CN104098644A - O-(piperidinyl) ethyl derivative of Cleistanone as well as preparation method and application thereof - Google Patents
O-(piperidinyl) ethyl derivative of Cleistanone as well as preparation method and application thereof Download PDFInfo
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- CN104098644A CN104098644A CN201410375181.6A CN201410375181A CN104098644A CN 104098644 A CN104098644 A CN 104098644A CN 201410375181 A CN201410375181 A CN 201410375181A CN 104098644 A CN104098644 A CN 104098644A
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- flowers
- piperidyl
- ethyl derivative
- ketone cleistanone
- cleistanone
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- XURLTFUKDPZAPN-QFIPXVFZSA-N Cleistanone Natural products O(C)[C@H]1OC(=O)c2c(-c3cc4OCOc4cc3)c3c(c(O)c12)cc(OC)c(OC)c3 XURLTFUKDPZAPN-QFIPXVFZSA-N 0.000 title claims abstract description 74
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- GEIFQLXIDUDMNZ-PCJVTFPHSA-N (4aR,4bR,6aR,8S,10aR,10bR,12R,12aR)-12-hydroxy-1,1,1',1',4a,10a,10b-heptamethyl-3'-methylidenespiro[3,4,4b,5,6,6a,7,9,10,11,12,12a-dodecahydrochrysene-8,2'-cyclopentane]-2-one Chemical compound CC1(C)CCC(=C)[C@@]11C[C@@H](CC[C@H]2[C@]3(C[C@@H](O)[C@H]4C(C)(C)C(=O)CC[C@@]42C)C)[C@@]3(C)CC1 GEIFQLXIDUDMNZ-PCJVTFPHSA-N 0.000 claims abstract description 50
- 206010019280 Heart failures Diseases 0.000 claims abstract description 22
- 150000002576 ketones Chemical class 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 235000002639 sodium chloride Nutrition 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 230000000747 cardiac effect Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- 238000007914 intraventricular administration Methods 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- 230000008602 contraction Effects 0.000 claims description 3
- 210000004165 myocardium Anatomy 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229960004839 potassium iodide Drugs 0.000 claims description 3
- 235000007715 potassium iodide Nutrition 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000009194 climbing Effects 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000035488 systolic blood pressure Effects 0.000 claims description 2
- 230000002861 ventricular Effects 0.000 claims description 2
- 239000000496 cardiotonic agent Substances 0.000 claims 7
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 241000282465 Canis Species 0.000 description 3
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000785597 Cleistanthus Species 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 230000002107 myocardial effect Effects 0.000 description 2
- 238000012109 statistical procedure Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- SIZYMRQJSFQZSF-UHFFFAOYSA-N CC(C)(CC1)C(CC2)(CC(CC3)C2(C)C(C)(CC2OCCN4CCCCC4)C3C(C)(CC3)C2C(C)(C)C3=O)C1=C Chemical compound CC(C)(CC1)C(CC2)(CC(CC3)C2(C)C(C)(CC2OCCN4CCCCC4)C3C(C)(CC3)C2C(C)(C)C3=O)C1=C SIZYMRQJSFQZSF-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, particularly to an O-(piperidinyl) ethyl derivative of Cleistanone as well as a preparation method for the O-(piperidinyl) ethyl derivative of the Cleistanone and the application of the O-(piperidinyl) ethyl derivative of the Cleistanone in preparing drugs for resisting heart failure. The invention synthesizes a novel O-(piperidinyl) ethyl derivative of the Cleistanone and discloses the preparation method thereof. Pharmacological experiment results show that the O-(piperidinyl) ethyl derivative of the Cleistanone has the function of resisting heart failure and has the value of developing drugs for resisting heart failure.
Description
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry field, be specifically related to close O-(piperidyl) ethyl derivative, the preparation method and its usage of flowers and trees ketone Cleistanone.
