CN104784190A - Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure - Google Patents
Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure Download PDFInfo
- Publication number
- CN104784190A CN104784190A CN201510213239.1A CN201510213239A CN104784190A CN 104784190 A CN104784190 A CN 104784190A CN 201510213239 A CN201510213239 A CN 201510213239A CN 104784190 A CN104784190 A CN 104784190A
- Authority
- CN
- China
- Prior art keywords
- renal failure
- acute renal
- muell
- miq
- arg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XURLTFUKDPZAPN-QFIPXVFZSA-N Cleistanone Natural products O(C)[C@H]1OC(=O)c2c(-c3cc4OCOc4cc3)c3c(c(O)c12)cc(OC)c(OC)c3 XURLTFUKDPZAPN-QFIPXVFZSA-N 0.000 title claims abstract description 35
- 208000033626 Renal failure acute Diseases 0.000 title claims abstract description 33
- 201000011040 acute kidney failure Diseases 0.000 title claims abstract description 33
- 208000009304 Acute Kidney Injury Diseases 0.000 title claims abstract description 32
- 208000012998 acute renal failure Diseases 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title abstract description 6
- GEIFQLXIDUDMNZ-PCJVTFPHSA-N (4aR,4bR,6aR,8S,10aR,10bR,12R,12aR)-12-hydroxy-1,1,1',1',4a,10a,10b-heptamethyl-3'-methylidenespiro[3,4,4b,5,6,6a,7,9,10,11,12,12a-dodecahydrochrysene-8,2'-cyclopentane]-2-one Chemical compound CC1(C)CCC(=C)[C@@]11C[C@@H](CC[C@H]2[C@]3(C[C@@H](O)[C@H]4C(C)(C)C(=O)CC[C@@]42C)C)[C@@]3(C)CC1 GEIFQLXIDUDMNZ-PCJVTFPHSA-N 0.000 claims description 31
- 241000785597 Cleistanthus Species 0.000 claims description 31
- 150000002576 ketones Chemical class 0.000 claims description 30
- 239000002023 wood Substances 0.000 claims description 30
- 241001597008 Nomeidae Species 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 7
- 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 4
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 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 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-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
- 150000001875 compounds Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 230000006870 function Effects 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 230000003907 kidney function Effects 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 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
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 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
- 206010030302 Oliguria Diseases 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
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 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
- 239000002207 metabolite Substances 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and particularly discloses an O-(benzimidazolyl) ethyl derivative of cleistanone, a preparation method and an application thereof in preparation of a medicine for resisting acute renal failure. A novel O-(benzimidazolyl) ethyl derivative of cleistanone is synthesized and the preparation method is disclosed. The pharmacological experiment shows that the O-(benzimidazolyl) ethyl derivative of cleistanone has the effect of resisting the acute renal failure and has a value for developing the medicine to resist the acute renal failure.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) be the clinical syndrome caused by many reasons, be found in clinical departments patient, sickness rate is high and often have serious consequences, its feature is that (a few hours are to a couple of days) renal function sharply declines in a short time, clinical manifestation is acute oliguria (urine volume <400mLPd) or anuria (urine volume <100mLPd), in body, nitrogen matter metabolite is discharged and is produced obstacle, there is azotemia rapidly, water and electrolyte, acid base imbalance, and cause each system corresponding function imbalance of whole body.The principal element of acute renal failure is caused to be the sharply minimizing of renal blood flow, and the oxidative stress caused due to nephridial tissue ischemia and cell injury, finally cause the deterioration of renal tissue structural damage and function.There is no the generally acknowledged effective medicine for the treatment of acute renal failure clinically at present, only by correcting water-electrolyte balance, correcting the symptomatic treatment measures such as acidosis and improving symptom, the later stage also needs to maintain body function by hemodialysis.Improving kidney perfusion obstacle and alleviating in Renal tissues damage and have 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 the potential drug obtaining high-efficiency low-toxicity there is important value most.
The compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume2011, Issue22,pages 4108 – 4111, August 2011) compound, we have carried out structural modification to compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, obtain a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, and its anti-acute renal failure activity is evaluated, it is active that it has anti-acute renal failure.
Summary of the invention
The invention discloses a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant, its structure is:
Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) with benzimidazole generation substitution reaction.
The preparation method of further Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 15mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the benzimidazole of 1180mg, mixture reflux 5h; After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three times, merge organic facies; Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1.5, v/v, collects the brown solid that namely brown concentrated elution band obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The object of this invention is to provide the purposes that Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) is used for the treatment of acute renal failure, namely for the preparation of the purposes for the treatment of acute renal failure medicine.
Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) of the present invention has obvious therapeutical effect to acute renal failure disease.
Find that Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) 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 any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound II per (273mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg, 10mmol), mixture reflux 5h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.5, v/v), collects brown concentrated elution band, the concentrated brown solid (105.2mg, 36%) namely obtaining compound III.
1H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.68(d,J＝25.0Hz,2H),7.31(s,1H),7.21(s,1H),4.65(s,1H),4.56(s,1H),4.14(d,J＝7.9Hz,2H),4.05(s,1H),3.93(s,2H),2.51(d,J＝127.9Hz,1H),2.37(s,1H),2.28(d,J＝15.8Hz,2H),2.22(s,1H),1.90(s,2H),1.83(s,1H),1.66(s,2H),1.62–1.49(m,4H),1.29(t,J＝17.7Hz,3H),1.19(d,J＝14.3Hz,2H),1.11(d,J＝7.6Hz,7H),1.02(dd,J＝42.5,9.8Hz,13H),0.88(s,3H),0.80(s,1H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.57(s),154.46(s),146.57(s),139.24(s),134.35(s),124.01(s),123.47(s),118.67(s),110.97(s),105.19(s),74.62(s),67.84(s),59.73(s),52.52(s),51.17(s),47.88(s),45.48(s),44.08(s),42.26(s),41.75(s),40.61(s),40.13(s),38.83(s),38.62(s),37.22(s),36.24(s),33.30(s),32.92(s),29.86(s),27.16(s),26.04(s),24.24(s),23.92(s),20.75(s),18.43(s),17.97(s),16.93(s).
HRMS(ESI):m/z[M+H]
+calcd for C
39H
57N
2O
2:585.4420；found:585.4416。
Embodiment 4 compound III is to the therapeutical effect of acute renal failure rat
(1) experimental technique
Intramuscular injection glycerol is adopted to cause Acute Renal Failure Rats animal model.Select the healthy male SD rat 30 of 180 ~ 220g, be divided into 3 groups at random: sham operated rats (intramuscular injection normal saline); Model group (intramuscular injection glycerol); Compound III group (compound III 0.6mg/Kg, intramuscular injection glycerol), each group rat tail vein injection saline or compound III immediately after glycerol modeling, be administered once after 12 and 24 hours again.
(2) observation index
Rat last is put into metabolic cage and is collected twenty-four-hour urine after giving compound III or normal saline, stay latter 6 hours of urine with 4% chloral hydrate intraperitoneal injection of anesthesia, adopt laser Doppler flowmetry to measure after modeling and bilateral renal blood flow after treatment, average as single animal renal blood flow; Get blood and prepare serum, measure blood BUN and Cre (all by the operation of test kit description).
(3) experimental result
1. compound III can increase acute renal failure Mouse Kidney blood flow
Table 1 compound III is on the impact of acute renal failure Mouse Kidney blood flow
* P<0.05vs acute renal failure model group
2. compound III is to the protective effect of acute renal failure Mouse Kidney function tool
Acute renal failure rat intravenous injection normal saline is after 24 hours, and serum BUN and Cre is in table 2.Acute renal failure model group, apparently higher than sham operated rats, illustrates that model group animal renal function injury is serious.Compound III can improve the renal function (P<0.05) of acute renal failure rat.In table 2.
The each rats in test groups renal function index of table 2 compares
* P<0.05vs acute renal failure model group
Conclusion: compound III can protect the function of kidney, can be used for preparing anti-acute renal failure medicine.
The preparation of embodiment 5 compound III tablet involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 6 compound III capsule involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (4)
1. one kind has Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) and the application of pharmaceutically acceptable salt in treatment acute renal failure medicine thereof of structure shown in formula III:
2. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) and the application of pharmaceutically acceptable salt in treatment acute renal failure medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) improves the reduction of the renal blood flow amount caused by acute renal failure.
3. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) and the application of pharmaceutically acceptable salt in treatment acute renal failure medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) improves the rising of the serum BUN that acute renal failure causes.
