CN102557885A - Novel diphenylbutadiene derivative and applications thereof in drug - Google Patents
Novel diphenylbutadiene derivative and applications thereof in drug Download PDFInfo
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Abstract
The invention relates to applications of a novel diphenylbutadiene derivative as an immunosuppressive agent in a drug. In the invention, the characteristics of structural properties and physiological activities and the like of natural polyphenol compounds are used for reference. The invention provides a novel diphenylbutadiene derivative, a preparation method of the new compound and applications of the novel diphenylbutadiene derivative in a drug thereof. The new compound has significant activity of an anti-inflammation skin disease. The new compound and drug combination thereof can be used for treating the diseases related with immunity and autoimmunity.
Description
Technical field
The present invention relates to the diphenyl diethylene compound, be specifically related to diphenyl diethylene verivate (structural formula I) and the application in medicine thereof.The invention still further relates to the preparation method of this compounds; Medicine monomer, preparation and drug regimen or unite use with other active substances or therapy; The activity that suppresses various cytokines, protein kinase is as various immunity of treatment and autoimmunization diseases associated.
Background of invention
The human immune system is used for protecting health, opposing to cause the external mikrobe and the material of infection or disease.Compound regulation mechanism has guaranteed that immunoreactive target is that invasion is engaged in or biology, rather than to the host, sometimes, these control mechanisms are unjustified, and can form autoimmune response.Not controlled immunoreactive result is serious organ, cell, tissue injury.For example inflammatory diseases no matter be chronic or acute inflammation, all is common autoimmune response disease.Chronic inflammation is considered to a kind of long-term (several weeks or several months) inflammation; Wherein active inflammation; Disorganization and recovery are simultaneous (R.S.Cotran, v.Kumar and S.L.Robbins, the Robbins pathological basis of Disease of W.B.Suanders Co.; The 75th page, 1989).Though after the chronic inflammation acute inflammation may take place, also possibly develop into a kind of beginning of unmentionalbe disease at any time, for example become permanent infection (like white plaque, syphilis and fungi infestation); This permanent infection causes a kind of tardy anaphylaxis, and long-term exposure is in the toxin of interior life (for example raise blood plasma lipide) or external (for example asbestos, cigarette coke tar, surgical sutures); Perhaps immunoreation (rheumatoid arthritis is for example taken place in autologous tissue; Lupus erythematosus, various sclerosis, psoriasis).Therefore chronic inflammatory diseases comprises many common medical symptoms, rheumatoid arthritis for example, restenosis, psoriasis; Various sclerosis, surgical adhesions, white plaque, chronic pneumonia and bronchitis (asthma for example; Pneumoconiosis, chronic obstructive pulmonary disease, nasal polyp and pulmonary fibrosis).
Thing, scar and skin injury.Also be one of reveal any symptoms of some dermatosis, for example eczema, psoriasis, fash, lupus erythematosus or the like.Dermatitis is bringing out of environmental factors under many circumstances, also there are some researches prove relevant with family heredity.Though a lot of to the inflammatory disease of the skin medicine at present, go back especially effectively medicine of none.Prior treatment method is no matter be that externally applied agent or system's medication all have spinoff clearly.Externally applied agent commonly used has amcinonide, and the most right effect of this type medicine is obvious, and is quick, but can cause the atrophy of skin and go pigmented, also can cause absorbing the spinoff 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.
