CN104473937A - Application of O-(imidazole)ethyl derivative of cleistanone in preparation of anti-heart-failure medicine - Google Patents
Application of O-(imidazole)ethyl derivative of cleistanone in preparation of anti-heart-failure medicine Download PDFInfo
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- CN104473937A CN104473937A CN201410758959.1A CN201410758959A CN104473937A CN 104473937 A CN104473937 A CN 104473937A CN 201410758959 A CN201410758959 A CN 201410758959A CN 104473937 A CN104473937 A CN 104473937A
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- imidazole radicals
- ethyl derivative
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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 57
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 92
- 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 description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 241000785597 Cleistanthus Species 0.000 claims description 35
- 150000002576 ketones Chemical class 0.000 claims description 34
- 239000002023 wood Substances 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 12
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 9
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 9
- 239000000496 cardiotonic agent Substances 0.000 claims description 9
- 230000000747 cardiac effect Effects 0.000 claims description 7
- 238000007914 intraventricular administration Methods 0.000 claims description 4
- 230000008602 contraction Effects 0.000 claims description 3
- 210000004165 myocardium Anatomy 0.000 claims description 3
- 230000009194 climbing Effects 0.000 claims description 2
- 230000035488 systolic blood pressure Effects 0.000 claims description 2
- 230000002861 ventricular Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241001597008 Nomeidae Species 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing 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
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229960002275 pentobarbital sodium Drugs 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 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
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229940079593 drug Drugs 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
- 238000007689 inspection Methods 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000012109 statistical procedure Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 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
- 229920002472 Starch Polymers 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
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- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000005622 photoelectricity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- 210000003437 trachea Anatomy 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the fields of organic synthesis and medicinal chemistry, and specifically relates to O-(imidazole)ethyl derivatives of cleistanone, a preparation method of the derivatives, and an application of the derivatives in preparation of an anti-heart-failure medicine. The invention discloses new O-(imidazole)ethyl derivatives of cleistanone and discloses the preparation method of the derivatives. Pharmacological experiments indicate that the O-(imidazole)ethyl derivatives of cleistanone have an anti-heart-failure function and have a value in development of the anti-heart-failure medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O-(imidazole radicals) ethyl derivative, the preparation method and its usage of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Background technology
Heart failure (hear failure, 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.
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.
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 has important value.
The compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume 2011, 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, obtain O-(imidazole radicals) ethyl derivative of a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, 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-(imidazole radicals) ethyl derivative of a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, its structure is:
O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) O-bromoethyl derivant (II) and the imidazoles generation substitution reaction of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtain O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
The preparation method of O-(imidazole radicals) ethyl derivative (III) of further 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 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 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, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant (II) of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 35mL acetonitrile, adds the Anhydrous potassium carbonate of 690mg wherein, the potassium iodide of 252mg and the imidazoles of 870mg, mixture reflux 3h; After reaction terminates, reactant liquor is poured in 45mL 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=100:0.2, v/v, collects brown and concentrates elution band namely to obtain the brown solid of O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, O-(imidazole radicals) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention has good anti-heart failure effect.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 be limited by claim.
Detailed description of the invention
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 people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution 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 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, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
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)。
13C NMR(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.
The synthesis of O-(imidazole radicals) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound II per (273mg, 0.5mmol) is dissolved in the middle of 35mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture reflux 3h.After reaction terminates, reactant liquor is poured in 45mL 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.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:0.2, v/v), collecting brown concentrates elution band namely to obtain the brown solid (157.6mg, 59%) of O-(imidazole radicals) ethyl derivative of Cleistanone.
1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.15(s,1H),6.74(s,1H),4.61(s,1H),4.52(t,J＝33.6Hz,4H),3.86(s,2H),2.63(s,1H),2.34(s,1H),2.22(d,J＝12.3Hz,2H),2.18(s,1H),1.86(s,2H),1.77(s,1H),1.62(d,J＝4.2Hz,3H),1.53(s,1H),1.46(d,J＝5.8Hz,2H),1.41(s,1H),1.35(d,J＝5.7Hz,2H),1.27(s,1H),1.22(t,J＝6.9Hz,3H),1.01(s,6H),0.93(d,J＝12.0Hz,13H),0.84(s,3H),0.76(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.55(s),154.43(s),139.74(s),128.08(s),119.24(s),105.13(s),74.61(s),67.62(s),59.67(s),52.51(s),51.14(s),47.82(s),44.10(d,J＝5.7Hz),42.22(s),41.69(s),40.60(s),40.09(s),38.78(s),38.63(s),37.18(s),36.19(s),33.30(s),32.89(s),29.81(s),27.16(s),26.00(s),24.19(s),23.92(s),20.70(s),18.38(s),17.92(s),16.92(s).
