CN105343044A - Composition and application thereof in anti-rhinitis drug - Google Patents
Composition and application thereof in anti-rhinitis drug Download PDFInfo
- Publication number
- CN105343044A CN105343044A CN201510757692.9A CN201510757692A CN105343044A CN 105343044 A CN105343044 A CN 105343044A CN 201510757692 A CN201510757692 A CN 201510757692A CN 105343044 A CN105343044 A CN 105343044A
- Authority
- CN
- China
- Prior art keywords
- rhinitis
- compositions
- compound
- application
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the fields of organic synthesis and medicinal chemistry, and in particular relates to a composition and application thereof in preparing an anti-rhinitis drug. The invention discloses a composition and a preparation method thereof. Based upon pharmacological experiments, the composition disclosed by the invention has an anti-rhinitis effect, so that the composition has the value of developing the anti-rhinitis drug.
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 (Fan-YuMengetal. in 2011, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) 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 45% and 55%.
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 compound S chiglautoneA
Document (the Fan-YuMengetal. that the people such as the preparation method reference Fan-YuMeng of compound S chiglautoneA (I) deliver, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SchiglautoneA
By Compound I (502mg, 1.00mmol) be dissolved in 15mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 6mL.Mixture stirs 8h at 35 degrees Celsius.After 8h, 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 3 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 (508mg, 71%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ13.40(s,1H),6.10(s,1H),5.63(s,1H),5.53(s,1H),3.85(d,J＝11.2Hz,4H),3.52(d,J＝10.8Hz,4H),2.96(s,1H),2.20(s,1H),2.16(s,2H),2.00(s,1H),1.84(d,J＝13.9Hz,4H),1.69(s,1H),1.58(dd,J＝22.2,8.5Hz,4H),1.51(s,1H),1.47(s,1H),1.26(dd,J＝9.1,4.4Hz,4H),1.21(s,1H),1.08–0.98(m,4H),0.96-0.94(m,9H),0.94-0.85(m,6H).
13CNMR(125MHz,DMSO-d6)δ211.46(s),209.14(s),170.06(s),161.12(s),143.51(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]
-calcdforC
34H
51Br
2O
6:715.2032；found715.2027.
The synthesis of O-(diethylin) ethyl derivative (III) of embodiment 3SchiglautoneA
Compound II per (358mg, 0.5mmol) is dissolved in the middle of 10mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (168mg, 1.0mmol) and diethylamine (2920mg, 40mmol), mixture reflux 8h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 2 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 (231.2mg, 66%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ20.07(s,1H),6.13(s,1H),6.06(s,1H),5.55(s,1H),3.52(d,J＝5.1Hz,4H),3.01(s,1H),2.89(s,8H),2.72(s,2H),2.64(s,2H),2.40(s,2H),2.22(s,1H),2.10(s,1H),1.89(d,J＝18.6Hz,4H),1.72(d,J＝8.4Hz,2H),1.62(d,J＝11.5Hz,2H),1.55(s,1H),1.50(s,1H),1.40(d,J＝9.3Hz,2H),1.33–1.27(m,3H),1.25(s,1H),1.14(s,12H),1.08–0.60(m,19H).
13CNMR(125MHz,DMSO-d6)δ211.64(s),209.43(s),170.46(s),161.60(s),144.10(s),132.71(s),127.95(s),86.25(s),82.80(s),67.46(s),66.70(s),57.84(s),52.91(s),52.75(s),52.29(s),48.15(s),46.37(s),41.36(s),38.76(s),38.62(s),35.42(s),34.04(s),30.43(s),29.67(s),26.91(s),25.78(s),24.44(s),22.81(s),21.64(s),21.25(s),20.20(s),18.97(s),18.50(s),15.57(s),12.85(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
73N
2O
6:701.5469；found:701.5465。
The synthesis of the O-(two hydroxyethylamines) ethyl derivative (IV) of embodiment 4SchiglautoneA
Compound II per (358mg, 0.5mmol) is dissolved in 15mL acetonitrile, adds Anhydrous potassium carbonate (0.345g, 2.5mmol), potassium iodide (0.084g, 0.5mmol) and diethanolamine (1.0514g, 10mmol), mixture reflux 9h.Pour in cold water by reactant liquor after reaction terminates, with dichloromethane extraction three times, merge organic facies, use water and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent.Product, with purification by silica gel column chromatography (petroleum ether/acetone 100:1, v/v), obtains the faint yellow solid (0.199g, 52%) of compound IV.
