CN104083383B - The application in preparing anti-acute renal failure medicine of O-(piperidyl) ethyl derivative of Cleistanone Cleistanone - Google Patents
The application in preparing anti-acute renal failure medicine of O-(piperidyl) ethyl derivative of Cleistanone Cleistanone Download PDFInfo
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- CN104083383B CN104083383B CN201410374420.6A CN201410374420A CN104083383B CN 104083383 B CN104083383 B CN 104083383B CN 201410374420 A CN201410374420 A CN 201410374420A CN 104083383 B CN104083383 B CN 104083383B
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- cleistanone
- piperidyl
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- 0 CCC(CC1)(CC2(CC3)C(C)(C)CCC2(C)C)C3(C)C(C)(CC2OCCBr)C1(*)C(C)(CC1)C2C(C)(C)C1=O Chemical compound CCC(CC1)(CC2(CC3)C(C)(C)CCC2(C)C)C3(C)C(C)(CC2OCCBr)C1(*)C(C)(CC1)C2C(C)(C)C1=O 0.000 description 1
Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O (piperidyl) ethyl derivative of Cleistanone Cleistanone, preparation method and in the purposes prepared on anti-acute renal failure medicine.The present invention has synthesized O (piperidyl) ethyl derivative of a new Cleistanone Cleistanone, and discloses its preparation method.Pharmacological experiment shows, O (piperidyl) ethyl derivative of the Cleistanone Cleistanone 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 Cleistanone Cleistanone's
O-(piperidyl) ethyl derivative, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) is the Comprehensive Clinical caused by many reasons
Levying, it is seen that in clinical departments patient, sickness rate is high and often has serious consequences, its feature is (to count in a short time
Hour to a couple of days) renal function drastically declines, and clinical manifestation is acute oliguria (urine volume < 400mLPd) or anuria
(urine volume < 100mLPd), internal nitrogen matter metabolite discharges and produces obstacle, azotemia occurs rapidly, water and
Electrolyte, acid base imbalance, and cause whole body each system corresponding function to lack of proper care.Cause the main of acute renal failure
Factor is the drastically minimizing of renal blood flow, and the oxidative stress that causes due to nephridial tissue ischemia and cell injury,
Ultimately result in the deterioration of renal tissue structural damage and function.There is no generally acknowledged treatment acute kidney clinically at present
Decline effective medicine, is only capable of, by correcting water-electrolyte balance, correcting the symptomatic treatment measures such as acidosis and improving disease
Shape, the later stage also need to by hemodialysis maintain body function.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
The potential drug obtaining high-efficiency low-toxicity has important value.
The compound Cleistanone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh Thi
Thanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis with
a New Carbon Skeleton.Volume2011,Issue22,Pages4108 4111, August2011)
Compound, we have carried out structural modification to compound Cleistanone Cleistanone, it is thus achieved that one new
O-(piperidyl) ethyl derivative of Cleistanone Cleistanone, and its anti-acute renal failure activity is carried out
Evaluating, it has anti-acute renal failure activity.
Summary of the invention
The invention discloses O-(piperidyl) ethyl derivative of a Cleistanone Cleistanone, its structure
For:
O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone of the present invention can pass through following side
Prepared by method:
(1) Cleistanone Cleistanone (I) reacts with glycol dibromide and obtains Cleistanone Cleistanone
O-bromoethyl derivant (II)；
(2) O-bromoethyl derivant (II) of Cleistanone Cleistanone and piperidines generation substitution reaction system
Obtain O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone.
The further preparation method of O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone
For:
(1) 440mg compound Cleistanone Cleistanone (I) is dissolved in 10mL benzene, adds in solution
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 immediately
It is extracted twice, merges organic phase solution；Then to organic phase solution successively with water and saturated aqueous common salt washing 3
Secondary, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed solvent and is obtained product crude product；Product crude product silicon
Gel column chromatography eluting, flowing is mutually: petroleum ether/acetone=100:1, v/v, collects yellow and concentrates elution band and get final product
Yellow solid to O-bromoethyl derivant (II) of Cleistanone Cleistanone.
