CN101648865B - Polyphenol acrylic acid derivative and application thereof in medicaments - Google Patents
Polyphenol acrylic acid derivative and application thereof in medicaments Download PDFInfo
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- CN101648865B CN101648865B CN 200810070133 CN200810070133A CN101648865B CN 101648865 B CN101648865 B CN 101648865B CN 200810070133 CN200810070133 CN 200810070133 CN 200810070133 A CN200810070133 A CN 200810070133A CN 101648865 B CN101648865 B CN 101648865B
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- 239000003814 drug Substances 0.000 title claims abstract description 49
- 235000013824 polyphenols Nutrition 0.000 title abstract description 19
- -1 Polyphenol acrylic acid derivative Chemical class 0.000 title abstract description 17
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- 238000000034 method Methods 0.000 claims description 18
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 16
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to an acrylic acid compound, in particular to a polyphenol acrylic acid derivative and application thereof in medicaments. The invention borrows ideas from the characteristics of structural properties, physiologically activities and the like of polyphenol cinnamic acid and polyphenol diphenylethene, provides a novel polyphenol acrylic acid derivative (polyphenol cinnamic acid derivative), and simultaneously provides a preparation method and application in the medicaments of the novel compound. The novel compound has very significant activities in eczema resistance, psoriasis resistance, allergy resistance and pruritus resistance. The novel compound and a medicament composition of the novel compound can be used for treating the diseases correlative with allergy, inflammation, hyperplasia and the like.
Description
Technical field
The present invention relates to acrylic compound, be specifically related to polyphenol acrylic acid derivative and the application in medicine thereof.
Background technology
Phenylacrylic acid (styracin) derivative often extensively is distributed in occurring in nature with the natural component of plant, generally all has certain physiologically active.Exist at occurring in nature, for the known polyphenol styracin of people just like coffic acid [(E)-3-(3, the 4-dihydroxy phenyl) vinylformic acid], it is present in many fruit, in vegetables and the coffee, all be a good antioxidant [1] in vitro and in vivo, the derivative CAPE of subcutaneous injection or oral coffic acid and it can effectively suppress the growth of tumour and the transfer of cancer cells, and this effect is [2] that the activity by inhibitory enzyme MMP-9 realizes.People find that also CAPE has antimitotic, the physiologically actives such as anti-inflammatory and immunomodulatory [3].Coffic acid, CAPE etc. are present in natural Polyphenols cinnamic acid derivative, and on phenyl ring 3 and 4 of two phenolic hydroxyl group many places, seldom have to be in 3,5 derivative by perhaps 2,4.Only in the spending of Ipomoea asarifolia plant, extract trans-3-(3,5-dihydroxy phenyl)-2-vinylformic acid [4], but do not had the bibliographical information of relevant physiologically active.
The derivative of stilbene is present in natural plant and the microorganism in a large number, and wherein the Polyphenols derivative especially causes people's attention because of the physiologically active that it has various uniquenesses.For example (Pinosylvin 3, and 5-dihydroxy-benzene ethene [5-(2-phenyl vinyl)-Resorcinol] has antimycotic activity, is the antimycotic weapons of confierophyte [5] such as pine tree for pinosylvin.Research in recent years finds that pinosylvin also has the activity [6] of pre-preventing leukemia and cancer.The various derivatives of pinosylvin also have various physiologically actives, and for example the derivative of pinosylvin can suppress the generation [7] of prostaglandin E2.The compound very similar to the pinosylvin structure also has trans-resveratrol [Resveratrol, 5-[2-(4-hydroxy phenyl) vinyl]-1,3-dihydroxy-benzene], trans-resveratrol is found to be present in [8] in the red wine at first, it is the derivative of the most deep toluylene studied of people, its various physiologically actives are constantly found by people, research and utilization.It can reduce the sickness rate [9] of cardiovascular systems, can extending life [10], and the formation of prophylaxis of tumours [11], anti-oxidant [12], anti-inflammatory [13].In addition, trans-resveratrol can be used for the treatment of eczema, psoriasis and acne [14] as dermatologic.Another is 1 years old, the derivative of 2-toluylene: 5-(2-phenyl vinyl)-2-sec.-propyl-1, the 3-dihydroxy-benzene is separated from luminous bacillus (Photorhabdus), except having obvious anti-microbial activity, also has the activity [15] of good treatment inflammation, psoriasis and eczema.The derivative of above-mentioned three stilbene has common characteristics, and two phenolic hydroxyl groups on a phenyl ring all are to be in 1,3 exactly, and so special molecular structure layout may play an important role aspect the molecular physiology activity.And in the cinnamic acid derivative molecule of this layout and above-mentioned polyphenol, 3,5 layouts of phenolic hydroxyl group are consistent.
