CN105232535A - Composition and application thereof in anti-rhinitis drugs - Google Patents
Composition and application thereof in anti-rhinitis drugs Download PDFInfo
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- CN105232535A CN105232535A CN201510419805.4A CN201510419805A CN105232535A CN 105232535 A CN105232535 A CN 105232535A CN 201510419805 A CN201510419805 A CN 201510419805A CN 105232535 A CN105232535 A CN 105232535A
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Abstract
The invention relates to the fields of organic synthesis and medicinal chemistry, and in particular relates to a composition and application thereof in anti-rhinitis drugs. The invention discloses a composition and a preparation method thereof. Pharmacological experiments show that the composition disclosed by the invention has an anti-rhinitis effect, and the composition has a value of being developed into anti-rhinitis drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Rhinitis is common clinical and frequently-occurring disease, and the generation of rhinitis is main relevant with anaphylaxis, belongs to the category of immune inflammation.At present, treatment rhinitis mainly adopt the antihistamine drug such as teldane or the Claritin such as tranilast, ketotifen, these medicines to the chronicity of rhinitis and recurrent exerbation curative effect poor or invalid.Therefore, definite ingredients, quality controllable and safely and efficiently micromolecular compound in development treatment of rhinitis medicine, there is potential value.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound I that the present invention relates to is one and delivers (AntonellaMaggioetal. in 2011, 2011.Artalbicacid, asesquiterpenewithanunusualskeletonfromArtemisiaalba (Asteraceae) fromSicily.TetrahedronLetters, 52 (2011) 4543 – 4545) compound, we have carried out structural modification to Compound I, obtain two new derivants and compound III and compound IV, and prepared compositions by compound III and compound IV, and the anti-rhinitis activity of said composition is evaluated, it is active that it has anti-rhinitis.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 40% and 60%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, compositions of the present invention has good anti-rhinitis effect.Pharmaceutically acceptable salt of the present invention has same drug effect.
Compositions 10mg/kg oral administration, raises inhibited to scratch nose, sneeze reaction and nasal cavity vascular permeability of rat caused by antigen (ovalbumin) and histamine, therefore, can be used for the medicine preparing treatment rhinitis.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compd A rtalbicacid
Document (the AntonellaMaggioetal. that the people such as the preparation method reference AntonellaMaggio of compd A rtalbicacid (I) deliver, 2011.Artalbicacid, asesquiterpenewithanunusualskeletonfromArtemisiaalba (Asteraceae) fromSicily.TetrahedronLetters, 52 (2011) 4543 – 4545) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2Artalbicacid
By Compound I (266mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 16h at 40 degrees Celsius.After 16h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 5 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.0, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (272mg, 73%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ11.41(s,1H),6.06(s,1H),5.76(s,1H),4.99(s,1H),4.71(s,1H),4.56(s,1H),3.86(s,2H),3.54(s,2H),2.65(s,1H),2.43(s,2H),2.33(s,2H),2.10(s,1H),1.64(s,3H),1.54(s,1H),1.44(s,2H),0.95(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05(s),109.43(s),81.86(s),70.27(s),57.68(s),41.26(s),39.07(s),38.86(s),35.69(s),33.36(s),30.72(s),20.44(s),18.42(s).
HRMS(ESI)m/z[M+H]
+calcdforC
17H
26BrO
4:373.1014；found373.1017.
The synthesis of O-(diethylin) ethyl derivative (III) of embodiment 3Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and diethylamine (1460mg, 20mmol), mixture reflux 12h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 4 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (111.3mg, 61%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ11.52(s,1H),δ6.13(s,1H),5.81(s,1H),4.73(s,1H),4.62(d,J＝10.9Hz,2H),3.59(s,2H),2.92(s,4H),2.68(d,J＝10.5Hz,3H),2.56(s,2H),2.48(s,2H),2.22(s,1H),1.70(s,3H),1.54(d,J＝10.2Hz,3H),1.16(s,6H),1.00(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05(s),109.43(s),81.86(s),67.06(s),57.68(s),52.53(s),47.72(s),41.30(s),39.06(s),38.85(s),35.68(s),30.72(s),20.44(s),18.42(s),12.35(s).
