CN103467281A - Phenol derivative and application thereof - Google Patents

Phenol derivative and application thereof Download PDF

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CN103467281A
CN103467281A CN2013103170620A CN201310317062A CN103467281A CN 103467281 A CN103467281 A CN 103467281A CN 2013103170620 A CN2013103170620 A CN 2013103170620A CN 201310317062 A CN201310317062 A CN 201310317062A CN 103467281 A CN103467281 A CN 103467281A
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acid
dihydroxyl
dimethoxy
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aralkyl
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CN103467281B (en
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李建雄
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WUHAN INNERSE PHARMACEUTICALS Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
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    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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Abstract

The invention discloses a phenol derivative and application thereof, belonging to the technical field of medicines. The phenol derivative comprises a compound as represented by a structural formula I, II or III and pharmaceutically acceptable salt, ester and amide thereof. In the formula I, II or III as described in the specification, R1 is selected from the group consisting of an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, halogen and an acyl group, R2 and R3 are independently selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group and an acyl group, respectively, and R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an aryl group and an aralkyl group, respectively. The invention also discloses application of the compound or the pharmaceutically acceptable salt, ester and amide thereof in preparation of drugs used for treating immune diseases, inflammations or autoimmune diseases.

Description

A kind of phenol derivatives and application thereof
Technical field
The invention belongs to medical technical field, particularly a kind of phenol derivatives and the application in the medicine of preparation treatment immunological disease, inflammation or autoimmune disorder thereof.
Background technology
Resorcylic acid, dihydroxyphenyl acetic acid and dihydroxy-benzene propanoic derivatives are the compounds with various active that a class is widely known by the people, it is extensive in distributed in nature.Relevant alkylation dihydroxyl product exists (Suzuki, Y.Phytochemistry, 1999.52 (2): 281 – 201 Zhou Houde in wheat, barley, rye and ginkgo, Liu Yuhuan, Li Ruizhen, Han Dongping, the money phenanthrene, burnt handsome, Ruan Rongsheng, Food science, 2008,29 (08): 680-684), their meta-bolitess in human body and animal body are exactly mainly corresponding resorcylic acid and dihydroxy-benzene propanoic derivatives (Ross, A.B.; p; Kamal-Eldin, of Chromatography B A.2004.Journal, 809 (1): 125 – 130) .2-normal hexane-5-n-propane-1,3 dihydroxy-benzene is a kind of microbiotic (Kanda, the N. that Pseudomonas sp. produces; Ishizaki, N.; Inoue, N.; Oshima, M. and Handa, A.The Journal of antibiotics, 1975.28 (12): 935 – 942).
Because natural derivative and the synthesis of derivatives of this analog derivative shows a series of physiologically actives, they have more and more excited the interest of people to it.Resorcylic acid, dihydroxyphenyl acetic acid and dihydroxy-benzene propanoic derivatives physiologically active comprise anti-oxidant, antibiotic, reduce cholesterol, antimycotic, antiviral, analgesia, anticancer, (the J.Li such as anti-inflammatory, D.Zhang, X.Zhu, Z.He, S.Liu, M.Li, J.Pang, and Y.Lin, 2011, Mar Drugs.9 (10): 1887 – 1901; S.M.Fiuza, C.Gomes, L.J.Teixeira,
Figure BDA00003568189800012
m.N.D.S.Cordeiro, N.Milhazes, F.Borges, M.P.M.Marques, 2004, Bioorganic& Medicinal Chemistry, 12 (13): 3581 – 3589).
Resorcylic acid and dihydroxyphenyl acetic acid derivative can be produced as raw material through chemical reaction by the benzene replaced easily, and the dihydroxy-benzene propionic acid can be by corresponding styracin hydrogenating reduction preparation.Resorcylic acid, in the basic structure of dihydroxyphenyl acetic acid and dihydroxy-benzene propanoic derivatives, the replacement of phenyl ring can cause a large amount of different derivatives (P.Sharma, J.Chem.Pharm.Res., 2011,3 (2): 403-423).From the angle of bio-transformation, this compounds can be transformed from corresponding alkyl or aromatic ring group.In the basic structure of cinnamic acid derivative, the replacement of phenyl ring can cause a large amount of different derivatives (P.Sharma, J.Chem.Pharm.Res., 2011,3 (2): 403-423).From the biosynthesizing route, cinnamic acid derivative and stilbene derivatives relevant (Austin MB, Noel JP, Nat.Prod.Rep., 2003,20:79-110).
The unsaturated derivative that the dihydroxy-benzene propanoic derivatives is corresponding is exactly cinnamic acid derivative, also is cinnamic acid derivative.Cinnamic acid derivative is also a kind of compound with various active be widely known by the people, and it is in distributed in nature extensive (P.Sharma, J.Chem.Pharm.Res., 2011,3 (2): 403-423).In recent years, because natural derivative and the synthesis of derivatives of cinnamic acid derivative shows a series of physiologically actives, thereby more and more excited the interest of people to it.The cinnamic acid derivative physiologically active comprises the tuberculosis disease, and anti-diabetic is anti-oxidant, antibiotic, protects the liver, and central nervous system suppresses, and reduces cholesterol, antimycotic, hypoglycemic, and anti-malarial is antiviral, analgesia, cytotoxicity, anti-inflammatory etc.Cinnamic acid derivative is widely used in makeup as UV light absorber and fragrance matter simultaneously.