Eczema is a kind of skin inflammation, shows as redness, itch, fash, often with overspill, scar and skin injury.The cause of disease of eczema is relevant with family heredity allergies, and the morbidity of eczema is again bringing out of environmental factors under many circumstances.There are some researches prove between heredity allergy and the karyomit(e) it is that very significant association is arranged.For this disease especially effective medicine of neither one also.Present methods for the treatment of to this disease is no matter be that externally applied agent or system's medication have side effect clearly.Externally applied agent commonly used has amcinonide, and this class medicine can cause the atrophy of skin and go pigmented, also can cause absorbing the side effect that causes because of system.External application or system use immunosuppressor, S-Neoral for example, and FK-506 or other similar medicines all can cause severe side effect.UV-irradiation also is a kind of method for the treatment of eczema, but the irradiation of UV-light has the possibility that causes skin carcinoma.
Psoriasis also shows as inflammatory diseases usually, and the skin hyperplasia incrustation of fish scale sample occurs, so be called again ichthyosis.The people who suffers from this disease accounts for about 3% of total population.The psoriasic cause of disease also imperfectly understands, and it has been generally acknowledged that it is relevant with improperization of keratinocyte function, and is also relevant with inflammation or immune disorder.Also there is different types in psoriasis, and the position of severity and morbidity also can be distinguished to some extent.Psoriasis treatment also has external application and two kinds of methods of systematic treating, still, no matter the sort of method has significant side effect.Externally applied agent commonly used has coal tar, Vitamin D3 500,000 I.U/GM, and vitamin A and hormone medicine, but these methods for the treatment of are all not bery desirable, and side effect is clearly arranged.As system's medication medicine methotrexate, S-Neoral and other immunosuppressor are arranged, also have palladium, red ruthenium and anti-proliferative drug, these all medicines have very important toxic side effect.
Summary of the invention
The present invention has used for reference the characteristics such as the structural performance of polyphenol styracin and polyphenol toluylene and physiologically active, the new polyphenol acrylic acid derivative of one class (polyphenol cinnamic acid derivative) is provided, simultaneously, the preparation method of this class new compound and the application in medicine also are provided, and this class new compound has very significant antieczematic, psoriasis, antianaphylaxis and antipruritic active.
Compound of Formula I of the present invention and acceptable salt pharmaceutically thereof:
Wherein:
R
1Be selected from a) H, b) alkyl, thiazolinyl, alkynyl, cycloalkyl or aralkyl, c) halogen;
R
2And R
3Independently be selected from separately following group:
A) H, b) alkyl, cycloalkyl or aralkyl, c) acyl group;
X is selected from following group:
a)R
6，b)OR
7，c)NR
8R
9；
R
6, R
7, R
8And R
9Independently be selected from following group:
A) H, b) alkyl, cycloalkyl or aralkyl; C) aryl.
Compound of Formula I of the present invention has the isomer of the trans of double bond structure and cis-configuration Z or E formula, the present invention includes whole isomer of compound;
Preferred compound is R wherein
2And R
3Compound for hydrogen, methyl and ethanoyl.R
4And R
5Be hydrogen, alkyl, particularly preferred compound is R wherein
1Be hydrogen and alkyl.
Preferred examples of compounds is following compound:
3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid;
3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate;
N-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide;
3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid-2-styroyl ester.
Described compound of Formula I of the present invention can form salt, is included in the pharmaceutically salt of acceptable organic or inorganic soda acid formation.
The preparation method of compound of Formula I of the present invention, synthesize by the described method of following synthetic route chart:
The reaction conditions of each step chemical reaction is as follows in the said synthesis route:
A) solvent: acetone; Reagent: methyl-sulfate, salt of wormwood; Reaction conditions: reflux 24 hours;
B) solvent: Nitromethane 99Min.; Reagent: aluminum chloride, haloalkane; Reaction conditions: 60 ℃, 24 hours;
C) solvent: anhydrous diethyl ether; Reagent: Lithium Aluminium Hydride; Reaction conditions: 0 ℃, 2 hours;
D) solvent: methylene dichloride; Reagent: pyridine chromic anhydride hydrochloride; Reaction conditions: normal temperature, 2 hours;
E) solvent: pyridine; Reagent: propanedioic acid; Reaction conditions: 70 ℃, 7 hours;
F) solvent: reagent: thionyl chloride, adding alcohol or amine obtained the product of wanting after the first step chloride was finished;
G) solvent: methylene dichloride; Reagent: boron tribromide; Reaction conditions: 0 ℃, 24 hours.
Employed method all is the classical way in the organic chemical reactions in this route map, and an experienced technician can be according to the synthetic compound of Formula I of method described in the synthetic route way.
The compound of general formula I of the present invention is as medicine or its combination of the disease relevant with immunity, autoimmunization and hyperplasia such as treatment eczema, psoriasis, allergy, itch and inflammation.
