CN106580991A - Applications of Harrisotone A derivative composition in anti-heart failure drugs - Google Patents
Applications of Harrisotone A derivative composition in anti-heart failure drugs Download PDFInfo
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- CN106580991A CN106580991A CN201610907738.5A CN201610907738A CN106580991A CN 106580991 A CN106580991 A CN 106580991A CN 201610907738 A CN201610907738 A CN 201610907738A CN 106580991 A CN106580991 A CN 106580991A
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- heart failure
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- harrisotone
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- 206010019280 Heart failures Diseases 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 14
- BMTORNFHNMDAAJ-UHFFFAOYSA-N harrisotone A Natural products CC(=CCC1(CC=C(C)C)C(=C(C(=O)C)C(=O)C2(CC3C(CCC3(C)O)C(C)(O)C2)C1=O)O)C BMTORNFHNMDAAJ-UHFFFAOYSA-N 0.000 title abstract description 10
- 229940079593 drug Drugs 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 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 17
- 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
- 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
- 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
- 230000007423 decrease Effects 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 2
- 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
- 230000001154 acute 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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 4
- 208000035126 Facies Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 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
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229960002275 pentobarbital sodium Drugs 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 240000006015 Harrisonia perforata Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 229930191860 harrisotone Natural products 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 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
- 125000000830 polyketide group Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 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
- 238000002627 tracheal intubation Methods 0.000 description 2
- 238000005406 washing Methods 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
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 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
- 229920002472 Starch Polymers 0.000 description 1
- 230000002159 abnormal effect Effects 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
- 239000012267 brine Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 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
- 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000002513 implantation Methods 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
- 229960004194 lidocaine Drugs 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
- 238000002156 mixing 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
- 230000035935 pregnancy Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000007575 pulmonary infarction 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 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
- 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
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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 present invention discloses applications of the composition of the O-(diethylamino)ethyl derivative and the O-(piperazinyl)ethyl derivative of Harrisotone A in anti-heart failure drugs, particularly applications of a Harrisotone A derivative composition in anti-heart failure drugs. The invention relates to the field of organic synthesis and pharmaceutical chemistry, particularly to a Harrisotone A derivative composition and uses of the Harrisotone A derivative composition in anti-heart failure drugs. The present invention discloses a Harrisotone A derivative composition and a preparation method thereof. According to the present invention, the pharmacological experiment results show that the Harrisotone A derivative composition has the anti-heart failure effect, and can be developed into the anti-heart failure drug.
Description
Technical field
The present invention relates to organic synthesiss and medicinal chemistry art, and in particular to compositionss, preparation method and its usage.
Background technology
Heart failure (heart failure, HF) refers to that cardiac function causes heart pump blood volume to meet tissue metabolism extremely
A kind of pathological and physiological condition for needing.The cause of disease is that in itself diastole is limited for cardiac overload, cardiac muscle, and caused by any reason just
Beginning myocardial damage；And infect, anemia, gestation, childbirth, cardiac arrhythmia, pulmonary infarction, hyperthyroidism, diabetes, suppress the induction of heart medicine plus
Weight HF.Pathogeny is it is considered that the mechanism that HF occurs development is abnormal hemodynamics；The later stage eighties 20th century is recognized
The activation of nerve-endocrine hormone plays an important role (sympathetic ↑ NE ↑ RAS ↑ wait activation)；" cardiac muscle is gradually specify that after the nineties
Reinvent " (remodelling) it is the fundamental mechanism for causing the generation of heart failure to develop.Heart failure is divided into acute heart failure and the chronic heart again
Decline.
At present for the treatment of heart failure, clinically without specific medicament, most of medicine is while symptoms of heart failure is alleviated
With inevitable toxic and side effects, compound or lead compound are found from natural product and structural modification is carried out obtain it
Derivant, so as to the potential drug for obtaining high-efficiency low-toxicity most has important value.
Compound I according to the present invention be one deliver within 2009 (Sheng Yin et al.,
2009.Harrisotones A–E,five novel prenylated polyketides with a rare
spirocyclic skeleton from Harrisonia perforata.Tetrahedron 65(2009)1147–1152)
Compound, we have carried out structural modification to compound I, obtain two new derivants i.e. compound III and compound
IV, and compositionss are prepared for compound III and compound IV and the anti-heart failure activity of said composition is evaluated, its tool
There is anti-heart failure activity.
The content of the invention
The invention discloses a new compositionss, 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 20% and 80%.
Compositionss disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows that the compositionss of the present invention have preferably anti-heart failure effect.The present invention's pharmaceutically can connect
The salt received has same drug effect.
By the following examples the present invention is further detailed explanation, but protection scope of the present invention is not by concrete real
Any restriction of example is applied, but is defined in the claims.