Background technology
Heart failure (hear failure, HF) refers to that heart function causes heart pump blood volume can not meet a kind of pathological and physiological condition of tissue metabolism's needs extremely.The cause of disease is that cardiac overload, myocardium diastole own are limited, and the initial myocardial damage that causes of any reason; And infect, anaemia, gestation, childbirth, arrhythmia, pulmonary infarction, hyperthyroidism, diabetes, inhibition 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 is recognized the activation of nerve-endocrine hormone play an important role (sympathetic ↑ NE ↑ RAS ↑ wait activation); After the nineties, clear and definite gradually " Myocardial Remodeling " is (remodelling) fundamental mechanism that causes the generation development of heart failure.Heart failure is divided into again acute heart failure and chronic heart failure.
The current treatment for heart failure, there is no clinically specific medicament, most of medicine has inevitable toxic side effect when alleviating symptoms of heart failure, from natural product, find compound or lead compound and carry out structural modification and obtain its derivative, thereby the potential drug that obtains high-efficiency low-toxicity has important value.
The compound the present invention relates to closes flowers and trees ketone Cleistanone and 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 close flowers and trees ketone Cleistanone to compound and have carried out structural modification, obtained the new O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative, and its anti-heart failure activity is evaluated, it is active that it has anti-heart failure.
Summary of the invention
The invention discloses O-(piperidyl) ethyl derivative that closes flowers and trees ketone Cleistanone, its structure is:
The present invention closes O-(piperidyl) ethyl derivative (III) of flowers and trees ketone Cleistanone and can prepare by method below:
(1) close flowers and trees ketone Cleistanone (I) and react the O-bromotrifluoromethane derivative (II) that obtains closing flowers and trees ketone Cleistanone with glycol dibromide;
(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone makes with piperidines generation substitution reaction O-(piperidyl) ethyl derivative (III) that closes flowers and trees ketone Cleistanone.
The preparation method who further closes O-(piperidyl) ethyl derivative (III) of flowers and trees ketone Cleistanone is:
(1) 440 mg compounds are closed to flowers and trees ketone Cleistanone (I) and be dissolved in 10 mL benzene, to the Tetrabutyl amonium bromide that adds 0.04 g in solution, 50% sodium hydroxide solution of the glycol dibromide of 3.760 g and 6 mL; Mixture stirs 24 h at 25 degrees Celsius; After 24h, reaction solution 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, moving phase is: sherwood oil/acetone=100:1, v/v, collects the yellow yellow solid of concentrating elution band to obtain closing the O-bromotrifluoromethane derivative (II) of flowers and trees ketone Cleistanone.
(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone of 273 mg is dissolved in the middle of 20 mL acetonitriles, adds wherein the Anhydrous potassium carbonate of 345 mg, the piperidines of the potassiumiodide of 84 mg and 852 mg, mixture reflux 16 h; After reaction finishes, reaction solution is poured in 20 mL frozen water, used equivalent dichloromethane extraction three times, merge organic phase; Water and saturated common salt water washing merge organic phase 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, moving phase is: sherwood oil/acetone=100:0.5, v/v, collects yellow yellow colloidal solid 157.0 mg that concentrate elution band to obtain closing O-(piperidyl) ethyl derivative (III) of flowers and trees ketone Cleistanone.
Compound disclosed by the invention can be made pharmacy acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, O-(piperidyl) ethyl derivative (III) that closes flowers and trees ketone Cleistanone of the present invention has good anti-heart failure effect.Pharmacy acceptable salt of the present invention and its compound have same drug effect.
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.
Embodiment
The preparation that embodiment 1 compound closes flowers and trees ketone Cleistanone
Compound closes document (the Van Trinh Thi Thanh et al. that the preparation method of flowers and trees ketone Cleistanone (I) delivers 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.
Embodiment 2 closes O-bromotrifluoromethane derivative (II) synthetic of flowers and trees ketone Cleistanone
Compound I (440 mg, 1.00 mmol) is dissolved in to 10 mL benzene, in solution, adds Tetrabutyl amonium bromide (TBAB) (0.04 g), 50% sodium hydroxide solution of glycol dibromide (3.760 g, 20.00 mmol) and 6 mL.Mixture stirs 24 h at 25 degrees Celsius.After 24h, reaction solution 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.(moving phase is product purification by silica gel column chromatography for crude product: sherwood oil/acetone=100:1, v/v), collect the yellow yellow solid (344 mg, 63%) of concentrating elution band to obtain Compound I I.
