Example 10: 3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid

3- ^{(3, 5} _ _ _ ^4-yloxy two Yue-isopropylphenyl) acrylic acid ^2.5 g (0.01 mol) dissolved in 100 ml of methylene Yue dioxane, and the solution was cooled to 0 ° C, At this temperature, a solution of 1 ml of boron tribromide in 10 ml of dichloromethane was slowly added dropwise. After the dropwise addition was completed, stirring was continued at this temperature for 24 hours. 200 ml of water was slowly added at 0 ° C, and the product was extracted with 200 ml of ethyl acetate, and washed twice with 200 ml of 2N hydrochloric acid and once with 200 water. The organic phase was dried over anhydrous sodium sulfate. EtOAcjjjjjjjjjj ) 1.8 g of acrylic acid with a yield of 81%. 1H wake up R CCD30D, ppm) δΐ.25 ( d, 6H ), 3.50 (hept, 1H) , 6.25 (d, 1H), 6.45 ( s, 2H ) , 7.42 (d, 1H) ₀ 13CNMR ( CD30D, ppm) 519.5, 24.2, 106.2, 116.2, 123.8, 132.3, 145.7, 156.5, 169.5. MS: 223 (M+l).

 Synthesis Example 11: Oxyl 3-(3,5-dihydroxy-4-cyclopropenyl)acrylate

The synthesis method was exactly the same as that of Synthesis Example 10, the yield of decyl 3-(3,5-dihydroxy-4-isopropylphenyl)acrylate was 85%, and the solvent for crystallization was ethyl acetate-petroleum ether (1 : 9). 1H wake up R (CDC13, ppm) 51.35 ( d, 6H ), 3.45 (hept, 1H) , 3.80 ( s, 3H ) , 5.35 (s, 2H), 6.35 (d, 1H), 6.55 (s, 2H) , 7.55 (d, 1H). MS: 237 (M+l) ₀

 Synthesis Example 12: Oxyl 3-(3,5-dihydroxy-4-cyclopropenyl)-2-phenylethyl ester

The synthesis method was exactly the same as that of Synthesis Example 10, the yield of 3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid-2-phenylethyl ester was 80%, and the solvent for crystallization was ethyl acetate. - petroleum ether (1: 9). 1HNMR (CDC13, ppm) δΐ.32 ( d, 6H ) , 3.02 ( t, 2H ) , 3.50 (hept, 1H), 4.32 (t,

2H), 6.34 (d, 1H), 6.62 (s, 2H), 7.23 (m, 5H), 7.60 (d, 1H). MS: 327 (M+l).

 Synthesis Example 13: The synthesis method of nitrogen-benzyl-3-(3,5-dihydroxy-4-isopropylphenyl)acrylamide was identical to that of Synthesis Example 10, nitrogen-benzyl-3-(3, The yield of 5-dihydroxy-4-isopropylphenyl)acrylamide was 72%, and the solvent for crystallization was ethyl acetate-petroleum ether (2:8). 1H wake up R (CDC13, ppm) δΐ.34 ( d, 6H ), 4.38 (d, 2H) , 5.80 (br s, 1H), 6.36 (d, 1H),

6.65 (s, 2H), 7.29 (m, 5H), 7.42 (d, 1H). MS: 312 (M+l) ₀

 Biological experiment of the compound of formula I of the present invention

 Experiments for the following biological activity tests have been established and known in the art, so only a brief description is provided herein.

 1. Test for in vivo anti-inflammatory activity of a compound of formula I;

 In vivo anti-inflammatory activity is demonstrated using standard mouse edema animal models. Briefly, Balb/c rats were divided into several groups of 4 each;

 The first group applied 20 μl of 0.01% (w/v) phorbol -12-myristate-13-acetate (TPA, an agent that causes inflammatory edema) to the right ear of each mouse;

 In the second group, 20 μl of 0.01% (w/v) TPA was applied to the right ear of each mouse, and a commercial anti-inflammatory compound calcitriol 20 μl (2% ethanol solution) was applied to the same ear;

 The remaining groups were applied 20 μl (2% ethanol solution) of the compound of the present invention to the same ear after applying 20 μl of 0.01% (w/v) TPA to the right ear of each mouse;

 The thickness of the mouse ears was tested two hours later to determine the degree of edema in the ears of the mice and compared with the group using only TPA, and the inhibition rate of the edema of the compound of the present invention for each test was obtained. As summarized in Table 1, the compound of the formula I of the present invention has [strong anti-inflammatory activity.