Compound of Formula I of the present invention can be used for comprising the medicine of specific immunity, autoimmunization and struvite disease and situation relevant with transplant rejection or that cause transplant rejection.
Being applied to of compound of the present invention comprises the medicine of the illness that treatment (comprising improvement, reduction, eliminate or cure pathogeny or symptom) and/or prevention (comprise substantial or limit fully, prevent or avoid) are relevant with above-mentioned activity.Such application still is not limited to the illness that treats and/or prevents following scope by following example explanation.
For example: transplant rejection; Myocardial infarction during the organ transplantation; The ischemia that apoplexy or other reasons cause or the provide protection of reperfusion injury; Transplantation tolerance is induced; Sacroiliitis; Inflammatory bowel; Contact hypersensitivity; The retardance anaphylaxis; Psoriasis; Eczema; Contact dermatitis; Anaphylactic disease is irritated (asthma, spring fever, allergic rhinitis) or skin allergy of respiratory for example; Acute inflammatory response (for example acute respiratory distress syndrome and local ischemia/reperfusion injury); Dermatomyositis; The limitation bald head; Chronic actinic dermatitis; Systemic sclerosis; Restenosis; Surgical adhesions; Pulmonary tuberculosis and chronic inflammation tuberculosis (for example, asthma, Pneumonoconiosis, chronic obstructive pulmonary disease etc.).
The present invention also provides described compound of Formula I to be used for the treatment of and prevents above-mentioned illness, for example the medicine of atopic illness.
The application that the present invention also provides described compound of Formula I to be combined with the other treatment agent.Can be with other treatment agent known to those skilled in the art, cyclosporin A for example, vitamin A, Vitamin D3 500,000 I.U/GM, FK506 and rapamycin etc. uses in the present invention with compound of the present invention.Using when of the present invention, such other treatment agent may be before the compounds of this invention administration, or when administration, or administration after, use, also can make the combination preparation use with the compounds of this invention.
The present invention also provide comprise at least a can be with the compound of Formula I of the above-mentioned illness of effective treatment and the pharmaceutical composition of a kind of pharmaceutically acceptable carrier or thinner.
Composition of the present invention can contain other and be those skilled in the art's reagent in common knowledge, may be by using conventional solid or liquid vehicle or thinner, and one class be suitable for needed administering mode medicated premix (for example, vehicle, tackiness agent, sanitas, stablizer, seasonings etc.) prepared according to the well-known technique of field of pharmaceutical preparations.
The drug regimen that contains compound of the present invention can be for being suitable for general, the form of oral and/or local use.For example, pharmaceutical composition may be the form of one " the aseptic injection aqueous solution " or " oil emulsion ", pharmaceutically acceptable dispersion agent and/or tensio-active agent preparation that this injection liquid or emulsion can be suitable according to known utilization.In operable acceptable vehicle and solution, can be water, Green's solution and isotonic sodium chlorrde solution.
To also the compound of general formula I being prepared with the form of " suppository " with the medicine of rectal administration.These compositions can be by preparing medicine and a kind of suitable non-stimulated mixed with excipients, this vehicle is solid under conventional temperature, but be liquid under rectal temperature, therefore thawing discharges medicine in rectum, and such material is theobroma oil and polyoxyethylene glycol.
Can be tablet for oral preparation, lozenge, lozenge, the aqueous solution or oil solution, dispersible powder or granula, emulsion, hard or soft capsule, or syrup.The composition of oral use can be according to the method preparation of any pharmaceutical compositions known in the art.Contain active ingredient and the mixture that is fit to the nontoxic pharmaceutically acceptable vehicle of making tablet in the tablet, these vehicle can be inert diluents for example, such as calcium carbonate, and yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent are such as W-Gum or Lalgine; Tackiness agent, such as starch, gel or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum powder.
Pharmaceutical composition of the present invention can also be oil-in-water emulsifying agent form.Oil phase can be a vegetable oil, for example sweet oil or peanut oil, or a kind of mineral oil for example whiteruss or these mixture.Suitable emulsifying agent can be naturally occurring phosphatide, soybean for example, Yelkin TTS, and ester or the partial ester of source and lipid acid and hexitol acid anhydrides.These preparations also may contain sustained release dosage, sanitas, seasonings and tinting material.
Use for the part, can use the emulsifiable paste that contains formula I compound, ointment, jello, solution or suspension etc.The preparation of such local application's preparation has been unusual proven technique in the field of pharmaceutical preparations.For local application, these compounds also can be made pulvis or sprays.
Stoichiometric level can be effective to treat the above-mentioned illness that indicates in about 0.01-200 mg/kg body weight every day, and perhaps each patient can about 0.5 milligram of metering administration to about 10 grams every day.To depend on many factors to the specific stoichiometric level with special patient, comprise the age, healthy state, sex, diet, administration time, route of administration, drainage rate, drug regimen and specified disease and the severity of being treated.