Inflammation is that the human immune system replys a kind of complex biological of destructive stimulus, and these destructive stimuluses comprise the exotic disease substance, stimulator and self cells injury.The inflammation effect is exactly the process that body is eliminated destructive stimulus.But over-drastic, unusual replying can bring the infringement of self body, and cause autoimmune disorder.Research shows some tetter.For example eczema, psoriasis, even the generation of cancer are caused by the abnormal activation of intravital protein kinase.NF-Kappa B and multiple related to cancer (Michael Karin, " NF-kB and Cancer:Mechanisms and Targets " for example
Molecular Carcinogenesis,
Volume 45, and Issue 6P355-361,2006), another research show psoriasic generation also with NF-Kappa B have close getting in touch (
Nair RPEt al, " Genome-wide scan reveals association of psoriasis with IL-23and NF-kappaB pathways "
Nat Genet.2009 Feb; 41 (2): 199-204.Epub 2009 Jan 25.).Protein kinase with similarity also has LCK (Tyrosylprotein kinase) (Chun W.Yap et al, " SVM Model for Virtual Screening of Lck Inhibitors " J.Chem.Inf.Model., 49; 877-885,2009), Lipoxygenase (LOX) lipoxidase (Thomas E Adrian; " Lipoxygenase and cyclooxygenase metabolism:new insights in treatment and chemoprevention of pancreatic cancer " Molecular Cancer, Vol 2-10,2003); (J.J.Voorhees; Et al., " Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of Psorisais and other Dermatoses " Arch.Dermato., Vol.119; 541; 47, July, 1983).Appeal three kinds of kinases and all in immunity system, play an important role, also inseparable relation is arranged with the generation of inflammation.Compound of the present invention all has very strong vitro inhibition active to LCK and LOX, and compound of the present invention also has inhibition activity in the very strong body to inflammation, and therefore compound of the present invention can be used to treat various inflammatory skin diseases.
Summary of the invention
The invention describes structure and the preparation method of this type new compound and the application in medicine of a series of new small molecule organic cpds.This type new compound has restraining effect clearly to kinases important in the immunity system, and the activity of very significant inflammation-inhibiting is also arranged.
Compound of the present invention has the structure of general formula I and acceptable salt pharmaceutically thereof:
Wherein:
R
1Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, naphthenic base or aralkyl, carbonyl, halogen, nitro, amino, the substituted amido of alkyl, carboxamido-group, sulfoamido, hydroxyl and alkoxyl group;
R
2And R
3Independently be selected from hydrogen, alkyl, naphthenic base or aralkyl, acyl group separately;
R
4, R
5, R
6And R
7Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, naphthenic base or aralkyl, carbonyl, halogen, hydroxyl, alkoxyl group, nitro, amino, carboxyl, ester group, the substituted amido of alkyl, carboxamido-group, sulfoamido, sulfydryl and sulfonic group;
R
8, R
9, R
10And R
11Independently be selected from hydrogen, alkyl, carbonyl, carboxyl and ester group;
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 and along anti-various combinations, the present invention includes the whole cis-trans-isomers and the isotope isomer of compound;
Preferred compound is R wherein
2And R
3Compound for hydrogen, methyl and ethanoyl.Preferred especially compound is R wherein
1Be hydrogen and alkyl.
Preferred examples of compounds is following compound:
1-(3, the 5-dihydroxy phenyl)-4-phenyl-divinyl
1-(3,5-dihydroxyl-4-ethyl base phenyl)-4-phenyl-divinyl;
1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl;
1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-(4-aminomethyl phenyl)-divinyl;
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.
Acceptable salt can be used as medicine on described compound of Formula I of the present invention and the pharmacology thereof, or with the form of drug regimen be used for enteron aisle, venous, muscle or partial topical administration.
The compound of general formula I of the present invention or its combination can be used as the kinase whose suppressor factor of immune system protein, are used to treat the disease relevant with immunity system.
The compound of general formula I of the present invention can be used as medicine or its combination of inflammatory skin diseases such as treatment eczema, allergic dermatitis, neurodermatitis, comedo.
The compound of general formula I of the present invention is as medicine or its combination of cell hyperplastic diseases such as treatment psoriasis, cancer.
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 through following example shows.
