CN105920007A - Applications of composition of Virosaine A piperazinyl derivative and Virosaine A imidazolyl derivative in medicines for resisting heart failure - Google Patents
Applications of composition of Virosaine A piperazinyl derivative and Virosaine A imidazolyl derivative in medicines for resisting heart failure Download PDFInfo
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- CN105920007A CN105920007A CN201610279939.5A CN201610279939A CN105920007A CN 105920007 A CN105920007 A CN 105920007A CN 201610279939 A CN201610279939 A CN 201610279939A CN 105920007 A CN105920007 A CN 105920007A
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- 239000000203 mixture Substances 0.000 title claims abstract description 54
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 16
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 16
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 10
- 206010007556 Cardiac failure acute Diseases 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 230000000747 cardiac effect Effects 0.000 claims description 6
- 210000004165 myocardium Anatomy 0.000 claims description 5
- 238000007914 intraventricular administration Methods 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 230000009194 climbing Effects 0.000 claims description 2
- 230000008602 contraction Effects 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 8
- 230000007423 decrease Effects 0.000 claims 2
- 230000001154 acute effect Effects 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000012043 crude product 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
- FSDTUOKRYYZAQY-AEAJCJRFSA-N (1S,6S,8R,9R,12S,15R)-8-hydroxy-5,10-dioxa-11-azapentacyclo[7.6.0.02,6.06,12.011,15]pentadec-2-en-4-one Chemical compound O[C@@H]([C@@H]1ON23)C[C@@]45[C@@H]3CC[C@@H]2[C@@H]1C4=CC(=O)O5 FSDTUOKRYYZAQY-AEAJCJRFSA-N 0.000 description 3
- 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 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229960002275 pentobarbital sodium Drugs 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound 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 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 240000007003 Flueggea virosa Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 241000867909 Securinega Species 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
- 229930013930 alkaloid Natural products 0.000 description 2
- 210000000709 aorta Anatomy 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
- 238000011161 development Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 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
- 210000005240 left ventricle Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 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
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000037005 anaesthesia Effects 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
- 239000000919 ceramic Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960004679 doxorubicin Drugs 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
- 239000000284 extract Substances 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
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 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
- 238000000034 method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000005622 photoelectricity Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (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 pharmaceutical chemistry, and in particular relates to a composition and applications of the composition in preparing medicines for resisting heart failure. The invention discloses the composition and a preparation method of the composition. The pharmacological experiment proves that the composition provided by the invention has the effect of resisting heart failure, and has the value of being developed into the medicines for resisting heart failure.
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 (hear failure, HF) refers to that cardiac function is abnormal and causes heart pump blood volume can not meet tissue metabolism's need
A kind of pathological and physiological condition wanted.The cause of disease is that cardiac overload, myocardium diastole own are limited, and any reason cause initial
Myocardial damage；And infect, anemia, gestation, childbirth, cardiac arrhythmia, pulmonary infarction, hyperthyroidism, diabetes, suppression heart medicine induction increase the weight of
HF.Pathogeny is it is considered that the mechanism that HF occurs development is abnormal hemodynamics；The later stage eighties 20th century recognizes god
The activation of warp-endocrine hormone plays an important role (sympathetic ↑ NE ↑ RAS ↑ wait activation)；" cardiac muscle weight is gradually specify that after the nineties
Mould " (remodelling) be cause heart failure occur development fundamental mechanism.Heart failure is divided into again acute heart failure and chronic heart failure.
At present for the treatment of heart failure, not having specific medicament clinically, major part medicine is while alleviating symptoms of heart failure
There is inevitable toxic and side effects, from natural product, find compound or lead compound and carry out structural modification and obtain it
Derivant, thus the potential drug obtaining high-efficiency low-toxicity most has important value.
The compound I that the present invention relates to be one within 2012, deliver (Bing-Xin Zhao et al.,
2012.Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an
Unprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–
3099) compound, we have carried out structural modification to compound I, it is thus achieved that two new derivants i.e. compound III and changes
Compound IV, and it is prepared for compositions with compound III and compound IV and heart failure activity anti-to said composition is evaluated,
It has anti-heart failure activity.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, said composition
The mass percent of middle compound III and compound IV is respectively 65% and 35%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositions of the present invention has preferable anti-heart failure effect.The present invention pharmaceutically can connect
The salt being subject to 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 concrete real
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Virosaine A
Document (the Bing-that the preparation method of compound Virosaine A (I) is delivered with reference to Bing-Xin Zhao et al.
Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped Securinega
Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic Letters
14 (2012) 3,096 3099) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2Virosaine A
Compound I (235mg, 1.00mmol) is dissolved in 20mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB)
(0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 5mL.Mixture is Celsius 35
Degree stirring 8h.After 8h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Washing organic phase solution 3 times with water and saturated aqueous common salt successively, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed molten
Agent obtains product crude product.Product crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), receives
Collection brown is concentrated elution band and flings to solvent and i.e. obtain the brown ceramic powder (261mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H),
3.43 (s, 2H), 3.33 (s, 1H), 2.26 (s, 1H), 1.58 (d, J=9.8Hz, 3H), 1.41 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81
(s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
The synthesis of O-(piperazinyl) ethyl derivative (III) of embodiment 3Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (168mg, 1.0mmol) and Piperazine anhydrous (3446mg, 40mmol), mixture is heated to reflux 3h.Reaction
After end, reactant liquor is poured in frozen water, extract 2 times with equivalent dichloromethane, merge organic facies.Successively with water and saturated common salt
Organic facies after water washing merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates elution band and wave
Solvent is gone i.e. to obtain the Light brown solid (123.2mg, 71%) of compound III.
1H NMR(500MHz,DMSO-d6)δ5.90(s,1H),4.04(s,1H),3.59(s,1H),3.50(s,2H),
(3.40 d, J=65.9Hz, 1H), 2.64 (s, 4H), 2.54 (s, 2H), 2.31 (s, 4H), 2.22 (s, 1H), 1.62 (s, 2H),
1.56(s,1H),1.43(s,2H),0.97(s,1H).
13C NMR(125MHz,DMSO-d6)δ171.84(s),106.72(s),79.94(s),74.33(s),66.72(d,
J=9.2Hz), 54.45 (s), 54.16 (s), 45.25 (s), 44.20 (s), 35.56 (s), 25.86 (s), 21.87 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H26N3O4:348.1923；found:348.1927.
The synthesis of O-(imidazole radicals) ethyl derivative (IV) of embodiment 4Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 25mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture is heated to reflux 2h.Reaction terminates
After reactant liquor is poured in 25mL frozen water, with equivalent dichloromethane extract 3 times, merge organic facies.Successively with water and saturated common salt
Organic facies after water washing merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:0.3, v/v), collects brown and concentrates elution band and wave
Solvent is gone i.e. to obtain the Light brown solid (144.1mg, 71%) of compound IV.
1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.12(s,1H),6.71(s,1H),5.99(s,1H),
4.09 (s, 1H), 3.89 (d, J=16.4Hz, 2H), 3.80 (s, 2H), 3.58 (s, 1H), 3.35 (s, 1H), 2.31 (s, 1H),
1.68(s,1H),1.58(s,2H),1.44(s,2H).
13C NMR(125MHz,DMSO-d6)13C NMR(125MHz,Common NMR Solvents)δ171.82(s),
139.64(s),128.67(s),119.31(s),106.70(s),79.92(s),74.31(s),67.61(s),66.66(s),
44.20(s),43.75(s),35.52(s),25.85(s),21.86(s).
HRMS(ESI):m/z[M+H]+calcd for C17H20N3O4:330.1454；found:330.1458.
Embodiment 5 compositions anti-heart failure activity
(1) experimental example: the compositions therapeutical effect to dog acute heart failure
1 material: animal--healthy adult dog body weight 12.5～13.5kg.Pentobarbital sodium (Sigma, import subpackage, rule
Lattice: 25g)；Instrument U.S. BIC16 leads physiograph (production of BIC Corp. of the U.S.)；Electromagnetic flowmeter (MFV-3200 type): day
This photoelectricity company produces.
The preparation of compositions: the powder that will cross the 65mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 35mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg compositions with the mixing of turbine stirring instrument,
Obtain the solution of compositions by the compositions of this 100mg of water dissolution during use.
2 test methods and result
Dog is randomly divided into 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 group 6.After fasting 12 hours, 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 from the apex of the heart
Pressure and rate of pressure change (± dp/dt thereofmax).Waltan-Brodie strain bow is implanted left ventricle antetheca, measures cardiac muscle and receive
Contracting power.With electromagnetic flowmeter determination ascending aorta blood flow.Using ascending aorta flow as cardiac output (CO), calculate heart and refer to
Number (CI), index (SI) of often fighting, work done (SW) of often fighting, left heart work done (LVW).Parameters record and BIC physiograph.Art
Half an hour after, 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 impact (n=6) on heart failure canine dp/dt of table 1 compositions
Compare with NS group,@p<0.05
The impact (n=6) on heart failure canine cardiac work of table 2 compositions
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 1,2, and compositions can dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt (with model group matched group
Relatively, p < 0.05).Compound III and compound IV can not dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt.
Table 3 compositions impact kinemic on heart failure canine (n=6)
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 3, compositions can dramatically increase Heart Failure Dogs cardiac output (compare with model control group, p <
0.05).Compound III and compound IV can not dramatically increase the cardiac output of Heart Failure Dogs.
Conclusion: compositions can significantly improve acute heart failure, can be used to preparation treatment or the medicine of prevention acute heart failure.
Compound III and compound IV can not significantly improve acute heart failure, should not be used to preparation treatment or the medicine of prevention acute heart failure.
