CN105853436A - Application of composition of pyrrolidine derivative and morpholinyl derivative of Virosaine A to medicine against acute renal failure - Google Patents
Application of composition of pyrrolidine derivative and morpholinyl derivative of Virosaine A to medicine against acute renal failure Download PDFInfo
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- CN105853436A CN105853436A CN201610278931.7A CN201610278931A CN105853436A CN 105853436 A CN105853436 A CN 105853436A CN 201610278931 A CN201610278931 A CN 201610278931A CN 105853436 A CN105853436 A CN 105853436A
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- renal failure
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- 0 C[C@]1([C@](C)(CC2)I(C)CCI[C@@]2(*)[C@]1(C[C@]1(*CC*2CCCC2)I)[C@@]2(*)[C@]1(O)I)C2=CC(O)=O Chemical compound C[C@]1([C@](C)(CC2)I(C)CCI[C@@]2(*)[C@]1(C[C@]1(*CC*2CCCC2)I)[C@@]2(*)[C@]1(O)I)C2=CC(O)=O 0.000 description 1
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a composition, a preparing method and an application of the composition in preparing medicine against acute renal failure, and discloses the composition and the preparing method thereof. Pharmacological experiments show that the composition has the effect of resisting acute renal failure, and has the value of developing medicine against acute renal failure.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and use thereof
On the way.
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 most has important value.
The compound I that the present invention relates to be one within 2012, deliver (Bing-Xin Zhao et al., 2012.
Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an
Unprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–3099)
Compound, we have carried out structural modification to compound I, it is thus achieved that two i.e. compound III of new derivant
With compound IV, and it is prepared for compositions acute kidney anti-to said composition with compound III and compound IV
The activity that declines is evaluated, and it has anti-acute renal failure activity.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, should
In compositions, the mass percent of compound III and compound IV is respectively 35% and 65%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide compositions for treating the purposes of acute renal failure, be i.e. used for preparing treatment acute
The purposes of renal failure medicine.
The 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 had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Virosaine A
The document that the preparation method of compound Virosaine A (I) is delivered with reference to Bing-Xin Zhao et al.
(Bing-Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped
Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic
Letters 14 (2012) 3,096 3099) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Virosaine A
Compound I (235mg, 1.00mmol) is dissolved in 20mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 5mL
Sodium hydroxide solution.Mixture stirs 8h at 35 degrees Celsius.After 8h, reactant liquor is poured in frozen water, immediately
It is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated common salt
Water washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Product
Crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates
Elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (261mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H),
3.43 (s, 2H), 3.33 (s, 1H), 2.26 (s, 1H), 1.58 (d, J=9.8Hz, 3H), 1.41 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81
(s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg,
20mmol), mixture is heated to reflux 1h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts 2 times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, concentrating under reduced pressure 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=100:1.5, v/v), collect faint yellow concentration elution band and i.e. obtain Virosaine
The faint yellow colloidal solid (111.6mg, 67%) of the O-(nafoxidine base) ethyl derivative (III) of A.
1H NMR(500MHz,DMSO-d6)δ5.92(s,1H),4.11(s,1H),3.66(s,1H),3.53(s,
2H), 3.45 (d, J=66.9Hz, 1H), 2.64 (s, 2H), 2.52 (s, 4H), 2.29 (s, 1H), 1.71 (s, 4H),
1.64(s,2H),1.61(s,1H),1.50(s,2H).
13C NMR(125MHz,DMSO-d6)δ171.83(s),106.73(s),79.97(s),74.35(s),66.72
(d, J=9.2Hz), 54.42 (d, J=17.1Hz), 44.23 (s), 35.58 (s), 25.86 (s), and 25.23 (s), 21.90
(s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O4:333.1814；found:333.1811.
The synthesis of O-(morpholinyl) ethyl derivative of embodiment 4 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and morpholine (1742mg, 20mmol),
Mixture is heated to reflux 1h.Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane
Extract three times, merge organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then use nothing
Aqueous sodium persulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product crude product silica gel column chromatography purify (stream
Move and be mutually: petroleum ether/acetone=100:1.0, v/v), collect yellow and concentrate elution band i.e. to obtain Virosaine A's
The yellow solid (IV) (125.3mg, 72%) of O-(morpholinyl) ethyl derivative.
