CN101648865A - 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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- CN101648865A CN101648865A CN 200810070133 CN200810070133A CN101648865A CN 101648865 A CN101648865 A CN 101648865A CN 200810070133 CN200810070133 CN 200810070133 CN 200810070133 A CN200810070133 A CN 200810070133A CN 101648865 A CN101648865 A CN 101648865A
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- 239000003814 drug Substances 0.000 title claims abstract description 53
- 235000013824 polyphenols Nutrition 0.000 title abstract description 19
- -1 Polyphenol acrylic acid derivative Chemical class 0.000 title abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 23
- 201000004624 Dermatitis Diseases 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 16
- 206010061218 Inflammation Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 15
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000004054 inflammatory process Effects 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 11
- 208000003251 Pruritus Diseases 0.000 claims abstract description 11
- 208000026935 allergic disease Diseases 0.000 claims abstract description 10
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- 206010020718 hyperplasia Diseases 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 7
- 230000036039 immunity Effects 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
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- 125000002252 acyl group Chemical group 0.000 claims description 2
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- 150000008442 polyphenolic compounds Chemical class 0.000 abstract description 6
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 abstract description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 abstract 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 abstract 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- YCVPRTHEGLPYPB-VOTSOKGWSA-N trans-pinosylvin Chemical compound OC1=CC(O)=CC(\C=C\C=2C=CC=CC=2)=C1 YCVPRTHEGLPYPB-VOTSOKGWSA-N 0.000 description 9
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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 ofstructural properties, physiologically activities and the like of polyphenol cinnamic acid and polyphenol diphenylethene, provides a novel polyphenol acrylic acid derivative (polyphenol cinnamic acidderivative), 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 transfer of growth of tumor and cancer cells, and this effect is [2] that the activity by inhibitory enzyme MMP-9 realizes.People find that also CAPE has antimitotic, physiologically actives such as anti-inflammatory and immunomodulatory [3].Coffic acid, CAPE etc. are present in natural Polyphenols cinnamic acid derivative, and two phenolic hydroxyl group many places 3 and 4 on phenyl ring, seldom have to be in 3,5 derivative by perhaps 2,4.Only in the spending of Ipomoea asarifolia plant, extract trans-3-(3, the 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)-1,3-dihydroxy-benzene] has antimycotic activity, is the antimycotic weapons of confierophyte [5] such as pine tree for pinosylvin.The pinosylvin of discovering in recent years 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 at first and is present in [8] in the red wine, 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 prolong life [10], 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 tangible anti-microbial activity, also has the activity [15] of good curing inflammation, psoriasis and eczema.The derivative of above-mentioned three stilbene has a common characteristic, and two phenolic hydroxyl groups on a phenyl ring all are to be in 1,3 exactly, and such specific molecule topology layout may play an important role aspect the molecule physiologically active.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.At this disease especially effective medicine of none also.At present to this treatment of diseases method, no matter be that externally applied agent or system's medication all 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 ichthyosis again.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 pronounced side effects.Externally applied agent commonly used has coal tar, Vitamin D3 500,000 I.U/GM, and vitamin A and hormone medicine, but these methods of treatment are all not really desirable, and side effect is clearly all 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 all have very important toxic side effect.
Summary of the invention
The present invention has used for reference 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 activity.
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 following group separately:
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 with immunity, autoimmunization and hyperplasia diseases associated 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.
Application of compound of the present invention is in the medicine that comprises 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 respiratory allergy (asthma, spring fever, allergic rhinitis) or skin allergy 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 present invention also provides described compound of Formula I and other treatment agent bonded to use.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 The compounds of this invention administration, or administration the time, 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 or the like) prepared according to the well-known technology 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 ", and this injection liquid or emulsion can use suitable pharmaceutically acceptable dispersion agent and/or tensio-active agent preparation according to known technology.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, as lime carbonate, and yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent are as W-Gum or Lalgine; Tackiness agent, as starch, gel or gum arabic; And lubricant, 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.Examples of suitable emulsifiers can be naturally occurring phosphatide, soybean for example, the ester or the partial ester of Yelkin TTS and 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 or the like.The preparation of such local application's preparation has been a 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 above-mentioned indicated illness 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 specific stoichiometric level, comprise the age, healthy state, sex, diet, administration time, route of administration, drainage rate, drug regimen and the specified disease and the severity of being treated with special patient.
Embodiment
The present invention will be described in more detail with following non-restrictive example.
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 embodiment 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.Stop to heat after-filtration and remove solid, acetone is removed in filtrate decompression distillation, 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 embodiment 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 embodiment 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 embodiment 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, allow reaction soln pass through the Magnesium Silicate q-agent pillar then, 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 embodiment 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 500 milliliters of ethyl acetate extraction products again, 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 embodiment 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, a 5-dimethoxy-4 '-isopropyl phenyl) acrylate chloride, is not further purified processing.
Synthetic embodiment 7:3-(3,5-dimethoxy-4 '-isopropyl phenyl) methyl acrylate.
The acyl chlorides (7.5 mmole) that dissolving 2 grams obtain in synthetic embodiment 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 embodiment 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 embodiment 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 embodiment 9: nitrogen-benzyl-3-(3,5-dimethoxy-4 '-isopropyl phenyl) acrylamide.
The acyl chlorides (7.5 mmole) that dissolving 2 grams obtain in synthetic embodiment 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 embodiment 10:3-(3,5-dihydroxyl-4-isopropyl phenyl) vinylformic acid.
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 embodiment 11:3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate.
Synthetic method and synthetic embodiment 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 embodiment 12:3-(3,5-dihydroxyl-4-isopropyl phenyl) methyl acrylate-2-phenyl chlorocarbonate.
