CN106074525A - The composition of Schiglautone A derivative is used for preparing anti-acute renal failure medicine - Google Patents
The composition of Schiglautone A derivative is used for preparing anti-acute renal failure medicine Download PDFInfo
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- CN106074525A CN106074525A CN201610416172.6A CN201610416172A CN106074525A CN 106074525 A CN106074525 A CN 106074525A CN 201610416172 A CN201610416172 A CN 201610416172A CN 106074525 A CN106074525 A CN 106074525A
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- acute renal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to composition, preparation method and in the purposes prepared on anti-acute renal failure medicine.The invention discloses a kind of composition and preparation method thereof.Pharmacological experiment shows, the composition 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 composition, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) is the clinical syndrome being caused by many reasons,
Being found in clinical departments patient, the incidence of disease is high and often has serious consequences, and its feature is (a few hours are to a couple of days) kidney in a short time
Function drastically declines, and clinical manifestation is acute oliguresis (urine volume < 400mLPd) or anuria (urine volume < 100mLPd), internal nitrogen matter generation
Thank to product and discharge generation obstacle, azotemia, water and electrolyte, disturbance of acid-base balance occur rapidly, and causes each system of whole body
Corresponding function is lacked of proper care.Cause the drastically minimizing that the principal element of acute renal failure is renal blood flow, and owing to nephridial tissue ischemic draws
The oxidative stress rising and cellular damage, ultimately result in the deterioration of renal tissue structural damage and function.There is no clinically at present
The effective medicine for the treatment of acute renal failure generally acknowledged, is only capable of, by correcting water-electrolyte balance, correcting the symptomatic treatments such as acid poisoning and arranging
Executing and improving symptom, the later stage also needs to maintain body function by haemodialysis.Improve kidney perfusion obstacle and mitigate kidney
Tissue damage aspect has the clinical medicine of obvious curative effects rare.
Find compound or lead compound and carry out structural modification and obtain its derivative from natural products, thus obtaining
The potential drug of high-efficiency low-toxicity has important value most.
The compound I that the present invention relates to be one within 2011, deliver (Fan-Yu Meng et al.,
2011.Schiglautone A,a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused
Skeleton from the Stems of Schisandra glaucescens.Organic Letters 13(2011)
1502 1505) compound, we have carried out structural modification to compound I, it is thus achieved that two i.e. compounds of new derivative
III and compound IV, and be prepared for composition with compound III and compound IV and said composition anti-acute renal failure activity is entered
Having gone evaluation, it has anti-acute renal failure activity.
Content of the invention
The invention discloses a new composition, said composition is made up of compound III and compound IV, this combination
In thing, the mass percent of compound III and compound IV is respectively 55% and 45%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide composition for treating the purposes of acute renal failure, be i.e. used for preparing treatment acute renal failure
The purposes of medicine.
The composition of the present invention has obvious therapeutic action to acute renal failure disease.
Research discovery composition by us can 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 by specifically in fact
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Schiglautone A
Document (the Fan-Yu that the preparation method of compound Schiglautone A (I) is delivered with reference to Fan-Yu Meng et al.
Meng et al.,2011.Schiglautone A,a New Tricyclic Triterpenoid with a Unique 6/
7/9-Fused Skeleton from the Stems of Schisandra glaucescens.Organic Letters
13 (2011) 1,502 1505) method.
The synthesis of O-bromoethyl derivative (II) of embodiment 2 Schiglautone A
Compound I (502mg, 1.00mmol) is dissolved in 15mL benzene, in solution, adds TBAB (TBAB)
(0.08g), 1,2-Bromofume (7.520g, 40.00mmol) and 50% sodium hydroxide solution of 6mL.Mixture is Celsius 35
Degree stirring 8h.After 8h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Washing organic phase solution 3 times with water and saturated aqueous common salt successively, then being dried with anhydrous sodium sulfate, last reduced pressure concentration is removed molten
Agent obtains product crude product.Product crude product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), receives
Collection brown is concentrated elution band and flings to the brown ceramic powder (508mg, 71%) that solvent i.e. obtains compound II.
1H NMR(500MHz,DMSO-d6)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).