Embodiment
The present invention will be described in more detail with following nonrestrictive embodiment.
The preparation method of described compound of Formula I, synthesize by the described method of following synthetic route chart:
The reaction conditions of each step chemical reaction is as follows in the said synthesis route:
A) solvent: acetone; Reagent: methyl-sulfate, salt of wormwood; Reaction conditions: reflux 24 hours.
B) solvent: Nitromethane 99Min.; Reagent: aluminum chloride, haloalkane; Reaction conditions: 60 ℃, 24 hours.
C) solvent: anhydrous diethyl ether; Reagent: Lithium Aluminium Hydride; Reaction conditions: 0 ℃, 2 hours.
D) solvent: methylene dichloride; Reagent: pyridine chromic anhydride hydrochloride; Reaction conditions: normal temperature, 2 hours.
E) solvent: pyridine; Reagent: propanedioic acid; Reaction conditions: 70 ℃, 7 hours.
F) solvent: reagent: thionyl chloride, adding alcohol or amine obtained the product of wanting after the first step chloride was finished.
G) solvent: methylene dichloride; Reagent: boron tribromide; Reaction conditions: 0 ℃, 24 hours.
Synthetic example 1:3, the 5-dimethoxy p-methyl.
In 300 milliliters of acetone, add concentration and be 0.1 mole 3,5-resorcylic acid 15.4 grams, concentration are salt of wormwood 70 grams that 0.3 mole methyl-sulfate 38 grams and concentration are 0.5 mole, formed system reflux 15 hours under good agitation condition.Solids removed by filtration behind the stopped heating, filtrate decompression distillation are removed acetone, and residue was with 1: 6 ethyl acetate: the sherwood oil crystallization, obtain product 3, and 5-dimethoxy p-methyl 18 restrains productive rate 94%.1HNMR(CDCl3，ppm)δ4.2(s，6H)，4.6(s，3H)，6.3(t，1H，J＝2.2Hz)，7.2(d，2H，J＝2.2Hz)。MS：197(M+1)。
Synthetic example 2:3,5-dimethoxy-4 '-isopropyl acid methyl esters.
To be dissolved with concentration be 0.1 mole 3,5-dimethoxy p-methyl 20 gram and concentration are to add aluminum trichloride (anhydrous) 20 in 0.11 mole the Nitromethane 99Min. solution of dibromopropane 14 grams to restrain, formed solution was 80 ℃ of heated and stirred 24 hours, decompression steams solvent, residue is dissolved in 500 milliliters of ethyl acetate, with 500 ml waters washing 3 times, organic solution with anhydrous sodium sulfate drying after, decompression steams solvent, residue silica gel chromatography product, 1: 10 ethyl acetate of elutriant: sherwood oil obtains 3,5-dimethoxy-4 '-isopropyl acid methyl esters 17 grams, productive rate: 65%.1HNMR(CDCl3，ppm)δ1.61(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+1)。
Synthetic example 3:3,5-dimethoxy-4 '-Isobutyl Benzyl Carbinol.
Suspension Lithium Aluminium Hydride 2.26 grams (0.07 mole) in 500 milliliters of anhydrous diethyl ethers, at 0 ℃, have under the well-stirred condition, in this suspension, drip 3,5-dimethoxy-4 '-isopropyl acid methyl esters 24 gram (0.1 mole) solution in 100 milliliters of ether.Be that reaction system is warmed up to room temperature naturally after dripping, continue to stir the Lithium Aluminium Hydride that adds 5 milliliters of saturated aqueous common salt cancellation surpluses after 30 minutes.Behind the filtering solid, decompression steams solvent, and residue is recrystallization in methanol-water (8: 2) system, obtains 3,5-dimethoxy-4 '-Isobutyl Benzyl Carbinol, 18 grams, productive rate: 86%.1HNMR(CDCl3，ppm)δ1.33(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+1)。
Synthetic example 4:3,5-dimethoxy-4 '-isopropyl benzene formaldehyde.
In the system of 200 milliliters of the methylene dichloride that is suspended with pyridine chromic anhydride 43 grams (0.2 mole), add 3,5-dimethoxy-4 '-Isobutyl Benzyl Carbinol 21 gram (0.1 mole) solution in 50 milliliters of methylene dichloride, the reaction system that forms stirred after 1 hour, add 600 milliliters of ether, then allow reaction soln pass through the Magnesium Silicate q-agent pillar, obtain weak yellow liquid, after decompression steams solvent, residue crystallization in ethyl acetate-sherwood oil system, obtain 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde 17 grams, productive rate 82%.1HNMR(CDCl3，ppm)δ1.32(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+1)。
Synthetic example 5:3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid.