1H NMR(500MHz,DMSO-d6)δ5.95(s,1H),4.12(s,1H),3.68(s,1H),3.63(d,J
=8.4Hz, 1H), 3.61 (s, 4H), 3.57 3.26 (m, 3H), 2.61 (s, 2H), 2.56 (s, 2H), 2.51
2.03 (m, 5H), 1.70 (d, J=3.1Hz, 1H), 1.65 (d, J=25.6Hz, 1H), 1.52 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.85(s),106.73(s),79.95(s),74.34(s),66.75
(t, J=4.6Hz), 54.46 (s), 52.93 (s), 44.22 (s), 35.55 (s), 25.88 (s), 21.89 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O5:349.1763；found:349.1761.
Embodiment 5 compositions therapeutical effect to acute renal failure rat
(1) experimental technique
The preparation of compositions: powder and the grinding of the 35mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 65mg compound IV of rear mistake 200 mesh net loads in tubule with cover and mixes with turbine stirring instrument
I.e. obtain 100mg compositions, during use, obtain the solution of compositions by the compositions of this 100mg of water dissolution.
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 5 groups: sham operated rats (intramuscular injection normal saline)；Model group (flesh
Meat glycerol injection)；It is administered intervention group (compositions, compound III or compound IV 0.6mg/Kg, muscle
Glycerol injection), each group rat tail vein injection saline or treat reagent thing, 12 Hes immediately after glycerol modeling
It is administered once again after 24 hours.
(2) observation index
Rat last is administered or puts into after normal saline metabolic cage and collects twenty-four-hour urine, stays and urinates latter 6 hours with 4%
Chloral hydrate intraperitoneal injection of anesthesia, uses laser Doppler flowmetry to measure after modeling and bilateral renal blood after treatment
Flow, averages as single animal renal blood flow；Take blood and prepare serum, measure blood BUN and Cre (all
Operate by test kit description).
(3) experimental result
1. compositions can increase acute renal failure Mouse Kidney blood flow
Compositions can dramatically increase acute renal failure Mouse Kidney blood flow, and compound III and compound IV is without this
Effect.
The impact on acute renal failure Mouse Kidney blood flow of table 1 compositions
* P < 0.05vs acute renal failure model group
2. compositions 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.Compositions can be improved
The renal function (P < 0.05) of acute renal failure rat, 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: compositions can protect the function of kidney, can be used to prepare anti-acute renal failure medicine.And chemical combination
Thing 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
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100
Sheet.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated system
Become 100.
Claims (6)
1. a compositions, is characterized by that said composition is made up of, in said composition compound III and compound IV
The mass percent of compound III and compound IV is respectively 35% and 65%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the change of compound III
The powder of compound IV is sufficiently mixed according to mass percent respectively 35% and 65%.
3. a compositions as claimed in claim 1 application in treatment acute renal failure medicine.
4. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described
The reduction of the renal blood flow amount caused by composition for improved acute renal failure.
5. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described
The rising of the serum BUN that composition for improved acute renal failure causes.
6. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described
The rising of change of serum C re that composition for improved acute renal failure causes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278931.7A CN105853436A (en) | 2016-04-28 | 2016-04-28 | Application of composition of pyrrolidine derivative and morpholinyl derivative of Virosaine A to medicine against acute renal failure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278931.7A CN105853436A (en) | 2016-04-28 | 2016-04-28 | Application of composition of pyrrolidine derivative and morpholinyl derivative of Virosaine A to medicine against acute renal failure |
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| Publication Number | Publication Date |
|---|---|
| CN105853436A true CN105853436A (en) | 2016-08-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610278931.7A Withdrawn CN105853436A (en) | 2016-04-28 | 2016-04-28 | Application of composition of pyrrolidine derivative and morpholinyl derivative of Virosaine A to medicine against acute renal failure |
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| CN (1) | CN105853436A (en) |
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2016
- 2016-04-28 CN CN201610278931.7A patent/CN105853436A/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| BING-XIN ZHAO等: "Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an unprecedented Skeleton from Flueggea virosa", 《ORGANIC LETTERS》 * |
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Application publication date: 20160817 |