Table 1. Results of in vivo anti-inflammatory activity of a portion of a compound of formula I of the invention: Treatment compound edema inhibition rate%

3-(3,5-Dihydroxy-4-isopropylphenyl)acrylic acid 91

 Methyl 3-(3,5-dihydroxy-4-isopropylphenyl)acrylate 68

 Calcitriol 41

 2. An embodiment of the compound of formula I of the present invention for use in the treatment of human eczema

 Eczema is manifested as inflammation to a certain extent, but the cause of eczema is very complicated, and it is also related to immunity and autoimmune system. There is no animal model yet, so this experiment is a voluntary patient with eczema. For the experimental object. The treatment is a topical treatment, that is, a topical treatment. The preparation is used as a cream, and the active ingredient is 3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid of the present invention, and the content is 1%, and the application method is once every day in the affected area, and the medicine is continuously administered for 4 weeks. A cycle of judgment for efficacy. The subject in this example was asked to stop using any other therapeutic medication for two weeks prior to the test. There were 18 volunteers participating in the present embodiment, and the compound of the present invention has an effective rate of 100% and a cure rate of 80% or more in the treatment of the 18 volunteers. The following are exemplified by three typical examples.

 Volunteer patients 1 , female, 49 years old, has a palm-sized erythema on the back and abdomen, and is accompanied by a rash. The itching sensation at the lesion was obvious. The hospital doctor diagnosed allergic eczema, probably due to the patient's use of Haci's five-row needle. The patient has used a variety of topical drugs, but none of them has a significant therapeutic effect. Volunteer 1 After the cream containing the compound of the present invention was used, the itching disappeared quickly, and the redness of the inflammation disappeared after four days of continuous administration, and the lesion completely disappeared after one week of continuous administration, and the skin completely returned to normal, leaving only some Skin pigmentation.

Volunteer patient 2, male, 26 years old, has a erythematous area on his arm, with papules, blisters, etc., because itching causes scratches and skin lesions, spills and erosion. I have used hormone drugs and have certain effects, but there is no essential improvement. In the volunteer patient 2, after using the cream containing the compound of the present invention, the itching disappeared quickly, and the symptom was significantly improved after 5 days of administration. After 10 days of administration, the redness of the large piece disappeared, leaving only a small amount. Herpes, and continue After four weeks of treatment, the lesions basically disappeared and the skin returned to normal.

 Volunteer 3, male, 35 years old, a part of the skin on the front of the calf is rough, crusted, scratched, partially red and swollen, with papules. The patient has a 5-year medical history, has used a variety of dermatological and systemic drugs, and his condition has not improved significantly. He has basically given up treatment before volunteering to use the drug of this invention, but occasionally apply some moisturizer. Volunteer 3 After the use of the cream containing the compound of the present invention, itching also disappeared very quickly. After 4 weeks of use of the cream containing the compound of the present invention, the skin scarring has disappeared, the lesion area is shrinking, part of the skin Back to normal, the condition has improved significantly.

 3. An embodiment of the compound of formula I of the present invention for use in the treatment of psoriasis drugs in humans

 Psoriasis is a very difficult skin disease to treat, and the factors of the disease are complicated. It is related to inflammation, cell proliferation, immunity and autoimmunity, but it has not completely solved the cause of the disease and effective treatment. There is also no effective animal model for psoriasis to study. Therefore, experimentation in volunteer patients is the only way to effectively determine the effectiveness of drugs on psoriasis. The treatment is a topical treatment, that is, a topical treatment. The preparation is a cream, and the active ingredient is 3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid of the present invention in an amount of 1%. The method of application is to apply once a day to the affected area, and continuous administration for 4 weeks is a therapeutic judgment cycle. The subject in this example was asked to stop using any other therapeutic drug for two weeks prior to the test. There are 15 volunteers participating in this embodiment, and the compound of the present invention has an effective rate of 85 % in treating these 15 volunteers, and the cure rate is 50% or more. The following is a typical example of three volunteers.