In 200 milliliters of pyridines, dissolve 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde 21 grams (0.1 mole), 2 milliliters of propanedioic acid 11 grams (0.11 mole) and piperidines, formed solution is 70 ℃ of heating, stirred 8 hours, after the question response system is cooled to room temperature, slowly add 500 milliliters of the hydrochloric acid of 6N, add again 500 milliliters of ethyl acetate extraction products, organic phase 500 milliliters of washed twice of hydrochloric acid of 6N, 500 milliliters of washings of water once, behind anhydrous sodium sulfate drying, decompression steams solvent, residue methanol-water (8: 2) mixed system crystallization, obtain 3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid 23 grams, productive rate 93%.1HNMR(CDCl3，ppm)δ1.23(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+1)。
Synthetic example 6:3-(3,5-dimethoxy-4 '-isopropyl phenyl) acrylate chloride.
In 100 milliliters of thionyl chloride, dissolve 3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid 25 grams (0.1 mole), formed vlil 5 hours.After heating is finished, steam thionyl chloride, add 50 milliliters of dry toluene, pressurization steams toluene again, takes residual thionyl chloride out of with this.Residue is 3-(3,5-dimethoxy-4 '-isopropyl phenyl) acrylate chloride, is not further purified processing.
Synthetic example 7:3-(3,5-dimethoxy-4 '-isopropyl phenyl) methyl acrylate.
The acyl chlorides (7.5 mmole) that dissolving 2 grams obtain in synthetic example 6 in 100 milliliters of anhydrous tetrahydro furans, in this solution, add 2 milliliters of anhydrous methanols, the reaction system stirring heating steamed solvent after refluxing 1 hour, residue is through silica gel chromatography, elutriant is ethyl acetate-sherwood oil (1: 20) system, obtain 3-(3,5-dimethoxy-4 '-isopropyl phenyl) methyl acrylate 1.3 grams, productive rate 65%.1HNMR(CDCl3，ppm)δ1.24(d，6H)，3.61(hept，1H)，3.80(s，3H)，3.83(s，6H)，6.36(d，1H)，6.64(s，2H)，7.70(d，1H)。MS：265(M+1)。
Synthetic example 8:3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid-2-phenyl chlorocarbonate.
The acyl chlorides (7.5 mmole) that dissolving 2 grams obtain in synthetic example 6 in 100 milliliters of anhydrous tetrahydro furans, in this solution, add 2 gram 2-phenylethyl alcohols (16 mmole), the reaction system stirring heating steamed solvent after refluxing 1 hour, residue is through silica gel chromatography, elutriant is ethyl acetate-sherwood oil (1: 20) system, obtain 3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid-2-phenyl chlorocarbonate 1.7 grams, productive rate 64%.1HNMR(CDCl3，ppm)δ1.22(d，6H)，3.03(t，2H)，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+1)。
Synthetic example 9: nitrogen-benzyl-3-(3,5-dimethoxy-4 '-isopropyl phenyl) acrylamide.
The acyl chlorides (7.5 mmole) that dissolving 2 grams obtain in synthetic example 6 in 100 milliliters of anhydrous tetrahydro furans, in this solution, add 2 gram benzylamines (18.7 mmole), the reaction system stirring heating steamed solvent after refluxing 1 hour, residue is through silica gel chromatography, elutriant is ethyl acetate-sherwood oil (1: 15) system, obtain 3-(3,5-dimethoxy-4 '-isopropyl phenyl) acryloyl benzylamine 1.6 grams, productive rate 62%.1HNMR(CDCl3，ppm)δ1.23(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+1)。
Synthetic example 10:3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid.
With 3-(3,5-dimethoxy-4 '-isopropyl phenyl) vinylformic acid 2.5 (0.01 mole) gram is dissolved in 100 milliliters of methylene dichloride, and this solution is cooled to 0 ℃, slowly dripping the solution of 2 milliliters of boron tribromides in 10 milliliters of methylene dichloride under this temperature.After dripping, remain under this temperature and stirred 24 hours.Slowly add 200 ml waters at 0 ℃, product is with 200 milliliters of ethyl acetate extractions, and with 200 milliliters of 2N hydrochloric acid washed twice, 200 water washings once.Organic phase with anhydrous sodium sulfate drying after, decompression steams solvent, residue obtains 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid 1.8 grams, productive rate 81% with ethyl acetate-sherwood oil (2: 8) crystallization.1HNMR(CD3OD，ppm)δ1.25(d，6H)，3.50(hept，1H)，6.25(d，1H)，6.45(s，2H)，7.42(d，1H)。13CNMR(CD3OD，ppm)δ19.5，24.2，106.2，116.2，123.8，132.3，145.7，156.5，169.5。MS：223(M+1)。
Synthetic example 11:3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate.