Recently, bibliographical information one group of unique stilbene derivatives replaced, in this group derivative, two hydroxyls are at 3 and 5, also have between two hydroxyls 4 of a substituting group simultaneously.The special compound of this class has, anti-infection activity active to kinase whose inhibition, influential to T lymphocyte, scavenger cell, neutrophil leucocyte and mastocyte, can also regulate and control panimmunity and inflammatory activity (US Patent7,868,047 and US Patent7,321,050).Our recent findings, except this uniqueness on a phenyl ring replaces the stilbene derivatives of form, resorcylic acid, dihydroxyphenyl acetic acid and dihydroxy-benzene propanoic derivatives also have powerful biological activity.These phenol derivativess of the present invention facilitate the exploitation of preparation simultaneously, can make different preparations, can be for different diseases.The present invention is exactly relevant these new resorcylic acids, the structure of the derivatives such as dihydroxyphenyl acetic acid and dihydroxy-benzene propionic acid, synthetic method, their drug regimen and their purposes in the treatment disease.
Summary of the invention
The present invention is disclosed herein is that some have the compound of structural formula I, II or III and pharmacologically acceptable salts, ester or the acid amides of this compound, and these compounds that contain effective dose (compound that comprises structural formula I, II or III with and pharmacologically acceptable salts, ester or acid amides) are as pharmaceutical composition and the application of these compounds in the medicine of preparation treatment immunological disease, inflammation or autoimmune disorder of immunomodulator.
On the one hand, the embodiment of the present invention provides a kind of phenol derivatives, and this phenol derivatives comprises compound with structural formula I, II or III or its pharmacy acceptable salt, ester, acid amides, and its concrete structure formula is as follows:
Structural formula I:
Formula II:
Figure BDA00003568189800031
Formula II I:
Wherein, in formula I, R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group etc.; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group etc.; But work as R lduring for sec.-propyl or bromine, R 2and R 3can not be methyl simultaneously.
In formula II, R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group etc.; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group etc.; R 4and R 5respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl etc.
In formula III, R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group etc.; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group etc.; R 4, R 5, R 6and R 7respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl etc.
Particularly, in formula I, II and III, the alkyl that alkyl is 1-18 carbon, as ethyl, sec.-propyl or butyl etc.;
The ring that cycloalkyl is 3-6 carbon;
The thiazolinyl that thiazolinyl is 2-18 carbon, as vinyl, pseudoallyl etc.;
The alkynyl that alkynyl is 2-18 carbon, as ethynyl, proyl etc.;
The aryl that aryl is 6-18 carbon, as phenyl, Nai Ji, to methylbenzene etc.;
The aralkyl that aralkyl is 7-18 carbon, as phenmethyl, 2-styroyl, 3-hydrocinnamyl etc.;
Halogen is F, Cl, Br or I;
Saturated or the undersaturated acyl group that acyl group is 1-18 carbon, as ethanoyl etc.
More specifically, in formula I, R lbe selected from ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen, methyl or ethanoyl.
Preferably, the phenol derivatives in the embodiment of the present invention is selected from:
3,5-dihydroxyl-4-ethyl benzoate,
3,5-dihydroxyl-4-isopropyl acid,
3,5-dihydroxyl-4-butylbenzoic acid,
3,5-dimethoxy-4 '-ethyl benzoate,
3,5-dimethoxy-4 '-butylbenzoic acid,
3,5-diacetoxy-4-ethyl benzoate,
3,5-diacetoxy-4-isopropyl acid,
3,5-diacetoxy-4-butylbenzoic acid.
More specifically, in formula II, R lbe selected from methyl, ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen or methyl, R 4and R 5respectively independently selected from hydrogen or methyl.
Preferably, the phenol derivatives in the embodiment of the present invention is selected from:
3,5-dihydroxyl-4-ethylbenzene acetic acid,
3,5-dihydroxyl-4-isopropyl phenylacetate,
3,5-dihydroxyl-4-butylbenzene acetic acid,
3,5-dihydroxyl-4-ethyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-sec.-propyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-butyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-ethylbenzene acetic acid,
3,5-dimethoxy-4 '-isopropyl phenylacetate,
3,5-dimethoxy-4 '-butylbenzene acetic acid,
3,5-dimethoxy-4 '-ethyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-butyl-Alpha-Methyl toluylic acid.
More specifically, in formula III, R lbe selected from ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen or methyl, R 4, R 5, R 6and R 7respectively independently selected from hydrogen or methyl.
Preferably, the phenol derivatives in the embodiment of the present invention is selected from:
3,5-dihydroxyl-4-ethylbenzene propionic acid,
3,5-dihydroxyl-4-isopropyl benzene propionic acid,
3,5-dihydroxyl-4-butylbenzene propionic acid,
3,5-dimethoxy-4 '-ethylbenzene propionic acid,
3,5-dimethoxy-4 '-isopropyl benzene propionic acid,
3,5-dimethoxy-4 '-butylbenzene propionic acid.
