CN104083378B - The application in preparing cardiotonic agents of the dimethylamine derivative of Cleistanone Cleistanone - Google Patents
The application in preparing cardiotonic agents of the dimethylamine derivative of Cleistanone Cleistanone Download PDFInfo
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- CN104083378B CN104083378B CN201410290719.3A CN201410290719A CN104083378B CN 104083378 B CN104083378 B CN 104083378B CN 201410290719 A CN201410290719 A CN 201410290719A CN 104083378 B CN104083378 B CN 104083378B
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone derivant, preparation method and in the purposes preparing on cardiotonic agents.The present invention has synthesized a new Cleistanone Cleistanone derivant, and discloses its preparation method.Pharmacological experiment shows, the Cleistanone Cleistanone derivant of the present invention has anti-heart failure effect, has the value of exploitation cardiotonic agents.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone derivant, preparation method and its usage.
Background technology
Heart failure (hearfailure, HF) refers to that cardiac function is abnormal and causes that 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 is it is considered that the mechanism that development occurs HF is abnormal hemodynamics；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 that development occurs causing heart failure 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 alleviating 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 has important value most.
The compound Cleistanone Cleistanone that the present invention relates to is one and delivers (VanTrinhThiThanhetal., 2011.Cleistanone:ATriterpenoidfromCleistanthusindochinen siswithaNewCarbonSkeleton. in 2011Volume2011,Issue22,Pages4108 4111, August2011) compound, compound Cleistanone Cleistanone has been carried out structural modification by us, it is thus achieved that a new Cleistanone Cleistanone derivant, and its anti-heart failure activity has been evaluated, it has anti-heart failure activity.
Summary of the invention
The invention discloses a Cleistanone Cleistanone derivant, its structure is:
Cleistanone Cleistanone derivant (III) of the present invention can be prepared by following method:
(1) Cleistanone Cleistanone (I) and glycol dibromide are obtained by reacting O-bromoethyl derivant (II) of Cleistanone Cleistanone；
(2) O-bromoethyl derivant (II) of Cleistanone Cleistanone prepares Cleistanone Cleistanone derivant (III) with dimethylamine generation substitution reaction.
The preparation method of further Cleistanone Cleistanone derivant (III) is:
(1) 440mg compound Cleistanone 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 to organic phase solution successively with water and saturated common salt water washing 3 times, then drying with anhydrous sodium sulfate, 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 solid that namely yellow concentration elution band obtains O-bromoethyl derivant (II) of Cleistanone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanone Cleistanone of 273mg being dissolved in the middle of 20mL acetonitrile, be added thereto to the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the dimethylamine of 900mg, mixture is heated to reflux 16h；Reactant liquor is poured in frozen water after terminating by reaction, with equivalent dichloromethane extraction three times, merges organic facies；Organic facies after merging with water and saturated common salt water washing successively, then dry with anhydrous sodium sulfate, 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 faint yellow concentration elution band and namely obtains the faint yellow solid of Cleistanone Cleistanone derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, Cleistanone Cleistanone derivant (III) of the present invention has good anti-heart failure effect.The pharmaceutically acceptable salt of the present invention has same drug effect with its compound.
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 is defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanone Cleistanone
The preparation method of compound Cleistanone (I) is with reference to VanTrinhThiThanh et al. document (VanTrinhThiThanhetal. delivered, 2011.Cleistanone:ATriterpenoidfromCleistanthusindochinen siswithaNewCarbonSkeleton.Volume2011, Issue22, pages4108 4111, August2011) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Cleistanone Cleistanone
By compound I (440mg, 1.00mmol) it is dissolved in 10mL benzene, in solution, adds 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 to organic phase solution successively with water and saturated common salt water washing 3 times, then drying with anhydrous sodium sulfate, 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 yellow and concentrates elution band namely to obtain the yellow solid (344mg, 63%) of Compound II per.
null1HNMR(500MHz,DMSO-d6)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).
null13CNMR(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]+calcdforC32H52BrO2:547.3151；found547.3159.