Volunteer patient 1, female, 33 years old, has a psoriasis lesion area of about 100 square centimeters on the back, which is characterized by redness, thickening, roughness, crusting and scaling, and a strong itching. A variety of topical and oral drugs have been used, but none of them have a significant effect. Two weeks after stopping the medication, the ointment containing the drug of the present invention was started, and on the day of administration, the itching sensation disappeared, and the skin became red and swollen the next day. It was relieved, and the condition improved day by day. After 4 weeks of continuous medication, the psoriasis lesion completely disappeared, leaving only some skin pigmentation.

 Volunteer patient 2, female, 42 years old, has a large area of psoriasis from the thigh to the calf. The appearance is similar to that of a volunteer patient. There is a psoriasis with an area of more than 200 square centimeters on the front of the thigh. The ointment containing the medicament of the present invention is used only in the range of not more than 100 cm 2 in the middle of the psoriasis, once a day, after 4 weeks of continuous application, the skin where the ointment is applied has completely recovered to normal in the skin. Surroundings, the skin condition of the unapplied area also improved significantly, showing the effect of the spread of this ointment on the surrounding area.

 Volunteer patients 3, male, 51 years old, with scattered head, coin-sized plaque psoriasis, has a history of 5 years, has used various internal and external medicines, and has no obvious effect. After using the ointment containing the drug of the present invention, the feeling of itching quickly disappeared, and the phenomenon of redness and swelling of the plaque was relieved at the initial stage of administration, but after a few days passed, the condition was slowed down, and the drug was continuously administered. After 4 weeks, the condition improved significantly, but there was no case where the plaque completely returned to normal. If the medication continues, the condition can be further improved.

 Psoriasis is a disease associated with inflammation, immunity/autoimmunity and cell proliferation. The compounds of the present invention have a significant effect on psoriasis. Therefore, the compounds of the present invention may have an inhibitory function in addition to anti-inflammatory and immunomodulatory functions. The role of cell proliferation.

 4. Examples of the compound of the general formula I of the present invention for use in human anti-inflammatory and anti-allergic drugs

Dermatitis caused by mosquito bites in insect bite dermatitis is the most common. Mosquitoes puncture the skin through their mouthparts, and their saliva or venom invades the skin. Because the insect's saliva or venom gland contains a variety of anti-smoke, sometimes the body becomes red and swollen after being bitten by mosquitoes, and parts that are not easily bitten are also present. This kind of package, this is an allergic reaction. About 20 people voluntarily used ointments containing the compounds of the present invention. To deal with inflammation and allergies caused by mosquito bites, the efficiency is 100%. The itching caused by the mosquito bite disappeared within 1 minute of the medication, and the redness caused by the mosquito bite disappeared within 5 minutes. Applying the ointment immediately after the mosquito bites will not cause itching and redness.

 5. Activity analysis of a compound of formula I of the invention as a protein kinase inhibitor

 Lck is a protein tyrosine kinase that activates T-cells via antigen receptors of T-cells [16], so Lck inhibitors are a potential for the treatment of diseases associated with abnormal activation of T-cells. . These diseases include diseases that can be classified as immune and autoimmune, such as inflammation (including colitis, rheumatoid arthritis, glomerulonephritis), fibrosis of the lungs, psoriasis, skin allergies, arteriosclerosis, allergic asthma, etc. [ 17].

 Standard analytical methods for the inhibitory activity of compounds against Lck can be found in the patent literature [18]. The results of the analysis are listed in the table below.

Table 2. Inhibitory activity of partial kinase protein kinase Lck of the present invention

 From the data in Table 2, it can be seen that the three compounds in the table have a certain degree of inhibitory activity against protein kinase Lck, although the etiology of eczema, psoriasis, inflammation and allergies is not completely related to Lck kinase, but the compound of the present invention The inhibitory activity against Lck illustrates to some extent the effectiveness of the compounds of the invention in the treatment of the above mentioned diseases. references:

[1] M Hirose, Y Takesada, H Tanaka, S Tamano, T Kato and T Shirai. "Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4- Me thoxy phenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model". Carcinogenesis 19: (1998) 207 - 212.