Synthetic method and synthetic embodiment 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 embodiment 13: nitrogen-benzyl-3-(3,5-dihydroxyl-4-isopropyl phenyl) acrylamide.
Synthetic method and synthetic embodiment 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 set up 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-acetate 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, on same ear, smear commercial anti-inflammatory compound calcitriol 20 microlitres (2% ethanolic soln) for second group;
Remaining group is smeared The compounds of this invention 20 microlitres (2% ethanolic soln) on 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 inhibiting rate of the compound of the present invention of every kind of test to 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 inflammation to a certain extent, but the reason that causes the eczema illness is very complicated, with immunity and autoimmunization system relation is arranged also, also do not have good animal experimental model at present, so this experiment is to be experimental subjects with the voluntary patient who suffers from the eczema illness.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, a 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 being tried.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 illustrated with three exemplary below more than 80%.
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's pin and cause.The patient used multiple externally applied agent, but did not have a kind of medicine that the obvious treatment effect 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 disappears after four days at continuous use, the back focus completely dissolve of one week of continuous use, and skin is replied normally fully, only stays some skin pigments.
Aspiration patient 2, the man, 26 years old, an erythema oedema zone is arranged on arm, 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 tangible improvement after medication in continuous 5 days, redness at medication sheet after 10 days disappears, only residual a spot of papulo-vesicle, 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, the part red swelling of the skin has papule.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 abandoned treatment basically before aspiration is used medicine of the present invention, just smears some skin cream frequently.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 part skin is replied normal, and the state of an illness has tangible 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 all, but does not also crack the reason of its morbidity and the effective way of treatment so far fully.Psoriasis also is not have effective animal experimental model can supply research, and therefore, doing experiment on one's body the aspiration patient is the method for unique effective judgement medicine to 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, a 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 being tried.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 illustrated with three exemplary below more than 50%.
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 effects 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, red swelling of the skin just alleviated to some extent in second day, 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 all at left and right sides thigh, outward appearance is similar with the illness that aspiration patient 1 is suffered 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 for 4 weeks continuously, the ground side skin of smearing ointment has recovered normal fully, around this piece skin, the local skin of not smearing also has tangible improvement, demonstrates the effect that the curative effect of this ointment spreads towards periphery.
Aspiration patient 3, the man, 51 years old, head had dispersive, 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 obvious effects.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 tangible 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, immunity/autoimmunization and hyperplasia diseases associated, compound of the present invention has clearly curative effect to psoriasis, therefore, compound of the present invention also has 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 multiple antigenic component in the leach liquor of 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 people more than 20 to use the ointment that contains The compounds of this invention to handle inflammation and allergy that mosquito bite causes voluntarily approximately, 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, and it is by the antigen receptor activation T-cell [16] of T-cell, so the inhibitor of Lck is exactly, and a kind of potential is used for the treatment of and the relevant some diseases of the improper activation of T-cell.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 or the like [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 |
Three compounds from the data of table 2 are shown as can be seen all have to a certain degree inhibition activity for protein kinase Lck, though 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.
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Claims (8)
1. the compound of general formula I, or its salt:
R wherein
1Be selected from:
A) alkyl, thiazolinyl, alkynyl, cycloalkyl or aralkyl;
B) halogen;
R
2And R
3Independently be selected from following group separately:
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;
Two keys be configured as Z or E formula.
2. compound of Formula I as claimed in claim 1, wherein R
2And R
3Be H.
3. the compound of general formula I as claimed in claim 1 or 2, wherein X is OH.
4. as the described compound of Formula I of claim 1-3, wherein R
1Be alkyl.
5. compound of Formula I as claimed in claim 1 is selected from:
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.
6. the preparation method of compound of Formula I as claimed in claim 1, 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.
7. the application of compound of Formula I as claimed in claim 1 in medicine comprises compound of Formula I or its salt, with a kind of carrier that pharmaceutically can receive or vehicle; Be used for the treatment of the medicine that comprises inflammation, allergy, hyperplasia, immunity and autoimmune illness, or be used for the treatment of the medicine of diseases such as itch, allergy, eczema, psoriasis and acne, or be used for the medicine of the prevention and the treatment of cancer.
8. a pharmaceutical composition comprises the described compound of Formula I of claim 1 or its salt, with a kind of carrier that pharmaceutically can receive or vehicle.
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Cited By (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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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20170231922A1 (en) * | 2016-02-16 | 2017-08-17 | Horizon GenoMed Therapeutics, Inc | 3, 5-dihydroxy-4-isopropylstilbene (dhis) as miticidal agent and its therapeutic uses |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK99993D0 (en) * | 1993-09-03 | 1993-09-03 | Statens Seruminstitut | TREATMENT AND PROPHYLAXIS OF DISEASES CAUSED BY PARASITES OR BACTERIA |
| MA26461A1 (en) * | 1997-01-08 | 2004-12-20 | Hoffmann La Roche | NOVEL BENZO (E) ISOINDOLES AND BENZO (H) ISOQUINOLEINS, MEDICAMENTS CONTAINING SAME, PROCESSES FOR THEIR PREPARATION, AND THEIR USE IN THE TREATMENT OR PREVENTION OF CENTRAL NERVOUS SYSTEM DISORDERS. |
| CN101092336B (en) * | 2006-06-23 | 2010-06-16 | 赵昱 | Compound in cinnamic alcohol category, preparation method and usage |
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2008
- 2008-08-16 CN CN 200810070133 patent/CN101648865B/en not_active Expired - Fee Related
Cited By (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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| Publication number | Publication date |
|---|---|
| CN101648865B (en) | 2013-03-20 |
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