4. a kind of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) and the application of pharmaceutically acceptable salt in treatment acute renal failure medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) improves the rising of the change of serum C re that acute renal failure causes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510213239.1A CN104784190A (en) | 2015-04-29 | 2015-04-29 | Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510213239.1A CN104784190A (en) | 2015-04-29 | 2015-04-29 | Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104784190A true CN104784190A (en) | 2015-07-22 |
Family
ID=53549693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510213239.1A Pending CN104784190A (en) | 2015-04-29 | 2015-04-29 | Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104784190A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074525A (en) * | 2016-06-13 | 2016-11-09 | 南京广康协生物医药技术有限公司 | The composition of Schiglautone A derivative is used for preparing anti-acute renal failure medicine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083383A (en) * | 2014-07-31 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of O-(piperidyl)ethyl derivative of cleistanone to preparation of medicines for resisting acute renal failure (ARF) |
| CN104095856A (en) * | 2014-06-27 | 2014-10-15 | 南京大学 | Application of diethylamine derivative of Cleistanone in preparation of medicine resistant to acute renal failure |
| CN104434929A (en) * | 2014-11-05 | 2015-03-25 | 南京广康协生物医药技术有限公司 | Application of Cleistanone O-(piperazinyl)ethyl derivative in preparation of acute renal failure resisting drugs |
-
2015
- 2015-04-29 CN CN201510213239.1A patent/CN104784190A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095856A (en) * | 2014-06-27 | 2014-10-15 | 南京大学 | Application of diethylamine derivative of Cleistanone in preparation of medicine resistant to acute renal failure |
| CN104083383A (en) * | 2014-07-31 | 2014-10-08 | 南京广康协生物医药技术有限公司 | Application of O-(piperidyl)ethyl derivative of cleistanone to preparation of medicines for resisting acute renal failure (ARF) |
| CN104434929A (en) * | 2014-11-05 | 2015-03-25 | 南京广康协生物医药技术有限公司 | Application of Cleistanone O-(piperazinyl)ethyl derivative in preparation of acute renal failure resisting drugs |
Non-Patent Citations (1)
| Title |
|---|
| VAN TRINH THI THANH 等: "Cleistanone:a triterpenoid from Cleistanthus indochinensis with a new carbon skeleton", 《EUR.J.ORG.CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074525A (en) * | 2016-06-13 | 2016-11-09 | 南京广康协生物医药技术有限公司 | The composition of Schiglautone A derivative is used for preparing anti-acute renal failure medicine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104083383B (en) | The application in preparing anti-acute renal failure medicine of O-(piperidyl) ethyl derivative of Cleistanone Cleistanone | |
| CN104814968A (en) | Application of 0-(1H-tetrazole)ethyl derivative of Cleistanone to preparation of anti-heart-failure medicine | |
| CN104095856A (en) | Application of diethylamine derivative of Cleistanone in preparation of medicine resistant to acute renal failure | |
| CN104188980B (en) | O-(morpholinyl) ethyl derivative of Cleistanone Cleistanone, preparation method and its usage | |
| CN104083379B (en) | The dimethylamine derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is preparing the application in anti-rhinitis medicament thing | |
| CN104784190A (en) | Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure | |
| CN104434929B (en) | The application in preparing anti-acute renal failure medicine of O-(piperazinyl) ethyl derivative of Cleistanone | |
| CN104098644A (en) | O-(piperidinyl) ethyl derivative of Cleistanone as well as preparation method and application thereof | |
| CN105193793A (en) | Composition and application thereof in anti-ARF (Acute Renal Failure) drugs | |
| CN104666310A (en) | Application of O-(triazolyl) ethyl derivative of Cleistanone in preparation of medicine resistant to acute renal failure | |
| CN105343082A (en) | Composition and application of composition in medicines for resisting acute renal failure | |
| CN105267195A (en) | Composition and application of composition to acute renal failure resisting drugs | |
| CN104758298A (en) | Application of O-(1H-tetrazolyl) ethyl derivative of cleistanone in preparation of medicines for treating or preventing renal fibrosis | |
| CN104188983A (en) | Application of Cleistanone O-(morpholinyl)ethyl derivative in preparation of heart failure resisting drugs | |
| CN105287585A (en) | Composition and application of composition in medicine for resisting acute renal failure | |
| CN104402964A (en) | Cleistanone O-(imidazolyl) ethyl derivative, and preparation method and application thereof | |
| CN104906091A (en) | Application of O-(diethylin)ethyl derivative of Daphmalenine A in preparing acute renal failure resisting drugs | |
| CN104784176A (en) | Application of derivative of Daphmalenine A in preparation of acute renal failure resisting drugs | |
| CN105343076A (en) | Composition and application thereof in acute renal failure resisting drug | |
| CN106822107A (en) | The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for anti-acute renal failure | |
| CN105250307A (en) | Composition and application thereof to acute renal failure (ARF) resistant medicines | |
| CN105250289A (en) | Composition and application thereof to acute renal failure (ARF) resistant medicines | |
| CN105213395A (en) | Compositions and the application in anti-acute renal failure medicine thereof | |
| CN105125556A (en) | Composition and application thereof in drugs for resisting acute renal failure | |
| CN106038542A (en) | Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150722 |
|
| RJ01 | Rejection of invention patent application after publication |