CN105920005A - Application of composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines - Google Patents
Application of composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 46
- 208000033626 Renal failure acute Diseases 0.000 title claims abstract description 35
- 201000011040 acute kidney failure Diseases 0.000 title claims abstract description 35
- 208000009304 Acute Kidney Injury Diseases 0.000 title claims abstract description 34
- 208000012998 acute renal failure Diseases 0.000 title claims abstract description 34
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title abstract description 5
- 125000002883 imidazolyl group Chemical group 0.000 title abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 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 13
- 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 12
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 4
- 230000008327 renal blood flow Effects 0.000 claims description 4
- 210000002966 serum Anatomy 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 210000003734 kidney Anatomy 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 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 6
- 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
- 230000006870 function Effects 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 6
- 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
- 239000012043 crude product Substances 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection 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
- 210000002700 urine Anatomy 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
- 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
- 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
- 230000017531 blood circulation Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000003208 petroleum Substances 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 240000007003 Flueggea virosa Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 241000867909 Securinega Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 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
- 230000006378 damage Effects 0.000 description 2
- 239000003792 electrolyte Substances 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
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 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
- 210000005084 renal tissue Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing 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
- 230000001225 therapeutic effect Effects 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 208000001889 Acid-Base Imbalance Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000003126 Anuria Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- CFNHVUGPXZUTRR-UHFFFAOYSA-N CCCNCCN Chemical compound CCCNCCN CFNHVUGPXZUTRR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- AMSDWLOANMAILF-UHFFFAOYSA-N OCC[n]1cncc1 Chemical compound OCC[n]1cncc1 AMSDWLOANMAILF-UHFFFAOYSA-N 0.000 description 1
- 206010030302 Oliguria Diseases 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 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
- 239000000284 extract Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003462 vein 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 discloses an application of a composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines; the invention relates to the fields of organic synthesis and medicinal chemistry, and in particular to the composition, a preparation method and the application of the composition in preparing the acute renal failure resisting medicines. The invention discloses the composition and the preparation method thereof. Pharmacological experiments show that the composition disclosed by the invention has an effect on resisting acute renal failure, and the composition has a value of developing the acute renal failure resisting medicines.
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
Acute renal failure (Acute Renal Failure, ARF) is the clinical syndrome caused by many reasons,
Being found in clinical departments patient, sickness rate is high and often has serious consequences, and its feature is (a few hours are to a couple of days) kidney in a short time
Function drastically declines, and clinical manifestation is acute oliguria (urine volume < 400mLPd) or anuria (urine volume < 100mLPd), internal nitrogen matter generation
Thank to product and discharge generation obstacle, azotemia, water and electrolyte, acid base imbalance occur rapidly, and causes each system of whole body
Corresponding function is lacked of proper care.Causing the principal element of acute renal failure is the drastically minimizing of renal blood flow, and owing to nephridial tissue ischemia draws
The oxidative stress risen and cell injury, ultimately result in the deterioration of renal tissue structural damage and function.There is no clinically at present
The effective medicine for the treatment of acute renal failure generally acknowledged, is only capable of, by correcting water-electrolyte balance, correcting the symptomatic treatments such as acidosis and arranging
Executing and improve symptom, the later stage also needs to maintain body function by hemodialysis.Improve kidney perfusion obstacle and alleviate kidney
Tissue injury's aspect has the clinical medicine of obvious curative effects rare.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus obtaining
The potential drug of 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 acute renal failure activity anti-to said composition is commented
Valency, it has anti-acute renal 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 40% and 60%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide compositions for treating the purposes of acute renal failure, be i.e. used for preparing treatment acute renal failure
The purposes of medicine.
The compositions of the present invention has obvious therapeutical effect to acute renal failure disease.
Find that compositions can improve the function of kidney by our research.
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 2 Virosaine 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 3 Virosaine 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 4 Virosaine 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 therapeutical effect to acute renal failure rat
(1) experimental technique
The preparation of compositions: the powder that will cross the 40mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 60mg 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.
Intramuscular injection glycerol is used to cause Acute Renal Failure Rats animal model.Select 180～220g healthy male SD
Rat 30, is randomly divided into 5 groups: sham operated rats (intramuscular injection normal saline)；Model group (intramuscular injection glycerol)；It is administered and intervenes
Group (compositions, compound III or compound IV 0.6mg/Kg, intramuscular injection glycerol), each group rat is vertical after glycerol modeling
I.e. tail vein injection saline or treat reagent thing, is administered once after 12 and 24 hours again.
(2) observation index
Rat last is administered or puts into after normal saline metabolic cage and collects twenty-four-hour urine, stays urine to be hydrated chlorine with 4% in latter 6 hours
Aldehyde intraperitoneal injection of anesthesia, uses laser Doppler flowmetry to measure after modeling and bilateral renal blood flow after treatment, averages
As single animal renal blood flow；Take blood and prepare serum, measure blood BUN and Cre (all operating by test kit description).
(3) experimental result
1. compositions can increase acute renal failure Mouse Kidney blood flow
Compositions can dramatically increase acute renal failure Mouse Kidney blood flow, and compound III and compound IV acts on without this.
The impact on acute renal failure Mouse Kidney blood flow of table 1 compositions
* P < 0.05vs acute renal failure model group
2. compositions has protective effect to acute renal failure Mouse Kidney function
Acute renal failure rat intravenous injection normal saline is after 24 hours, and serum BUN and Cre is shown in Table 2.Acute renal failure model group
Apparently higher than sham operated rats, illustrate that model group animal renal function injury is serious.Compositions can improve the kidney merit of acute renal failure rat
Energy (P < 0.05), and compound III and compound IV acts on without this.It is shown in Table 2.
Table 2 each rats in test groups renal function index compares
* P < 0.05vs acute renal failure model group
Conclusion: compositions can protect the function of kidney, can be used to prepare anti-acute renal failure medicine.And compound III
Kidney can not be protected with compound IV, should not be used to prepare anti-acute renal failure medicine.
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 (6)
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 40% and 60%,
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 40% and 60%.
3. a compositions as claimed in claim 1 application in treatment acute renal failure medicine.
4. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described compositions changes
The reduction of kind renal blood flow amount caused by acute renal failure.
5. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described compositions changes
The rising of the serum BUN that kind acute renal failure causes.
6. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described compositions changes
The rising of change of serum C re that kind acute renal failure causes.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278600.3A CN105920005A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278600.3A CN105920005A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines |
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| CN105920005A true CN105920005A (en) | 2016-09-07 |
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| CN201610278600.3A Pending CN105920005A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazinyl and imidazolyl derivatives of Virosaine A in acute renal failure resisting medicines |
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| Country | Link |
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| CN (1) | CN105920005A (en) |
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2016
- 2016-04-28 CN CN201610278600.3A patent/CN105920005A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| BING-XIN ZHAO等: "Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa", 《ORGANIC LETTERS》 * |
| 王鸿泰等: "一叶萩碱、黄芪联合治疗肾性贫血", 《中国现代医学杂志》 * |
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