Particularly preferably, the phenol derivatives in the embodiment of the present invention is selected from:
3,5-dihydroxyl-4-ethyl benzoate,
3,5-dihydroxyl-4-isopropyl acid,
3,5-dihydroxyl-4-ethylbenzene acetic acid,
3,5-dihydroxyl-4-isopropyl phenylacetate,
3,5-dihydroxyl-4-ethyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-sec.-propyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-ethylbenzene propionic acid,
3,5-dihydroxyl-4-isopropyl benzene propionic acid.
On the other hand, the embodiment of the present invention also provides the preparation method of this phenol derivatives, and the preparation method is as follows:
The compound that structural formula provided by the invention is III can be by corresponding styracin reduction preparation, reduction reaction:
Figure BDA00003568189800051
Aforementioned styracin can be synthetic by the following method by the intermediate benzaldehyde derivative.This intermediate benzaldehyde derivative itself can be by literature method synthetic (Chinese patent: publication number be 1688535,2005).
Styracin precursor synthetic route 1.Perkin reaction reaction:
Figure BDA00003568189800052
Route 2.Knoevenagel condensation reaction:
Figure BDA00003568189800061
Route 3.Claisen – Schmidt condensation reaction:
Figure BDA00003568189800062
Route 4.Heck reaction:
In other compound of the present invention (formula I and II), some can come by corresponding ester hydrolysis, and these esters can be synthetic by following method or other currently known methods by intermediate benzaldehyde derivative and benzene methyl chloride derivative.This intermediate benzaldehyde derivative and benzene methyl chloride derivative itself can be by literature method synthetic (Chinese patent: publication number be 1688535A, 2005).
Reaction scheme 1. hydrolysis reaction (Me can be also other ester or other derivative):
Figure BDA00003568189800071
Reaction scheme 2. deprotection reactions:
Figure BDA00003568189800072
Deprotection reaction ester hydrolysis simultaneously becomes corresponding acid.
Reaction scheme 3. multisteps are synthetic:
Figure BDA00003568189800081
Also have synthetic that other method also can be for compound of the present invention on document, the embodiment of the present invention describes in detail no longer one by one.
Wherein, the pharmaceutically receptible salt in the present invention also can prepare, and this is because compound of the present invention has the ability of salify.Pharmaceutically receptible salt can combine and form with mineral acid and/or organic acid, mineral alkali and/or organic bases by this compound, applicable acid comprises hydrochloric acid, sulfuric acid, nitric acid, Phenylsulfonic acid, acetic acid, toxilic acid, tartrate etc., and these are all acceptables pharmaceutically.Simultaneously, other purposes of these salt, for example the purposes for the production of these compounds or non-medicament purpose is also the scope that the present invention is contained.Pharmaceutically ester commonly used comprises methyl esters, ethyl ester, propyl ester (comprising isopropyl ester), long-chain fat alcohol ester, phenylcarbinol ester or phenylpropyl alcohol alcohol ester etc.Pharmaceutically acid amides commonly used comprises non-substituted acid amides, methane amide, ethanamide or diethylamide etc.The preparation method of the pharmacy acceptable salt of these compounds, ester, acid amides is common technique in this area, therefore the embodiment of the present invention is omitted, describes in detail.
On the other hand, the embodiment of the present invention also provides a kind of pharmaceutical composition, the above-mentioned phenol derivatives that said composition contains effective dose and pharmaceutically acceptable thinner and/or carrier, this phenol derivatives is compound or its salt with structural formula I, II or III, ester, acid amides etc.Specifically refer to the aforementioned description for phenol derivatives, the embodiment of the present invention no longer describes in detail.Wherein, pharmaceutically acceptable thinner and/or carrier are that common auxiliary material technician in the art is easy to expect.
Particularly, the example of embodiment of the present invention Chinese traditional medicine composition has various solid forms (tablet, pill, capsule, small-particle, powder and suppository etc.) and liquid form (solution, suspension, emulsion) in a suitable drug regimen of the administration form such as oral, external application, injection and rectum.These formulas can only contain pure compound of the present invention, may be also and a carrier, or with other the combination of active compound.Perhaps, these need sterilization while being combined in as injection liquid.For external application, preferably make creme, ointment, gel, solution or suspension etc. containing this phenol derivatives (for external application this purpose, wash saliva, gargle should be included).
Wherein, the single dose that in embodiment of the present invention Chinese medicine composition, the effective constituent phenol derivatives may produce with carrier combinations, the content of effective constituent in this single dose may be because of the main body for the treatment of and different variation of mode taken, an oral formula for example, but the effective constituent intrinsic energy be 0.5 milligram to 5 grams, the content of compatible carrier may account for 5% to 95% of total content with it.Each dose unit generally comprises the effective constituent of about 1 milligram to about 500 milligrams, is generally 25 milligrams, 50 milligrams, 100 milligrams, 200 milligrams, 300 milligrams, 400 milligrams, 500 milligrams, 600 milligrams, 800 milligrams or 1000 milligrams.
On the other hand, the embodiment of the present invention also provides the application of aforementioned phenol derivatives in the medicine of preparation treatment immunological disease, inflammation or autoimmune disorder.