Synthetic method and synthetic example 10 are identical, and the productive rate of 3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate is 85%, and the crystallization solvent is ethyl acetate-sherwood oil (1: 9).1HNMR(CDCl3，ppm)δ1.35(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+1)。
Synthetic example 12:3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate-2-phenyl chlorocarbonate.
Synthetic method and synthetic example 10 are identical, and the productive rate of 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid-2-phenyl chlorocarbonate is 80%, and the crystallization solvent is ethyl acetate-sherwood oil (1: 9).1HNMR(CDCl3，ppm)δ1.32(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+1)。
Synthetic example 13: nitrogen-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide.
Synthetic method and synthetic example 10 are identical, and the productive rate of nitrogen-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide is 72%, and the crystallization solvent is ethyl acetate-sherwood oil (2: 8).1HNMR(CDCl3，ppm)δ1.34(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+1)。
The biological experiment of compound of Formula I of the present invention.
For the experiment of the test of following biologic activity be this area established with known, so only provide brief description at this.
1. the test of compound of Formula I interior anti-inflammatory activity;
Interior anti-inflammatory activity is to use the mouse edema animal model of standard to prove.Briefly, the Balb/c mouse is divided into several groups, 4 every group;
First group of auris dextra to each mouse smeared 20 microlitres 0.01% (w/v) ripple alcohol-12-myristic acid-13-acetic acid fat (TPA, a kind of reagent that causes the inflammatory edema) that boils;
Smear 20 microlitre 0.01% (w/v) TPA to the auris dextra of each mouse after, smear commercial anti-inflammatory compound calcitriol 20 microlitres (2% ethanolic soln) at same ear for second group;
Remaining group is smeared the compounds of this invention 20 microlitres (2% ethanolic soln) at same ear smear 20 microlitre 0.01% (w/v) TPA to the auris dextra of each mouse after;
The thickness of test mouse ear compares with the edema degree of definite mouse ear and with a group with TPA after two hours, draws the compound of the present invention of every kind of test to the inhibiting rate of edema.Such as table 1 summary, compound of Formula I of the present invention has very strong anti-inflammatory activity.
The interior anti-inflammatory activity result of table 1. part compound of Formula I of the present invention:
| The treatment compound | Edema inhibiting rate % |
| 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid | 91 |
| 3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate | 68 |
| Calcitriol | 41 |
2. compound of Formula I of the present invention is used for the treatment of the embodiment of human body eczema medicine.
Eczema show as to a certain extent inflammation, but the reason that causes the eczema illness is very complicated, with immunity and autoimmunization system relation is arranged also, also do not have at present good animal experimental model, so this experiment is that to suffer from the voluntary patient of eczema illness be experimental subjects.What treatment was adopted is local therapeutic approaches, i.e. externally applied agent method.Preparation adopts creme, and activeconstituents is the compounds of this invention 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid, and content is 1%, and use-pattern is to smear once in the affected part every day, and 4 weeks of continuous use are that a curative effect is judged the cycle.Study subject in the present embodiment is required to stop using any other medicine for treatment thing fortnight before tested.The volunteer who participates in the present embodiment has 18, and compound of the present invention is 100% in treatment the efficient of these 18 volunteers, and curative ratio is more than 80%, and the below is illustrated with three exemplary.
The aspiration patient 1, the woman, 49 years old, waist and belly be the back have hand size erythema each one, also with erythema.The scratchiness of affected area clearly, doctor is diagnosed as allergic eczema through hospital, may since the patient use and breathe out kind five-element needle and cause.The patient used multiple externally applied agent, but did not have a kind of medicine that obvious result for the treatment of is arranged.Patient 1 is after having used the creme that contains the compounds of this invention for aspiration, and itch has disappeared soon, and rubescent inflammation disappeared at continuous use in four days afterwards, continuous use focus completely dissolve after one week, and skin is replied normally fully, only stays some skin pigments.
Aspiration patient 2, the man, 26 years old, at arm one erythema oedema zone is arranged, on papule, bubble etc. are arranged, cause skin to decrease because itch causes scratching, overspill and erosion are arranged.Once use hormone medicine, certain effect was arranged, but do not have the improvement of essence.After aspiration patient 2 has used the creme that contains the compounds of this invention, itch also is to have disappeared soon, illness has had obvious improvement after medication in continuous 5 days, redness at medication sheet after 10 days disappears, residual a small amount of papulo-vesicle only, and after around the continuation medication, focus disappears substantially, and it is normal that skin recovers.
Aspiration patient 3, the man, 35 years old is coarse, incrustation in the positive a part of cutaneous manifestations of shank, and scratch is arranged, partial skin is red and swollen, and papule is arranged.The medical history in existing 5 years of this patient was used various dermatologics and systemic medicine, and the state of an illness does not all have significantly to take a turn for the better, and has basically abandoned treatment before aspiration is used medicine of the present invention, just frequently smears some skin cream.Patient 3 is after having used the creme that contains the compounds of this invention for aspiration, and itch has disappeared equally soon, after continuous 4 weeks of process using and contain the creme of the compounds of this invention, the skin incrustation disappears, the focus area is dwindling, and partial skin is replied normal, and the state of an illness has obvious improvement.