1H?NMR(500?MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5?Hz,1H),3.87(d,J＝26.5?Hz,2H),3.57(s,2H),2.40(d,J＝14.0?Hz,1H),2.39(d,J＝14.0?Hz,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＝3.3?Hz,1H),1.54(d,J＝3.3?Hz,1H),1.50(d,J＝1.2?Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3?Hz,2H),1.34(d,J＝15.3?Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0?Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C?NMR(125?MHz,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＝1.1?Hz),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.
Embodiment 3 closes O-(piperidyl) ethyl derivative (III) synthetic of flowers and trees ketone Cleistanone
Compound I I (273 mg, 0.5 mmol) is dissolved in the middle of 20 mL acetonitriles, adds wherein Anhydrous potassium carbonate (345 mg, 2.5 mmol), potassiumiodide (84 mg, 0.5 mmol) and piperidines (852 mg, 10 mmol), mixture reflux 16 h.After reaction finishes, reaction solution is poured in 20 mL frozen water, used equivalent dichloromethane extraction three times, merge organic phase.Water and saturated common salt water washing merge organic phase 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 (moving phase is: sherwood oil/acetone=100:0.5, v/v), collect the yellow yellow colloidal solid (157.0 mg, 57%) of concentrating elution band to obtain O-(piperidyl) ethyl derivative of Cleistanone.
1H?NMR(500?MHz,DMSO-d6)δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,2H),2.57(s,2H),2.47(dd,J＝44.3,41.4?Hz,6H),2.29(s,1H),2.22(s,1H),2.19(s,1H),1.82(s,1H),1.65(s,2H),1.58(d,J＝8.0?Hz,2H),1.53–1.46(m,6H),1.39(t,J＝7.8?Hz,5H),1.30(dd,J＝21.8,9.9?Hz,4H),1.16(d,J＝0.4?Hz,2H),1.06(s,6H),0.91(s,1H),0.88(s,12H),0.85–0.57(m,4H).
13C?NMR(125?MHz,DMSO-d6)δ216.69(s),154.70(s),105.53(s),74.75(s),67.02(s),59.85(s),55.00(d,J＝14.4?Hz),52.87(s),51.30(s),48.09(s),44.44(s),42.38(s),41.98(s),40.93(s),40.25(s),39.07(s),38.99(s),37.34(s),36.48(s),33.66(s),33.05(s),30.10(s),27.52(s),26.16(s),24.80(s),24.59(s),24.06(s),23.65(s),21.05(s),18.56(s),18.21(s),17.28(s).
HRMS(ESI):m/z[M+H]
+calcd?for?C
37H
62NO
2:552.4781；found:552.4787。
The anti-heart failure of O-(piperidyl) ethyl derivative of embodiment 4 Cleistanone is active
(1) therapeutic action of the O-of experimental example: Cleistanone (piperidyl) ethyl derivative to dog acute heart failure
1 material: animal--healthy adult dog body weight 12.5～13.5 kg.Vetanarcol (Sigma, import packing, specification: 25g); Instrument U.S. BIC16 leads physiograph (production of U.S. BIC Corp.); Magnetic flow meter (MFV-3200 type): Japanese photoelectricity company produces.
2 test methods and result
Dog is divided into NS group (waiting capacity solvent) at random, the O-of gastric infusion Cleistanone (piperidyl) ethyl derivative 1.0 mg/kg groups, 6 every group.After fasting 12 hours, the 40 mg/kg anesthesia of intravenous injection vetanarcol, trachea cannula, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram(ECG.Left side opening chest, plugs in conduit to left constant pressure and rate of pressure change (± dp/dt thereof from the apex of the heart
max).Waltan-Brodie strain bow is implanted to left ventricle antetheca, measure myocardial contraction.With electromagnetic flowmeter determination aorta ascendens volume of blood flow.Using aorta ascendens flow as cardiac output (CO), calculate cardiac index (CI), the index (SI) of often fighting, the work done (SW) of often fighting, left heart work done (LVW).Parameters record and BIC physiograph.Postoperative half an hour, it is stable that parameters reaches.From femoral vein constant speed gasing injection vetanarcol (0.5 mL/kgmin), with ± dp/dt
maxdropping to approximately 1000 mHg/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 check, carries out statistical procedures.