[2] TAE-WOOK CHUNG, SUNG-KWON MOONl, YOUNG-CHAE CHANG*, JEONG-HEON KO, YOUNG-CHOON LEE, GUN CHO, SOO-HYUN KIM, JONG-GUK KIM and CHEORL-HO KIM ₀ "Novel and Therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regress ion of hepatoma growth and metastasis by dual mechanism "The FASEB Journal. 2004; 18: 1670-1681.

 [3] K. NATARAJAN, SANJAYA SINGH, TERRENCE R. BURKE, JR. t, DEZIDER GRUNBERGERt, AND BHARAT B. AGGAR L "Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-KB". Proc. Natl. Acad. Sci. USA Vol. 93, p. 9090-9095, August 1996, Immunology

 [4] Eloi Pale, Marie Kouda-Bonaf os, Mouhouss ine Nacro, Maurice Vanhaelen, Renee Vanhaelen-Fastre. " Two tr iacylated and tetraglucosylated ant ho cyan ins from

 I omoea asarifolia flowers" , Phytochemistry 64 (2003) 1395 - 1399.

[5] H. ERDTMANan d E. RENNERFELTS. V. Papperstidn.47, 45 (1944)

[6] Kathryn Roupe, Steven Hal 1 s, Neal M. Davies, Determination and assay validation of pinosy lvin in rat serum: application to drug metabolism and pharmacokinetics , Journal of Pharmaceutical and Biomedical

Analysis 38 (2005) [7] Eun-Jung Park, Hye-Young Mina, Yong-Hyun Ahn, Cheol-Man Bae, Jae-Ho

Pyee and Sang Kook Lee, Bioorganic & Medicinal Chemistry Letters

Volume 14, Issue 23, 6 December 2004, Pages 5895-5898

 [8] B. B. Aggarwal, A. Bhardwa j, R. S. Aggarwal, N. P. Seeram, S.

Shishodia, Y. Takada, Anticancer Res. 24 (2004) 2783 - 2840.

 [9] Renaud S, Ruf JC (1994) . "The French paradox: vegetables or wine".

Circulation 90 (6): 3118 - 9.

 [10] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. "Small molecule activators of s ir tuins extend Saccharomyces cerevisiae Lifespan". Nature. 2003 Sep 11; 425 (6954): 191-6.

 [11] Athar M, Back JH, Tang X, Kim KH, Kopelovich L, Bickers DR, Kim AL (2007) . "Resveratrol: a review of preclinical studies for human cancer prevention". Toxicol. Appl. Pharmacol. 224 (3 ): 274 - 83. 2006.

[12] Cao Y, Fu ZD, Wang F, Liu HY, Han R (2005). "Anti-angiogenic activity of resveratrol, a natural compound from medicinal plants". Journal of Asian natural products research 7 (3): 205 - 13. 2005.

[13] Das, Samar jit; Das, Dipak K. "Ant i-Inf 1 animator y Responses of Resveratrol" Inflammation & Al lergy - Drug Targets (Formerly Current Drug Targets - Inflammation & Allergy), Volume 6, Number 3 , September 2007, pp. 168-173 (6).

[14] Maria Teresa Pel 1 iccia, Attilio Giannel la and Jenny Giannel la. US2001/005607L [15] John M. Webster, Genhui Chen, J ianxiong Li, Kai ji Hu and Jiang Zhu. WO 01/42231.

 [16] AE Nel "T-cel 1 activation through antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. " J. Allergy Clin Immunol, 109, 5, 758-770 , 2002

 [17] J. H. Hanke et al., Inf lamm. Res., 1995, 357

 [18] ROTH, Gerald, J ϋ rgen "USE OF LCK INHIBITOR FOR TREATMENT OF

IMMUNOLOGIC DISEASES", (WO/2004/017948)

Claims

Rights request 1. A compound of formula I, or a salt thereof:

