CN105213395A - Compositions and the application in anti-acute renal failure medicine thereof - Google Patents
Compositions and the application in anti-acute renal failure medicine thereof Download PDFInfo
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- CN105213395A CN105213395A CN201510662684.6A CN201510662684A CN105213395A CN 105213395 A CN105213395 A CN 105213395A CN 201510662684 A CN201510662684 A CN 201510662684A CN 105213395 A CN105213395 A CN 105213395A
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and the purposes on the anti-acute renal failure medicine of preparation thereof.The invention discloses a kind of composition and method of making the same.Pharmacological experiment shows, compositions of the present invention has the effect of anti-acute renal failure, has the value developing anti-acute renal failure medicine.
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 (AcuteRenalFailure, 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 I that the present invention relates to is one and delivers (Fan-YuMengetal. in 2011, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) compound, we have carried out structural modification to Compound I, obtain two new derivants and compound III and compound IV, and prepared compositions by compound III and compound IV and the anti-acute renal failure activity of said composition is evaluated, it is active that it has anti-acute renal failure.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 5% and 95%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The object of this invention is to provide the purposes that compositions is used for the treatment of acute renal failure, namely for the preparation of the purposes for the treatment of acute renal failure medicine.
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 any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound S chiglautoneA
Document (the Fan-YuMengetal. that the people such as the preparation method reference Fan-YuMeng of compound S chiglautoneA (I) deliver, 2011.SchiglautoneA, aNewTricyclicTriterpenoidwithaUnique6/7/9-FusedSkeletonf romtheStemsofSchisandraglaucescens.OrganicLetters13 (2011) 1502 – 1505) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SchiglautoneA
By Compound I (502mg, 1.00mmol) be dissolved in 15mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 6mL.Mixture stirs 8h at 35 degrees Celsius.After 8h, 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=100:1.0, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (508mg, 71%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ13.40(s,1H),6.10(s,1H),5.63(s,1H),5.53(s,1H),3.85(d,J＝11.2Hz,4H),3.52(d,J＝10.8Hz,4H),2.96(s,1H),2.20(s,1H),2.16(s,2H),2.00(s,1H),1.84(d,J＝13.9Hz,4H),1.69(s,1H),1.58(dd,J＝22.2,8.5Hz,4H),1.51(s,1H),1.47(s,1H),1.26(dd,J＝9.1,4.4Hz,4H),1.21(s,1H),1.08–0.98(m,4H),0.96-0.94(m,9H),0.94-0.85(m,6H).
13CNMR(125MHz,DMSO-d6)δ211.46(s),209.14(s),170.06(s),161.12(s),143.51(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]
-calcdforC
34H
51Br
2O
6:715.2032；found715.2027.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3SchiglautoneA
Compound II per (358mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (168mg, 1.0mmol) and pyrrolidine (2840mg, 40mmol), mixture reflux 6h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 4 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 and flings to the brown ceramic powder (215.8mg, 62%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ13.06(s,1H),6.10(s,1H),5.65(d,J＝43.0Hz,2H),3.61(s,2H),3.52(s,2H),3.01(s,1H),2.77(s,1H),2.67(d,J＝14.2Hz,4H),2.51(s,8H),2.37(s,2H),2.23(s,1H),1.92–1.81(m,5H),1.73(s,1H),1.68(d,J＝3.5Hz,8H),1.61–1.53(m,4H),1.44(d,J＝64.7Hz,2H),1.28(dd,J＝21.0,9.0Hz,4H),1.08–0.98(m,4H),0.96(d,J＝20.0Hz,6H),0.94(d,J＝20.0Hz,3H),0.90(d,J＝20.0Hz,3H),0.86(d,J＝20.0Hz,3H).
13CNMR(125MHz,DMSO-d6)δ211.57(s),209.27(s),170.21(s),161.23(s),143.64(s),132.16(s),127.88(s),86.09(s),82.55(s),67.09(s),66.24(s),57.29(s),54.51(d,J＝17.1Hz),52.85(s),52.04(s),45.90(s),40.79(s),38.71(s),38.45(s),35.16(s),33.69(s),29.96(s),29.11(s),26.86(s),25.61(s),25.33(s),24.19(s),22.44(s),21.18(s),20.70(s),20.13(s),18.81(s),18.25(s),15.20(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
69N
2O
6:697.5156；found:697.5151。
The synthesis of O-(piperazinyl) ethyl derivative (IV) of embodiment 4SchiglautoneA
By Compound II per (358mg, 0.5mmol) be dissolved in the middle of 30mL acetonitrile, add Anhydrous potassium carbonate (1380mg wherein, 10.0mmol), potassium iodide (336mg, 2.0mmol) with Piperazine anhydrous (3446mg, 40mmol), mixture reflux 6h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects light brown and concentrates elution band namely to obtain the Light brown solid (261.4mg, 72%) of compound IV.
