CN103724334A - Novel allergic reaction-resistant benzocyclothiophthene compounds - Google Patents
Novel allergic reaction-resistant benzocyclothiophthene compounds Download PDFInfo
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Abstract
The invention provides novel allergic reaction-resistant benzocyclothiophthene compounds, particularly benzocyclothiophthene compounds shown as a chemical formula I. The benzocyclothiophthene compounds have the advantages of resisting histamine and asthma and reducing the side effects of sedation. The invention further provided pharmaceutically acceptable salts and configurational isomers. The compounds and the pharmaceutically acceptable salts and configurational isomers can be prepared into clinical compositions and corresponding dosage forms in combination with pharmaceutically acceptable auxiliary materials.
Description
Technical field
The present invention relates to a kind of Benzocycloheptathiopcompounds compounds of new anti-allergic.
Background technology
Within 1906, von Pirquet has proposed " Allergy " word.Its concept is: the state of a kind of " having changed reactivity " that body produces antigenic stimulation, i.e. " transformation reactions ".This state may be protectiveness, has produced immunizing power (immunity); Also can be destructive, produce allergy (hypersensitivity or supersensitivity).Today, Allergy mono-word is often used as the synonym of the allergy (IgE-mediated hypersensitivity) of IgE mediation, and the allergy of IgE mediation is roughly equivalent to the anaphylaxis it has often been said at home.
30 national anaphylactic disease epidemiology survey results that world's transformation reactions tissue is announced show: in 1,200,000,000 total populations of these countries, 22% (25 000 ten thousand people) suffers from the anaphylactic disease of IgE mediation, as allergic rhinitis, asthma, conjunctivitis, eczema, food anaphylaxis, drug allergy and severe allergic reaction etc., affect children and adult's quality of life, serious systemic anaphylaxis is threat to life even.According to WHO, estimate, approximately there are 1. 5 hundred million asthmatic patients in the whole world, and wherein more than 50% adult and at least 80% child patient bring out by irritated factor, and die from every year asthma person more than 180,000 people.
During by 2010, the whole world suffers from allergy by the people who has 40% to 50%, and wherein the sales volume of global allergic rhinitis medicine has reached 6,000,000,000 dollars.WHO classifies anaphylactic disease as 21 century as and needs one of three large diseases of primary study and control.The sickness rate of China's anaphylactic disease is up to 37.3% according to statistics, and southeastern coastal areas sickness rate is higher than inland, and particularly the flourishing regional sickness rate of industry will be higher than rural area in big city, and this is mainly the caused allergic rhinitis of atmospheric pollution, or even asthma.The use of the underproof finishing material of other, paint, and underproof makeup flow out market, the people who makes to suffer from allergic dermatitis transfers toward and increases.
Pathology and clinical manifestation that the biologically active substance that Claritin discharges after must being activated by mastocyte according to anaphylactic disease at present just can cause allergic reaction, biologically active substance comprises histamine, leukotriene, platelet activity factor etc., Claritin is mainly divided into antibiont active substance medicine, as antihistaminic, leukotriene inhibitors etc., another kind is transformation reactions medium sustained-release agent, as mastocyte membrane stabilizer.In addition, eosinophilic granulocyte antiblastic, hormones, immunomodulator also occupy certain market in Claritin.H wherein
1antihistaminic plays vital effect in treatment in allergic disease, and belongs to the whole world maximum medicine of being prescribed.Antihistaminic has developed into the third generation at present, and wherein first-generation antihistaminic, as dexchlorpheniramine, hydroxyzine have quick absorption and metabolism, needs administration every day 3-4 time, height lipotropy and easily through hemato encephalic barrier, cause the calm deficiency of living; Mainly as Loratadine etc., may there is rare but serious cardiovascular side effects in s-generation antihistaminic; Third generation antihistamine drug has overcome above-mentioned shortcoming, but still has the partially narrow shortcoming for the treatment of face.