3. compound of Formula I of the present invention is used for the treatment of the embodiment of human body psoriasis medicine.
Psoriasis is a kind of dermatosis of extremely difficult treatment, and the factor of morbidity is very complicated, with inflammation, hyperplasia, immunity and autoimmunization etc. relation is arranged, but does not also crack so far the reason of its morbidity and the effective way for the treatment of fully.Psoriasis also is not have effective animal experimental model can supply research, and therefore, doing experiment with it the aspiration patient is that unique effective judgement medicine is to the method for psoriasis validity.What treatment was adopted is local therapeutic approaches, i.e. externally applied agent method.Preparation adopts creme, and activeconstituents is the compounds of this invention 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid, and content is 1%.Use-pattern is to smear once in the affected part every day, and 4 weeks of continuous use are that a curative effect is judged the cycle.Study subject in the present embodiment is required to stop using any other medicine for treatment thing fortnight before tested.The volunteer who participates in the present embodiment has 15, and compound of the present invention is 85% in treatment the efficient of these 15 volunteers, and curative ratio is more than 50%, and the below is illustrated with three exemplary.
Aspiration patient 1, the woman, 33 years old, there were about 100 sq psoriasis focus districts at the back, showed as red swelling of the skin, thickened, coarse and incrustation and furfur are arranged, and scratchiness is strong.Once use multiple externally applied agent and oral medicine, but do not have a kind of medicine that obvious effect is arranged.Bring into use the ointment that contains medicine of the present invention after two weeks of discontinuing medication, on the same day of medication, scratchiness has just disappeared, the second day red swelling of the skin just alleviates to some extent, the state of an illness takes a turn for the better day by day, and continuous use is the completely dissolve of psoriasis focus after 4 week, only stays some skin pigments.
Aspiration patient 2, the woman, 42 years old, to shank the big area psoriasis is arranged at left and right sides thigh, outward appearance is similar with the illness that aspiration patient 1 suffers from, the psoriasis that has an area to surpass 200 square centimeters in the thigh front is used as the object of drug treating, the ointment that contains medicine of the present invention only uses in the psoriasic middle of this piece is no more than 100 square centimeters scope, smear every day once, after smearing continuously for 4 weeks, the ground side skin of smearing ointment has recovered normal fully, around this piece skin, the local skin of not smearing also has obvious improvement, demonstrates the effect that the curative effect of this ointment spreads towards periphery.
Aspiration patient 3, the man, 51 years old, head had dispersion, the psoriasis en plaques of coin size, the medical history in existing 5 years was used various for oral administration and externally applied agents, did not all have an obvious effect.After having used the ointment that contains medicine of the present invention, the sensation of itch has disappeared soon, the phenomenon of patch redness alleviates very fast at the initial stage of medication, but after a few days ago passing by, alleviating of the state of an illness is slower, and continuous use is after 4 weeks, the state of an illness has obvious improvement, do not recover normal situation fully but patch occurs, if continue medication, the state of an illness can be further improved.
Psoriasis is one and inflammation, the disease that immunity/autoimmunization and hyperplasia are relevant, compound of the present invention has clearly curative effect to psoriasis, therefore, compound of the present invention also may have the effect of inhibition of cell proliferation except anti-inflammatory and immunoregulatory function are arranged.
4. compound of Formula I of the present invention is used for the embodiment of human body anti-inflammatory and Claritin.
The dermatitis that mosquito bite causes in insect dermatitis is modal.Mosquito is stabbed skin by its mouthpart, and its saliva or venom are invaded skin, owing to contain the plurality of antigens composition in the leach liquor of the saliva of mosquito or poison gland, these antigens can produce atopic reaction with antibody and cause inflammation after entering human body skin.Sometimes human body by mosquito bite after whole body red and swollen bag has appearred, anaphylaxis that Here it is this bag also appearred, in the position that bites that is difficult for getting stung by.There is approximately people more than 20 to use voluntarily the ointment that contains the compounds of this invention to process inflammation and allergy that mosquito bite causes, efficiently reaches 100%.The itch that produces behind the mosquito bite has just disappeared in 2 minutes in medication, and the redness that produces behind the mosquito bite disappeared in 5 minutes.Behind mosquito bite, smear ointment at once and just itch and redness can not occur.
5. compound of Formula I of the present invention is as the activation analysis of kinases inhibitor.
