CN105232509A - Composition and application thereof to anti-heart-failure drugs - Google Patents
Composition and application thereof to anti-heart-failure drugs Download PDFInfo
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- CN105232509A CN105232509A CN201510757511.2A CN201510757511A CN105232509A CN 105232509 A CN105232509 A CN 105232509A CN 201510757511 A CN201510757511 A CN 201510757511A CN 105232509 A CN105232509 A CN 105232509A
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Abstract
The invention relates to the fields of organic synthesis and pharmaceutical chemistry, in particular to a composition and application thereof to preparation of anti-heart-failure drugs. The invention discloses the composition and a preparing method thereof. Pharmacology experiments show that the composition has an anti-heart-failure effect and has the value of developing the anti-heart-failure 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
Heart failure (hearfailure, HF) refers to that cardiac function is abnormal and causes heart pump blood volume can not meet a kind of pathological and physiological condition of tissue metabolism's needs.The cause of disease is that cardiac overload, myocardium diastole own are limited, and the initial myocardial damage that any reason causes; And infect, anemia, gestation, childbirth, cardiac arrhythmia, pulmonary infarction, hyperthyroidism, diabetes, suppression heart medicine bring out and increase the weight of HF.Pathogeny thinks that the mechanism that HF occurs to develop is abnormal hemodynamics in the past; The later stage eighties 20th century recognizes that the activation of nerve-endocrine hormone plays an important role (sympathetic ↑ NE ↑ RAS ↑ wait activation); Specify that after the nineties that " Myocardial Remodeling " (remodelling) is the fundamental mechanism causing the generation of heart failure to develop gradually.Heart failure is divided into again acute heart failure and chronic heart failure.
At present for the treatment of heart failure, there is no specific medicament clinically, major part medicine has inevitable toxic and side effects while alleviation symptoms of heart failure, 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-heart failure activity of said composition is evaluated, it is active that it has anti-heart failure.
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 35% and 65%.
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-heart failure effect.Pharmaceutically acceptable salt of the present invention has same drug effect.
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。
The anti-heart failure of embodiment 5 compositions is active
(1) experimental example: compositions is to the therapeutical effect of dog acute heart failure
1 material: animal--healthy adult dog body weight 12.5 ~ 13.5kg.Pentobarbital sodium (Sigma, import subpackage, specification: 25g); Instrument U.S. BIC16 leads physiograph (production of BIC Corp. of the U.S.); Electromagnetic flowmeter (MFV-3200 type): Japanese photoelectricity company produces.
The preparation of compositions: loaded by the powder of 65mg compound IV crossing 200 order nets after crossing the powder of the 35mg 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.
2 test methods and result
Dog is divided at random NS group (waiting capacity solvent), gastric infusion compositions 1.0mg/kg group, compound III 1.0mg/kg group and compound IV 1.0mg/kg group, often organizes 6.Fasting is after 12 hours, and intravenous injection pentobarbital sodium 40mg/kg anaesthetizes, tracheal intubation, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram.Breast is opened in left side, plugs in conduit to left room pressure and rate of pressure change (± dp/dt thereof from the apex of the heart
max).Waltan-Brodie strain bow is implanted left ventricle antetheca, measures myocardial contraction.With electromagnetic flowmeter determination ascending aorta blood flow.Using ascending aorta flow as cardiac output (CO), calculate cardiac index (CI), index (SI) of often fighting, work done (SW) of often fighting, left heart work done (LVW).Parameters record and BIC physiograph.Postoperative half an hour, parameters reaches stable.From femoral vein constant speed gasing injection pentobarbital sodium (0.5mL/kgmin), with ± dp/dt
maxdropping to about 1000mHg/s is that leading indicator forms acute heart failure.After acute heart failure model stability, each treated animal duodenum gives relative medicine.Between group, T inspection, carries out statistical procedures.
Table 1 compositions is on the impact (n=6) of heart failure canine dp/dt
Compare with NS group,
p<0.05
Table 2 compositions is on the impact (n=6) of heart failure canine cardiac work
* p<0.05 is compared with before administration; Compare with NS group
p<0.05
Result is as shown in table 1,2, and compositions significantly can increase SW, the LVW ,+dp/dt (comparing with model group matched group, p<0.05) of Heart Failure Dogs.Compound III and compound IV significantly can not increase SW, the LVW ,+dp/dt of Heart Failure Dogs.
Table 3 compositions is on the kinemic impact of heart failure canine (n=6)
* p<0.05 is compared with before administration; Compare with NS group
p<0.05
Result is as shown in table 3, and compositions significantly can increase the cardiac output (comparing with model control group, p<0.05) of Heart Failure Dogs.Compound III and compound IV significantly can not increase the cardiac output of Heart Failure Dogs.