13C NMR(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]-calcd for C34H51Br2O6:715.2032；found 715.2027.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative (III) of embodiment 3 Schiglautone A
Be dissolved in compound II (358mg, 0.5mmol) in the middle of 15mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and 1H-tetrazole (1401mg, 20mmol), mixture is heated to reflux 5h.Reaction
Reactant liquor is poured in 20mL frozen water after end, extract three times with equivalent dichloromethane, merge organic phase.Use water and saturated successively
Organic phase after brine It merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Cause
For tautomerization, 1H-tetrazole base and two kinds of substitution products of 2H-tetrazole base can be generated at reaction conditions.Product is thick
Product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1, v/v), collects faint yellow concentration elution band, then will
Faint yellow elution band concentrates, and is purified (flowing is mutually: petroleum ether/acetone=100:0.5, v/v) by silica gel column chromatography, collects successively
Two flaxen elution bands, concentrate front 1 elution band and i.e. obtain the faint yellow solid (79.8mg, 23%) of compound III.
1H NMR(500MHz,DMSO-d6)δ16.29(s,1H),9.99(s,1H),9.93(s,1H),6.25(s,1H),
5.76 (s, 1H), 5.40 (s, 1H), 4.57 (s, 1H), 4.38 (s, 1H), 4.32 (s, 1H), 4.21 (s, 1H), 3.96 (d, J=
11.9Hz,4H),3.33(s,1H),2.55(s,1H),2.51(s,2H),2.39(s,1H),1.98(s, 3H),1.82–1.76
(m, 3H), 1.73 (s, 1H), 1.65 (d, J=6.5Hz, 2H), 1.60 (s, 1H), 1.53 (s, 1H), 1.47 1.37 (m, 4H),
1.30 (s, 1H), 1.19 (s, 1H), 1.10 (t, J=12.5Hz, 3H), 1.08 (t, J=12.5Hz, 9H), 1.03 (s, 3H),
0.86(s,3H).
13C NMR(125MHz,DMSO-d6)δ211.72(s),209.42(s),170.36(s),161.38(s),145.37
(s),143.80(s),132.29(s),128.04(s),86.25(s),82.68(s),66.14(s),65.60(s),57.33
(s),52.91(s),52.08(s),46.81(s),45.95(s),40.84(s),38.76(s),38.50(s),35.21(s),
33.74(s),30.01(s),29.16(s),26.91(s),25.66(s),24.23(s),22.51(s),21.22(s),20.74
(s),20.20(s),18.85(s),18.29(s),15.27(s).
HRMS(ESI):m/z[M+H]+calcd for C36H55N8O6:695.4245；found:695.4248.
The synthesis of O-(benzimidazolyl) ethyl derivative of embodiment 4 Schiglautone A
Be dissolved in compound II (358mg, 0.5mmol) in the middle of 15mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and benzimidazole (1180mg, 10mmol), mixture is heated to reflux 6h.Reaction
After end pour reactant liquor in frozen water into, extract three times with equivalent dichloromethane, merge organic phase.Use water and saturated common salt successively
Organic phase after water washing merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects brown and concentrates elution band, concentrates
I.e. obtain the brown solid (169.9mg, 43%) of compound IV.
1H NMR (500MHz, DMSO-d6) δ 13.32 (s, 1H), 8.38 (s, 2H), 7.66 (d, J=25.0Hz, 4H),
7.39 (s, 2H), 7.32 (s, 2H), 6.25 (s, 1H), 5.64 (d, J=18.7Hz, 2H), 4.34 (s, 1H), 4.28 (s, 1H),
4.18 (d, J=13.7Hz, 2H), 4.04 (s, 2H), 3.99 (s, 2H), 3.13 (s, 1H), 2.65 (s, 2H), 2.26 (s, 1H),
2.17 (s, 1H), 2.06 (s, 1H), 1.98 (s, 3H), 1.87 (d, J=16.4Hz, 2H), 1.66 (dd, J=8.0,6.6Hz,
4H), 1.62 (s, 1H), 1.49 (s, 1H), 1.41 (dd, J=19.6,10.4Hz, 2H), 1.37 (d, 2H), 1.20 1.11 (m,
4H), 1.07 (d, J=20.0Hz, 6H), 103 (d, J=20.0Hz, 3H), 1.01 (d, J=20.0Hz, 3H), 0.95 (d, J=
20.0Hz,3H).
