CN105439813A - Synthetic method of compound - Google Patents
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- CN105439813A CN105439813A CN201410390418.8A CN201410390418A CN105439813A CN 105439813 A CN105439813 A CN 105439813A CN 201410390418 A CN201410390418 A CN 201410390418A CN 105439813 A CN105439813 A CN 105439813A
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Abstract
The present invention provides a novel anti-inflammatory compound and a synthetic method thereof, and specifically, provides a synthetic method of a compound shown in formula 2. The method is as follows: contacting ethyl propiolate with lithium bromide in order to produce the compound shown in the formula 2. The compound shown in the formula 2 can be efficiently produced by the method.
Description
Technical field
The present invention relates to new anti-inflammatory compound and synthetic method thereof.Concrete, the present invention relates to the preparation method about 15 (R/S)-methyl-LXA4 is new.Particularly, the present invention relates to the preparation method of 15 (R/S)-methyl-LXA4 and its intermediate
Background technology
Inflammation has defence and damage double effect: excessively weak being not enough to of inflammation removes cause of disease, and excessive inflammatory reaction can cause killing and wounding of autologous tissue's cell.Thus, rational inflammatory process should maintain the balance between defence and damage.
Be that the inflammation of representative plays the unique effects limiting inflammatory intensity, promote inflammatory resolution just from limit system with lipoxin.More and more clinical and testing data shows, the inflammation such as lipoxin are the key mechanisms of the diseases related runaway development of inflammation from the obstacle that is abnormal, inflammatory resolution of limit factor metabolism and effect.
Lipoxin is a kind of tool biological activity, from leukocytic arachidonic acid metabolite.Act on polyunsaturated fatty acid by lipoxygenase and generate.The constitutional features of lipoxin comprises three hydroxyls and four conjugated double bonds in molecule, and the difference according to hydroxy position in molecule and conformation is divided into four kinds: LXA4, LXB4,15-epi-LXA4 and 15-epi-LXB4.
Lipoxin is Serhan, the people such as Hamberg and Samuelsson in the eicosane class family of Late Cambrian in 1984-product of quasi-arachidonic acid, mainly synthesized by transcellular pathway in the pathologic processes such as inflammation, in inflammatory reaction, play regulating effect widely.
The same with some polypeptide, lipoxin has very high affinity to LXA4 acceptor, and LXA4 acceptor is proved formyl peptide receptor sequence homology acceptor first, as acceptor (FPRL1).
After lipoxin and LXA4 receptors bind, play inflammation mediating effect+6 by regulating the activity of the signal path such as mitogen-activated protein kinase, protein kinase C and the transcription factor such as nuclear Factor-Kappa B and Activated protein-1.In addition, lipoxin also can by playing biological effect in conjunction with Leukotrienes sputum acceptor 1 and aromatic hydrocarbon receptor.
Lipoxin synthesizes mainly through cellular pathways, specifically has 3 approach.Article 1, approach 12-lipoxygenase and the synthesis of 5-lipoxygenase.At Endovascular, arachidonic acid by after 5-lipooxygenase pathway synthesis leukotriene A, is passed in thrombocyte, generates LXA4 or LXB4 by the catalysis of 12-lipoxygenase in white corpuscle.Article 2 approach is synthesized by 15-lipoxygenase, 5-lipoxygenase.After arachidonic acid also can be generated intermediate product by the catalysis of 15-lipoxygenase in epithelial cell, monocyte and eosinophilic granulocyte, then generate LXA4 or LXB4 by the 5-lipoxygenase catalysis in neutrophil leucocyte.Article 3 approach is cyclooxygenase-2, the 5-lipoxygenase route of synthesis of aspirin-induced.After the cyclooxygenase-2 in epithelial cell is by acetylsalicylic acid acetylize, it conversion of arachidonic acid cannot generate prostaglandin(PG), but has the function of 15R-lipoxygenase.Hydroxyl on the 15C of the lipoxin of this approach synthesis is R conformation, i.e. 15-epi-LXA4 and 15-epi-LXB4.