Conclusion: compositions significantly can improve acute heart failure, can be used for preparing the medicine for the treatment of or preventing acute heart failure.Compound III and compound IV significantly can not improve acute heart failure, should not be used to the medicine preparing treatment or prevention acute heart failure.
(2) experimental example compositions is on the impact of chronic heart failure rat
Test method and result
Rat 50, male and female half and half.10 as Normal group.40 lumbar injection doxorubicin hydrochloride 2mg/kg, 1 time weekly, totally 6 weeks, are divided into 4 groups when the 5th week at random, i.e. normal NS group and 3 gastric infusion 2.5mg/kg groups.Gastric infusion compositions 2.5mg/kg group, compound III 2.5mg/kg group and compound IV 2.5mg/kg group rose at the 5th week and give each group of compositions, compound III and compound IV gavage respectively, administration 21 days every day.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, peeling operation trachea intubate, the total tremulous pulse in right side of simultaneously dissociating, inserts homemade heart catherization (diameter 1mm is full of 1% heparin) through it, traces blood pressure curve; Continue again to insert, make it enter left ventricle by left arterial lobe, trace intraventricular pressure curve, Automatic analysis left ventricular systolic pressure (LVSP), maximum the climbing speed (+dp/dt of intraventricular pressure
max), intraventricular pressure maximum falling speed (-dp/dt
max) and survey the data such as myocardium maximal velocity of contraction (Vpm).Separately get 10 rats as Normal group, do not give doxorubicin hydrochloride, all the other operations are with above-mentioned, and between group, T inspection, carries out statistical procedures.
Table 4 compositions is on the impact (n=10) of chronic heart failure Cardiac Function in Rat
Compare with NS group,
△: p<0.05
Table 4 result of the test shows that compositions 2.5mg/kg significantly can raise the LVSP of the Heart Failure Wistar Rats caused by doxorubicin hydrochloride ,+dp/dt
max,-dp/dt
maxwith the reduction (comparing with NS group, P<0.05) of Vpm; Compound III 2.5mg/kg and compound IV 2.5mg/kg significantly can not raise the LVSP of the Heart Failure Wistar Rats caused by doxorubicin hydrochloride ,+dp/dt
max,-dp/dt
maxwith the reduction of Vpm.
Conclusion: compositions has the effect of significant treatment or preventing chronic heart failure, can be used for preparing the medicine for the treatment of or preventing chronic heart failure.Compound III and compound IV do not have the effect of significant treatment or preventing chronic heart failure, are not available to the medicine preparing treatment or preventing chronic heart failure.
The preparation of embodiment 6 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 7 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 35% and 65%,
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 35% and 65% according to mass percent and fully mix.
3. the application of a kind of compositions as claimed in claim 1 in cardiotonic agents.
4. the application of compositions in cardiotonic agents as claimed in claim 3, is characterized in that: described heart failure is acute heart failure.
5. the application of compositions in cardiotonic agents as claimed in claim 4, is characterized in that: described compositions can increase the heart acting of acute heart failure.
6. the application of a kind of compositions as claimed in claim 4 in cardiotonic agents, is characterized in that: described compositions can increase the cardiac output of acute heart failure.
7. the application of compositions in cardiotonic agents as claimed in claim 3, is characterized in that: described heart failure is chronic heart failure.
8. the application of compositions in cardiotonic agents as claimed in claim 7, is characterized in that: described compositions can increase the left ventricular systolic pressure of chronic heart failure.
9. the application of compositions in cardiotonic agents as claimed in claim 7, is characterized in that: described compositions can increase the maximum climbing speed of intraventricular pressure of chronic heart failure.
10. the application of compositions in cardiotonic agents as claimed in claim 7, is characterized in that: described compositions can increase the myocardium maximal velocity of contraction of chronic heart failure.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038548A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of anti-heart failure drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101367861A (en) * | 2007-08-15 | 2009-02-18 | 中国药科大学 | 2-hydroxyl-3-deoxidized pentacyclic triterpenoid and derivant, preparation method and uses thereof |
-
2015
- 2015-11-09 CN CN201510757511.2A patent/CN105232509A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101367861A (en) * | 2007-08-15 | 2009-02-18 | 中国药科大学 | 2-hydroxyl-3-deoxidized pentacyclic triterpenoid and derivant, preparation method and uses 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 |
|---|---|---|---|---|
| CN106038548A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of anti-heart failure drugs |
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Application publication date: 20160113 |