CN105287586A - Composition and application of composition to anti-heart-failure drugs - Google Patents
Composition and application of composition to anti-heart-failure drugs Download PDFInfo
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- CN105287586A CN105287586A CN201510746019.5A CN201510746019A CN105287586A CN 105287586 A CN105287586 A CN 105287586A CN 201510746019 A CN201510746019 A CN 201510746019A CN 105287586 A CN105287586 A CN 105287586A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a composition and an application of the composition to preparation of anti-inflammatory drugs. According to the composition and a preparation method of the composition, pharmacology experiments show that the composition achieves the anti-heart-failure effect, and has the value for 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 (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-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 25% and 75%.
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 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-(piperidyl) ethyl derivative (III) of embodiment 3Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and piperidines (852mg, 10mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in 20mL 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.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 (118.76mg, 63%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ13.93(s,1H),δ6.13(s,1H),5.83(s,1H),4.74(s,1H),4.64(s,1H),3.97(s,1H),3.56(s,2H),2.71(s,1H),2.61(s,2H),2.51(d,J＝4.4Hz,4H),2.46(s,4H),2.16(s,1H),1.69(s,3H),1.55(d,J＝13.5Hz,6H),1.44(d,J＝12.0Hz,3H),1.03(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.95(s),175.95(s),149.17(s),148.18(s),117.10(s),109.45(s),81.87(s),67.09(s),57.73(s),54.60(d,J＝12.4Hz),41.31(s),39.09(s),38.87(s),35.72(s),30.78(s),24.60(s),23.47(s),20.46(s),18.45(s).
HRMS(ESI):m/z[M+H]
+calcdforC
22H
36NO
4:378.2644；found:378.2639。
The synthesis of O-(morpholinyl) ethyl derivative (IV) of embodiment 4Artalbicacid
Compound II per (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and morpholine (1742mg, 20mmol), mixture reflux 6h.After reaction terminates, reactant liquor is poured in 30mL 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.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 (108.0mg, 57%) that namely solvent obtains compound IV.
1HNMR(500MHz,DMSO-d6)δ16.75(s,1H),δ6.13(dt,J＝4.0,1.9Hz,1H),5.83(dt,J＝3.9,1.8Hz,1H),4.79–4.68(m,2H),4.68–4.59(m,1H),3.58(dt,J＝15.2,8.1Hz,6H),2.79–2.38(m,11H),2.03(dd,J＝24.7,17.8Hz,1H),1.70(t,J＝2.0Hz,3H),1.50(ddd,J＝20.4,17.8,4.5Hz,3H),1.02(s,3H).
13CNMR(125MHz,DMSO-d6)δ201.95(s),175.95(s),149.18(s),148.19(s),117.12(s),109.45(s),81.88(s),67.10(s),66.88(s),57.72(s),54.57(s),53.02(s),41.31(s),39.09(s),38.90(s),35.72(s),30.78(s),20.47(s),18.46(s).
HRMS(ESI):m/z[M+H]
+calcdforC
21H
34NO
5:380.2437；found:380.2431。
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 75mg compound IV crossing 200 order nets after crossing the powder of the 25mg 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 25% and 75%,
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 25% and 75% 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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| Application Number | Priority Date | Filing Date | Title |
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| CN201510746019.5A CN105287586A (en) | 2015-11-05 | 2015-11-05 | Composition and application of composition to anti-heart-failure drugs |
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| CN201510746019.5A CN105287586A (en) | 2015-11-05 | 2015-11-05 | Composition and application of composition to anti-heart-failure drugs |
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- 2015-11-05 CN CN201510746019.5A patent/CN105287586A/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》 * |
| 文宏: "双氢青蒿素对肺动脉高压干预作用的实验研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
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