Total institute is known, and present physical environment goes from bad to worse, and the anaphylactogen that people are caused is no longer single, and the comprehensive allergy that multiple anaphylactogen compound action causes often comprises allergic rhinitis, allergic asthma, urticaria, insect bite disease etc.And the medicine of listing is basic only for a certain or two kinds of anaphylactic diseases are effective on the market, the treatment of compound anaphylactic disease is often needed to use multiple anti-allergy agent, to patient, bring burden economically on the one hand, it is the inconvenience that can excessively go up, more fatal is that drug combination brings serious untoward reaction due to the indefinite of mechanism or drug interaction to patient, even causes death.
Therefore, for development is a kind of, having that side effect is low, wide spectrum Claritin, is to have good social effect and economic benefit.
Summary of the invention
The present invention includes the Benzocycloheptathiopcompounds compounds of new anti-allergic, feature comprises formula I compound characteristic.The present invention also design packet contains pharmaceutical composition, the pharmaceutical dosage form of formula I compound and is suppressing transformation reactions and be used for the treatment of transformation reactions or the application of allergic conditions or disease.
Invent a kind of new new compound of Benzocycloheptathiopcompounds class with anti-allergic, it is characterized in that meeting the feature of formula I:
Formula I
Or its pharmacy acceptable salt, solvate or prodrug, wherein:
R1 is independently hydroxyl, methyl, ethyl, vinyl, methanol-based, ethanol based separately;
R2 is pyridine ring;
R3 is hydrogen, halogen, 0H, methyl, ethyl, vinyl, methanol-based, ethanol based independently of one another;
Alkali is independently pharmaceutically acceptable base, acid group separately.
Described R1 is preferably methyl, methanol-based;
Described R3 is preferably optimized choice hydrogen, 0H, methyl;
Described base can be 0H.
Described acid group derives from hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, oxalic acid, methylsulfonic acid, lactic acid, toxilic acid, stearic acid, gluconic acid.
The present invention also provides a kind of pharmaceutically acceptable pharmaceutical composition, and described pharmaceutical composition comprises formula 1 compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or thinner.
That is the benzocyclohepta that, described pharmaceutical composition is explained by formula I thiophene cry of certain animals derivative compound or its pharmacy acceptable salt, its solvate or prodrug and the acceptable auxiliary material of pharmacy form.
The acceptable auxiliary material of the Benzocycloheptathiopcompounds compounds of new anti-allergic and pharmacy forms composition, and is prepared into formulation.
The acceptable auxiliary material of the Benzocycloheptathiopcompounds compounds of new anti-allergic and pharmacy forms composition, is prepared into the formulation with the application on treatment allergic disease or obstacle.Comprise the formulation form that formula I compound composition is prepared into, comprise granule, suspensoid, oral liquid, nasal drop, tablet, capsule, dispersible tablet, slow releasing tablet, slow releasing capsule, aerosol, inhalation, ointment, gelifying agent, ointment.
The present invention also disclosed the composition that comprises formula I compound have treatment comprise suppress allergic response (for example, anti-histamine is replied), the effectiveness of stablize mastocyte (preventing that medium from discharging), blocking-up lipid medium (such as platelet activating factor (PAF) and leukotriene), anti-adhesion molecule and inhibition eosinophilic granulocyte hyperplasia.Main manifestations is in treatment allergic disease, obstacle or syndromes clinically.Described allergic disease or obstacle comprise: anaphylaxis, drug hypersensitivity, skin allergy, eczema, rhinallergosis, urticaria, atopic dermatitis, xeropthalmus, allergic contact transformation reactions, food hypersensitivity, allergic conjunctivitis, insect venom transformation reactions, bronchial asthma, atopic asthma, intrinsic asthma, occupational asthma, atopic asthma, adult respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD).
The application of described formulation: the dosage range of described formula I benzocyclohepta thiophene cry of certain animals derivative compound or its pharmacy acceptable salt, its solvate or prodrug is 0.0001-1mg/ kg body weight/sky.