For example: wet arthritis; Inflammatory bowel; Contact hypersensitivity; The retardance anaphylaxis; Psoriasis; Eczema; Contact dermatitis; Systemic lupus erythematosus, sclera off-balancesheet layer is scorching, posterior uveitis, postoperative infection systemic autoimmune diseases; Lichen planus, day kitchen sore, epidermis herpes, colitis, dermatomyositis, atopic dermatitis; Glomerulonephritis, tubulointerstitial nephritis, interstitial cystitis, vitiligo vulgaris is sick; Colitis, anaphylactic disease be irritated (asthma, spring fever, allergic rhinitis) or skin allergy of respiratory for example; Acute inflammatory response (for example ARDS and local ischemia/reperfusion injury); The limitation bald head; Farmersskin; Systemic sclerosis; Restenosis; Surgical adhesions; Pulmonary tuberculosis and chronic inflammation tuberculosis (for example, asthma, Pneumonoconiosis, chronic obstructive pulmonary disease etc.), t cell lymphoma, lymphoma, lymph source malignant tumour, lung cancer, solid cancer, malignant tumour shifts.
The present invention also provides described compound of Formula I to be used to treat and prevent above-mentioned illness, the for example medicine of atopic illness.
The present invention also provides described compound of Formula I and other treatment agent bonded to use.Can be with being the other treatment agent that those skilled in the art knew, cyclosporin A for example, vitamin A, Vitamin D3 500,000 I.U/GM, FK506 and rapamycin etc. uses with compound of the present invention in the present invention.Using when of the present invention, such other treatment agent maybe 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.
Compsn of the present invention can contain other and be total to the reagent of knowing for those skilled in the art; Possibly pass through to use conventional solid or liquid vehicle or thinner, and one type of medicated premix (for example, vehicle that is suitable for needed administering mode; Tackiness agent; Sanitas, stablizer, seasonings or the like) prepare 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 possibly 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 can the compound of general formula I being prepared with the form of " suppository " with the medicine of rectal administration.These compsns can be through 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.
Preparation for oral can be tablet, lozenge, lozenge, the aqueous solution or oil solution, dispersible powder or granula, emulsion, hard or soft capsule, or syrup.The compsn 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, like lime carbonate, and yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent are like W-Gum or Lalgine; Tackiness agent, like starch, gel or gum arabic; And lubricant, like Magnesium Stearate, Triple Pressed 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 MO 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 possibly 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-s 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.Specific stoichiometric level to special patient will depend on many factors, 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.
Embodiment
The present invention will be described in more detail with following non-restrictive example.
The preparation route and the preparation method of the compound of Formula I described in the present invention; Be through following compound 1-(3; 5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl (7) be prepared as that specific examples explains, other related compounds of general formula I prepare with similar approach.
Synthetic route chart is following:
The preparation of compound 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl (7) can adopt classical Friedel-Crafts reaction can introduce R from the commercial initiator that is easy to get 1 beginning
1Group obtains compound 2.Compound 2 is through LiAlH
4Perhaps NaBH
4-BF
3Reduction obtains compound 3.Concrete reaction instance is following:
Synthetic embodiment 1:3,5-dimethoxy-4 '-isopropyl acid (2).
To be dissolved with concentration be 0.1 mole 3,5-dimethoxybenzoic acid (1) 19 gram and concentration are to add aluminum trichloride (anhydrous) 20 grams in 0.11 mole the Nitromethane 99Min. solution of dibromopropane 14 gram, formed solution was 80 ℃ of heated and stirred 24 hours; Decompression steams solvent, and residue is dissolved in 500 milliliters of ETHYLE ACETATE, with 500 ml waters washing 3 times; Organic solution with anhydrous sodium sulfate drying after, the decompression steam solvent, residue is used the silica gel chromatography product; 1: 10 ETHYLE ACETATE of elutriant: sherwood oil; Obtain 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).
Use the same method and to synthesize R
1Be the various verivates of alkyl, the sulfuric acid that the present invention has also studied with 70-90% is catalyzer, the corresponding pure R of catalysis
1The Friedel-Crafts reaction that carries out addition after the-OH dehydration.Also obtain good reaction result.