Each compound in the present invention demonstrates immunoregulation activity in various degree, and example subsequently will illustrate these.Known those have the compound of immunoregulation activity in the literature, as the present invention's compound disclosed herein, be to treat various diseases as the effective constituent in medicine, as the rejection of clinical transplantation (comprises organ transplantation, acute grafing, heteroplastic transplantation and autograft, as utilized in the processing of burn), avoid ischemia or reperfusion injury, as ischemia and the repeatedly damage of perfusion caused, can also treat impatient infarct, apoplexy or Other diseases in organ transplantation, induce transplantation tolerance, treatment of arthritis (as rheumatic arthritis, ox-hide addiction type sacroiliitis, bone joint), multiple sclerosis, inflammatory bowel, comprise ulcerative colitis and Crohn's disease, lupus (systemic lupus erythematous), graft versus host disease (GVH disease), the T cell mediated hypersensitivity, comprise contact hypersensitivity, delayed hypersensitivity, seitan supersensitivity enteropathy (seitan allergy), the ox-hide addiction, contact dermatitis (comprise and being caused by toxicodendron), Hashimoto thyroiditis, dry syndrome, the autoimmune hyperthyroidism, as the Grave disease, bronzed disease, the suprarenal gland autoimmune disorder, Polyglandular Autoimmune Syndrome, the immunity alopecia, pernicious anemia, vitiligo, the immunity subpituitarism, Guillain Barre syndrome, the immunological disease that also has other is as glomerulonephritis, serum sickness, urticaria, anaphylactic disease is arranged again as respiratory system anaphylactic disease (asthma, ragweed fever, allergic rhinitis) or allergic, scleracierma, cutaneous T cell lymphoma, acute inflammatory response (as adult respiratory distress syndrome and ischemia reperfusion injury), dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema, behcets disease, palm toe pustulosis, pyoderma gangraenosum, Sai Zerui syndromes (Sezary's sydrome), atopic dermatitis, scleroderma.
The present invention also provides the pharmaceutical treatment that contains this phenol derivatives and the method for preventing above-mentioned disease, comprise the step of taking, at least one that give to need that the individuality for the treatment of uses significant quantity has molecular formula I, the compound of II or III and the pharmacologically acceptable salts of this compound, ester or acid amides.Also can with other medicament, as those, for the known medicament of expert, use simultaneously, comprise pharmaceutically acceptable thinner and/or carrier.In the method for the invention, front and back that these other medicament can compound be in the present invention taken or simultaneously take.
Particularly, the example of the drug regimen for the treatment of aforementioned diseases has various solid forms (tablet, pill, capsule, small-particle, powder and suppository etc.) and liquid form (solution, suspension, emulsion) in a suitable drug regimen of the administration form such as oral, external application, injection and rectum.These formulas can only contain pure compound of the present invention, may be also and a carrier, or with other the combination of active compound.Perhaps, these need sterilization while being combined in as injection liquid.For external application, preferably make creme, ointment, gel, solution or the suspension etc. that contain Compound I or V (for external application this purpose, wash saliva, gargle should be included).
Particularly, the mode of specifically taking of this pharmaceutical composition for the treatment of aforementioned diseases is: the about 0.01-140 milligram of per kilogram per weight medication every day is that a useful dosage level is treated above-mentioned various diseases, and another kind of the selection is exactly about 0.5 milligram of amount to 7 grams each patient every day.For example, the dosage of anti-inflammatory is per kilogram per weight about 0.01-50 milligram every day, or 0.5 milligram of each patient's medication every day is to 3.5 grams, and preferably 2.5 milligrams of every days are to the l gram.The single dose that in medicament, effective constituent may produce with carrier combinations, the content of effective constituent in this single dose may be because of the main body for the treatment of and different variation of mode taken, an oral formula for example, but the activeconstituents intrinsic energy be 0.5 milligram to 5 grams, the content of compatible carrier may account for 5% to 95% of total content with it.Each dose unit generally comprises the activeconstituents of about 1 milligram to about 500 milligrams, is generally 25 milligrams, 50 milligrams, 100 milligrams, 200 milligrams, 300 milligrams, 400 milligrams, 500 milligrams, 600 milligrams, 800 milligrams or 1000 milligrams.
Yet, be understandable that the given dose with a specific people is changed with several factors, these factors comprise the array mode of age, body weight, healthy state, sex, recipe, administration time, route of administration, drainage rate, medicine and the severity of the disease for the treatment of.Now the nonrestrictive example by subsequently comes the present invention for a more detailed description.
Embodiment
Embodiment 1: phenylpropionic acid series
Synthesizing of 3,5-dimethoxy-4 '-sec.-propyl styracin
A) 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde is pressed literature method production (Chinese patent: 1688535A, 2005)
B) 3,5-dimethoxy-4 '-sec.-propyl styracin synthetic
Add the stirring magneton in the round-bottomed flask of 100mL, the Beta-alanine of 15 gram propanedioic acid and 1.20 grams, then add 30mL pyridine and 13 grams 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde, reacting by heating thing to 130 ℃ left and right.After reaction completes substantially (being greater than 1.5 hours), reactant cools to room temperature, then pours in the frozen water of 120-150mL.Slowly neutralize this reaction mixture with the hydrochloric acid (6N) of about 50mL, until pH is acid, till precipitation no longer increases.Filter, and the water repetitive scrubbing, then dry and obtain 3,5-dimethoxy-4 '-sec.-propyl styracin, this 3,5-dimethoxy-4 '-sec.-propyl styracin is directly done following reaction.