Summary of the invention
The invention provides a kind of stem-winding method synthetic compound 15 (R/S)-methyl-lipoxin, productive rate and the purity of this compound and intermediate thereof can be significantly improved.Table 1 is the synthetic route of present method, is initial to final product 15 (R/S)-methyl-lipoxin from compound 1.As follows, we can by three compound Segment A in table 2, and B, C couple together and synthesize whole compound molecule. and utilize fragment D by Witting reaction, E synthesizes target molecule.Fragment D can also by the fragment F in shown route, and G synthesizes. and fragment E is obtained by fragment H, I hydrogen zirconium palladium chtalyst cross-coupling. and this synthetic route has a lot of beyond thought advantage.
Table 1
Table 2
The mild condition adopted in the complete synthesis operational path of target product involved in the present invention, environmental pollution are little and its process controllability strong, and whole synthesis technique is very ripe.Compared with existing synthesis technique, the present invention improves a lot to finished product and key intermediate yield and purity.
A first aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 20, it is characterized in that comprising: ethyl propiolate contacts with lithiumbromide, to obtain compound shown in formula 2; Compound shown in formula 3, tertiary butyl dimethyl silyl triflate contact with pyridine, to obtain compound shown in formula 4; Compound shown in described formula 4 contacts to obtain compound shown in formula 5 with HZrCp2Cl; Shown in formula 2, shown in compound with formula 5, compound contacts, to obtain compound shown in formula 6; Shown in described formula 6, compound contacts with DIBAL-D, to obtain compound shown in formula 7; Shown in shown formula 7, compound contacts with phosphorus tribromide, to obtain compound shown in formula 8; Shown in described formula 8, compound contacts with trimethyl phosphite, to obtain compound shown in formula 9; Shown in formula 10, compound contacts with Acetyl Chloride 98Min., to obtain compound shown in formula 11; Shown in described formula 11, compound contacts with CDI, to obtain compound shown in formula 12; Shown in described formula 12, compound contacts with hydrochloric acid, to obtain compound shown in formula 13; Shown in described formula 13, compound contacts with ethoxycarbonyl triphenylphosphine with aromatic acid, to obtain compound shown in formula 14; Shown in described formula 14, compound contacts with hydrogen, to obtain compound shown in formula 15; Shown in described formula 15, compound contacts with dicyclohexylcarbodiimide, to obtain compound shown in formula 16; Shown in described formula 16, compound contacts with Ph3P=CHCHO, to obtain compound shown in formula 17; Shown in compound shown in described formula 17 with lithium diisopropylamine, HMPA with described formula 9, compound contacts, to obtain compound shown in formula 18; Shown in described formula 18, compound contacts with acetic acid, to obtain compound shown in formula 19; Shown in described formula 19, compound contacts with sodium hydroxide, to obtain compound shown in formula 20
A second aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 2, it is characterized in that comprising: ethyl propiolate is contacted with lithiumbromide, so that compound shown in production 2
According to embodiments of the invention, it is characterized in that, described contact be acetic acid and acetonitrile composition mixing solutions in carry out.
According to embodiments of the invention, the volume ratio of acetic acid and acetonitrile is 1:2 ~ 2:1.
According to embodiments of the invention, the temperature range of reaction system be 40 DEG C to reflux temperature.
A third aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 6, it is characterized in that comprising: make compound shown in formula 2, bi triphenyl phosphorus palladium chloride contacts with diisobutyl aluminium hydride, so that compound shown in production 6
According to embodiments of the invention, it is characterized in that, described contact is carried out in tetrahydrofuran (THF).
According to embodiments of the invention, described contact is carried out in zinc chloride.
According to embodiments of the invention, the consumption of bi triphenyl phosphorus palladium chloride is 2% ~ 10% of compound molar weight shown in described formula 2.
According to embodiments of the invention, the temperature range of reaction system is that room temperature is to solution return temperature.
A fourth aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 7, it is characterized in that comprising: compound shown in formula 6 is contacted with DIBAL-D, so that compound shown in production 7
According to embodiments of the invention, the molar weight 1.2 times ~ 2.0 times that the consumption of DIBAL-D is compound shown in described formula 7.
A fifth aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 14, it is characterized in that comprising: make compound shown in formula 13, ethoxycarbonyl methylene triphenyl phosphine contacts with aromatic acid, so that compound shown in production 14
According to embodiments of the invention, it is characterized in that, described contact is carried out in toluene.
According to embodiments of the invention, the temperature range of reaction system is that room temperature is to solution return temperature.
A sixth aspect of the present invention, the present invention proposes the method for compound shown in a kind of preparation formula 18, it is characterized in that comprising: compound shown in compound with formula 17 shown in formula 9 is contacted, so that compound shown in production 18
According to embodiments of the invention, it is characterized in that, described contact is carried out in tetrahydrofuran (THF).