Lck is a protein tyrosine kinase, its antigen receptor activation T-cell [16] by the T-cell, so the inhibitor of Lck is exactly a kind of potential some diseases relevant with the improper activation of T-cell that be used for the treatment of.These diseases comprise can range immunity and autoimmune disease, inflammation (comprising colitis, rheumatic arthritis, glomerulonephritis) for example, and the lung-distension fibrosis, psoriasis, allergic, arteriosclerosis, allergic asthma etc. [17].
Compound has the analytical procedure of standard to the inhibition activity of Lck, can be referring to patent documentation [18], and analytical results is listed in the table below 2.
It is active that table 2. part of compounds protein kinase of the present invention Lck suppresses
| Compound | Lck suppresses active IC50 (μ M) |
| 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid | 0.26 |
| 3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate | 0.72 |
| N-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide | 0.48 |
| 3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid-2-styroyl ester | 2.20 |
Can find out that from the data of table 2 three compounds the table have inhibition to a certain degree active for protein kinase Lck, although eczema, psoriasis, the cause of disease of inflammation and irritated these diseases is not fully relevant with the Lck kinases, and still compound of the present invention has illustrated the validity of the compounds of this invention to above-mentioned disease treatment to a certain extent to the inhibition activity of Lck.
Reference:
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Claims (3)
1. be selected from following compound:
3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid,
3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate,
N-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide,
3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid-2-styroyl ester.
2. the preparation method of compound as claimed in claim 1, synthesize by the described method of following synthetic route chart:
Substituent R among the said synthesis route figure and X are respectively corresponding substituting group in the compound claimed in claim 1, and the reaction conditions of each step chemical reaction is as follows:
A) solvent: acetone; Reagent: methyl-sulfate, salt of wormwood; Reaction conditions: reflux 24 hours;
B) solvent: Nitromethane 99Min.; Reagent: aluminum chloride, haloalkane; Reaction conditions: 60 ℃, 24 hours;
C) solvent: anhydrous diethyl ether; Reagent: Lithium Aluminium Hydride; Reaction conditions: 0 ℃, 2 hours;
D) solvent: methylene dichloride; Reagent: pyridine chromic anhydride hydrochloride; Reaction conditions: normal temperature, 2 hours;
E) solvent: pyridine; Reagent: propanedioic acid; Reaction conditions: 70 ℃, 7 hours;
F) solvent, reagent: thionyl chloride, adding alcohol or amine obtained the product of wanting after the first step chloride was finished;
G) solvent: methylene dichloride; Reagent: boron tribromide; Reaction conditions: 0 ℃, 24 hours.
3. the application of compound as claimed in claim 1 in the preparation medicine, described pharmaceutical pack contains compound claimed in claim 1 and a kind of carrier that pharmaceutically can receive, be used for the treatment of inflammation, hyperplasia, immunity and autoimmune illness, or be used for the treatment of itch, allergy, psoriasis and comedo.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810070133 CN101648865B (en) | 2008-08-16 | 2008-08-16 | Polyphenol acrylic acid derivative and application thereof in medicaments |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106902099A (en) * | 2016-02-16 | 2017-06-30 | 周幼文 | The isopropyl toluylene of 3,5 dihydroxy 4 (DHIS) is used as acaricide and its therapeutic application |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011097797A1 (en) * | 2010-02-10 | 2011-08-18 | Peng Jinlian | Polyphenol acrylic acid derivative, preparation and use in preparing medicine thereof |
| CN102531814A (en) * | 2011-12-23 | 2012-07-04 | 张文生 | Preparation method for trans-cinnamic acid compound in water insoluble ionic liquid [bmim] PF6 |
| CN103193625A (en) * | 2013-04-24 | 2013-07-10 | 重庆市科学技术研究院 | Process for synthesizing 3-(3,5-dihydroxy-4-isopropylphenyl) acrylic acid |
| CN105687174A (en) * | 2014-11-25 | 2016-06-22 | 重庆市科学技术研究院 | Externally-used medicinal preparation for treatment of autoimmune dermatosis |
| CN113072488A (en) * | 2021-03-30 | 2021-07-06 | 广东工业大学 | Styrene derivative and synthesis method and application thereof |
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| CN101092336A (en) * | 2006-06-23 | 2007-12-26 | 赵昱 | Compound in cinnamic alcohol category preparation method and usage |
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| WO1995006628A1 (en) * | 1993-09-03 | 1995-03-09 | Statens Seruminstitut | Treatment and prophylaxis of diseases caused by parasites or bacteria |
| CN1243510A (en) * | 1997-01-08 | 2000-02-02 | 弗·哈夫曼-拉罗切有限公司 | Tricyclicbenzo [3] isoindole and benzo (h) isoquinoline |
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| CN106902099A (en) * | 2016-02-16 | 2017-06-30 | 周幼文 | The isopropyl toluylene of 3,5 dihydroxy 4 (DHIS) is used as acaricide and its therapeutic application |
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