Synthesizing of 3,5-dihydroxyl-4-sec.-propyl styracin
The mixture of 3,5-dimethoxy-4 '-sec.-propyl styracin (2.5 gram) and pyridine hydrochloride (6.7 gram), at 200 ℃, is heated 2 hours under the condition that has nitrogen gas stream to protect.After reaction mixture drops to room temperature, add hydrochloric acid and the 300 milliliters of ethyl acetate of 100 milliliters of 2N, by organic phase and water separately after, water extracts three times by 150 milliliters of ethyl acetate, combining extraction liquid, and use the saturated common salt water washing is used dried over sodium sulfate.Steam residue column chromatography separating purification after ethyl acetate, elutriant is ethyl acetate/hexane/acetic acid (50/50/1, volume ratio), obtains 3,5-dihydroxyl-4-sec.-propyl styracin.
Synthesizing of 3,5-dimethoxy-4 '-butyl styracin
Add 3.8mL N,N-dimethylacetamide and 7mL benzene in the there-necked flask of 100mL.Then pass into wherein hydrogen chloride gas about one hour, until N, N-dimethylacetamide precipitates with the form of hydrochloride.2 grams 3,5-dimethoxy-4 '-butyl benzaldehyde joins in reaction solution, is heated to 190-200 ℃, reclaims the benzene be steamed out, and allows reaction continue until complete.Then cooling, add 60mL water, and regulate pH to 9-10 with 20wt%NaOH solution, distillation is until distillate is transparent.Further add 15mL20wt%NaOH to regulate, and backflow 5-6 hour until reaction solution be can't see precipitation, filter reaction mixture.With hydrochloric acid (6N) neutralization filtrate slowly, until pH is strongly-acid, till precipitation no longer increases.Filter, and the water repetitive scrubbing, then dry and obtain the synthetic of 3,5-dimethoxy-4 '-butyl styracin, this 3,5-dimethoxy-4 '-butyl styracin synthetic directly cooked following reaction.
Synthesizing of 3,5-dihydroxyl-4-butyl styracin
The mixture of 3,5-dimethoxy-4 '-butyl styracin (2.5 gram) and pyridine hydrochloride (6.7 gram), at 200 ℃, is heated 2 hours under the condition that has nitrogen gas stream to protect.After reaction mixture drops to room temperature, add hydrochloric acid and the 300 milliliters of ethyl acetate of 100 milliliters of 2N, by organic phase and water separately after, water extracts three times by 150 milliliters of ethyl acetate, combining extraction liquid, and use the saturated common salt water washing is used dried over sodium sulfate.Steam residue column chromatography separating purification after ethyl acetate, elutriant is ethyl acetate/hexane/acetic acid (50/50/1, volume ratio), obtains 3,5-dihydroxyl-4-butyl styracin.
C) 3,5-dihydroxyl-4-isopropyl benzene propionic acid synthetic
By 3 of aforementioned preparation, 5-dihydroxyl-4-sec.-propyl styracin (0.25 gram) is dissolved among 50 milliliters of ethanol, adds Pd/C (25mg, 10%W/W).Pass into hydrogen (using balloon) in room temperature normal pressure downhill reaction liquid, follow the tracks of reaction.After having reacted, reaction solution is by the Celite(Celite) filter, evaporate to dryness, by the silicagel column purifying, use MeOH/CH 2cl 2(V/V=1:4) wash-out obtains the synthetic of 3,5-dihydroxyl-4-isopropyl benzene propionic acid.
D) 3,5-dimethoxy-4 '-isopropyl benzene propionic acid synthetic
By 3 of aforementioned preparation, 5-dimethoxy-4 '-sec.-propyl styracin (0.25 gram) is dissolved among 50 milliliters of ethanol, adds Pd/C (25mg, 10%W/W).Pass into hydrogen (using balloon) in room temperature normal pressure downhill reaction liquid, follow the tracks of reaction.After having reacted, reaction solution is by the Celite(Celite) filter, evaporate to dryness, by the silicagel column purifying, use MeOH/CH 2cl 2(V/V=1:4) wash-out obtains 3,5-dimethoxy-4 '-isopropyl benzene propionic acid.
E) 3,5-dihydroxyl-4-isopropyl benzene propionic acid synthetic
The mixture of 3,5-dimethoxy-4 '-isopropyl benzene propionic acid (2.5 gram) and pyridine hydrochloride (6.7 gram), at 200 ℃, is heated 2 hours under the condition that has nitrogen gas stream to protect.After reaction mixture drops to room temperature, add hydrochloric acid and the 300 milliliters of ethyl acetate of 100 milliliters of 2N, by organic phase and water separately after, water extracts three times by 150 milliliters of ethyl acetate, combining extraction liquid, and use the saturated common salt water washing is used dried over sodium sulfate.Steam residue column chromatography separating purification after ethyl acetate, elutriant is ethyl acetate/hexane/acetic acid (50/50/1, volume ratio), obtains 3,5-dihydroxyl-4-isopropyl benzene propionic acid.
