CN104095856B - The application in preparing anti-acute renal failure medicine of the diethylamine derivative of Cleistanone Cleistanone - Google Patents
The application in preparing anti-acute renal failure medicine of the diethylamine derivative of Cleistanone Cleistanone Download PDFInfo
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Cleistanone Cleistanone derivative, preparation method and in the purposes prepared on anti-acute renal failure medicine.The present invention has synthesized a new Cleistanone Cleistanone derivative, and discloses its preparation method.Pharmacological experiment shows, the Cleistanone Cleistanone derivative 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 and spread out
Biological, 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, the incidence of disease 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 oliguresis (urine volume < 400mLPd) or anuria
(urine volume < 100mLPd), internal nitrogen matter metabolite discharges and produces obstacle, azotemia occurs rapidly, water and
Electrolyte, disturbance of acid-base balance, 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 ischemic and cellular damage,
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 acid poisoning and improving disease
Shape, the later stage also need to by haemodialysis maintain body function.Improve kidney perfusion obstacle and alleviate kidney
Tissue damage aspect has the clinical medicine of obvious curative effects rare.
From natural products, find compound or lead compound and carry out structural modification and obtain its derivative, thus
The potential drug obtaining high-efficiency low-toxicity most 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.Volume 2011,Issue22,Pages4108 4111, August 2011)
Compound, we have carried out structural modification to compound Cleistanone Cleistanone, it is thus achieved that one new
Cleistanone Cleistanone derivative, and its anti-acute renal failure activity is evaluated, it has anti-urgency
Property renal failure activity.
Summary of the invention
The invention discloses a Cleistanone Cleistanone derivative, its structure is:
Cleistanone Cleistanone derivative (III) of the present invention can be prepared by following method:
(1) Cleistanone Cleistanone (I) reacts with glycol dibromide and obtains Cleistanone Cleistanone
O-bromoethyl derivative (II)；
(2) O-bromoethyl derivative (II) of Cleistanone Cleistanone and diethylamine generation substitution reaction
Prepare Cleistanone Cleistanone derivative (III).
Further the preparation method of Cleistanone Cleistanone derivative (III) is:
(1) 440mg compound Cleistanone Cleistanone (I) is dissolved in 10mL benzene, adds in solution
50% sodium hydroxide solution of the TBAB of 0.04g, the 1 of 3.760g, 2-Bromofume and 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 reduced pressure concentration 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 derivative (II) of Cleistanone Cleistanone.
(2) the O-bromoethyl derivative of the Cleistanone Cleistanone of 273mg is dissolved in the middle of 20mL acetonitrile,
It is added thereto to the Anhydrous potassium carbonate of 345mg, the KI of 84mg and the diethylamine of 1460mg, mixing
Thing is heated to reflux 8h；Reactant liquor is poured in frozen water after terminating by reaction, extracts three times with equivalent dichloromethane,
Merge organic phase；Organic phase after merging with water and saturated aqueous common salt washing successively, then do with anhydrous sodium sulfate
Dry, reduced pressure concentration is removed solvent and is obtained product crude product；Product crude product silica gel column chromatography is purified, and flowing is mutually:
Petroleum ether/acetone=100:1, v/v, collects faint yellow concentration elution band and i.e. obtains Cleistanone Cleistanone and spread out
The faint yellow colloidal solid of biological (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide Cleistanone Cleistanone derivative (III) to be used for treating acute renal failure
Purposes, i.e. for prepare treatment acute renal failure medicine purposes.
Cleistanone Cleistanone derivative (III) of the present invention has significantly treatment to acute renal failure disease
Effect.
Find that Cleistanone Cleistanone derivative (III) can improve the merit of kidney by our research
Energy.
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 human hairs 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.Volume 2011,Issue 22,
Pages 4,108 4111, August 2011) method.
The synthesis of O-bromoethyl derivative (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), 1,2-Bromofume (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
Salt solution washs 3 times, then is dried with anhydrous sodium sulfate, and last reduced pressure concentration is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purifies (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-(diethylin) 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), KI (84mg, 0.5mmol) and diethylamine (1460mg,
20mmol), mixture is heated to reflux 8h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts three times, merges organic phase.Organic phase after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Product crude product silica gel column chromatography is pure
Change (flowing is mutually: petroleum ether/acetone=100:1, v/v), collect faint yellow concentration elution band and i.e. obtain compound
The faint yellow colloidal solid (169.8mg, 63%) of III.