Specific embodiment
The preparation of the compound Harrisotone A of embodiment 1
Document (the Sheng Yin that the preparation method of compound Harrisotone A (I) is delivered with reference to Sheng Yin et al.
et al.,2009.Harrisotones A–E,five novel prenylated polyketides with a rare
spirocyclic skeleton from Harrisonia perforata.Tetrahedron 65(2009)1147–1152)
Method.
The synthesis of O- bromoethyl derivants (II) of embodiment 2Harrisotone A
Compound I (472mg, 1.00mmol) is dissolved in into 15mL benzene, tetrabutyl ammonium bromide (TBAB) is added in solution
(0.08g), 50% sodium hydroxide solution of glycol dibromide (3.760g, 20.00mmol) and 6mL.Mixture is Celsius 35
Degree stirring 3h.Reactant liquor is poured in frozen water after 3h, is extracted twice with dichloromethane immediately, merge organic phase solution.Then
To organic phase solution successively with water and saturated common salt water washing 2 times, then with anhydrous sodium sulfate drying, last concentrating under reduced pressure removes molten
Agent obtains product crude product.(mobile phase is product crude product silica gel column chromatography purification：Petroleum ether/acetone=100:1.5, v/v), receive
Collection brown concentrate elution band and fling to solvent obtain compound II yellow powder (602mg, 76%).
1H NMR(500MHz,DMSO-d6) δ 5.18 (s, 2H), 4.56 (s, 2H), 3.93 (d, J=16.7Hz, 4H), 3.79
(s, 2H), 3.62 (d, J=0.9Hz, 4H), 3.15 (s, 2H), 2.48 (s, 2H), 2.41 (d, J=9.4Hz, 4H), 2.27 (s,
1H), 1.95 (s, 1H), 1.88-1.80 (m, 8H), 1.77 (d, J=15.5Hz, 7H), 1.68 (s, 1H), 1.61 (s, 1H),
1.51 (s, 1H), 1.25 (d, J=58.1Hz, 1H), 1.15-0.75 (m, 6H).13C NMR(125MHz,DMSO-d6)δ
206.46(s),198.24(s),195.44(s),190.27(s),135.27(s),120.09(s),115.02(s),84.45
(s),76.58(s),74.12(s),63.67(s),62.76(s), 60.36(s),50.96(s),45.22(s),39.69(s),
36.61 (s), 34.40 (s), 32.63 (s), 30.81 (d, J=8.9Hz), 28.77 (s), 25.30 (s), 24.09 (d, J=
19.2Hz),22.77(s),18.20(s).
HRMS(ESI)m/z[M+H]+calcd for C34H50Br3O6:793.1137；found 793.1134.
The synthesis of O- (lignocaine) ethyl derivative (III) of embodiment 3Harrisotone A
Compound II (396mg, 0.5mmol) is dissolved in the middle of 15mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and diethylamine (2920mg, 40mmol), mixture is heated to reflux 3h.Reaction knot
Reactant liquor is poured in frozen water after beam, is extracted 2 times with equivalent dichloromethane, merge organic faciess.Successively with water and saturated aqueous common salt
Washing merge after organic faciess, then with anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent and obtains product crude product.Product crude product
Purify that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:1.5, v/v) brown concentration elution band, is collected, concentration is
Obtain compound III faint yellow solid (246.1mg, 64%).
1H NMR (500MHz, DMSO-d6) δ 5.13 (s, 2H), 4.19 (s, 2H), 3.52 (d, J=5.3Hz, 4H), 3.21
(s, 2H), 3.04 (s, 2H), 2.85 (s, 12H), 2.64 (d, J=13.5Hz, 4H), 2.33 (s, 3H), 2.18 (s, 1H), 2.11
(s, 2H), 2.04 (s, 1H), 1.98 (s, 1H), 1.88 (s, 1H), 1.77 (d, J=5.0Hz, 7H), 1.70 (d, J=15.5Hz,
7H),1.61(s,1H),1.54(s,1H),1.44(s,1H),1.37(s,1H),1.10(s,24H).
13C NMR(125MHz,DMSO-d6)δ206.30(s),198.04(s),195.18(s),190.07(s),135.11
(s),119.89(s),114.86(s),84.15(s),76.42(s),66.70(s),62.58(s),60.18(s),59.97
(s),52.53(s),51.93(s),50.76(s),47.69(s),45.04(s),39.51(s),36.43(s), 30.63(d,J
=8.9Hz), 28.61 (s), 25.10 (s), 23.93 (d, J=19.2Hz), 22.57 (s), 18.04 (s), 12.27 (s).
HRMS(ESI):m/z[M+H]+calcd for C46H80N3O6:770.6047；found:770.6044.