(2) O-bromoethyl derivant (II) of the Cleistanone Cleistanone of 273mg is dissolved in 20mL
In the middle of acetonitrile, it is added thereto to the Anhydrous potassium carbonate of 345mg, the potassium iodide of 84mg and the piperidines of 852mg,
Mixture is heated to reflux 16h；Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Alkane extracts three times, merges organic facies；Organic facies after merging with water and saturated aqueous common salt washing successively, then use
Anhydrous sodium sulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product；Product crude product silica gel column chromatography is purified,
Flowing is mutually: petroleum ether/acetone=100:0.5, v/v, collects yellow and concentrates elution band i.e. to obtain Cleistanone
The yellow gummy solid 157.0mg of O-(piperidyl) ethyl derivative (III) of Cleistanone.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone
For treating the purposes of acute renal failure, i.e. for preparing the purposes for the treatment of acute renal failure medicine.
O-(piperidyl) ethyl derivative (III) of the Cleistanone Cleistanone of the present invention is to acute renal failure
Disease has obvious therapeutical effect.
Research by us finds O-(piperidyl) ethyl derivative (III) energy of Cleistanone Cleistanone
Enough improve the function of kidney.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanone Cleistanone
The preparation method of compound Cleistanone Cleistanone (I) is with reference to Crinis Carbonisatus such as Van Trinh Thi Thanh
Document (Van Trinh Thi Thanh et al., the 2011.Cleistanone:A Triterpenoid from of table
Cleistanthus indochinensis with a New Carbon Skeleton.Volume2011,Issue22,
Pages4108 4111, August2011) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Cleistanone Cleistanone
Compound I (440mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.04g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, vertical
I.e. it is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated food
Saline washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1, v/v), collects yellow and concentrates
Elution band i.e. obtains the yellow solid (344mg, 63%) of compound II.
1H NMR(500MHz,DMSO-d6) δ 5.04 (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=1.2
Hz, 1H), 1.39 (d, J=15.3Hz, 2H), 1.34 (d, J=15.3Hz, 1H), 1.26 (dd, J=32.6,13.7
Hz, 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 C32H52BrO2:547.3151；found547.3159.
The synthesis of O-(piperidyl) ethyl derivative (III) of embodiment 3 Cleistanone Cleistanone
Compound II (273mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and piperidines (852mg, 10mmol),
Mixture is heated to reflux 16h.Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Alkane extracts three times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then use
Anhydrous sodium sulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product crude product silica gel column chromatography is purified
(flowing is mutually: petroleum ether/acetone=100:0.5, v/v), collects yellow and concentrates elution band i.e. to obtain Cleistanone
The yellow gummy solid (157.0mg, 57%) of O-(piperidyl) ethyl derivative.
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,2H),
2.57 (s, 2H), 2.47 (dd, J=44.3,41.4Hz, 6H), 2.29 (s, 1H), 2.22 (s, 1H), 2.19 (s, 1H),
1.82 (s, 1H), 1.65 (s, 2H), 1.58 (d, J=8.0Hz, 2H), 1.53 1.46 (m, 6H), 1.39 (t, J=
7.8Hz, 5H), 1.30 (dd, J=21.8,9.9Hz, 4H), 1.16 (d, J=0.4Hz, 2H), 1.06 (s, 6H),
0.91(s,1H),0.88(s,12H),0.85–0.57(m,4H).
13C NMR(125MHz,DMSO-d6)δ216.69(s),154.70(s),105.53(s),74.75(s),67.02
(s), 59.85 (s), 55.00 (d, J=14.4Hz), 52.87 (s), 51.30 (s), 48.09 (s), 44.44 (s), 42.38
(s),41.98(s),40.93(s),40.25(s),39.07(s),38.99(s),37.34(s),36.48(s),33.66(s),
33.05(s),30.10(s),27.52(s),26.16(s),24.80(s),24.59(s),24.06(s),23.65(s),
21.05(s),18.56(s),18.21(s),17.28(s).
HRMS(ESI):m/z[M+H]+calcd for C37H62NO2:552.4781；found:552.4787.
The treatment of acute renal failure rat is made by O-(piperidyl) ethyl derivative of embodiment 4Cleistanone
With
(1) experimental technique
Intramuscular injection glycerol is used to cause Acute Renal Failure Rats animal model.Select 180～220g health male
Property SD rat 30, is randomly divided into 3 groups: sham operated rats (intramuscular injection normal saline)；Model group (flesh
Meat glycerol injection)；O-(piperidyl) ethyl derivative group (O-(piperidyl) of Cleistanone of Cleistanone
Ethyl derivative 0.6mg/Kg, intramuscular injection glycerol), each group rat tail vein note immediately after glycerol modeling
Penetrate O-(piperidyl) ethyl derivative of normal saline or Cleistanone, be administered once again after 12 and 24 hours.