F) 3,5-dihydroxyl-4-isopropyl benzene propionic acid synthetic
3,5-dimethoxy-4 '-isopropyl benzene propionic acid (15 gram) is dissolved among dry methylene dichloride (100 milliliters), is chilled in-78 ℃, drip boron tribromide (5.7 milliliters, 60 mmoles) under nitrogen protection.This reaction system stirs 1 hour at-78 ℃, then rises to room temperature, continues under nitrogen protection stirring reaction 2 days.Add the water termination reaction, add subsequently 20wt%NaOH to adjust the pH value and be greater than 12.Remove organic phase, 100 milliliters of hexane washed twice for water, then adjust to 1 with the hydrochloric acid of 6N by the pH value, now with 200 milliliters of ethyl acetate extractions 3 times, merges the organic phase of extraction, by 50 milliliters of salt solution washed twice, uses anhydrous sodium sulfate drying.Obtain the first product purification by silica gel column chromatography after steaming solvent, obtain 3,5-dihydroxyl-4-isopropyl benzene propionic acid.
Embodiment 2:3,5-dimethoxy-4 '-ethylbenzene propionic acid and 3,5-dihydroxyl-4-ethylbenzene propionic acid synthetic
The synthetic method that the present embodiment and embodiment 1 adopt is basic identical, and difference is, with 3,5-dimethoxy-4 '-ethyl-cinnamic acid (0.25 gram), does raw material, by above-mentioned method, obtains corresponding product.
Can also prepare by identical method:
3,5-dihydroxyl-4-butylbenzene propionic acid, 3,5-dimethoxy-4 '-butylbenzene propionic acid.
Embodiment 3: phenylformic acid series synthetic
Synthesizing of 3,5-dihydroxyl-4-isopropyl acid
A) .3,5-dimethoxy-4 '-isopropyl acid methyl esters is pressed literature method production (Chinese patent: 1688535A, 2005)
B) .3,5-dihydroxyl-4-isopropyl acid synthetic
3,5-dimethoxy-4 '-isopropyl acid methyl esters (10 gram) is dissolved among dry methylene dichloride (100 milliliters), is chilled in-78 ℃, drip boron tribromide (5.5 milliliters) under nitrogen protection.This reaction system stirs 1 hour at-78 ℃, then rises to room temperature, continues under nitrogen protection stirring reaction 2 days.Add the water termination reaction, add subsequently 20wt%NaOH to adjust the pH value and be greater than 12.Remove organic phase, 100 milliliters of hexane washed twice for water, then adjust to 1 with the hydrochloric acid of 6N by the pH value, now with 200 milliliters of ethyl acetate extractions 3 times, merges the organic phase of extraction, by 50 milliliters of salt solution washed twice, uses anhydrous sodium sulfate drying.Steam after solvent and obtain first product and obtain 3,5-dihydroxyl-4-isopropyl acid with purification by silica gel column chromatography.
Can prepare by identical method:
3,5-dihydroxyl-4-ethyl benzoate, 3,5-dihydroxyl-4-butylbenzoic acid, 3,5-dimethoxy-4 '-ethyl benzoate, 3,5-dimethoxy-4 '-butylbenzoic acid, 3,5-diacetoxy-4-ethyl benzoate, 3,5-diacetoxy-4-isopropyl acid, 3,5-diacetoxy-4-butylbenzoic acid.
Embodiment 4: the preparation of toluylic acid series
Synthesizing of 3,5-dimethoxy-4 '-isopropyl phenylacetate
A, put into 10g small-particle sodium cyanide (98%) in the 100mL round-bottomed flask that cooling tube and application of sample funnel are housed, and the water of 20mL.With water-bath heated mixt stirring, dissolve most of sodium cyanide.Then by 20g3,5-dimethoxy-4 '-isopropyl benzene methyl chloride is dissolved in the solution of 25g ethanol, by the application of sample funnel, at one hour, with interior, slowly dropwises.Back flow reaction is until reacted (about 5 hours).Cooling, filter, and with a small amount of washing with alcohol solid, filtrate is concentrated do 3,5-dimethoxy-4 '-sec.-propyl phenethyl cyanogen.
B, in the round-bottomed flask of 250mL, add the sulphuric acid soln mixed of the 42mL vitriol oil and 28mL water, and the prussiate of top gained.Back flow reaction three hours, cooling, pour among the frozen water of 100mL, filter to obtain first product.First product, by the silicagel column purifying, is used MeOH/CH 2cl 2(V/V=1:4) wash-out obtains 3,5-dimethoxy-4 '-isopropyl phenylacetate.
Embodiment 5:3,5-dihydroxyl-4-isopropyl phenylacetate synthetic
The mixture of 3,5-dimethoxy-4 '-isopropyl phenylacetate (2.5 gram) and pyridine hydrochloride (7 gram), at 200 ℃, is heated 2 hours under the condition that has nitrogen gas stream to protect.After reaction mixture drops to room temperature, add hydrochloric acid and the 300 milliliters of ethyl acetate of 100 milliliters of 2N, by organic phase and water separately after, water extracts three times by 150 milliliters of ethyl acetate, combining extraction liquid, and use the saturated common salt water washing is used dried over sodium sulfate.Steam residue column chromatography separating purification after ethyl acetate, elutriant is ethyl acetate/hexane/acetic acid (50/50/1, volume ratio), obtains 3,5-dihydroxyl-4-isopropyl phenylacetate.