13C NMR(125MHz,DMSO-d6)δ211.30(s),208.98(s),169.90(s),160.96(s),146.28
(s),143.34(s),139.64(s),133.48(s),131.85(s),127.61(s),123.92(s), 123.35(s),
118.55(s),110.85(s),85.79(s),82.26(s),67.74(s),67.20(s),57.00(s),52.56(s),
51.73(s),45.63(s),44.94(s),40.49(s),38.42(s),38.17(s),34.86(s),33.40(s),29.68
(s),28.81(s),26.57(s),25.33(s),23.88(s),22.17(s),20.89(s),20.39(s),19.86(s),
18.52(s),17.87(s),14.93(s).
HRMS(ESI):m/z[M+H]+calcd for C48H63N4O6:791.4748；found:791.4744.
The therapeutic action to acute renal failure rat for embodiment 5 composition
(1) experimental technique
The preparation of composition: the powder of the 55mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding
The powder of the 45mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg composition with the mixing of turbine stirring instrument,
Dissolve, with water, the solution that the composition of this 100mg obtains composition during use.
Intramuscular injection glycerine is used to cause Acute Renal Failure Rats animal model.Select the healthy male SD of 180～220g
Rat 30, is randomly divided into 5 groups: sham-operation group (intramuscular injection physiological saline)；Model group (intramuscular injection glycerine)；It is administered and intervene
Group (composition, compound III or compound IV 0.6mg/Kg, intramuscular injection glycerine), each group rat is vertical after glycerine modeling
I.e. tail vein injection saline or treat reagent thing, is administered once after 12 and 24 hours again.
(2) observation index
Rat last is administered or puts into after physiological saline metabolic cage and collects twenty-four-hour urine, stays urine to be hydrated with 4% for latter 6 hours
Chloral intraperitoneal injection of anesthesia, uses laser Doppler flowmetry to measure after modeling and bilateral renal CBF after treatment, is averaged
Value is as single animal renal blood flow；Take blood and prepare serum, measure blood BUN and Cre (all by the operation of kit specification).
(3) experimental result
1. composition can increase acute renal failure Mouse Kidney CBF
Composition can dramatically increase acute renal failure Mouse Kidney CBF, and compound III and compound IV acts on without this.
The impact on acute renal failure Mouse Kidney CBF for table 1 composition
* P < 0.05vs acute renal failure model group
2. composition 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, illustrate that model group animal kidney function damage is serious.Composition can improve the kidney work(of acute renal failure rat
Energy (P < 0.05), and compound III and compound IV acts on without this.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: composition can protect the function of kidney, can be used to prepare anti-acute renal failure medicine.And compound III
Kidney can not be protected with compound IV, should not be used to prepare anti-acute renal failure medicine.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositions, the customary adjuvant 18 grams of tablet is prepared in addition, mixes, and conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositions, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixes, encapsulated makes 100.
Claims (6)
1. a composition, is characterized by that said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 55% and 45%,
2. the preparation method of composition as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be respectively 55% and 45% according to mass percent and be sufficiently mixed.
3. a composition as claimed in claim 1 application in treatment acute renal failure medicine.
4. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes
The reduction of kind renal blood flow amount caused by acute renal failure.
5. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes
The rising of the serum BUN that kind acute renal failure causes.
6. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes
The rising of change of serum C re that kind acute renal failure causes.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758298A (en) * | 2015-04-15 | 2015-07-08 | 南京大学 | Application of O-(1H-tetrazolyl) ethyl derivative of cleistanone in preparation of medicines for treating or preventing renal fibrosis |
| 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 |
| CN105267195A (en) * | 2015-11-09 | 2016-01-27 | 常州南京大学高新技术研究院 | Composition and application of composition to acute renal failure resisting drugs |
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- 2016-06-13 CN CN201610416172.6A patent/CN106074525A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758298A (en) * | 2015-04-15 | 2015-07-08 | 南京大学 | Application of O-(1H-tetrazolyl) ethyl derivative of cleistanone in preparation of medicines for treating or preventing renal fibrosis |
| 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 |
| CN105267195A (en) * | 2015-11-09 | 2016-01-27 | 常州南京大学高新技术研究院 | Composition and application of composition to acute renal failure resisting drugs |
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Application publication date: 20161109 |