The synthesis of O- (piperazinyl) ethyl derivative of embodiment 4Harrisotone A
Compound II (396mg, 0.5mmol) is dissolved in the middle of 16mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and Piperazine anhydrous (6892mg, 80mmol), mixture is heated to reflux 1h.Reaction
Reactant liquor is poured in 15mL frozen water after end, is extracted 2 times with equivalent dichloromethane, merge organic faciess.Successively with water and saturation
Brine It merge after organic faciess, then with anhydrous sodium sulfate drying, concentrating under reduced pressure removes solvent and obtains product crude product.Produce
(mobile phase is thing crude product silica gel column chromatography purification：Petroleum ether/acetone=100:1.5, v/v), collect light brown and concentrate eluting
Band obtain compound IV Light brown solid (286.9mg, 71%).
1H NMR (500MHz, DMSO-d6) δ 5.14 (s, 2H), 4.21 (s, 2H), 3.53 (d, J=6.2Hz, 4H), 3.09
(s, 2H), 3.05 (s, 2H), 2.66 (s, 12H), 2.57-2.53 (m, 4H), 2.33 (d, J=15.0Hz, 15H), 2.24 (s,
1H), 2.14 (s, 2H), 2.10 (s, 1H), 2.00 (s, 1H), 1.88 (d, J=10.5Hz, 3H), 1.79 (d, J=5.0Hz,
7H), 1.71 (d, J=15.5Hz, 7H), 1.63 (s, 1H), 1.55 (s, 1H), 1.46 (s, 1H), 1.15-1.05 (m, 8H).
13C NMR(125MHz,DMSO-d6)δ206.30(s),198.04(s),195.28(s),190.07(s),135.11
(s),119.89(s),114.86(s),84.25(s),76.42(s),66.70(s),62.58(s),60.18(s), 59.97
(s),54.35(s),54.16(s),53.66(s),50.78(s),45.24(s),45.06(s),39.49(s),36.45(s),
30.61 (d, J=8.9Hz), 28.61 (s), 25.10 (s), 23.93 (d, J=19.2Hz), 22.58 (s), 18.04 (s).
HRMS(ESI):m/z[M+H]+calcd for C46H77N6O6:809.5905；found:809.5901.
The anti-heart failure activity of the compositionss of embodiment 5
(1) experimental example：Therapeutical effect of the compositionss to dog acute heart failure
1 material：Animal -- healthy adult dog 12.5～13.5kg of body weight.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 types)：Day
This photoelectricity company produces.
The preparation of compositionss：The powder of the 20mg compound III of 200 mesh nets will be crossed after grinding and 200 is crossed after grinding
The powder of the 80mg compound IV of mesh net is fitted in tubule with cover and obtains 100mg compositionss with the mixing of turbine stirring instrument,
The solution of compositionss is obtained when using with the compositionss of water dissolution this 100mg.
2 test methods and result
Dog is randomly divided into into NS groups (waiting capacity solvent), gastric infusion compositionss 1.0mg/kg group, compound III
1.0mg/kg groups and compound IV 1.0mg/kg groups, 6 per group.After fasting 12 hours, intravenous injection pentobarbital sodium 40mg/
Kg is anaesthetized, tracheal intubation, artificial respiration, monitors aortic pressure (AP) and electrocardiogram.Breast is opened in left side, and conduit is inserted to left room from the apex of the heart
Pressure and its rate of pressure change (± dp/dtmax).By Waltan-Brodie strain bow implantation left ventricle antethecas, determine 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 are recorded and BIC physiographs.Art
Half an hour after, parameters reach stable.From femoral vein constant speed gasing injection pentobarbital sodium (0.5mL/kgmin), with ± dp/
dtmaxDrop to about 1000mHg/s and form acute heart failure for leading indicator.After acute heart failure model stability, each group animal
Duodenum gives relative medicine.T inspections, carry out statistical procedures between group.
Impact (n=6) of the compositionss of table 1 to heart failure canine dp/dt
Compare with NS groups,@p<0.05
Impact (n=6) of the compositionss of table 2 to heart failure canine cardiac work
Compare * p with before administration<0.05；Compare with NS groups@p<0.05
As a result as shown in table 1,2, compositionss can dramatically increase SW, the LVW ,+dp/dt of Heart Failure Dogs (with model group matched group
Relatively, p<0.05).Compound III and compound IV can not dramatically increase SW, the LVW ,+dp/dt of Heart Failure Dogs.
The compositionss of table 3 are on the kinemic impact of heart failure canine (n=6)
Compare * p with before administration<0.05；Compare with NS groups@p<0.05
As a result as shown in table 3, compositionss can dramatically increase the cardiac output of Heart Failure Dogs and (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：Compositionss can significantly improve acute heart failure, can be used to the medicine for preparing treatment or prevention acute heart failure.