(2) the experimental example compositions impact on chronic heart failure rat
Test method and result
Rat 50, male and female half and half.10 are only used as Normal group.40 lumbar injection doxorubicin hydrochloride 2mg/kg, often
Week 1 time, totally 6 weeks, when the 5th week, it is randomly divided into 4 groups, i.e. normal NS group and 3 gastric infusion 2.5mg/kg groups.Gastric infusion combines
Thing 2.5mg/kg group, compound III 2.5mg/kg group and compound IV 2.5mg/kg group rose at the 5th week and give group respectively every day
Compound, compound III and each group of compound IV gavage, be administered 21 days.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, operation
Peeling off trachea and intubate, the total tremulous pulse in right side of simultaneously dissociating, (diameter 1mm is full of 1% liver to insert homemade heart catherization through it
Element), trace blood pressure curve；It is further continued for inserting so that it is enter left ventricle by left arterial lobe, trace intraventricular pressure curve, automatically
Analyzing and processing left ventricular systolic pressure (LVSP), intraventricular pressure maximum climbing speed (+dp/dtmax), intraventricular pressure maximum falling speed
(-dp/dtmax) and survey the data such as cardiac muscle maximal velocity of contraction (Vpm).Separately take 10 rats as Normal group, do not give
Doxorubicin hydrochloride, remaining operation is with above-mentioned, and between group, T inspection, carries out statistical procedures.
The impact (n=10) on chronic heart failure Cardiac Function in Rat of table 4 compositions
Compare with NS group,△: p < 0.05
Table 4 result of the test shows that compositions 2.5mg/kg can significantly raise the Heart Failure Wistar Rats that caused by doxorubicin hydrochloride
LVSP ,+dp/dtmax,-dp/dtmaxReduction (comparing with NS group, P < 0.05) with Vpm；Compound III 2.5mg/kg and chemical combination
Thing IV 2.5mg/kg can not significantly raise the LVSP ,+dp/dt of the Heart Failure Wistar Rats caused by doxorubicin hydrochloridemax,-dp/dtmaxWith
The reduction of Vpm.
Conclusion: compositions has significantly treatment or the effect of preventing chronic heart failure, can be used to preparation treatment or prevention
The medicine of chronic heart failure.Compound III and compound IV does not have significantly treatment or the effect of preventing chronic heart failure, it is not possible to
It is used for preparing treatment or the medicine of preventing chronic heart failure.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated makes 100.
Claims (10)
1. a compositions, is characterized by that said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 65% and 35%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be sufficiently mixed according to mass percent respectively 65% and 35%.
A kind of compositions the most as claimed in claim 1 application in cardiotonic agents.
4. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure is the acute heart
Decline.
5. compositions application in cardiotonic agents as claimed in claim 4, it is characterised in that: described compositions can increase
The heart acting of extra urgaent dispatch heart failure.
A kind of compositions the most as claimed in claim 4 application in cardiotonic agents, it is characterised in that: described compositions can
To increase the cardiac output of acute heart failure.
7. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure is the chronic heart
Decline.
8. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions can increase
Add the left ventricular systolic pressure of chronic heart failure.
9. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions can increase
Add the intraventricular pressure maximum climbing speed of chronic heart failure.
10. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions is permissible
Increase the myocardium maximal velocity of contraction of chronic heart failure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610279939.5A CN105920007A (en) | 2016-04-28 | 2016-04-28 | Applications of composition of Virosaine A piperazinyl derivative and Virosaine A imidazolyl derivative in medicines for resisting heart failure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610279939.5A CN105920007A (en) | 2016-04-28 | 2016-04-28 | Applications of composition of Virosaine A piperazinyl derivative and Virosaine A imidazolyl derivative in medicines for resisting heart failure |
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|---|---|
| CN105920007A true CN105920007A (en) | 2016-09-07 |
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| CN201610279939.5A Withdrawn CN105920007A (en) | 2016-04-28 | 2016-04-28 | Applications of composition of Virosaine A piperazinyl derivative and Virosaine A imidazolyl derivative in medicines for resisting heart failure |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412101A (en) * | 2015-11-15 | 2016-03-23 | 淄博齐鼎立专利信息咨询有限公司 | Application of Virosaines A in preparing medicine for treating or preventing chronic heart failure |
-
2016
- 2016-04-28 CN CN201610279939.5A patent/CN105920007A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412101A (en) * | 2015-11-15 | 2016-03-23 | 淄博齐鼎立专利信息咨询有限公司 | Application of Virosaines A in preparing medicine for treating or preventing chronic heart failure |
Non-Patent Citations (2)
| Title |
|---|
| BING-XIN ZHAO ET. AL.: ""Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an unprecedented Skeleton from Flueggea virosa"", 《ORGANIC LETTERS》 * |
| WEN ZHANG,ET.AL.: "Chemical synthesis and biological activities of Securinega alkaloids", 《JORUNAL OF CHINESE PHARMACEUTICAL SCIENCES》 * |
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