The O-of table 1 Cleistanone (piperidyl) ethyl derivative is on the impact of heart failure canine dp/dt (n=6, X ± s)
Compare with NS group,
@p<0.05,
@@p<0.01
The O-of table 2 Cleistanone (piperidyl) ethyl derivative is on the impact of heart failure canine cardiac work (n=6, X ± s)
With comparison * p<0.05 before administration, * * p<0.01; Compare with NS group
@p<0.05,
@@p<0.01
Result is as shown in table 1,2, and the O-of Cleistanone (piperidyl) ethyl derivative can increase SW, the LVW ,+dp/dt (with the comparison of model group control group, p<0.05or p<0.01) of Heart Failure Dogs.The O-of Cleistanone (piperidyl) ethyl derivative can increase SW, the LVW ,+dp/dt (with the comparison of model group control group, p<0.01or p<0.05) of Heart Failure Dogs.
The O-of table 3 Cleistanone (piperidyl) ethyl derivative is on the kinemic impact of heart failure canine (n=6, X ± s)
With comparison * p<0.05 before administration, * * p<0.01; Compare with NS group
@p<0.05,
@@p<0.01
Result is as shown in table 3, and the O-of Cleistanone (piperidyl) ethyl derivative can increase the cardiac output (with model control group comparison, p<0.01or p<0.05) of Heart Failure Dogs.The O-of Cleistanone (piperidyl) ethyl derivative can increase the cardiac output (with model control group comparison, p<0.01or p<0.05) of Heart Failure Dogs.
The O-of conclusion: Cleistanone (piperidyl) ethyl derivative can significantly improve acute heart failure, can be used for preparing the medicine for the treatment of or prophylaxis of acute heart failure.
(2) impact of the O-of experimental example Cleistanone (piperidyl) ethyl derivative on chronic heart failure rat
Test method and result
30 of rats, male and female half and half.10 as Normal group.20 abdominal injection doxorubicin hydrochloride 2mg/kg, 1 time weekly, totally 6 weeks, are divided into 2 groups in the time of the 5th week, i.e. O-(piperidyl) the ethyl derivative 2.5mg/kg group of normal NS group and gastric infusion Cleistanone at random.O-(piperidyl) the ethyl derivative 2.5mg/kg group of stomach administration Cleistanone played each group of O-(piperidyl) ethyl derivative gavage that gives Cleistanone every day, administration 21 days at the 5th week.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, peeling operation tracheae intubate, the total artery in right side that simultaneously dissociates, inserts homemade ventricle intubate (diameter 1mm is full of 1% heparin) through it, traces blood pressure curve; Continue again to insert, make it by left side arterial valve, enter left ventricle, 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 operate with above-mentioned, and between group, T check, carries out statistical procedures.
The O-of table 4 Cleistanone (piperidyl) ethyl derivative is on the impact of chronic heart failure Cardiac Function in Rat (n=10)
Compare with NS group,
△: p<0.05,
△ △: p<0.01
Table 4 test-results shows can significantly the raise LVSP of the Heart Failure Wistar Rats that caused by doxorubicin hydrochloride of O-(piperidyl) the ethyl derivative 2.5mg/kg of Cleistanone ,+dp/dt
max,-dp/dt
max(compare with NS group, P<0.01) with the reduction of Vpm.
The O-of conclusion: Cleistanone (piperidyl) ethyl derivative 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.
The preparation of O-(piperidyl) the ethyl derivative tablet of embodiment 5 Cleistanone involved in the present invention
Get a kind of in the middle of O-(piperidyl) ethyl derivative of 20 grams of Cleistanone or its pharmacy acceptable salt, add 180 grams of conventional auxiliary materials preparing tablet, mix, conventional tabletting machine is made 1000.