The synthesis of O-(dimethylamino) ethyl derivative (III) of embodiment 3 Cleistanone Cleistanone
Compound II per (273mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to Anhydrous potassium carbonate (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and dimethylamine (900mg, 20mmol), mixture is heated to reflux 16h.Reactant liquor is poured in frozen water after terminating by reaction, with equivalent dichloromethane extraction three times, merges organic facies.Organic facies after merging with water and saturated common salt water washing successively, then dry with anhydrous sodium sulfate, 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 faint yellow concentration elution band and namely obtains the faint yellow solid (160.7mg, 61%) of Compound II per I.
null1HNMR(500MHz,DMSO-d6)δ5.02(s,1H),4.81(s,1H),3.85(s,1H),3.51(s,2H),2.84(s,6H),2.64(s,2H),2.38(d,J=13.0Hz,2H),2.26(s,1H),2.17(s,1H),2.17(s,1H),1.83(s,1H),1.66(s,2H),1.54(d,J=6.0Hz,2H),1.46(d,J=0.9Hz,2H),1.34(d,J=13.5Hz,3H),1.26(dd,J=31.1,13.9Hz,4H),1.16(d,J=13.5Hz,2H),1.07(s,6H),0.98(s,1H),0.85(s,12H),0.76(s,3H),0.73(s,1H).
13CNMR(125MHz,DMSO-d6)δ216.60(s),154.51(s),105.19(s),74.62(s),65.68(s),59.75(s),57.63(s),52.57(s),51.18(s),47.87(s),45.54(s),44.12(s),42.29(s),41.79(s),40.62(s),40.12(s),38.82(s),38.67(s),37.25(s),36.29(s),33.32(s),32.92(s),29.85(s),27.20(s),26.07(s),24.29(s),23.94(s),20.73(s),18.42(s),18.00(s),16.97(s).
HRMS(ESI):m/z[M+H]+calcdforC34H58NO2:512.4468；found:512.4463.
The preparation of embodiment 4 Compound II per involved in the present invention and III tablet
Taking the one in the middle of 20 g of compound II or III or its pharmaceutically acceptable salt, the customary adjuvant 180 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 1000.
The preparation of embodiment 5 Compound II per involved in the present invention and III capsule:
Taking the one in the middle of 20 g of compound II or III or its pharmaceutically acceptable salt, customary adjuvant such as starch 180 grams of capsule are prepared in addition, mixing, encapsulated make 1000.
The anti-heart failure activity of O-(dimethylamino) ethyl derivative (III) of embodiment 6 Cleistanone Cleistanone
(1) experimental example: the Compound II per I therapeutical effect to 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.
2 test methods and result
Dog is randomly divided into NS group (waiting capacity solvent), gastric infusion Compound II per I1.0mg/kg group, often group 6.After fasting 12 hours, intravenous injection pentobarbital sodium 40mg/kg anaesthetizes, tracheal intubation, artificial respiration, monitors aortic pressure (AP) and electrocardiogram.Breast is opened in left side, from the plug in conduit of the apex of the heart to left chamber pressure and rate of pressure change (± dp/dt thereofmax).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/kg min), with ± dp/dtmaxDropping 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.
The table 1 Compound II per I impact (n=6, X ± s) on heart failure canine dp/dt
Compare with NS group,P < 0.05,p<0.01
The table 2 Compound II per I impact (n=6, X ± s) on heart failure canine cardiac work
Compare with before administration*P < 0.05,**p<0.01；Compare with NS groupP < 0.05,p<0.01
Result is such as shown in table 1,2, and Compound II per I can increase the SW of Heart Failure Dogs, LVW ,+dp/dt (comparing, p < 0.05orp < 0.01) with model group matched group.Compound II per I can increase the SW of Heart Failure Dogs, LVW ,+dp/dt (comparing, p < 0.01orp < 0.05) with model group matched group.