According to embodiments of the invention, in reaction system, add alkali and HPMA.
According to embodiments of the invention, described alkali is LDA, n-BuLi, NaH.
According to embodiments of the invention, the temperature range of reaction system be-78 DEG C to room temperature.
According to embodiments of the invention, the consumption of described alkali and 1.1 times of reaction substrate molar weight ~ 1.5 times.
Embodiment
Embodiment described below is exemplary, is intended to for explaining the present invention, and can not be interpreted as limitation of the present invention.
Example
Example is below the disclosure of involved abbreviation in this patent
The synthesis of 15 (R/S)-methyl-LXA4
Step 1: prepare compound 2
Be dissolved in by ethyl propiolate (5.0g, 51mmol) in the mixing solutions of acetic acid (10mL) and acetonitrile (10mL), add lithiumbromide (4.3g, 51mmol), reaction solution stirs 2 hours under 60 degree.After reaction completes, be cooled to room temperature, add 50mL water in system, and extract by ethyl acetate.Organic phase saturated common salt water washing, and with after anhydrous sodium sulfate drying, filter, concentrate and obtain 8.2g compound 2, yield 91%.GC/MS:177；
1H-NMR(DMSO-d6):δ＝6.80(d,J＝10.8Hz,1H),6.62(d,J＝10.8Hz,1H),1.40(q,2H),0.85(t,3H).
Step 2: prepare compound 4
Compound 2 (5.6g, 40mmol) and tertiary butyl dimethyl silyl triflate (11.6g, 44mmol) are dissolved in methylene dichloride (60mL) and add 10mL pyridine under room temperature.Reaction system stirs 4 hours under 60 degree, after question response completes, concentrates solvent at reduced pressure conditions, adds 80mL acetic acid ethyl dissolution, and with water, saturated common salt water washing, with anhydrous sodium sulfate drying, obtains 8.3g compound 3 after filtering and concentrating, yield 81%.
1H-NMR(DMSO-d6):δ＝3.40(s,1H),1.65(s,3H),1.65(2H,m),1.35(m,2H),1.30(m,4H,),1.01(s,9H),0.88(t,3H),0.25(s,6H).
Step 3: prepare compound 5
Compound 4 (2.54g, 10mmol) and HZrCp2Cl (3.08g, 12mmol) are dissolved in tetrahydrofuran (THF) (50mL), this reaction system at room temperature stirs 12 hours.Add 100mL water after question response completes, and extract 3 times by ethyl acetate, merge organic phase, and use saturated common salt water washing, after anhydrous sodium sulfate drying, filtering and concentrating obtains compound 5, is directly used in next step reaction, is not further purified.
Step 4: prepare compound 6
By compound 5 (4.86g, 9.5mmol) with compound 2 (1.68g, 9.5mmol) be dissolved in tetrahydrofuran (THF) (50mL), the zinc chloride of bi triphenyl phosphorus palladium chloride (5%, 330mg) and diisobutyl aluminium hydride (10%) and trace is joined in above-mentioned system.Reaction system refluxes 12 hours under nitrogen protection, with TLC monitoring in reaction process, after having reacted; be cooled to the water that room temperature adds 100mL, and extract 3 times by ethyl acetate, merge organic phase; use saturated common salt water washing, anhydrous sodium sulfate drying, after filtering and concentrating, obtain thick product.2.0g compound 6 is obtained, yield 56% after going out product combiflash companion purifying.(two steps)
Step 5: prepare compound 7
Compound 6 (3.54g, 10mmol) is dissolved in 50mL methylene dichloride, system dry ice-propanone bath cooling.The lower dichloromethane solution (1.5M, 50mL) dripping DIBAL-D of cooling, time for adding is no less than 30 minutes, dropwises rear stable system and rises to zero degree stirring 2 disappearance.Use the cancellation of 2M ammonium chloride solution after completion of the reaction.Separate organic layer, organic layer uses water, 5% sodium hydrogen carbonate solution and saturated common salt water washing respectively, and with anhydrous magnesium sulfate drying, obtains thick product after filtering and concentrating, and with obtaining 2.52g compound 7 after column chromatography purification, yield 81%.