Compared with the prior art, the described new new compound of the Benzocycloheptathiopcompounds class with anti-allergic of the present invention has (comprising compd A) anti-allergic effects of wide spectrum, and without the calm side effect of ketotifen, simultaneously because the compound N atom of this invention is sentenced ionic condition, water-soluble apparently higher than ketotifen, at gi tract, discharge rapidly, rapid-action; Simultaneously water miscible increase, has reduced the level by hemato encephalic barrier, avoids the maincenter side effect that brought by it, has obvious advantage.
Fig. 1 is experimental data one of the present invention;
Fig. 2 is experimental data two of the present invention;
Fig. 3 is experimental data three of the present invention.
Embodiment
By the following examples and experimental example the present invention is further described, and in fact and do not mean that it is limited.
The invention provides the inhibitor of a kind of new transformation reactions and atopic reaction, particularly as described in the Benzocycloheptathiopcompounds compounds described of Formula I, they have the antihistamine of being used for the treatment of and anti-asthma, and can reduce the advantage of calm side effect; This invention also provides pharmacy acceptable salt, configurational isomer; Form and can be applicable to clinical composition and corresponding formulation with pharmaceutically acceptable auxiliary material.
Compd A:
In an embodiment, provide a kind of compound as atopic reaction inhibitor of the present invention (hereinafter referred to as: compd A) there is following structural formula, and its synthetic method be provided:
Compd A
The preparation method of compd A all adopts the synthetic method of generally knowing can obtain target compound: by processing 3,5-lutidine with NBS and AIBN in the solvent mixture at chloroform and tetracol phenixin, obtain compound 3-brooethyl-5-methyl-pyridine.The alkylation of ketotifen and 3-brooethyl-5-methyl-pyridine obtains 4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit]-4, establish-10-of 9-dihydro-1-thia-benzo [f] ketone, reacts and reaches fumarate with fumaric acid.
Composition and formulation:
At pharmaceutical composition of the present invention, refer to the required auxiliary material of described activeconstituents and the formulation of expection administration is prepared according to certain program, the formulation of described administration comprises granule, suspensoid, oral liquid, nasal drop, tablet, capsule, dispersible tablet, slow releasing tablet, slow releasing capsule, aerosol, inhalation, ointment, gelifying agent, ointment etc.
In following embodiment, the present invention openly contains the preparation method as the pharmaceutical composition of the compd A of the invention of activeconstituents.Be below to execute representational tablet, slow releasing tablet, aerosol, the gelifying agent of providing of example to have carried out preparation explanation, unaccounted part is to adopt pharmacy conventional formulation preparation means.
Embodiment 2:
Synthetic compound A:4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit]-4, establish-10-of 9-dihydro-1-thia-benzo [f] ketone.
By processing 3,5-lutidine (1) with NBS and AIBN in the solvent mixture at chloroform and tetracol phenixin, obtain compound 3-brooethyl-5-methyl-pyridine (2).Ketotifen (3) obtains 4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit with the alkylation of 3-brooethyl-5-methyl-pyridine (2)]-4,9-dihydro-1-thia-benzo [f] establish-10-ketone (4), compound (4) reacts with fumaric acid and reaches fumarate (5).
Experimental example 1,
The prophylactic effect of compd A to the passive cutaneous anaphylaxis (Evans Blue dyestuff seepage) of transformation reactions in body: IgE-mediation.
Passive cutaneous anaphylaxis test is a kind of method of more sensitive test specific antibody titre.By the serum of tested material sensitized animal (containing abundant IgE antibody), give intact animal intradermal injection, the Fc end of IgE and the special receptors bind on the mastocyte surface of skin, the mixture of formation IgE, makes mastocyte sensitization.When antigen is attacked, the Fab of IgE end combination on antigen and mastocyte surface, cause the change of IgE molecular structure, cause mast cell degranulation, discharge Anaphylactic mediator as histamine, slow reacting substance etc., the permeability of local skin blood vessel is increased, make the concurrently injected Evans Blue dyestuff of intravenous injection antigen ooze out painted at this skin place.According to local skin indigo plant, dye scope or degree, can judge the size that vascular permeability changes, then judge the degree of skin allergy.The absorption value that can find out compd A and ketotifen in table is suitable, and is significantly less than untreated control group, illustrates that compound passive cutaneous anaphylaxis to IgE-mediation the same as ketotifen has prophylactic effect.See Fig. 1.
