CN104906091A - Application of O-(diethylin)ethyl derivative of Daphmalenine A in preparing acute renal failure resisting drugs - Google Patents
Application of O-(diethylin)ethyl derivative of Daphmalenine A in preparing acute renal failure resisting drugs Download PDFInfo
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- CN104906091A CN104906091A CN201510280477.4A CN201510280477A CN104906091A CN 104906091 A CN104906091 A CN 104906091A CN 201510280477 A CN201510280477 A CN 201510280477A CN 104906091 A CN104906091 A CN 104906091A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a Daphmalenine A derivative, a preparation method and application of the Daphmalenine A derivative in preparing acute renal failure resisting drugs. The new Daphmalenine A derivative is obtained through synthesis, and the preparation method of the Daphmalenine A derivative is disclosed. A pharmacology experiment shows that the Daphmalenine A derivative has the acute renal failure resisting function and the value for developing the acute renal failure resisting drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Daphmalenine A 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 D aphmalenine A that the present invention relates to is one and within 2011, delivers (Yu Zhang et al., 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) compound, we have carried out structural modification to Compound D aphmalenine A, obtain a new Daphmalenine A 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 Daphmalenine A derivant, its structure is:
Daphmalenine A derivant (III) of the present invention is by method preparation below:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Daphmalenine A;
(2) O-bromoethyl derivant (II) and the diethylamine generation substitution reaction of Daphmalenine A obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
The preparation method of O-(diethylin) ethyl derivative (III) of further Daphmalenine A is: 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene by (1), the tetrabutyl ammonium bromide of 0.08g is added in solution, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 6mL; Mixture stirs 12h at 35 degrees Celsius; After 12h, 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 4 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=100:1.5, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Daphmalenine A.
(2) by Compound II per (263mg, 0.5mmol) be dissolved in the middle of 20mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) with diethylamine (1460mg, 20mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction four 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.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1, v/v), collect the yellow yellow gummy solid (196.8mg, 76%) concentrating elution band namely to obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
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 Daphmalenine A 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.
Daphmalenine A derivant (III) of the present invention has obvious therapeutical effect to acute renal failure disease.
Find that Daphmalenine A 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 D aphmalenine A
Document (the Yu Zhang et al. that the people such as the preparation method reference Yu Zhang of Compound D aphmalenine A (I) deliver, 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2Daphmalenine A
By Compound I (419mg, 1.00mmol) be dissolved in 10mL 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 12h at 35 degrees Celsius.After 12h, 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 4 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=100:1.5, v/v), collects the yellow yellow solid (320mg, 61%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ3.84(d,J＝1.6Hz,2H),3.76–3.50(m,5H),3.42(s,2H),3.09(s,1H),2.99(s,1H),2.88(s,1H),2.70(s,1H),2.64(d,J＝19.1Hz,3H),2.45(d,J＝5.6Hz,3H),2.33(s,1H),2.19–2.12(m,5H),2.07(s,1H),1.97(d,J＝9.2Hz,3H),1.84–1.76(m,3H),1.69(s,1H),1.15(s,1H),1.04(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.71(s),211.07(s),176.65(s),66.24(s),65.38(s),63.59(s),59.42(s),54.79(s),52.18(s),46.22(s),46.01(s),45.50(s),45.27(s),40.33(s),37.86(s),37.61(s),36.27(s),34.26(s),30.89(s),28.52(s),26.04(s),25.24(s),8.50(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
25H
37BrNO
6:526.1804；found 526.1801.
The synthesis of O-(diethylin) ethyl derivative (III) of embodiment 3Daphmalenine A
Compound II per (263mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and diethylamine (1460mg, 20mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction four 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.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1, v/v), collect the yellow yellow gummy solid (196.8mg, 76%) concentrating elution band namely to obtain O-(diethylin) ethyl derivative (III) of Daphmalenine A.
1H NMR(500MHz,DMSO-d6)δ3.78(s,1H),3.68(s,3H),3.45(s,2H),3.09(s,1H),2.94(d,J＝59.8Hz,5H),2.79(s,1H),2.71(d,J＝10.0Hz,2H),2.63(d,J＝1.4Hz,4H),2.43(t,J＝16.7Hz,3H),2.36(d,J＝5.9Hz,1H),2.19–2.12(m,5H),2.09–2.00(m,4H),1.90(dd,J＝10.7,8.0Hz,1H),1.85(d,J＝23.9Hz,1H),1.72(s,1H),1.65(s,1H),1.13(d,J＝7.0Hz,7H),1.06(s,3H).
13C NMR(125MHz,,DMSO-d6)δ219.80(s),211.16(s),176.74(s),66.30(s),63.64(s),61.62(s),59.51(s),54.88(s),52.27(s),51.99(s),47.76(s),46.30(s),46.06(s),45.55(s),45.26(s),40.31(s),37.86(s),37.63(s),36.28(s),30.87(s),28.53(s),26.01(s),25.23(s),12.37(s),8.50(s).
HRMS(ESI):m/z[M+H]
+calcd for C
29H
47N
2O
6:519.3434；found:519.3429。
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 5 groups at random: sham operated rats (intramuscular injection normal saline); Model group (intramuscular injection glycerol); Administration intervention group (compound III or compound IV 0.6mg/Kg, intramuscular injection glycerol), each group rat tail vein injection saline or medicine immediately after glycerol modeling, be administered once after 12 and 24 hours again.
Triethylamine (compound IV) is commercially available analytical pure.
(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. compound III can increase acute renal failure Mouse Kidney blood flow
Compound III significantly can increase acute renal failure Mouse Kidney blood flow, and compound IV acts on without this.
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, and compound IV acts 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: compound III can protect the function of kidney, can be used for preparing anti-acute renal failure medicine.And compound IV can not protect kidney, be not available to prepare 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 Daphmalenine A 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 Daphmalenine A 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: DaphmalenineA derivant (III) improves the reduction of the renal blood flow amount caused by acute renal failure.
3. a kind of Daphmalenine A 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: DaphmalenineA derivant (III) improves the rising of the serum BUN that acute renal failure causes.
4. a kind of Daphmalenine A 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: DaphmalenineA derivant (III) improves the rising of the change of serum C re that acute renal failure causes.
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2015
- 2015-05-27 CN CN201510280477.4A patent/CN104906091A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| YU ZHANG等: ""Daphmalenines A and B: Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense"", 《EUR.J.ORG.CHEM》 * |
| 左菊英 等: ""川芎嗪抗慢性肾衰竭的临床研究"", 《临床医学》 * |
| 李震宇 等: "虎皮楠生物碱研究进展", 《有机化学》 * |
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Application publication date: 20150916 |