1H-NMR(DMSO-d6):δ＝6.28(m,1H),6.25(m,1H),5.78(m,2H),5.68(m,1H),5.60(m,1H),1.55(s,3H),1.50(2H,m),1.31(m,2H),1.27(m,4H,),1.00(s,9H),0.85(t,3H),0.21(s,6H).
Step 6: prepare compound 8
Phosphorus tribromide (1.23g, 4.52mmol) is placed in the round-bottomed flask of 50mL, and cools with dry ice-propanone bath.Drip the diethyl ether solution 15mL of compound 7 (3.37g, 10.8mmol) subsequently.After dropwising, be slowly warming up to-25 degree stirrings and remove cooling bath after 30 minutes.Stirred at rt for another 3.5 hours, after having reacted, pours into reaction solution in the saturated sodium bicarbonate solution containing ice.Organic phase is got in layering, aqueous phase ether extraction, merges organic phase, uses anhydrous sodium sulfate drying after the water washing of organic phase saturated common salt.Obtain thick product compound 8 after extracting solution is concentrated, be directly used in next step reaction.
LC/MS:[M+H]＝375
Step 7: prepare compound 9
Compound 8 (2.5g, 6.6mmol) is dissolved in 10mL acetonitrile, adds trimethyl phosphite (900mg, 7.26mmol).Reaction solution stirs in room temperature under nitrogen protection and spends the night.After having reacted, add 60mL water, aqueous phase ether extraction, ether layer saturated sodium bicarbonate solution washs, saturated common salt water washing, and with anhydrous sodium sulfate drying, obtain thick product after extracting solution is concentrated, and obtain 2.36g compound 9 after purifying with combiflash companion, yield 87%.
Step 8: prepare compound 11
Compound 10 (2.68g, 20mmol) to be dissolved in 30mL methyl alcohol and to be cooled with an ice bath, Acetyl Chloride 98Min. (1.63g, 21mmol) is added drop-wise in solution slowly.Dropwise rear reaction system and at room temperature stir 3 hours.After having reacted, poured into by reaction solution in 100mL water, aqueous phase ethyl acetate is extracted.Organic phase saturated sodium bicarbonate solution washs, saturated common salt water washing, and with anhydrous sodium sulfate drying, obtains thick product, and obtain 2.2g compound 11 after purifying with combiflash companion, yield 74% after extracting solution is concentrated.
1H-NMR(DMSO-d6):δ＝4.86(m,1H),3.86(s,2H),3.34(s,3H),3.25(m,2H),2.68(s,2H),1.86(m,2H).
Step 9: prepare compound 12
Compound 11 (2.2g, 14.8mmol) to be dissolved in 20mL acetonitrile and to add CDI (2.4g, 14.8mmol).Reaction solution stirs 6 hours at a reflux temperature.After having reacted, reaction solution is poured into water, and extracts by ethyl acetate, the salt acid elution of organic phase 1N, saturated common salt water washing, and with anhydrous sodium sulfate drying, after extracting solution is concentrated, obtain thick product 2.23g compound 12, direct and for next step.
Step 10: prepare compound 13
Compound 12 (2.23g, 12.8mmol) is dissolved in (dioxane: water=3:1, V/V) in the mixing solutions of 20mL dioxane and water, adds the hydrochloric acid soln of 4N.Reaction solution stirs 5 hours at the temperature of backflow.React rear concentrated solvent and obtained 2.0g compound 13, be directly used in next step reaction.
Step 11: prepare compound 14
Compound 13 (3.2g, 20mmol) is dissolved in 30mL toluene, adds aromatic acid (20mmol) and ethoxycarbonyl methylene triphenyl phosphine (7.3g, 21mmol).Reaction solution backflow is spent the night.After having reacted, after concentrated solvent, obtain oily matter, after dissolving with 50mL methylene dichloride, use water, 5% sodium hydrogen carbonate solution and saturated common salt water washing respectively, and with anhydrous magnesium sulfate drying, thick product is obtained after filtering and concentrating, and with obtaining 2.86g compound 14 after column chromatography purification, yield 62%.
1H-NMR(DMSO-d6):δ＝6.86(m,1H),5.85(d,1H),4.23-4.26(m,2H),4.04(t,2H),3.98(m,2H),2.52(m,2H),1.66(t,3H).