Experimental example 2,
Compd A suppresses the cytokine IL-6 of the allergen induction of external mastocyte generation.
By Western blotting protein determination method, in abdominal cavity mastocyte, add anti-DNP IgE (10 μ gL 1) sensitization, 37 ℃ of substratum are hatched 6 h; After changing clothes, add respectively 1,10, compd A and ketotifen effect 30 min of 100um/ml, clean; Each group adds respectively TNP-BAS (10 ngmL 1) to stimulate 6h.After centrifugal, remove upper strata liquid, add lysate, 4 ℃ centrifugal, gets supernatant liquor and survey protein concentration.Result significantly reduces the IL-6 that mastocyte produces after showing compd A effect, and suitable with ketotifen.(see figure 2).
Experimental example 3,
Compd A suppresses eosinophils propagation.
With reference to method patent (publication number WO2013000406) Suo Shu, measure the restraining effect of compd A to eosinophils propagation, experimental result has confirmed that compd A can significantly suppress the propagation of eosinophilic granulocyte, and compare and there is significant difference with ketotifen, see Fig. 3.
Experimental example 4,
The research of the calm side effect of compd A.
This test adopts the improved sedative experiment technology of report in United States Patent (USP) 4659716.When being about to Physostigmine (1.9mg/kg, s.c.) and giving the mouse according to 10 animals groupings of each plastics cage (11cm*26cm*13cm), produce the lethality rate of 90-100%.Before Physostigmine administration, give mouse tranquilizer, can make mouse be protected and survive.This research adopts the front 60min oral administration of compound A of Physostigmine administration, calculates the survival number after Physostigmine administration 30min.The mouse survival number that can find out compd A from following table is obviously less than positive controls, basically identical with blank group, illustrates that compd A is without sedative effect.
| Group | Dosage | Survival number |
| Blank group (solvent) | —— | 1/10 |
| Administration group (compd A) | 1mg/kg | 3/10 |
| Positive controls (ketotifen) | 1mg/kg | 8/10 |
Embodiment 3,
The preparation of compd A tablet (1000):
Compd A 3g, Microcrystalline Cellulose 30g, lactose 700g, calcium stearate 20g, pigment 300mg.
Activeconstituents (compd A) is mixed with lactose and Mierocrystalline cellulose until form homogeneity mixture, add color lake and further mix, finally sneak into calcium stearate, and adopt the shallow concave punch of certain specification that gained mixture is pressed into tablet.
Can be by changing activeconstituents to vehicle or being prepared by the ratio of tablet final weight to the tablet of other specification.
Embodiment 4,
The preparation of compd A slow releasing capsule:
The mode that compd A is progressively increased with lactose, Microcrystalline Cellulose equivalent mixes, then water makes softwood, with extruding spheronization, is prepared into 20-30 object band pill core;
A certain amount of talcum powder is added to the water to dispersed with stirring even, then adds especially strange NE30D that it is fully disperseed, then stir 45min, standby.
Band pill core is put into fluidized-bed, regulate various parameters, make ball core fully in fluidized state, evenly spray into standby coating liquid, make ball core weightening finish 6%-8%.After dressing completes, stop spraying, and fluidized bed airflow temperature is adjusted to 50 degree, and keep 45-60min, the micropill after slaking is filled and be get final product according to certain dosage.
Resulting medicine should meet the related request of sustained release preparation in < < Chinese Pharmacopoeia > > (2010 editions) appendix.
Embodiment 5,
The preparation of compd A aerosol:
Weight percentages:
Compd A, 30mg, 0.18%;
Ethanol, 1g, 6.25%;
HFA-134a , 15g , 93.6%;
By compd A, with after dissolve with ethanol, the filling method of two steps is packed into HFA-134A and get final product.