The preparation of O-(piperidyl) the derivatized composite capsule of embodiment 6 Cleistanone involved in the present invention
Get a kind of in the middle of O-(piperidyl) ethyl derivative of 20 grams of Cleistanone or its pharmacy acceptable salt, add the conventional auxiliary material of preparing capsule as 180 grams of starch, mix, encapsulatedly make 1000.
Claims (10)
1. the O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and a pharmacy acceptable salt thereof with structure shown in formula III:
。
2. the preparation method who closes O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone as claimed in claim 1, is characterized by:
(1) close flowers and trees ketone Cleistanone (I) and react the O-bromotrifluoromethane derivative (II) that obtains closing flowers and trees ketone Cleistanone with glycol dibromide;
(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone makes with piperidines generation substitution reaction O-(piperidyl) ethyl derivative (III) that closes flowers and trees ketone Cleistanone.
。
3. the preparation method who closes O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone as claimed in claim 2, is characterized by:
(1) 440 mg compounds are closed to flowers and trees ketone Cleistanone (I) and be dissolved in 10 mL benzene, to the Tetrabutyl amonium bromide that adds 0.04 g in solution, 50% sodium hydroxide solution of the glycol dibromide of 3.760 g and 6 mL; Mixture stirs 24 h at 25 degrees Celsius; After 24h, reaction solution 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, moving phase is: sherwood oil/acetone=100:1, v/v, collects the yellow yellow solid of concentrating elution band to obtain closing the O-bromotrifluoromethane derivative (II) of flowers and trees ketone Cleistanone.
(2) the O-bromotrifluoromethane derivative (II) that closes flowers and trees ketone Cleistanone of 273 mg is dissolved in the middle of 20 mL acetonitriles, adds wherein the Anhydrous potassium carbonate of 345 mg, the piperidines of the potassiumiodide of 84 mg and 852 mg, mixture reflux 16 h; After reaction finishes, reaction solution is poured in 20 mL frozen water, used equivalent dichloromethane extraction three times, merge organic phase; Water and saturated common salt water washing merge organic phase 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, moving phase is: sherwood oil/acetone=100:0.5, v/v, collects yellow yellow colloidal solid 157.0 mg that concentrate elution band to obtain closing O-(piperidyl) ethyl derivative (III) of flowers and trees ketone Cleistanone.
4. O-(piperidyl) ethyl derivative (III) and the application of pharmacy acceptable salt in cardiotonic agents thereof of closing flowers and trees ketone Cleistanone as claimed in claim 1.
5. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 4, is characterized in that: described heart failure is acute heart failure.
6. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 5, is characterized in that: described in close the heart acting that O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone and pharmacy acceptable salt thereof increase acute heart failure.
7. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 5, is characterized in that: described in close the cardiac output that O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone and pharmacy acceptable salt thereof increase acute heart failure.
8. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 4, is characterized in that: described heart failure is chronic heart failure.
9. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 8, is characterized in that: described in close the left ventricular systolic pressure that O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone and pharmacy acceptable salt thereof increase chronic heart failure.
10. a kind of O-that closes flowers and trees ketone Cleistanone (piperidyl) ethyl derivative and the application of pharmacy acceptable salt in cardiotonic agents thereof with structure shown in formula III as claimed in claim 8, is characterized in that: described in close the maximum climbing speed of intraventricular pressure and the myocardium maximal velocity of contraction that O-(piperidyl) ethyl derivative of flowers and trees ketone Cleistanone and pharmacy acceptable salt thereof increase chronic heart failure.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
| 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 |
| 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 |
Citations (1)
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| CN103923157A (en) * | 2014-04-04 | 2014-07-16 | 海南师范大学 | Preparation method of drypetes congestiflora stem extract |
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| CN103923157A (en) * | 2014-04-04 | 2014-07-16 | 海南师范大学 | Preparation method of drypetes congestiflora stem extract |
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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》 * |
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 |
| CN104447938B (en) * | 2014-11-05 | 2016-11-30 | 南京大学 | O-(piperazinyl) ethyl derivative of Cleistanone, preparation method and its usage |
| CN104402964A (en) * | 2014-12-10 | 2015-03-11 | 南京大学 | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof |
| 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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