CN104095860A - Application of O-(pyrrolidin) ethyl derivative of Cleistanone in preparing anti-inflammatory drugs - Google Patents
Application of O-(pyrrolidin) ethyl derivative of Cleistanone in preparing anti-inflammatory drugs Download PDFInfo
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- CN104095860A CN104095860A CN201410375097.4A CN201410375097A CN104095860A CN 104095860 A CN104095860 A CN 104095860A CN 201410375097 A CN201410375097 A CN 201410375097A CN 104095860 A CN104095860 A CN 104095860A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and particularly to an O-(pyrrolidine) ethyl derivative of Cleistanone, a preparation method for the O-(pyrrolidine) ethyl derivative of the Cleistanone and the application of the O-(pyrrolidine) ethyl derivative of the Cleistanone in preparing anti-inflammatory drugs. The invention synthesizes a novel O-(pyrrolidine) ethyl derivative of the Cleistanone and discloses the preparation method thereof. Pharmacological experiment results show that the O-(pyrrolidine) ethyl derivative of the Cleistanone has the anti-inflammatory effect and has the value of developing anti-inflammatory drugs.
Description
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry field, be specifically related to O-(nafoxidine base) ethyl derivative, the preparation method and its usage of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Background technology
Inflammation occurs in part, also can affect whole body simultaneously.Local Clinical symptoms is red, hot, swollen, bitterly and dysfunction.Red, heat is due to due to inflammation local vascular dilation, blood flow accelerate.Swollen is because local inflammation is congested, blood flow composition oozes out and causes.Research and development have the medicine of antiinflammatory action and for alleviating, verify, palliate the agonizing sufferings significant.
There is the problem that toxicity is large, safety is low in the current existing medicine for the treatment of of inflammation, find compound or lead compound and carry out structural modification to obtain its derivant, thereby the potential drug that obtains high-efficiency low-toxicity has important value from natural product.
The compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone the present invention relates to is one and within 2011, delivers (Van Trinh Thi Thanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton.
volume 2011, and 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, obtained O-(nafoxidine base) ethyl derivative of a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, and its inflammatory activity is evaluated, it has inflammatory activity.
Summary of the invention
O-(nafoxidine base) ethyl derivative that the invention discloses a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, its structure is:
O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of the present invention wood ketone Cleistanone can be prepared by method below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) reacts the O-bromoethyl derivant (II) that obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone with glycol dibromide;
(2) the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pyrrolidine generation substitution reaction make O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Further the preparation method of O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in to 10mL benzene, to the tetrabutyl ammonium bromide that adds 0.04g in solution, 50% sodium hydroxide solution of the glycol dibromide of 3.760g and 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reactant liquor is poured in frozen water, used immediately dichloromethane extraction twice, merge organic phase solution; Then to organic phase solution successively water and saturated common salt water washing 3 times, 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 of concentrating elution band 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 wood ketone Cleistanone of 273mg is dissolved in the middle of 20mL acetonitrile, adds wherein the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the pyrrolidine of 1420mg, mixture reflux 8h; After reaction finishes, reactant liquor is poured in frozen water, used equivalent dichloromethane extraction three times, merge organic facies; Water and saturated common salt water washing merge organic facies afterwards successively, then use anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed solvent and 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 faint yellow gluey solid that faint yellow concentrated elution band obtains O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Compound disclosed by the invention can be made pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The application of O-(nafoxidine base) ethyl derivative (III) that the object of this invention is to provide Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone in preparing anti-inflammatory drug.Described inflammation is aseptic inflammation.
The beneficial effect that O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is applied in preparing anti-inflammatory drug is as follows:
First proved O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone there is effective antiinflammatory effect.Adopted mice ear model and rat agar foot swelling model due to classical dimethylbenzene, O-(nafoxidine base) ethyl derivative (III) of observing Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is the antiinflammatory action to laboratory animal within a certain period of time.Research shows:
1, the mice ear due to O-(nafoxidine base) ethyl derivative (III) xylol of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has obvious inhibitory action.
2, to rat agar, foot swelling has obvious inhibitory action to O-(nafoxidine base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
The specific embodiment
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 preparation method of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is delivered with reference to people such as Van Trinh Thi Thanh, 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
Synthesizing of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound I (440mg, 1.00mmol) is dissolved in to 10mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB) (0.04g), 50% sodium hydroxide solution of glycol dibromide (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, used immediately dichloromethane extraction twice, merge organic phase solution.Then to organic phase solution successively water and saturated common salt water washing 3 times, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.(mobile phase is product purification by silica gel column chromatography for crude product: petroleum ether/acetone=100:1, v/v), collect the yellow yellow solid (344mg, 63%) of concentrating elution band to obtain Compound I I.
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)。
13CNMR(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.
