CN104814967A - Application of cleistanthus sumatranus ketone O-(1H-tetrazole base) ethyl ramification to preparing rhinitis-resisting medicine - Google Patents
Application of cleistanthus sumatranus ketone O-(1H-tetrazole base) ethyl ramification to preparing rhinitis-resisting medicine Download PDFInfo
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Abstract
The invention discloses application of cleistanthus sumatranus ketone O-(1H-tetrazole base) ethyl ramification to preparing a rhinitis-resisting medicine, relates to the field of rhinitis and medicines, and particularly relates to a cleistanthus sumatranus ketone Cleistane derivative, a preparing method and application of the derivative to preparing the rhinitis-resisting medicine. The new cleistanthus sumatranus ketone Cleistane derivative is synthesized, and the preparing method is disclosed. Pharmacology tests show that the cleistanthus sumatranus ketone Cleistane derivative has the rhinitis-resisting effect, and has the value for developing the rhinitis-resisting medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, 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 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume 2011, Issue 22,pages 4108 – 4111, August 2011) compound, we have carried out structural modification to compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, obtain a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, and its anti-rhinitis activity is evaluated, it is active that it has anti-rhinitis.
Summary of the invention
The invention discloses a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, its structure is:
Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) with 1H-tetrazole generation substitution reaction.
The preparation method of further Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, 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, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 15mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the 1H-tetrazole of 1401mg, mixture reflux 10h; After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three 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; Because tautomerization, 1H-tetrazole base and 2H-tetrazole base two kinds of substitution products can be generated at reaction conditions; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1, v/v, collects faint yellow concentrated elution band; Concentrated by elution band, with purification by silica gel column chromatography, mobile phase is again: petroleum ether/acetone=100:0.5, v/v, namely concentrated front 1 elution band obtains the faint yellow solid of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) of the present invention has good anti-rhinitis effect.Pharmaceutically acceptable salt of the present invention has same drug effect with its compound.
Compound III 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 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of Compound C leistanone (I) deliver, 2011.Cleistanone:A Triterpenoid from Cleistanthusindochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, 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, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound II per (273mg, 0.5mmol) be dissolved in the middle of 15mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) with 1H-tetrazole (1401mg, 20mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three 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.Because tautomerization, 1H-tetrazole base and 2H-tetrazole base two kinds of substitution products can be generated at reaction conditions.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1, v/v), collect yellow concentrated elution band, again elution band is concentrated, with purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collect two flaxen elution bands successively, namely concentrated front 1 elution band obtains the faint yellow solid (56.5mg, 21%) of compound III.
1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),4.63(s,1H),4.53(s,1H),4.33(d,J＝4.7Hz,2H),4.26(s,1H),3.88(s,2H),2.37(d,J＝3.0Hz,2H),2.26(d,J＝13.0Hz,2H),2.20(s,1H),1.89(s,2H),1.81(s,1H),1.65(d,J＝15.0Hz,3H),1.56(s,2H),1.54–1.47(m,3H),1.42(s,1H),1.30(dd,J＝26.0,22.6Hz,3H),1.22(s,1H),1.04(s,6H),0.96(s,12H),0.87(d,J＝5.4Hz,4H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.58(s),154.48(s),145.25(s),105.20(s),74.64(s),65.63(s),59.74(s),52.54(s),51.19(s),47.89(s),47.02(s),44.11(s),42.27(s),41.76(s),40.63(s),40.14(s),38.85(s),38.66(s),37.23(s),36.26(s),33.33(s),32.94(s),29.88(s),27.19(s),26.05(s),24.26(s),23.95(s),20.75(s),18.45(s),17.99(s),16.95(s).
HRMS(ESI):m/z[M+H]
+calcd for C
33H
53N
4O
2:537.4169；found:537.4161。
The preparation of embodiment 4 Compound II per involved in the present invention and III tablet
Get the one in the middle of 20 g of compound II or III or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 5 Compound II per involved in the present invention and III capsule:
Get the one in the middle of 20 g of compound II or III or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Embodiment 6 the compounds of this invention III 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.
From table 1, compound III (10mg/kg) obviously suppresses the sneeze of allergic rhinitis rat caused by ovalbumin and nose reaction of scratching.
Table 1 the compounds of this invention III causes the impact of rat allergic rhinitis on ovalbumin
* p<0.05, * * p<0.01, compares with matched group
Embodiment 7 the compounds of this invention III 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 compounds of this invention III (10mg/kg) obviously reduces the sneeze number of times of rhinitis rat caused by histamine, to nose reaction of scratching in suppression trend.
Table 2 the compounds of this invention III causes the impact of rat rhinitis on histamine
* p<0.05, * * p<0.01, compares with matched group
The impact that embodiment 8 the compounds of this invention III 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 compounds of this invention III (10mg/kg) obviously suppresses the nasal cavity vascular permeability of allergic rhinitis rat caused by ovalbumin.
The impact that table 3 the compounds of this invention III causes rat nasal cavity vascular permeability to raise on ovalbumin
* p<0.01, compares with matched group
From table 4, the compounds of this invention III 10mg/kg obviously reduces the nasal cavity vascular permeability of rat caused by histamine.
The impact that table 4 the compounds of this invention III causes rat nasal cavity blood flow permeability to raise on histamine
* p<0.01, compares with matched group
Conclusion: compound III 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.
Claims (8)
1. there is Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof of structure shown in formula III,
2. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 1, is characterized by: the rhinitis of described rhinitis caused by antigen.
3. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 2, is characterized by: described antigen is ovalbumin.
4. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 3, is characterized by: described derivant can suppress scratch caused by ovalbumin nose number of times and sneeze reaction.
5. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 3, is characterized by: described derivant can suppress the rising of nasal cavity vascular permeability caused by ovalbumin.
6. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 1, is characterized by: the rhinitis of described rhinitis caused by histamine.
7. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 6, is characterized by: described derivant can suppress scratch caused by histamine nose number of times and sneeze reaction.
8. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant and the application of pharmaceutically acceptable salt in anti-rhinitis medicament thing thereof with structure shown in formula III according to claim 6, is characterized by: described derivant can suppress the rising of nasal cavity vascular permeability caused by histamine.
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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 (3)
| 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 |
| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
-
2015
- 2015-04-15 CN CN201510178931.5A patent/CN104814967A/en active Pending
Patent Citations (3)
| 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 |
| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| VAN TRINH THI THANH 等: "Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton", 《EUR. J. ORG. CHEM.》 * |
| 蒙丽丽等: "具有生物活性的天然三萜化合物的研究进展", 《广西植物》 * |
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 |
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