Embodiment 6,
The preparation of compd A gelifying agent
Step 1: get 5.0g chitosan, add the hydrochloric acid soln 0.1mL of distilled water 900mL and 0.1mol/L, stir and make its natural peptization to dissolving completely;
Step 2: add Sodium Benzoate 5.0g and compound A-13 0mg again, stir evenly, adding distil water is adjusted total amount to 1000mL;
Step 3: with 1.0mol/L sodium hydroxide solution adjust pH to 5.8～6.2, stir evenly sterilizing packing and get final product.
Claims (11)
1. the Benzocycloheptathiopcompounds compounds of new anti-allergic meets the feature of formula I:
Formula I
Or its pharmacy acceptable salt, solvate or prodrug, wherein:
R1 is independently hydroxyl, methyl, ethyl, vinyl, methanol-based, ethanol based separately; R2 is pyridine ring;
R3 is hydrogen, halogen, 0H, methyl, ethyl, vinyl, methanol-based, ethanol based independently of one another;
Alkali is independently pharmaceutically acceptable base, acid group separately.
2. according to claim 1, described R1 is preferably methyl, methanol-based; R3 is preferably optimized choice hydrogen, 0H, methyl; Base can be 0H; Acid group derives from hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, oxalic acid, methylsulfonic acid, lactic acid, toxilic acid, stearic acid, gluconic acid.
3. according to claim 1; the acceptable auxiliary material of described Benzocycloheptathiopcompounds compounds and pharmacy forms composition; be prepared into the formulation with the application on treatment allergic disease or obstacle, described formulation comprises pharmaceutically acceptable granule, suspensoid, oral liquid, nasal drop, tablet, capsule, dispersible tablet, slow releasing tablet, slow releasing capsule, aerosol, inhalation, ointment, gelifying agent, ointment; Described allergic disease or obstacle comprise: anaphylaxis, drug hypersensitivity, skin allergy, eczema, rhinallergosis, urticaria, atopic dermatitis, xeropthalmus, allergic contact transformation reactions, food hypersensitivity, allergic conjunctivitis, insect venom transformation reactions, bronchial asthma, atopic asthma, intrinsic asthma, occupational asthma, atopic asthma, adult respiratory distress syndrome and chronic obstructive pulmonary disease.
4. according to claim 3, the benzocyclohepta that described composition is explained by formula I thiophene cry of certain animals derivative compound or its pharmacy acceptable salt, its solvate or prodrug and the acceptable auxiliary material of pharmacy form.
5. according to claim 3, the dosage range of described formula I benzocyclohepta thiophene cry of certain animals derivative compound or its pharmacy acceptable salt, its solvate or prodrug is 0.0001-1mg/ kg body weight/sky.
6. according to the described compound of claim 1, there is following structural formula:
Be called compd A, its synthetic method adopts conventional synthetic method to obtain: by processing 3,5-lutidine with NBS and AIBN in the solvent mixture at chloroform and tetracol phenixin, obtain compound 3-brooethyl-5-methyl-pyridine; The alkylation of ketotifen and 3-brooethyl-5-methyl-pyridine obtains 4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit]-4, establish-10-of 9-dihydro-1-thia-benzo [f] ketone, reacts and reaches fumarate with fumaric acid.
7. compound according to claim 6, is characterized in that, synthetic compound A:4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit]-4, establish-10-of 9-dihydro-1-thia-benzo [f] ketone,
By processing 3,5-lutidine (1) with NBS and AIBN in the solvent mixture at chloroform and tetracol phenixin, obtain compound 3-brooethyl-5-methyl-pyridine (2); Ketotifen (3) obtains 4-[1-methyl-(5-Yue base-pyridin-3-yl Yue yl) piperidines-4-subunit with the alkylation of 3-brooethyl-5-methyl-pyridine (2)]-4,9-dihydro-1-thia-benzo [f] establish-10-ketone (4), compound (4) reacts with fumaric acid and reaches fumarate (5).