HRMS(ESI):m/z[M+H]
+calcdforC
21H
36NO
4:366.2644；found:366.2640。
The synthesis of the O-(nafoxidine base) ethyl derivative (IV) of embodiment 4Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture reflux 8h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.0, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (107.1mg, 59%) that namely solvent obtains compound IV.
1HNMR(500MHz,DMSO-d6)δ14.01(s,1H),6.15(s,1H),5.83(s,1H),4.75(s,1H),4.63(s,1H),3.96(s,1H),3.58(s,2H),2.70(d,J＝6.1Hz,3H),2.56–2.49(m,8H),2.09(s,1H),1.68(d,J＝10.0Hz,7H),1.58(s,2H),1.44(s,1H),1.02(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.85(s),175.85(s),149.07(s),148.11(s),117.03(s),109.33(s),81.78(s),67.00(s),57.64(s),54.44(d,J＝17.1Hz),41.20(s),38.98(s),38.79(s),35.64(s),30.70(s),25.21(s),20.35(s),18.36(s).
HRMS(ESI):m/z[M+H]
+calcdforC
21H
34NO
4:364.2488；found:364.2491。
Embodiment 5 present composition causes the impact of rat allergic rhinitis on ovalbumin
Male SD rat, body weight 180 ~ 220g, lumbar injection ovalbumin 1mg and gel aluminum hydroxide 10mg, inject 1 time next day of thereafter, totally 7 times.Began from the 14th day, every day instills 1mg/ml ovalbumin normal saline solution 10ul at rat both sides nasal cavity, totally 7 times.Last is observed rat sneeze in 30 minutes at once and is wiped the number of times of nose after instiling, trial drug instils in ovalbumin last and orally to give for first 1 hour.
The preparation of compositions: the powder of the powder of 40mg compound III and 60mg compound IV is loaded to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions.
From table 1, compositions (10mg/kg) obviously suppresses the sneeze of allergic rhinitis rat caused by ovalbumin and nose reaction of scratching.Compound III and compound IV act on without this.
Table 1 present composition causes the impact of rat allergic rhinitis to ovalbumin
* p<0.05, compares with matched group
Embodiment 6 present composition is on the impact of the rat rhinitis that histamine causes
Male SD rat, body weight 180 ~ 220g, orally to give after trial drug 1 hour, and both sides nasal cavity instillation 1M histamine normal saline solution 10ul, observes the number of times of rat sneeze and wiping nose in 30 minutes.
From table 2, the present composition (10mg/kg) obviously reduces the sneeze number of times of rhinitis rat caused by histamine, to nose reaction of scratching in suppression trend.Compound III and compound IV act on without this.
Table 2 present composition causes the impact of rat rhinitis to histamine
* p<0.05, compares with matched group
The impact that embodiment 7 present composition causes rat nasal cavity vascular permeability to raise on ovalbumin, histamine
Male SD rat, body weight 180 ~ 220g, observe with active sensitization rat and normal rat the nasal cavity vascular permeability that ovalbumin and histamine cause respectively to raise, the method of sensitization of rat is tested with allergic rhinitis, after initial immunity the 14th day, rats by intraperitoneal injection pentobarbital sodium 40mg/kg, after anesthesia from trachea to nasal intubation, be connected this intubate with constant flow pump after fixing (0.25ml/min0, with 37 DEG C of normal saline flushing nasal cavities 10 minutes, thereafter the blue normal saline solution 5ml/kg of rat tail vein injection 1%Evans, perfusate is collected 10 minutes after 3 minutes.At sensitized rats and normal rat, respectively containing ovalbumin 1mg/ml and histamine 40ug/ml in perfusate, the perfusate collected from nasal cavity through 1200 × g centrifugal 10 minutes, the Evans indigo plant concentration in 620nm place colorimetric determination supernatant, test medicine and antigen or histamine perfusion first 1 hour oral administration.