Synthesizing of O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound I I (273mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds wherein Anhydrous potassium carbonate (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture reflux 8h.After reaction finishes, reactant liquor is poured in frozen water, used equivalent dichloromethane extraction three times, merge organic facies.Water and saturated common salt water washing merge organic facies afterwards successively, then use anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product for crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1, v/v), collect the faint yellow gluey solid (185.3mg, 69%) that faint yellow concentrated elution band obtains O-(nafoxidine base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
1H?NMR(500MHz,DMSO-d6)δ5.08(s,1H),4.89(s,1H),4.43(s,1H),3.59(s,2H),2.62(s,2H),2.58(s,4H),2.49(s,1H),2.44(s,1H),2.35(s,1H),2.25(s,1H),2.22(s,1H),1.88(s,1H),1.85–1.63(m,6H),1.61–1.52(m,4H),1.44(d,J＝13.7Hz,3H),1.32(dd,J＝19.4,11.7Hz,4H),1.21(d,J＝1.1Hz,2H),1.11(s,6H),0.95(s,1H),0.93(s,12H),0.86–0.78(m,4H).
13C?NMR(125MHz,DMSO-d6)δ216.53(s),154.42(s),105.13(s),74.59(s),66.74(s),59.64(s),55.67(s),54.13(s),52.47(s),50.14(s),47.83(s),45.04(s),43.22(s),41.70(s),40.56(s),40.09(s),39.79(s),38.60(s),37.16(s),36.21(s),34.27(s),32.87(s),28.83(s),27.13(s),25.13(s),24.83(s),24.19(s),23.95(s),20.70(s),18.39(s),17.92(s),14.87(s).
HRMS(ESI):m/z[M+H]
+calcd?for?C
36H
60NO
2:538.4624；found:538.4628。
O-(nafoxidine base) the ethyl derivative antiinflammatory pharmacodynamic study of embodiment 4 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Test material
1. Kunming (KM) plants mice: male, 6 weeks, 18.5-22.5g, was provided by Jiangsu Province's Experimental Animal Center.
2. rat (Wistar): male, weight 140～160g, is provided by Jiangsu Province's Experimental Animal Center.
Test method
1. the effect of O-(nafoxidine base) ethyl derivative (compound III) of gavage Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone to mice ear inflammation: get 50 of weight 18.5～22.5g healthy male mices, be divided at random 3 groups, 10 every group.O-(nafoxidine base) the ethyl derivative 2.5mgkg of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
-1, aspirin group (200mgkg
-1), blank group (normal saline).Difference gastric infusion, continuous 7d, 1h after the 7th day gavage, 3 groups of mices are all evenly coated with dimethylbenzene 0.02mL forward and backward of mouse right ear, prepare auricle inflammatory model.After 1h, mice is put to death in collare dislocation, along auricle baseline, cuts two ears, with diameter 8mm card punch, lays round auricle respectively at the same position of two ears, weighs and is accurate to 0.0001g.With electronic balance, divide another name quality immediately, left and right two ears of usining are of poor quality as swelling, and calculate its swelling and suppression ratio.
Swelling=auris dextra sheet weight-left auricle weight
The average swelling * 100% of suppression ratio=(the average swelling of the average swelling-administration of matched group group)/matched group
2. the effect of O-(nafoxidine base) ethyl derivative to the foot swelling of rat agar of gavage Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone: get 24 of the healthy male Wistar rats of weight 140～160g, be divided at random 3 groups.O-(nafoxidine base) the ethyl derivative 2.5mgkg of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
-1, aspirin group (200mgkg
-1), blank group (normal saline).Gastric infusion respectively, 7d continuously, 1h after the 7th day gavage, the right back foot of rat the swollen acute inflammation model of subcutaneous injection 10g/L agar 0.1mL preparation foot of wasting time, surveys its right back sufficient normal volume with rat foot cubic content measurement instrument.Cause scorching after 1,5,8h measures respectively the right back sufficient volume of each Mus, and calculates swelling.
Result of the test
1, the impact of O-(nafoxidine base) ethyl derivative on mice ear inflammation of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Cause after inflammation, each is organized mouse right ear and occurs at once highly red and swollen phenomenon.Mice ear due to O-(nafoxidine base) the ethyl derivative group xylol of aspirin group and Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone all has obvious inhibitory action, the results are shown in Table 1.
The impact of O-(nafoxidine base) the ethyl derivative xylol induced mice auricle edema of table 1 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compare * P<0.001, * * P<0.001 with model group
2, the impact of O-(nafoxidine base) ethyl derivative administration on the foot swelling of rat agar of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
After injection agar, each organizes rat foot claw all swelling phenomenon to a certain degree.Under perusal, model group swelling is rubescent the most obvious, and slightly swelling is without obvious rubescent phenomenon for aspirin group, and O-(nafoxidine base) the ethyl derivative group of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has swelling without obvious rubescent phenomenon.O-(nafoxidine base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has inhibitory action to rat foot is swollen, in Table 2.