Synthetic embodiment 2:3,5-dimethoxy-4 '-Isobutyl Benzyl Carbinol (3).
Suspension Lithium Aluminium Hydride 2.5 grams (0.12 mole) at 0 ℃, have under the well-stirred condition in 500 milliliters of anhydrous diethyl ethers, in this suspension-s, drip 3,5-dimethoxy-4 '-isopropyl acid (2) 22 gram (0.1 mole) solution in 100 milliliters of THF.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 3:3,5-dimethoxy-4 '-isopropyl benzene formaldehyde (4).
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 of formation stirred after 1 hour; Add 600 milliliters of ether; Let reaction soln pass through the Magnesium Silicate q-agent pillar then, obtain weak yellow liquid, after decompression steams solvent; Residue crystallization in ETHYLE 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 4:3-phenyl allyl group diethyl phosphonate (5)
In the system that 33 gram triethyl-phosphites (0.2 mole) are arranged, add 3-phenyl chlorallylene 15 grams (0.1 mole); The system that is generated was 100 degree heating 6 hours, and responseless raw material is removed in underpressure distillation then; Obtain a viscous liquid; Be midbody compound (5), product is further purified, and productive rate is in 100%.
Synthetic embodiment 5:1-(3,5-dimethoxy-4 '-isopropyl phenyl)-4-phenyl-divinyl (6)
At 0 ℃, have 20 the gram 3-phenyl allyl group diethyl phosphonates (0.1 mole) dry tetrahydrofuran solution in (150 milliliters), in batches; Slowly add 4 gram NaH (60%, 0.1 mole), make it be warmed up to room temperature naturally after adding, in reaction system, drip 17 grams 3; The solution of 5-dimethoxy-4 '-isopropyl benzene formaldehyde in 30 milliliters of THFs is added dropwise to complete the afterreaction system and is warmed up to 50 degree, and stirring reaction is 2 hours under this temperature; After question response was accomplished, cool to room temperature added 300 ml waters; With 200 milliliters of extraction products of ETHYLE ACETATE, steam volume after, residue is used recrystallizing methanol; Obtain 1-(3,5-dimethoxy-4 '-isopropyl phenyl)-4-phenyl-divinyl 20.5 grams.1.40 (6H, d, J=7Hz), 3.47 (1H, 7 heavy peaks, J=7Hz), 3.95 (6H; S), 6.52 (2H, s), 6.57 (1H, d, J=15.38Hz), 6.61 (1H; D, J=15.01Hz), 6.78 (1H, dd, J=15.01,10.44Hz); 6.94 (1H, dd, J=15.38,10.26Hz), 7.19-7.42 (5H, m) .MS:309 (M+1).
Synthetic embodiment 6:1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl (7) but in 200 milliliters of three-necked bottles, add 60 pyridine hydrochlorides, 20 milliliters of N-Methyl pyrrolidone and 20 gram 1-(3,5-dimethoxy-4 '-isopropyl phenyl)-4-phenyl-divinyl; This system is spent heated and stirred 4 hours 65, behind the cool to room temperature under nitrogen protection; Add the aqueous hydrochloric acid of 100 milliliters of 2N, with 300 milliliters of extraction products of ETHYLE ACETATE, extraction liquid is with the aqueous hydrochloric acid washed twice of 50 milliliters of 2N; After steaming solvent; Residue is used the toluene recrystallization, obtains 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl 12 grams.NMR (CDCl3,300MHz) y:1.39 (6H, d, J=7Hz), 3.46 (1H, 7 heavy peaks, J=7Hz); 4.99 (2H, s), 6.50 (2H, s), 6.55 (1H, d, J=15.38Hz); 6.58 (1H, d, J=15.01Hz), 6.76 (1H, dd, J=15.01,10.44Hz); 6.91 (1H, dd, J=15.38,10.26Hz), 7.19-7.43 (5H, m) .MS:281 (M+1).