Step 12: prepare compound 15
Compound 14 (2.0g, 8.7mmol) is dissolved in 15mL ethanol, adds palladium carbon (10%, 200mg).Reaction solution is stirred overnight at room temperature in 2 normal atmosphere hydrogen.After having reacted, filter, obtain 1.86g compound 15 after concentrated solvent, be directly used in next step.
Step 13: prepare compound 16
Compound 15 (3.0g, 12.9mmol) is dissolved in 25mL dichloro acetic acid, adds dicyclohexylcarbodiimide (2.92g, 14.1mmol).Reaction solution at room temperature stirs 8 hours.By solvent concentration after having reacted, and use water, 5% sodium hydrogen carbonate solution and saturated common salt water washing respectively after dissolving with 60mL methylene dichloride, and with anhydrous magnesium sulfate drying, after filtering and concentrating, obtain thick product 2.8g compound 16, be directly used in next step reaction.
Step 14: prepare compound 17
Compound 16 (2.5g, 10.8mmol) is dissolved in 30mL methylene dichloride, adds Ph3P=CHCHO (3.28g, 10.8mmol).Reaction solution at room temperature stirs 12 hours.After having reacted, solution uses water, 5% sodium hydrogen carbonate solution and saturated common salt water washing respectively, and with anhydrous magnesium sulfate drying, obtains thick product after filtering and concentrating, and with obtaining 2.0g compound 14 after column chromatography purification, yield 72%.
Step 15: prepare compound 18
Compound 17 (3.3g, 12.9mmol) is dissolved in 25mL tetrahydrofuran (THF), and is cooled to-78 degree with dry ice-propanone bath, slowly drip lithium diisopropylamine (1.65g, 15.4mmol).After dropwising, stir 30 minutes, more slowly rise to room temperature.Add HMPA (2.77g, 15.4mmol) and compound 9 again.This reaction system at room temperature stirs spends the night.Be cooled with an ice bath after having reacted, add the hydrochloric acid soln 150mL of 2M.Solution saturated common salt water washing, and with anhydrous magnesium sulfate drying, after filtering and concentrating, obtain thick product, and obtain 3.8g compound 18 after purifying with combiflash companion, yield 55%
Step 16: prepare compound 19
Compound 18 (1.8g, 3.4mmol) is dissolved in the mixing solutions (30mL1:1) of methyl alcohol and acetic acid.This solution at room temperature stirs 18 hours.After reaction completes, under reduced pressure, concentrated solvent obtains thick product, and after acetic acid ethyl dissolution, organic phase is with using water, 5% sodium hydrogen carbonate solution and saturated common salt water washing respectively, and obtain 1.0g compound 19 with after dried over mgso through filtering and concentrating, yield 70%.
Step 17: prepare compound 20
Compound 19 (1.0g, 2.4mmol) is dissolved in 20mL methyl alcohol, adds the sodium hydroxide solution of 2M.Reaction solution at room temperature stirs 15 hours.After having reacted, regulate PH to 5, obtain target product 600mg compound 20, yield 68%.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.
Claims (10)
1. a method for compound shown in preparation formula 20, is characterized in that comprising:
Ethyl propiolate contacts with lithiumbromide, to obtain compound shown in formula 2;
Compound shown in formula 3, tertiary butyl dimethyl silyl triflate contact with pyridine, to obtain compound shown in formula 4;
Compound shown in described formula 4 contacts to obtain compound shown in formula 5 with HZrCp2Cl;
Shown in formula 2, shown in compound with formula 5, compound contacts, to obtain compound shown in formula 6;
Shown in described formula 6, compound contacts with DIBAL-D, to obtain compound shown in formula 7;
Shown in shown formula 7, compound contacts with phosphorus tribromide, to obtain compound shown in formula 8;
Shown in described formula 8, compound contacts with trimethyl phosphite, to obtain compound shown in formula 9;
Shown in formula 10, compound contacts with Acetyl Chloride 98Min., to obtain compound shown in formula 11;
Shown in described formula 11, compound contacts with CDI, to obtain compound shown in formula 12;
Shown in described formula 12, compound contacts with hydrochloric acid, to obtain compound shown in formula 13;
Shown in described formula 13, compound contacts with ethoxycarbonyl triphenylphosphine with aromatic acid, to obtain compound shown in formula 14;
Shown in described formula 14, compound contacts with hydrogen, to obtain compound shown in formula 15;
Shown in described formula 15, compound contacts with dicyclohexylcarbodiimide, to obtain compound shown in formula 16;
Shown in described formula 16, compound contacts with Ph3P=CHCHO, to obtain compound shown in formula 17;
Shown in compound shown in described formula 17 with lithium diisopropylamine, HMPA with described formula 9, compound contacts, to obtain compound shown in formula 18;
Shown in described formula 18, compound contacts with acetic acid, to obtain compound shown in formula 19;
Shown in described formula 19, compound contacts with sodium hydroxide, to obtain compound shown in formula 20
2. a method for compound shown in preparation formula 2, is characterized in that comprising: ethyl propiolate is contacted with lithiumbromide, so that compound shown in production 2
3. method according to claim 2, is characterized in that, described contact be acetic acid and acetonitrile composition mixing solutions in carry out;
Optionally, the volume ratio of acetic acid and acetonitrile is 1:2 ~ 2:1;
Optionally, the temperature range of reaction system be 40 DEG C to reflux temperature.