HRMS(ESI):m/z[M+H]
+calcd for C
35H
55N
2O
2 +:535.4264；found:535.4259。
The anti-heart failure of O-(imidazole radicals) ethyl derivative of embodiment 4Cleistanone is active
(1) O-(imidazole radicals) ethyl derivative of experimental example: Cleistanone 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.
2 test methods and result
Dog is divided at random NS group (waiting capacity solvent), O-(imidazole radicals) the ethyl derivative 1.0mg/kg group of gastric infusion Cleistanone, 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.
O-(imidazole radicals) ethyl derivative of table 1Cleistanone is on the impact (n=6) of heart failure canine dp/dt
Compare with NS group,
@p<0.05
O-(imidazole radicals) ethyl derivative of table 2Cleistanone 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 O-(imidazole radicals) ethyl derivative of Cleistanone can increase the SW of Heart Failure Dogs, LVW ,+dp/dt (comparing with model group, p<0.05or p<0.01).O-(imidazole radicals) ethyl derivative of Cleistanone can increase SW, the LVW ,+dp/dt (comparing with model group, p<0.05) of Heart Failure Dogs.
O-(imidazole radicals) ethyl derivative of table 3Cleistanone 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 O-(imidazole radicals) ethyl derivative of Cleistanone can increase the cardiac output (comparing with model group, p<0.05) of Heart Failure Dogs.O-(imidazole radicals) ethyl derivative of Cleistanone can increase the cardiac output (comparing with model group, p<0.05) of Heart Failure Dogs.
O-(imidazole radicals) ethyl derivative of conclusion: Cleistanone significantly can improve acute heart failure, can be used for preparing the medicine for the treatment of or preventing acute heart failure.
(2) O-(imidazole radicals) ethyl derivative of experimental example Cleistanone is on the impact of chronic heart failure rat
Test method and result
Rat 30, male and female half and half.10 as Normal group.20 lumbar injection doxorubicin hydrochloride 2mg/kg, 1 time weekly, totally 6 weeks, are divided into 2 groups when the 5th week at random, i.e. O-(imidazole radicals) the ethyl derivative 2.5mg/kg group of normal NS group and gastric infusion Cleistanone.O-(imidazole radicals) the ethyl derivative 2.5mg/kg group of stomach administration Cleistanone played at the 5th week each group of O-(imidazole radicals) the ethyl derivative gavage giving Cleistanone every day, administration 21 days.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.
O-(imidazole radicals) ethyl derivative of table 4Cleistanone 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 O-(imidazole radicals) the ethyl derivative 2.5mg/kg of Cleistanone 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.
O-(imidazole radicals) ethyl derivative of conclusion: Cleistanone 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-(imidazole radicals) the ethyl derivative tablet of embodiment 5 Cleistanone involved in the present invention
Get the one in the middle of O-(imidazole radicals) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of O-(imidazole radicals) the derivatized composite capsule of embodiment 6 Cleistanone involved in the present invention
Get the one in the middle of O-(imidazole radicals) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (8)
1. one kind has O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III:
2. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized in that: described heart failure is acute heart failure.
3. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 2, is characterized in that: O-(imidazole radicals) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone increases the heart acting of acute heart failure.
4. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 2, is characterized in that: O-(imidazole radicals) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone increases the cardiac output of acute heart failure.
5. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 1, is characterized in that: described heart failure is chronic heart failure.
6. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 5, is characterized in that: O-(imidazole radicals) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone increases the left ventricular systolic pressure of chronic heart failure.
7. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 5, is characterized in that: O-(imidazole radicals) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone increases the maximum climbing speed of intraventricular pressure of chronic heart failure.
8. a kind of O-(imidazole radicals) ethyl derivative and the application of pharmaceutically acceptable salt in cardiotonic agents thereof with the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III as claimed in claim 5, is characterized in that: O-(imidazole radicals) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone increases the myocardium maximal velocity of contraction of chronic heart failure.
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| CHIMMANI RAMESH: "Arylnaphthalide Lignans from Cleistanthus collinus1)", 《CHEM. PHARM. BULL》 * |
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