Table 3 Compound II per I is on the kinemic impact of heart failure canine (n=6, X ± s)
Compare with before administration*P < 0.05,**p<0.01；Compare with NS groupP < 0.05,p<0.01
Result is as shown in table 3, and Compound II per I can increase the cardiac output (comparing, p < 0.01orp < 0.05) of Heart Failure Dogs with model control group.Compound II per I can increase the cardiac output (comparing, p < 0.01orp < 0.05) of Heart Failure Dogs with model control group.
Conclusion: Compound II per I can significantly improve acute heart failure, it is possible to be used for the medicine preparing treatment or prevention acute heart failure.
(2) the experimental example Compound II per I impact on chronic heart failure rat
Test method and result
Rat 30, male and female half and half.10 are only used as Normal group.20 lumbar injection doxorubicin hydrochloride 2mg/kg, 1 time weekly, totally 6 weeks, are randomly divided into 2 groups when the 5th week, i.e. normal NS group and gastric infusion Compound II per I2.5mg/kg group.Stomach administration Compound II per I2.5mg/kg group rose at the 5th week and gives each group of Compound II per I gavage every day, was administered 21 days.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, peeling operation trachea also intubates, the total tremulous pulse in right side of simultaneously dissociating, and inserts homemade heart catherization (diameter 1mm is full of 1% heparin) through it, traces blood pressure curve；It is further continued for inserting so that it is 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 pressuremax), intraventricular pressure maximum falling speed (-dp/dtmax) and survey the data such as cardiac muscle maximal velocity of contraction (Vpm).Separately taking 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.
The table 4 Compound II per I impact (n=10) on chronic heart failure Cardiac Function in Rat
Compare with NS group,△: p < 0.05,△△: p < 0.01
Table 4 result of the test shows that Compound II per I2.5mg/kg can significantly raise the LVSP ,+dp/dt of the Heart Failure Wistar Rats caused by doxorubicin hydrochloridemax,-dp/dtmaxReduction (comparing with NS group, P < 0.01) with Vpm.
Conclusion: Compound II per I has the effect of significant treatment or preventing chronic heart failure, it is possible to be used for preparing the medicine for the treatment of or preventing chronic heart failure.
Claims (8)
1. there is Cleistanone Cleistanone derivant and the pharmaceutically acceptable salt application in preparing cardiotonic agents thereof of structure shown in formula III,
2. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 1, it is characterised in that: described heart failure is acute heart failure.
3. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 2, it is characterised in that: the heart acting of acute heart failure can be increased.
4. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 2, it is characterised in that: the cardiac output of acute heart failure can be increased.
5. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 1, it is characterised in that: described heart failure is chronic heart failure.
6. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 5, it is characterised in that: the left ventricular systolic pressure of chronic heart failure can be increased.
7. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 5, it is characterised in that: the maximum climbing speed of intraventricular pressure of chronic heart failure can be increased.
8. a kind of Cleistanone Cleistanone derivant with structure shown in formula III and pharmaceutically acceptable salt application in preparing cardiotonic agents thereof as claimed in claim 5, it is characterised in that: the myocardium maximal velocity of contraction of chronic heart failure can be increased.
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| CN104814968A (en) * | 2015-04-15 | 2015-08-05 | 南京广康协生物医药技术有限公司 | Application of 0-(1H-tetrazole)ethyl derivative of Cleistanone to preparation of anti-heart-failure medicine |
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Non-Patent Citations (2)
| Title |
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| Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton;Van Trinh Thi Thanh 等;《European Journal Organic Chemistry》;20111231;第2011卷(第22期);4108–4111 * |
| 熊果酸及五环三萜同类物的研究进展;李宏杨等;《湖南工业大学学报》;20090930;第23卷(第5期);18-22、51 * |
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