4. a method for compound shown in preparation formula 6, is characterized in that comprising: make compound shown in formula 2, bi triphenyl phosphorus palladium chloride contacts with diisobutyl aluminium hydride, so that compound shown in production 6
5. method according to claim 4, is characterized in that, described contact is carried out in tetrahydrofuran (THF);
Optionally, described contact is carried out in zinc chloride;
Optionally, the consumption of bi triphenyl phosphorus palladium chloride is 2% ~ 10% of compound molar weight shown in described formula 2;
Optionally, the temperature range of reaction system is that room temperature is to solution return temperature.
6. a method for compound shown in preparation formula 7, is characterized in that comprising: compound shown in formula 6 is contacted with DIBAL-D, so that compound shown in production 7
Optionally, the consumption of the DIBAL-D molar weight 1.2 times ~ 2.0 times that is compound shown in described formula 7.
7. a method for compound shown in preparation formula 14, is characterized in that comprising: make compound shown in formula 13, ethoxycarbonyl methylene triphenyl phosphine contacts with aromatic acid, so that compound shown in production 14
8. method according to claim 7, is characterized in that, described contact is carried out in toluene;
Optionally, the temperature range of reaction system is that room temperature is to solution return temperature.
9. a method for compound shown in preparation formula 18, is characterized in that comprising: compound shown in compound with formula 17 shown in formula 9 is contacted, so that compound shown in production 18
10. method according to claim 9, is characterized in that, described contact is carried out in tetrahydrofuran (THF);
Optionally, alkali and HPMA is added in reaction system;
Wherein, described alkali is LDA, n-BuLi, NaH;
Optionally, the temperature range of reaction system be-78 DEG C to room temperature;
Optionally, the consumption of described alkali and 1.1 times ~ 1.5 times of reaction substrate molar weight.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994029262A1 (en) * | 1993-06-15 | 1994-12-22 | Brigham & Women's Hospital | Lipoxin compounds |
| WO1995001179A1 (en) * | 1993-06-29 | 1995-01-12 | Brigham & Women's Hospital | Modulation of inflammation related to columnar epithelia |
| US5650435A (en) * | 1991-04-01 | 1997-07-22 | Madara; James L. | Modulation of inflammation related to columnar epithelia |
| US6048897A (en) * | 1993-06-15 | 2000-04-11 | Brigham And Women's Hospital | Lipoxin compounds and their use in treating cell proliferative disorders |
-
2014
- 2014-08-08 CN CN201410390418.8A patent/CN105439813B/en not_active Withdrawn - After Issue
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5650435A (en) * | 1991-04-01 | 1997-07-22 | Madara; James L. | Modulation of inflammation related to columnar epithelia |
| WO1994029262A1 (en) * | 1993-06-15 | 1994-12-22 | Brigham & Women's Hospital | Lipoxin compounds |
| US6048897A (en) * | 1993-06-15 | 2000-04-11 | Brigham And Women's Hospital | Lipoxin compounds and their use in treating cell proliferative disorders |
| WO1995001179A1 (en) * | 1993-06-29 | 1995-01-12 | Brigham & Women's Hospital | Modulation of inflammation related to columnar epithelia |
Non-Patent Citations (1)
| Title |
|---|
| LAIN MACINNES, DAVID E.SCHORSTEIN: "LATENT INHIBITORS.PART 2. ALLYLIC INHIBITORS OF ALCOHOL DEHYDROGENASE", 《J.C.S.PERKIN I》 * |
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