Can prepare by identical method:
3,5-dihydroxyl-4-ethylbenzene acetic acid, 3,5-dihydroxyl-4-butylbenzene acetic acid, 3,5-dimethoxy-4 '-ethylbenzene acetic acid, 3,5-dimethoxy-4 '-butylbenzene acetic acid.
Embodiment 6:3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl toluylic acid synthetic
A. press synthetic 3, the 5-dimethoxy-4 ' of example 4a-sec.-propyl phenethyl cyanogen first product.First product is by the silicagel column purifying, with ethyl acetate/normal hexane (V/V=1:2) wash-out, obtain pure 3,5-dimethoxy-4 '-sec.-propyl phenethyl cyanogen.
Add the 55mL50wt% aqueous sodium hydroxide solution in the 250mL round-bottomed flask, 35 grams (0.2moles) 3, the triethylbenzene methyl chlorination amine salt of 5-dimethoxy-4 '-sec.-propyl phenethyl cyanogen and 0.5 gram (0.022mole).Under agitation, slowly add the methyl iodide (about 1 to 1.5 hours) of 31 grams (0.22moles) under 25 35 ℃ of –, then continue reaction 2 to 3 hours, follow the tracks of with TLC.After having reacted, add 75ml water and 20ml ethyl acetate, separate organic phase, water is extracting twice by the 20ml ethyl acetate, merges organic phase.20mL water and 20mL dilute hydrochloric acid (1N) washing for organic phase, then water washing, anhydrous magnesium sulfate drying, concentrate to obtain first product.First product is by the silicagel column purifying, and normal hexane (V/V=1:3) wash-out obtains 3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl phenethyl cyanogen.
B. in the round-bottomed flask of 250mL, add the sulphuric acid soln mixed of the 65mL vitriol oil and 40mL water, and the prussiate of top gained.Back flow reaction three hours, cooling, pour among the frozen water of 100mL, filter to obtain first product.First product, by the silicagel column purifying, is used MeOH/CH 2cl 2(V/V=1:4) wash-out obtains 3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl toluylic acid.
Embodiment 6:3,5-dihydroxyl-4-sec.-propyl-Alpha-Methyl toluylic acid synthetic
The mixture of 3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl toluylic acid (2.5 gram) and pyridine hydrochloride (7 gram), at 200 ℃, is heated 2 hours under the condition that has nitrogen gas stream to protect.After reaction mixture drops to room temperature, add hydrochloric acid and the 300 milliliters of ethyl acetate of 100 milliliters of 2N, by organic phase and water separately after, water extracts three times by 150 milliliters of ethyl acetate, combining extraction liquid, and use the saturated common salt water washing is used dried over sodium sulfate.Steam residue column chromatography separating purification after ethyl acetate, elutriant is ethyl acetate/hexane/acetic acid (50/50/1, volume ratio), obtains 3,5-dihydroxyl-4-sec.-propyl-Alpha-Methyl toluylic acid.
Same method can be synthesized:
3,5-dihydroxyl-4-ethyl-Alpha-Methyl toluylic acid, 3,5-dihydroxyl-4-butyl-Alpha-Methyl toluylic acid, 3,5-dimethoxy-4 '-ethyl-Alpha-Methyl toluylic acid, 3,5-dimethoxy-4 '-butyl-Alpha-Methyl toluylic acid.
Embodiment 7: the preparation of pharmaceutical composition:
3,5-dihydroxyl-4-isopropyl acid becomes emulsifiable paste by following formulated:
Figure BDA00003568189800141
Figure BDA00003568189800151
Embodiment 7: the preparation of pharmaceutical composition
3,5-dihydroxyl-4-isopropyl phenylacetate becomes emulsifiable paste by following formulated:
Figure BDA00003568189800152
Embodiment 9: the test of the drug activity of new compound
Validity to the oedema of being induced by TPA
Adopt the female mouse (Balb/c) in 10-12 week, moral is not as positive control for 0.5% benzene alkene, and phorbol-12 beans bandit acid esters-13-acetic ester (TPA) is as the oedema inductor.TPA and test all are dissolved in 100% ethanol with compound, get 20 microlitres and are coated in the mouse auris dextra, and six mouse are one group.The concentration of TPA is 0.01% (w/v).TPA processes after 6 hours and measures the mouse ear thickness to determine whether oedema alleviates.In each test, the parallel mouse group that TPA processes uses respectively 3,5-dihydroxyl-4-isopropyl acid, 3,5-dihydroxyl-4-isopropyl phenylacetate, 3,5-dihydroxyl-4-isopropyl benzene propionic acid, benzene alkene is moral or only use Ethanol Treatment not, and the inhibition level of oedema can obtain by the thickness of measuring ear, with per-cent mean with Ethanol Treatment after the difference of thickness of ear.