The biological experiment of compound of Formula I according to the invention.
For the experiment of the test of following BA be this area set up with known, so brief description only is provided at this.
1. the test of compound of Formula I interior anti-inflammatory activity;
Interior anti-inflammatory activity is with the mouse edema animal model of standard proof.Briefly, the Balb/c mouse is divided into several groups, 4 every group;
First group of auris dextra to each mouse smeared 20 microlitre 0.01% (w/v) phorbol-12-myristic acid-13-acetate fat (TPA, a kind of reagent that causes the inflammatory edema);
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 USP 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 % |
| 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl | 88 |
| 1-(3,5-dihydroxyl-4-isobutyl phenenyl)-4-phenyl-divinyl | 76 |
| CALCITRIOL USP | 39 |
2. compound of Formula I of the present invention is used to treat 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 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl, 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 asked to before being tried, stop using any other medicine for treatment thing fortnight.The volunteer who participates in the present embodiment has 18, and compound of the present invention is 90% in treatment the efficient of these 18 volunteers, and curative ratio is explained with three exemplary more than 60% below.
The aspiration patient 1, the woman, 51 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 dermatitis through hospital, maybe 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, 33 years old, 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.Used the creme that contains The compounds of this invention aspiration patient 2, illness has had tangible improvement after medication in continuous 7 days, medication after 14 days large stretch of redness disappear; Only residual a spot of papulo-vesicle; And after around the continuation medication, focus disappears basically, 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 before aspiration is used medicine of the present invention, has abandoned treatment basically, 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 8 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 normally gradually, and the state of an illness has tangible improvement.
3. 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 through 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 getting into 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 10 to use the ointment that contains The compounds of this invention to handle inflammation and allergy that mosquito bite causes voluntarily approximately, efficiently reaches 96%.Because itch is scratched produce inflamed, after smearing ointment, eliminated itch soon behind the mosquito bite, the elimination comparison of inflammation is according to much fast.
4. compound of Formula I of the present invention is as the activation analysis of kinases inhibitor.TNF-α (tumour necrosis factor) is a kind of and system inflammation related cytokine, and it is one that can excite in numerous cytokines of acute phase reaction.The dominant role of TNF-α is to regulate immunocyte, can cause necrocytosis and cause inflammation, can also suppress the generation of tumour and duplicating of virus.But; The reaction of TNF-α over-drastic or abnormal reaction can cause a series of diseases relevant with autoimmune disorder again, for example: skin inflammation, eczema, similar rheumatism, ankylosing spondylitis, Crohn's disease, psoriasis, suppurative hidradenitis, asthma or the like.In case these diseases take place, the suppressor factor that usually needs TNF-α is treated.The present invention has selected the representational compound of part to carry out TNF-α to suppress active analysis; Analytical procedure is referring to document [McGeehan; G.M.etc " Regulation of Tumour Necrosis Factor-R Processing by a Metalloproteinase Inhibitor.Nature 1994; 370,558-61. "]
Table 2. part of compounds TNF-α of the present invention suppresses active
| Compound | TNF-α suppresses active IC50 (μ M) |
| 1-(3, the 5-dihydroxy phenyl)-4-phenyl-divinyl | 53 |
| 1-(3,5-dihydroxyl-4-ethyl base phenyl)-4-phenyl-divinyl | 28 |
| 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl | 22 |
| 1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-(4-aminomethyl phenyl)-divinyl | 46 |
| Pentoxyfylline (pentoxifylline) is as positive control | 38 |
Can find out that from the data of table 2 four compounds the table all have inhibition to a certain degree active for TNF-α; Though eczema; The cause of disease of inflammation and irritated these diseases is not to be controlled by TNF-α fully, but compound of the present invention has been explained the validity of The compounds of this invention to above-mentioned disease treatment to a certain extent to the inhibition activity of TNF-α.