Compound III and compound IV can not significantly improve acute heart failure, should not be used to the medicine for preparing treatment or prevention acute heart failure.
(2) impact of the experimental example compositionss to 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, 4 groups are randomly divided into when the 5th week, i.e., normal NS groups and 3 gastric infusion 2.5mg/kg groups.Gastric infusion is combined
Thing 2.5mg/kg groups, compound III 2.5mg/kg groups and compound IV 2.5mg/kg groups gave respectively group daily from the 5th week
Compound, compound III and compound IV gavage each groups, are administered 21 days.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, operation
Trachea and intubation are peeled off, while the total tremulous pulse in right side of dissociating, Jing homemade heart catherization (the diameter 1mm, full of 1% liver of its insertion
Element), trace blood pressure curve；It is further continued for insertion so as to left ventricle is entered by left arterial lobe, intraventricular pressure curve is traced, 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 myocardium maximal velocity of contraction (Vpm).10 rats are separately taken as Normal group, is not given
Doxorubicin hydrochloride, with above-mentioned, T inspections, carry out statistical procedures between group for remaining operation.
Impact (n=10) of the compositionss of table 4 to chronic heart failure Cardiac Function in Rat
Compare with NS groups,Δ：p<0.05
The result of the test of table 4 shows that compositionss 2.5mg/kg can be raised significantly by Heart Failure Wistar Rats caused by doxorubicin hydrochloride
LVSP ,+dp/dtmax,-dp/dtmax(compare with NS groups, P with the reduction of Vpm<0.05)；Compound III 2.5mg/kg and change
Compound IV 2.5mg/kg can not be raised significantly by the LVSP of Heart Failure Wistar Rats caused by doxorubicin hydrochloride ,+dp/dtmax,-dp/dtmax
With the reduction of Vpm.
Conclusion：Compositionss have significant treatment or the effect of preventing chronic heart failure, can be used to prepare treatment or prevent
The medicine of chronic heart failure.Compound III and compound IV do not have significant treatment or the effect of preventing chronic heart failure, it is not possible to
For preparing the medicine for the treatment of or preventing chronic heart failure.
The preparation of the composition tablet involved in the present invention of embodiment 6
2 grams of compositionss are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixed, conventional tablet presses make 100.
The preparation of the composition capsule involved in the present invention of embodiment 7
2 grams of compositionss are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixed, it is encapsulated to make 100.
Claims (10)
1. a kind of compositionss, it is characterized by 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 20% and 80%,
2. the preparation method of compositionss as claimed in claim 1, it is characterized by：By the powder of compound III and compound IV
Powder be respectively 20% and 80% according to mass percent and be sufficiently mixed.
3. application of a kind of compositionss in cardiotonic agents as claimed in claim 1.
4. application of the compositionss as claimed in claim 3 in cardiotonic agents, it is characterised in that：The heart failure is the acute heart
Decline.
5. application of the compositionss as claimed in claim 4 in cardiotonic agents, it is characterised in that：The compositionss can increase
The heart acting of extra urgaent dispatch heart failure.
6. application of a kind of compositionss in cardiotonic agents as claimed in claim 4, it is characterised in that：The compositionss can
To increase the cardiac output of acute heart failure.
7. application of the compositionss as claimed in claim 3 in cardiotonic agents, it is characterised in that：The heart failure is the chronic heart
Decline.
8. application of the compositionss as claimed in claim 7 in cardiotonic agents, it is characterised in that：The compositionss can increase
Plus the left ventricular systolic pressure of chronic heart failure.
9. application of the compositionss as claimed in claim 7 in cardiotonic agents, it is characterised in that：The compositionss can increase
Plus the intraventricular pressure maximum climbing speed of chronic heart failure.
10. application of the compositionss as claimed in claim 7 in cardiotonic agents, it is characterised in that：The compositionss can be with
Increase the myocardium maximal velocity of contraction of chronic heart failure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610907738.5A CN106580991A (en) | 2016-10-18 | 2016-10-18 | Applications of Harrisotone A derivative composition in anti-heart failure drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610907738.5A CN106580991A (en) | 2016-10-18 | 2016-10-18 | Applications of Harrisotone A derivative composition in anti-heart failure drugs |
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| Publication Number | Publication Date |
|---|---|
| CN106580991A true CN106580991A (en) | 2017-04-26 |
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ID=58556277
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| CN201610907738.5A Withdrawn CN106580991A (en) | 2016-10-18 | 2016-10-18 | Applications of Harrisotone A derivative composition in anti-heart failure drugs |
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2016
- 2016-10-18 CN CN201610907738.5A patent/CN106580991A/en not_active Withdrawn
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