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.85(s,1H),4.37(s,1H),3.54(s,
2H), 2.91 (s, 4H), 2.64 (s, 2H), 2.41 (d, J=17.2Hz, 2H), 2.30 (s, 1H), 2.21 (d, J=
22.5Hz, 2H), 1.82 (s, 1H), 1.65 (s, 2H), 1.58 (d, J=9.0Hz, 2H), 1.49 (d, J=5.7Hz,
2H), 1.39 (d, J=13.4Hz, 3H), 1.36 1.28 (m, 3H), 1.28 1.26 (m, 1H), 1.26 1.14
(m, 8H), 1.06 (s, 6H), 0.92 (d, J=19.4Hz, 13H), 0.82 (s, 3H), 0.71 (s, 1H).
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.65(s),
66.82 (s), 59.77 (s), 52.54 (d, J=3.0Hz), 51.21 (s), 47.92 (s), 47.73 (s), 44.13 (s),
42.30(s),41.77(s),40.65(s),40.17(s),38.86(s),38.68(s),37.26(s),36.27(s),
33.35(s),32.97(s),29.89(s),27.21(s),26.08(s),24.27(s),23.97(s),20.78(s),
18.46(s),18.01(s),16.98(s),12.33(s).
HRMS(ESI):m/z[M+H]+calcd for C36H62NO2:540.4781；found:540.4787.
The embodiment 4 compound III therapeutic action to acute renal failure rat
(1) experimental technique
Intramuscular injection glycerine 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-operation group (intramuscular injection physiological saline)；Model group (flesh
Meat glycerol injection)；Compound III group (compound III0.6mg/Kg, intramuscular injection glycerine), respectively organizes rat
Tail vein injection saline or compound III immediately after glycerine 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 physiological saline, stay after urine 6
Hour with 4% chloraldurate intraperitoneal injection of anesthesia, after using laser Doppler flowmetry to measure modeling and after treatment
Bilateral renal CBF, averages as single animal renal blood flow；Take blood and prepare serum, measure blood BUN
With Cre (all operating by kit specification).
(3) experimental result
1. compound III can increase acute renal failure Mouse Kidney CBF
The table 1 compound III impact on acute renal failure Mouse Kidney CBF
* P < 0.05vs acute renal failure model group
2. compound III has protective effect to acute renal failure Mouse Kidney function
Acute renal failure rat intravenous injection physiological saline is after 24 hours, and serum BUN and Cre is shown in Table 2.Acute
Renal failure model group, apparently higher than sham-operation group, illustrates that model group animal kidney function damage is serious.Compound III energy
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
Conclusion: compound III can protect the function of kidney, can be used to prepare anti-acute renal failure medicine.
The preparation of embodiment 5 compound involved in the present invention III tablet
Taking the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, the normal of tablet is prepared in addition
Rule auxiliary material 180 grams, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 6 compound involved in the present invention III capsule
Taking the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, capsule is prepared in addition
Customary adjuvant such as starch 180 grams, mixing, encapsulated make 1000.
Claims (4)
1. one kind has Cleistanone Cleistanone derivative (III) of structure shown in formula III and pharmaceutically can connect
The salt being subject to application in preparation treatment acute renal failure medicine:
A kind of Cleistanone Cleistanone derivative (III) with structure shown in formula III
And the application that pharmaceutically acceptable salt is in preparation treatment acute renal failure medicine, it is characterized by: Cleistanone
Cleistanone derivative (III) improves the reduction of the renal blood flow amount caused by acute renal failure.
A kind of Cleistanone Cleistanone derivative (III) with structure shown in formula III
And the application that pharmaceutically acceptable salt is in preparation treatment acute renal failure medicine, it is characterized by: Cleistanone
Cleistanone derivative (III) improves the rising of the serum BUN that acute renal failure causes.
A kind of Cleistanone Cleistanone derivative (III) with structure shown in formula III
And the application that pharmaceutically acceptable salt is in preparation treatment acute renal failure medicine, it is characterized by: Cleistanone
Cleistanone derivative (III) improves the rising of change of serum C re that acute renal failure causes.
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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 |
| 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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Non-Patent Citations (2)
| Title |
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| Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton;Van Trinh Thi Thanh, et al.;《Eur. J. Org. Chem.》;20110607;4108–4111 * |
| 甘草酸二铵防治心脏手术患者肾损伤72例;朱少铭 等;《医药导报》;20040930;第23卷(第9期);626-627 * |
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