1HNMR(500MHz,DMSO-d6)δ13.14(s,1H),6.14(s,1H),5.57(d,J＝21.3Hz,2H),3.59(s,2H),3.52(s,2H),3.01(s,1H),2.68(s,8H),2.57(d,J＝3.3Hz,4H),2.39(s,2H),2.34(d,J＝4.3Hz,8H),2.33(s,1H),2.22(s,1H),1.88(d,J＝11.7Hz,4H),1.79(s,1H),1.73(s,1H),1.66(s,1H),1.60–1.53(m,3H),1.50(s,1H),1.37(s,1H),1.28(dd,J＝21.3,8.7Hz,4H),1.07(d,J＝6.6Hz,2H),1.06(s,1H),0.99(t,J＝12.0Hz,3H),0.96(t,J＝12.5Hz,6H),0.94(t,J＝12.5Hz,3H),0.88(d,J＝20.0Hz,6H).
13CNMR(125MHz,DMSO-d6)δ211.55(s),209.25(s),170.19(s),161.22(s),143.62(s),132.14(s),127.86(s),86.08(s),82.53(s),67.07(s),66.22(s),57.27(s),54.54(s),54.24(s),52.84(s),52.00(s),45.88(s),45.35(s),40.76(s),38.67(s),38.45(s),35.12(s),33.65(s),29.96(s),29.07(s),26.83(s),25.61(s),24.15(s),22.43(s),21.16(s),20.68(s),20.11(s),18.76(s),18.23(s),15.18(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
71N
4O
6:727.5374；found:727.5379。
Embodiment 5 compositions is to the therapeutical effect of acute renal failure rat
(1) experimental technique
The preparation of compositions: loaded by the powder of 95mg compound IV crossing 200 order nets after crossing the powder of the 5mg compound III of 200 order nets and grinding after grinding to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions, obtains the solution of compositions by the compositions of this 100mg of water dissolution during use.
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 5 groups at random: sham operated rats (intramuscular injection normal saline); Model group (intramuscular injection glycerol); Administration intervention group (compositions, compound III or compound IV 0.6mg/Kg, intramuscular injection glycerol), each group rat tail vein injection saline or treat reagent thing immediately after glycerol modeling, is administered once after 12 and 24 hours again.
(2) observation index
Metabolic cage collection twenty-four-hour urine is put into after the administration of rat last 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. compositions can increase acute renal failure Mouse Kidney blood flow
Compositions significantly can increase acute renal failure Mouse Kidney blood flow, and compound III and compound IV act on without this.
Table 1 compositions is on the impact of acute renal failure Mouse Kidney blood flow
* P<0.05vs acute renal failure model group
2. compositions 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.Compositions can improve the renal function (P<0.05) of acute renal failure rat, and compound III and compound IV act on without this.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: compositions can protect the function of kidney, can be used for preparing anti-acute renal failure medicine.And compound III and compound IV can not protect kidney, should not be used to prepare anti-acute renal failure medicine.
The preparation of embodiment 6 composition tablet involved in the present invention
Get 2 grams of compositionss, add the customary adjuvant 18 grams preparing tablet, mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Get 2 grams of compositionss, add prepare capsule customary adjuvant as starch 18 grams, mixing, encapsulatedly makes 100.
Claims (6)
1. a compositions, it is characterized by said composition and be made up of compound III and compound IV, in said composition, the mass percent of compound III and compound IV is respectively 5% and 95%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: the powder of compound III and the powder of compound IV are respectively 5% and 95% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in treatment acute renal failure medicine.
4. the application of compositions as claimed in claim 3 in treatment acute renal failure medicine, is characterized by: the reduction of the renal blood flow amount caused by described composition for improved acute renal failure.
5. the application of compositions as claimed in claim 3 in treatment acute renal failure medicine, is characterized by: the rising of the serum BUN that described composition for improved acute renal failure causes.
6. the application of compositions as claimed in claim 3 in treatment acute renal failure medicine, is characterized by: the rising of the change of serum C re that described composition for improved acute renal failure causes.
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- 2015-10-14 CN CN201510662684.6A patent/CN105213395A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| FAN-YU MENG等: "Schiglautone A, a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused Skeleton from the Stems of Schisandra glaucescens", 《ORGANIC LETTERS》 * |
| 赵淑美: "五味子抗肾衰竭小议", 《山东中医杂志》 * |
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Application publication date: 20160106 |