The impact of O-(nafoxidine base) ethyl derivative on rat agar toes swelling of table 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compare * P<0.01 with model group
Conclusion: the mice ear due to O-(nafoxidine base) the ethyl derivative xylol of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone has obvious inhibitory action; To rat agar, foot swelling has obvious inhibitory action to O-(nafoxidine base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.O-(nafoxidine base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone can be for the preparation of anti-inflammatory drug.
The preparation of O-(nafoxidine base) the ethyl derivative tablet of embodiment 5 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood involved in the present invention ketone Cleistanone
Get a kind of in the middle of O-(nafoxidine base) ethyl derivative of 20 grams of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone or its pharmaceutically acceptable salt, add 180 grams of conventional adjuvants preparing tablet, mix, conventional tablet machine is made 1000.
The preparation of O-(nafoxidine base) the derivatized composite capsule of embodiment 6 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood involved in the present invention ketone Cleistanone
Get a kind of in the middle of O-(nafoxidine base) ethyl derivative of 20 grams of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone or its pharmaceutically acceptable salt, add the conventional adjuvant of preparing capsule as 180 grams of starch, mix, encapsulatedly make 1000.
Claims (5)
1. there is O-(nafoxidine base) ethyl derivative and the application of pharmaceutically acceptable salt in anti-inflammatory medicaments thereof of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III,
2. O-(nafoxidine base) ethyl derivative and the application of pharmaceutically acceptable salt in anti-inflammatory medicaments thereof of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1, is characterized by: described inflammation is aseptic inflammation.
3. O-(nafoxidine base) ethyl derivative and the application of pharmaceutically acceptable salt in anti-inflammatory medicaments thereof of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 2, is characterized by: described aseptic inflammation is that chemicals stimulation causes.
4. O-(nafoxidine base) ethyl derivative and the application of pharmaceutically acceptable salt in anti-inflammatory medicaments thereof of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 3, is characterized by: described chemicals is dimethylbenzene.
5. O-(nafoxidine base) ethyl derivative and the application of pharmaceutically acceptable salt in anti-inflammatory medicaments thereof of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 3, is characterized by: described chemicals is agar.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447938A (en) * | 2014-11-05 | 2015-03-25 | 南京大学 | O-(piperazinyl) ethyl derivative of cleistanone, preparation method of O-(piperazinyl) ethyl derivative of cleistanone and use of O-(piperazinyl) ethyl derivative of cleistanone |
| CN104721194A (en) * | 2015-04-15 | 2015-06-24 | 南京大学 | Applications of O-(1H-tetrazole) ethyl derivative of cleistanone in preparing anti-inflammatory drugs |
| CN104825467A (en) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of anti-inflammatory drugs |
| CN104887663A (en) * | 2015-05-12 | 2015-09-09 | 南京广康协生物医药技术有限公司 | Application of daphmalenine A ramification to preparing anti-inflammatory drugs |
-
2014
- 2014-07-31 CN CN201410375097.4A patent/CN104095860B/en not_active Expired - Fee Related
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| VAN TRINH THI THANH, ET AL.: "Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton", 《EUR. J. ORG. CHEM.》, 7 June 2011 (2011-06-07), pages 4108 - 4111 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447938A (en) * | 2014-11-05 | 2015-03-25 | 南京大学 | O-(piperazinyl) ethyl derivative of cleistanone, preparation method of O-(piperazinyl) ethyl derivative of cleistanone and use of O-(piperazinyl) ethyl derivative of cleistanone |
| CN104447938B (en) * | 2014-11-05 | 2016-11-30 | 南京大学 | O-(piperazinyl) ethyl derivative of Cleistanone, preparation method and its usage |
| CN104721194A (en) * | 2015-04-15 | 2015-06-24 | 南京大学 | Applications of O-(1H-tetrazole) ethyl derivative of cleistanone in preparing anti-inflammatory drugs |
| CN104825467A (en) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of anti-inflammatory drugs |
| CN104887663A (en) * | 2015-05-12 | 2015-09-09 | 南京广康协生物医药技术有限公司 | Application of daphmalenine A ramification to preparing anti-inflammatory drugs |
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Inventor after: Chai Guifeng Inventor after: Liang Hui Inventor after: Li Fuyan Inventor after: Zhang Guiying Inventor after: Shao Xiuying Inventor before: Wu Junyi Inventor before: Jiang Chunping Inventor before: Wu Junhua |
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Effective date of registration: 20160224 Address after: 9 first people's Hospital of Qingdao Development Zone, Huangpu Road, Huangdao District, Shandong, Qingdao 266555, China Applicant after: Chai Guifeng Address before: Metro Technology Building No. 69 Olympic Avenue in Jianye District of Nanjing city in Jiangsu province 210019 01 5 storey buildings Applicant before: Nanjing Guangkangxie Biomedical Technology Co., Ltd. |
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