Result shows, 3,5-dihydroxyl-4-isopropyl acid, 3,5-dihydroxyl-4-isopropyl phenylacetate, 3,5-dihydroxyl-4-isopropyl benzene propionic acid and benzene alkene not Dedu can significantly reduce oedema, and these have shown in the medicine that can be used for the treatment of immunological disease, inflammation or autoimmune disorder of the compound in the present invention.
Table 1
Medication Oedema inhibiting rate (%)
TPA (0.01%)+benzene alkene is moral (0.5%) not 12
TPA (0.0l%)+3,5-dihydroxyl-4-isopropyl acid (0.5%) 9
TPA (0.0l%)+3,5-dihydroxyl-4-isopropyl phenylacetate (0.5%) 9
TPA (0.0l%)+3,5-dihydroxyl-4-isopropyl benzene propionic acid (0.5%) 11
Table 1 means that dermal administration is of the present invention and has structure I, II, an anti-inflammatory activity of the compound of III or the benzene alkene ear edema model that moral is not induced TPA.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.

Claims (10)

1. a phenol derivatives, is characterized in that, comprises have structural formula (I), (II) or compound (III) or its pharmacy acceptable salt, ester, acid amides:
Structural formula I:
Figure FDA00003568189700011
Formula II:
Figure FDA00003568189700012
Formula II I:
Figure FDA00003568189700013
Wherein,
In formula (I), R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group; But work as R lduring for sec.-propyl or bromine, R 2and R 3can not be methyl simultaneously;
In formula (II), R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group; R 4and R 5respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
In formula (III), R lbe selected from alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, halogen or acyl group; R 2and R 3respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl or acyl group; R 4, R 5, R 6and R 7respectively independently selected from hydrogen, alkyl, cycloalkyl, aryl or aralkyl.
2. phenol derivatives according to claim 1, is characterized in that,
In formula (I), (II) with (III); the alkyl that described alkyl is 1-18 carbon; the ring that described cycloalkyl is 3-6 carbon; the thiazolinyl that described thiazolinyl is 2-18 carbon; the alkynyl that described alkynyl is 2-18 carbon; the aryl that described aryl is 6-18 carbon, the aralkyl that described aralkyl is 7-18 carbon, the saturated or undersaturated acyl group that described acyl group is 1-18 carbon.
3. phenol derivatives according to claim 1, is characterized in that,
In formula (I), R lbe selected from ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen, methyl or ethanoyl.
4. according to the described phenol derivatives of claim 1 or 3, it is characterized in that, described phenol derivatives is selected from:
3,5-dihydroxyl-4-ethyl benzoate,
3,5-dihydroxyl-4-isopropyl acid,
3,5-dihydroxyl-4-butylbenzoic acid,
3,5-dimethoxy-4 '-ethyl benzoate,
3,5-dimethoxy-4 '-butylbenzoic acid,
3,5-diacetoxy-4-ethyl benzoate,
3,5-diacetoxy-4-isopropyl acid,
3,5-diacetoxy-4-butylbenzoic acid.
5. phenol derivatives according to claim 1, is characterized in that,
In formula (II), R lbe selected from methyl, ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen or methyl, R 4and R 5respectively independently selected from hydrogen or methyl.
6. phenol derivatives according to claim 1 or 5, is characterized in that, described phenol derivatives is selected from:
3,5-dihydroxyl-4-ethylbenzene acetic acid,
3,5-dihydroxyl-4-isopropyl phenylacetate,
3,5-dihydroxyl-4-butylbenzene acetic acid,
3,5-dihydroxyl-4-ethyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-sec.-propyl-Alpha-Methyl toluylic acid,
3,5-dihydroxyl-4-butyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-ethylbenzene acetic acid,
3,5-dimethoxy-4 '-isopropyl phenylacetate,
3,5-dimethoxy-4 '-butylbenzene acetic acid,
3,5-dimethoxy-4 '-ethyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-sec.-propyl-Alpha-Methyl toluylic acid,
3,5-dimethoxy-4 '-butyl-Alpha-Methyl toluylic acid.
7. phenol derivatives according to claim 1, is characterized in that,
In formula (III), R lbe selected from ethyl, sec.-propyl or butyl, R 2and R 3respectively independently selected from hydrogen or methyl, R 4, R 5, R 6and R 7respectively independently selected from hydrogen or methyl.
8. according to the described phenol derivatives of claim 1 or 7, it is characterized in that, described phenol derivatives is selected from:
3,5-dihydroxyl-4-ethylbenzene propionic acid,
3,5-dihydroxyl-4-isopropyl benzene propionic acid,
3,5-dihydroxyl-4-butylbenzene propionic acid,
3,5-dimethoxy-4 '-ethylbenzene propionic acid,
3,5-dimethoxy-4 '-isopropyl benzene propionic acid,
3,5-dimethoxy-4 '-butylbenzene propionic acid.
9. contain one or more described compounds as arbitrary as claim 1-8 or its pharmacy acceptable salt, ester, acid amides and pharmaceutically acceptable thinner or/and the pharmaceutical composition of carrier.
10. the arbitrary described compound of claim 1-8 or its pharmacy acceptable salt, ester, the application of acid amides in the medicine of preparation treatment immunological disease, inflammation or autoimmune disorder.
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