 I Which is selected from:  An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, a halogen; R ₂ and R ₃ are each independently selected from the group consisting of:  H, alkyl, cycloalkyl, aralkyl and acyl; X is selected from the group below: R ₄ , 0R ₅ , and NR ₆ R ₇ ; R ₄ , R ₅ , 11 ₆ and 11 _{7 are} independently selected from the group consisting of:  H, alkyl, cycloalkyl, aralkyl and aryl; The configuration of the double bond is Z or E. The compound of formula I contains all cis and trans isomers and all isotopic isomers. 2. A compound of formula I, or a salt thereof, as a pharmaceutical or pharmaceutical composition:

Which is selected from:  H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, halogen; R ₂ and R ₃ are each independently selected from the group consisting of:  H, alkyl, cycloalkyl, aralkyl and acyl; X is selected from the group below: R ₄ , 0R ₅ , and NR ₆ R ₇ ; R ₄ , R ₅ , and 11 _{7 are} independently selected from the group consisting of:  H, alkyl, cycloalkyl, aralkyl and aryl; The configuration of the double bond is Z or E, and the compound of formula I contains all cis and trans isomers and all isotopic isomers. The compound of formula 2 as claimed in claim I 3., wherein R ₂ and preferably 11 to _113.  4. A compound of formula I according to claim 2 or 3, wherein preferably ^ is an alkyl group. 5. The compound of formula I according to claim 2 selected from the group consisting of:  3-(3,5-dihydroxy-4-isopropylphenyl)acrylic acid,  Methyl 3-(5,5-dihydroxy-4-isopropylphenyl)acrylate,  N-benzyl-3-(3,5-dihydroxy-4-isopropylphenyl)acrylamide,  3-(3,5-Dihydroxy-4-isopropylphenyl)acrylic acid 2-phenylethyl ester. 6. A process for the preparation of a compound of formula I according to claim 1 by the following synthetic route The method described in the figure is synthesized:

 The reaction conditions for each step of the chemical reaction in the above synthetic route are as follows:  a) Solvent: acetone; reagent: dimethyl sulfate, carbonic acid clock; reaction conditions: heating under reflux for 24 hours;  b) Solvent: nitromethane; reagent: aluminum trichloride, alkyl halide; reaction ^ 60. C, 24 small c) Solvent: anhydrous diethyl ether; reagent: lithium aluminum hydride; reaction conditions: 0 ° C, 2 hours; d) solvent: dichloromethane; reagent: pyridine chromic anhydride hydrochloride; reaction conditions: room temperature , 2 hours; e) Solvent: pyridine; reagent: malonic acid; reaction ^ 70 ° C, 7 hours;  f) Solvent: Reagent: thionyl chloride, after the first acid chlorination is completed, the alcohol or amine is added to obtain the desired product;  g) Solvent: dichloromethane; reagent: boron tribromide; reaction conditions: 0 ° C, 24 hours. A pharmaceutical or pharmaceutical composition comprising the compound of the formula I according to claim 2 or a salt thereof, And a pharmaceutically acceptable carrier or excipient.  8. The use of a compound of formula I according to claim 2 in a medicament comprising a compound of formula I or a salt thereof, or a pharmaceutical composition, and a pharmaceutically acceptable carrier or excipient for use as a protein An inhibitor of a kinase or cytokine that treats and prevents related diseases such as, but not limited to, hyperplasia and cancer.  9. The use of a compound of formula I according to claim 2 in a medicament comprising a compound of formula I or a salt thereof, or a pharmaceutical composition, and a pharmaceutically acceptable carrier or excipient for treatment Diseases associated with immunity and autoimmunity.  10. The use of a compound of formula I according to claim 2 in a medicament comprising a compound of formula I or a salt thereof, or a pharmaceutical composition, and a pharmaceutically acceptable carrier or excipient for treatment Allergies, itching, inflammation, asthma, allergic dermatitis, conjunctivitis, etc.  11. The use of a compound of formula I according to claim 2 in a medicament comprising a compound of formula I or a salt thereof, or a pharmaceutical composition, and a pharmaceutically acceptable carrier or excipient for treatment For the treatment of eczema, psoriasis.  12. The use of a compound of formula I according to claim 2 in a medicament comprising a compound of formula I or a salt thereof, or a pharmaceutical composition, and a pharmaceutically acceptable carrier or excipient for use as a calming Agent.