1HNMR(500MHz,DMSO-d6)δ17.77(s,1H),6.00(s,1H),5.40(s,1H),5.20(s,1H),3.37(d,J＝17.8Hz,4H),3.28(s,8H),2.87(s,1H),2.51(d,J＝6.5Hz,4H),2.43(s,8H),2.24(s,2H),2.06(d,J＝12.7Hz,2H),1.76–1.68(m,5H),1.57(s,1H),1.53–1.39(m,8H),1.36(s,1H),1.24(s,1H),1.20–1.14(m,3H),1.11(s,1H),0.94–0.82(m,10H),0.80(s,3H),0.76(s,3H),0.72(d,J＝20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.39(s),208.98(s),169.80(s),160.73(s),143.02(s),131.42(s),127.05(s),85.91(s),82.25(s),66.70(s),65.63(s),58.62(s),56.55(s),56.61(s),53.30(s),52.45(s),51.52(s),45.29(s),40.06(s),38.52(s),38.17(s),34.73(s),33.17(s),29.35(s),28.38(s),26.34(s),25.00(s),23.45(s),22.05(s),20.67(s),20.07(s),19.31(s),18.41(s),17.73(s),14.59(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
73N
2O
10:765.5265；found:765.5261。
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: loaded by the powder of 55mg compound IV crossing 200 order nets after crossing the powder of the 45mg compound III of 200 order nets and grinding after grinding to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions, obtains the solution of compositions by the compositions of this 100mg of water dissolution during use.
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 45% and 55%,
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 45% and 55% 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 |
|---|---|---|---|
| CN201510757692.9A CN105343044A (en) | 2015-11-09 | 2015-11-09 | Composition and application thereof in anti-rhinitis drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510757692.9A CN105343044A (en) | 2015-11-09 | 2015-11-09 | Composition and application thereof in anti-rhinitis drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105343044A true CN105343044A (en) | 2016-02-24 |
Family
ID=55319209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510757692.9A Pending CN105343044A (en) | 2015-11-09 | 2015-11-09 | Composition and application thereof in anti-rhinitis drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105343044A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074526A (en) * | 2016-06-13 | 2016-11-09 | 南京广康协生物医药技术有限公司 | The composition of Schiglautone A derivative is used for preparing anti-rhinitis medicament thing |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083379A (en) * | 2014-06-25 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of Cleistanone dimethylamine derivative in preparation of anti-rhinitis drugs |
| CN104188980A (en) * | 2014-08-11 | 2014-12-10 | 南京大学 | Cleistanone O-(morpholinyl)ethyl derivative and preparation method and application thereof |
-
2015
- 2015-11-09 CN CN201510757692.9A patent/CN105343044A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083379A (en) * | 2014-06-25 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of Cleistanone dimethylamine derivative in preparation of anti-rhinitis drugs |
| CN104188980A (en) * | 2014-08-11 | 2014-12-10 | 南京大学 | Cleistanone O-(morpholinyl)ethyl derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| FAN-YU MENG等: "Schiglautone A, a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused Skeleton from the Stems of Schisandra glaucescens", 《ORGANIC LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074526A (en) * | 2016-06-13 | 2016-11-09 | 南京广康协生物医药技术有限公司 | The composition of Schiglautone A derivative is used for preparing anti-rhinitis medicament thing |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105287598A (en) | Composition and application of composition in medicine for resisting rhinitis | |
| CN104083379B (en) | The dimethylamine derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is preparing the application in anti-rhinitis medicament thing | |
| CN104188980B (en) | O-(morpholinyl) ethyl derivative of Cleistanone Cleistanone, preparation method and its usage | |
| CN105343044A (en) | Composition and application thereof in anti-rhinitis drug | |
| CN104402964B (en) | O-(imidazole radicals) ethyl derivative of Cleistanone, preparation method and its usage | |
| CN105343080A (en) | Composition and application of composition in preparation of medicines for resisting rhinitis | |
| CN105287568A (en) | Composition and application thereof to rhinitis resistant medicines | |
| CN105250271A (en) | Composition and application of composition in rhinitis-resistant medicine | |
| CN104887662A (en) | Application of Daphmalenine A ramification to preparing rhinitis-resisting medicine | |
| CN105395558A (en) | Composition and application of same to medicine resistant to rhinitis | |
| CN105343091A (en) | Composition and application thereof in rhinitis resistant drugs | |
| CN104825468A (en) | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of anti-rhinitis drugs | |
| CN105343099A (en) | Composition and application thereof in anti-rhinitis drug | |
| CN104814967A (en) | Application of cleistanthus sumatranus ketone O-(1H-tetrazole base) ethyl ramification to preparing rhinitis-resisting medicine | |
| CN105287557A (en) | Composition and application thereof to rhinitis resistant medicines | |
| CN105232535A (en) | Composition and application thereof in anti-rhinitis drugs | |
| CN105434413A (en) | Composition and application thereof to anti-rhinitis medicine | |
| CN105168222A (en) | Composition and application of composition to anti-rhinitis medicine | |
| CN105055410A (en) | Composition 16080301030537 and application thereof in medicines of resisting rhinitis | |
| CN104873506A (en) | Application of O-(diethylamino) ethyl derivative of Daphmalenine A in preparation of anti-rhinitis drug | |
| CN106074526A (en) | The composition of Schiglautone A derivative is used for preparing anti-rhinitis medicament thing | |
| CN105267195A (en) | Composition and application of composition to acute renal failure resisting drugs | |
| CN106074512A (en) | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-rhinitis medicament thing | |
| CN105796561A (en) | Application of composition of piperazine-based and imidazole-based derivatives of virosaine A in rhinitis-resistant medicine | |
| CN106038544A (en) | Application of composition of Artalbic acid derivatives in preparation of anti-rhinitis drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160224 |