From table 3, the present composition (10mg/kg) obviously suppresses the nasal cavity vascular permeability of allergic rhinitis rat caused by ovalbumin.Compound III and compound IV act on without this.
The impact that table 3 present composition causes rat nasal cavity vascular permeability to raise on ovalbumin
* p<0.01, compares with matched group
From table 4, present composition 10mg/kg obviously reduces the nasal cavity vascular permeability of rat caused by histamine.Compound III and compound IV act on without this.
The impact that table 4 present composition causes rat nasal cavity blood flow permeability to raise on histamine
* p<0.01, compares with matched group
Conclusion: composition oral administration, raises have remarkable inhibitory action to scratch nose, sneeze reaction and nasal cavity vascular permeability of rat caused by antigen (ovalbumin) and histamine, therefore, can be used for the medicine preparing treatment rhinitis.Compound III and compound IV raise do not have remarkable inhibitory action to scratch nose, sneeze reaction and nasal cavity vascular permeabilitys of rat caused by antigen (ovalbumin) and histamine, therefore, are not useable for the medicine preparing treatment rhinitis.
The preparation of embodiment 8 composition tablet involved in the present invention
Get 2 grams of compositionss, add the customary adjuvant 18 grams preparing tablet, mixing, conventional tablet presses makes 100.
The preparation of embodiment 9 composition capsule involved in the present invention
Get 2 grams of compositionss, add prepare capsule customary adjuvant as starch 18 grams, mixing, encapsulatedly makes 100.
Claims (10)
1. a compositions, it is characterized by said composition and be made up of compound III and compound IV, in said composition, the mass percent of compound III and compound IV is respectively 40% and 60%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: the powder of compound III and the powder of compound IV are respectively 40% and 60% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in anti-rhinitis medicament thing.
4. the application of compositions according to claim 3 in anti-rhinitis medicament thing, is characterized by: the rhinitis of described rhinitis caused by antigen.
5. the application of compositions according to claim 4 in anti-rhinitis medicament thing, is characterized by: described antigen is ovalbumin.
6. the application of compositions according to claim 5 in anti-rhinitis medicament thing, is characterized by: described compositions can suppress scratch caused by ovalbumin nose number of times and sneeze reaction.
7. the application of compositions according to claim 5 in anti-rhinitis medicament thing, is characterized by: described compositions can suppress the rising of nasal cavity vascular permeability caused by ovalbumin.
8. the application of compositions according to claim 3 in anti-rhinitis medicament thing, is characterized by: the rhinitis of described rhinitis caused by histamine.
9. the application of compositions according to claim 8 in anti-rhinitis medicament thing, is characterized by: described compositions can suppress scratch caused by histamine nose number of times and sneeze reaction.
10. the application of compositions according to claim 8 in anti-rhinitis medicament thing, is characterized by: described compositions can suppress the rising of nasal cavity vascular permeability caused by histamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510419805.4A CN105232535A (en) | 2015-07-16 | 2015-07-16 | Composition and application thereof in anti-rhinitis drugs |
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| CN201510419805.4A CN105232535A (en) | 2015-07-16 | 2015-07-16 | Composition and application thereof in anti-rhinitis drugs |
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| CN105232535A true CN105232535A (en) | 2016-01-13 |
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| CN201510419805.4A Pending CN105232535A (en) | 2015-07-16 | 2015-07-16 | Composition and application thereof in anti-rhinitis drugs |
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2015
- 2015-07-16 CN CN201510419805.4A patent/CN105232535A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO,ET AL.: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
| JIN-BIN WU等: "Biologically Active Constituents of Centipeda minima: Sesquiterpenes of Potential Anti-allergy Activity", 《CHEM. PHARM. BULL.》 * |
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