Claims (9)
1. the compound of general formula I, or its salt:
R
1Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, naphthenic base or aralkyl, carbonyl, halogen, nitro, amino, the substituted amido of alkyl, carboxamido-group, sulfoamido, hydroxyl and alkoxyl group;
R
2And R
3Independently be selected from hydrogen, alkyl, naphthenic base or aralkyl, acyl group separately;
R
4, R
5, R
6And R
7Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, naphthenic base or aralkyl, carbonyl, halogen, hydroxyl, alkoxyl group, nitro, amino, carboxyl, ester group, the substituted amido of alkyl, carboxamido-group, sulfoamido, sulfydryl and sulfonic group;
R
8, R
9, R
10And R
11Independently be selected from hydrogen, alkyl, carbonyl, carboxyl and ester group;
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 and along anti-various combinations, the present invention includes the whole cis-trans-isomers and the isotope isomer of compound;
Preferred compound is R wherein
2And R
3Compound for hydrogen, methyl and ethanoyl.Preferred especially compound is R wherein
1Be hydrogen and alkyl.
2. compound of Formula I as claimed in claim 1, wherein R
2And R
3Be H.
3. like the described compound of Formula I of claim 1-2, wherein R
1Be alkyl.
4. compound of Formula I as claimed in claim 1 is selected from:
1-(3, the 5-dihydroxy phenyl)-4-phenyl-divinyl
1-(3,5-dihydroxyl-4-ethyl base phenyl)-4-phenyl-divinyl;
1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-phenyl-divinyl;
1-(3,5-dihydroxyl-4-isopropyl phenyl)-4-(4-aminomethyl phenyl)-divinyl;
5. the preparation method of compound of Formula I as claimed in claim 1, synthesize through the described method of following synthetic route chart:
6. medicine or pharmaceutical composition comprise the described compound of Formula I of claim 1 or its salt, and a kind of carrier that pharmaceutically can receive or vehicle.
7. like the application of the described compound of Formula I of claim 1-4 in medicine, comprise compound of Formula I or its salt, and a kind of carrier that pharmaceutically can receive or vehicle; Comprise inflammatory dermatitis, anaphylaxis dermatosis as treatment.
8. like the application of the described compound of Formula I of claim 1-4 in medicine, comprise compound of Formula I or its salt, and a kind of carrier that pharmaceutically can receive or vehicle; Medicine as treatment immunity and autoimmune skin disease disease.
9. like the application of the described compound of Formula I of claim 1-4 in medicine, comprise compound of Formula I or its salt, and a kind of carrier that pharmaceutically can receive or vehicle; Medicine as diseases such as treatment eczema, psoriasis and acnes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010600084 CN102557885A (en) | 2010-12-22 | 2010-12-22 | Novel diphenylbutadiene derivative and applications thereof in drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010600084 CN102557885A (en) | 2010-12-22 | 2010-12-22 | Novel diphenylbutadiene derivative and applications thereof in drug |
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| Publication Number | Publication Date |
|---|---|
| CN102557885A true CN102557885A (en) | 2012-07-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010600084 Pending CN102557885A (en) | 2010-12-22 | 2010-12-22 | Novel diphenylbutadiene derivative and applications thereof in drug |
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| Country | Link |
|---|---|
| CN (1) | CN102557885A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111943817A (en) * | 2020-07-27 | 2020-11-17 | 西安医学院 | Resveratrol analogue containing long conjugated structure and preparation method and application thereof |
-
2010
- 2010-12-22 CN CN 201010600084 patent/CN102557885A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111943817A (en) * | 2020-07-27 | 2020-11-17 | 西安医学院 | Resveratrol analogue containing long conjugated structure and preparation method and application thereof |
| CN111943817B (en) * | 2020-07-27 | 2023-05-16 | 西安医学院 | Resveratrol analogue containing long conjugated structure and preparation method and application thereof |
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Application publication date: 20120711 |