8. according to claim 3, the preparation of described compd A tablet (1000):
Compd A 3g, Microcrystalline Cellulose 30g, lactose 700g, calcium stearate 20g, pigment 300mg; Activeconstituents (compd A) is mixed with lactose and Mierocrystalline cellulose until form homogeneity mixture, add color lake and further mix, finally sneak into calcium stearate, and adopt the shallow concave punch of certain specification that gained mixture is pressed into tablet; Can be by changing activeconstituents to vehicle or being prepared by the ratio of tablet final weight to the tablet of other specification.
9. according to claim 3, the preparation of described compd A slow releasing capsule:
The mode that compd A is progressively increased with lactose, Microcrystalline Cellulose equivalent mixes, then water makes softwood, with extruding spheronization, is prepared into 20-30 object band pill core; A certain amount of talcum powder is added to the water to dispersed with stirring even, then adds especially strange NE30D that it is fully disperseed, then stir 45min, standby;
Band pill core is put into fluidized-bed, regulate various parameters, make ball core fully in fluidized state, evenly spray into standby coating liquid, make ball core weightening finish 6%-8%;
After dressing completes, stop spraying, and fluidized bed airflow temperature is adjusted to 50 degree, and keep 45-60min, the micropill after slaking is filled and be get final product according to certain dosage; Resulting medicine should meet the related request of sustained release preparation in < < Chinese Pharmacopoeia > > (2010 editions) appendix.
10. according to claim 3, the preparation of described compd A aerosol:
Weight percentages
Compd A, 30mg, 0.18%;
Ethanol, 1g, 6.25%;
HFA-134a , 15g , 93.6%;
By compd A, with after dissolve with ethanol, the filling method of two steps is packed into HFA-134A and get final product.
11. according to claim 3, the preparation of described compd A one gelifying agent:
Step 1: get 5.0g chitosan, add the hydrochloric acid soln 0.1mL of distilled water 900mL and 0.1mol/L, stir and make its natural peptization to dissolving completely;
Step 2: add Sodium Benzoate 5.0g and compound A-13 0mg again, stir evenly, adding distil water is adjusted total amount to 1000mL;
Step 3: with 1.0mol/L sodium hydroxide solution adjust pH to 5.8～6.2, stir evenly sterilizing packing and get final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107167969A (en) * | 2016-03-08 | 2017-09-15 | 三星显示有限公司 | Liquid crystal display device |
| CN109134447A (en) * | 2018-09-07 | 2019-01-04 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu pa is for fragrant impurity B and preparation method thereof and detection method |
| CN109180666A (en) * | 2018-09-07 | 2019-01-11 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu pa is for fragrant impurity C and preparation method thereof and detection method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5457099A (en) * | 1992-07-02 | 1995-10-10 | Sawai Pharmaceutical Co., Ltd. | Carbostyril derivatives and antiallergic agent |
| CN102822192A (en) * | 2010-01-22 | 2012-12-12 | 圣乔治医院医学院 | Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use |
| WO2013000406A1 (en) * | 2011-06-28 | 2013-01-03 | Lin Tongjun | Benzocycloheptanethiophene derivatives for anti-allergic reactions |
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2013
- 2013-12-28 CN CN201310737758.9A patent/CN103724334A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5457099A (en) * | 1992-07-02 | 1995-10-10 | Sawai Pharmaceutical Co., Ltd. | Carbostyril derivatives and antiallergic agent |
| CN102822192A (en) * | 2010-01-22 | 2012-12-12 | 圣乔治医院医学院 | Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use |
| WO2013000406A1 (en) * | 2011-06-28 | 2013-01-03 | Lin Tongjun | Benzocycloheptanethiophene derivatives for anti-allergic reactions |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107167969A (en) * | 2016-03-08 | 2017-09-15 | 三星显示有限公司 | Liquid crystal display device |
| CN109134447A (en) * | 2018-09-07 | 2019-01-04 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu pa is for fragrant impurity B and preparation method thereof and detection method |
| CN109180666A (en) * | 2018-09-07 | 2019-01-11 | 福建省闽东力捷迅药业有限公司 | A kind of fumaric acid Lu pa is for fragrant impurity C and preparation method thereof and detection method |
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Application publication date: 20140416 |