(2) observation index
Rat last puts into metabolism after giving O-(piperidyl) ethyl derivative of Cleistanone or normal saline
Twenty-four-hour urine collected by cage, stays latter 6 hours of urine with 4% chloral hydrate intraperitoneal injection of anesthesia, uses laser-Doppler
Blood flowmeter measures 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
O-(piperidyl) ethyl derivative of 1.Cleistanone can increase acute renal failure Mouse Kidney blood flow
The impact on acute renal failure Mouse Kidney blood flow of O-(piperidyl) ethyl derivative of table 1 Cleistanone
* P < 0.05vs acute renal failure model group
O-(piperidyl) ethyl derivative of 2.Cleistanone 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, illustrates that model group animal renal function injury is serious.Cleistanone
O-(piperidyl) ethyl derivative can improve the renal function (P < 0.05) of acute renal failure rat.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
O-(piperidyl) ethyl derivative of conclusion: Cleistanone can protect the function of kidney, can be used to
Prepare anti-acute renal failure medicine.
Embodiment 5 compound involved in the present invention II and the preparation of III tablet
Take in the middle of O-(piperidyl) ethyl derivative or its pharmaceutically acceptable salt of 20 grams of Cleistanone
One, addition prepares the customary adjuvant 180 grams of tablet, and mixing, conventional tablet presses makes 1000.
Embodiment 6 compound involved in the present invention II and the preparation of III capsule
Take in the middle of O-(piperidyl) ethyl derivative or its pharmaceutically acceptable salt of 20 grams of Cleistanone
One, addition prepares the customary adjuvant such as starch 180 grams of capsule, mixing, encapsulated makes 1000.
Claims (4)
1. O-(piperidyl) ethyl derivative (III) of a Cleistanone Cleistanone with structure shown in formula III
And the application that pharmaceutically acceptable salt is in preparation treatment acute renal failure medicine:
A kind of O-(piperazine of the Cleistanone Cleistanone with structure shown in formula III
Piperidinyl) application in preparation treatment acute renal failure medicine of ethyl derivative (III) and pharmaceutically acceptable salt thereof,
It is characterized by: O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone improves acute renal failure institute
The reduction of the renal blood flow amount caused.
A kind of O-(piperazine of the Cleistanone Cleistanone with structure shown in formula III
Piperidinyl) application in preparation treatment acute renal failure medicine of ethyl derivative (III) and pharmaceutically acceptable salt thereof,
It is characterized by: O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone improves acute renal failure and draws
The rising of the serum BUN risen.
A kind of O-(piperazine of the Cleistanone Cleistanone with structure shown in formula III
Piperidinyl) application in preparation treatment acute renal failure medicine of ethyl derivative (III) and pharmaceutically acceptable salt thereof,
It is characterized by: O-(piperidyl) ethyl derivative (III) of Cleistanone Cleistanone improves acute renal failure and draws
The rising of change of serum C re risen.
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| CN104666310A (en) * | 2015-03-10 | 2015-06-03 | 南京大学 | Application of O-(triazolyl) ethyl derivative of Cleistanone in preparation of medicine resistant to acute renal failure |
| CN104758297A (en) * | 2015-04-15 | 2015-07-08 | 南京大学 | Application of O-(1H-tetrazolyl) ethyl derivative of cleistanone in preparation of anti-osteoporosis medicines |
| CN104784190A (en) * | 2015-04-29 | 2015-07-22 | 南京大学 | Application of O-(benzimidazolyl) ethyl derivative of cleistanone in preparation of medicine for resisting acute renal failure |
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Effective date of registration: 20160629 Address after: 250013 Qilu Hospital, Shandong University, Lixia West Road, Lixia District, Shandong, Ji'nan 107, China Applicant after: Shandong Qilu Hospital Address before: Metro Technology Building No. 69 Olympic Avenue in Jianye District of Nanjing city in Jiangsu province 210019 01 5 storey buildings Applicant before: Nanjing Guangkangxie Biomedical Technology Co., Ltd. |
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