CN106344571A - Application of Atropurpuran derivative composition in medicine resistant to acute renal failure - Google Patents
Application of Atropurpuran derivative composition in medicine resistant to acute renal failure Download PDFInfo
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- CN106344571A CN106344571A CN201610616896.5A CN201610616896A CN106344571A CN 106344571 A CN106344571 A CN 106344571A CN 201610616896 A CN201610616896 A CN 201610616896A CN 106344571 A CN106344571 A CN 106344571A
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- renal failure
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention discloses application of an Atropurpuran derivative composition in medicine resistant to acute renal failure and relates to the field of organic synthesis and medicinal chemistry, in particular to the composition, a preparation method and application of the composition in preparing medicine resistant to acute renal failure. The invention discloses the composition and the preparation method thereof. Pharmacological experiments show that the composition has effect on resisting acute renal failure and has value in developing medicine resistant to acute renal failure.
Description
Technical field
The present invention relates to organic synthesiss and medicinal chemistry art are and in particular to compositionss, preparation method and its usage.
Background technology
Acute renal failure (acute renal failure, arf) is the clinical syndrome being caused by many reasons,
It is found in clinical departments patient, sickness rate is high and often has serious consequences, 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 oliguria (urine volume < 400mlpd) or anuria (urine volume < 100mlpd), internal nitrogen matter generation
Thank to product and discharge generation obstacle, azotemia, water and electrolyte, acid base imbalance occur rapidly, and causes each system of whole body
Corresponding function is lacked of proper care.Cause acute renal failure principal element be renal blood flow drastically minimizing, and because nephridial tissue ischemia draws
The oxidative stress rising and cell injury, ultimately result in the deterioration of renal tissue structural damage and function.Clinically there is no at present
The generally acknowledged effective medicine for the treatment of acute renal failure, is only capable of, by correcting water-electrolyte balance, correcting the symptomatic treatments such as acidosis and arranging
Apply and improve symptom, the later stage also needs to maintain body function by hemodialysis.Improve kidney perfusion obstacle and mitigate kidney
Tissue injury's aspect has the clinical medicine of obvious curative effects rare.
Find compound or lead compound and carry out structural modification and obtain its derivant, thus obtaining from natural product
The potential drug of high-efficiency low-toxicity has important value most.
Compound i according to the present invention be one deliver within 2009 (pei tang et al.,
2009.atropurpuran,a novel diterpene with an unprecedented pentacyclic cage
skeleton,from aconitum hemsleyanum var.atropurpureum.tetrahedron letters 50
(2009) 460 462) compound, we have carried out structural modification to compound i, and obtaining two new derivants is chemical combination
Thing iii and compound iv, and with compound iii and compound iv be prepared for compositionss and to said composition anti-acute renal failure activity
Evaluated, it has anti-acute renal failure activity.
Content of the invention
The invention discloses new compositionss, said composition is made up of compound iii and compound iv, said composition
The mass percent of middle compound iii and compound iv is respectively 55% and 45%.
Compositionss disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide compositionss are used for treating the purposes of acute renal failure, that is, it is used for preparation treatment acute renal failure
The purposes of medicine.
The compositionss of the present invention have obvious therapeutical effect to acute renal failure disease.
Find that compositionss 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 subject to concrete reality
Apply any restriction of example, but be defined in the claims.
Specific embodiment
The preparation of embodiment 1 compound a tropurpuran
Document (the pei tang et that the preparation method of compound a tropurpuran (i) is delivered with reference to pei tang et al.
al.,2009.atropurpuran,a novel diterpene with an unprecedented pentacyclic
cage skeleton,from aconitum hemsleyanum var.atropurpureum.tetrahedron letters
50 (2009) 460 462) method.
The synthesis of o- bromoethyl derivant (ii) of embodiment 2 atropurpuran
Compound i (312mg, 1.00mmol) is dissolved in 10ml benzene, adds tetrabutyl ammonium bromide (tbab) in solution
(0.08g), 50% sodium hydroxide solution of glycol dibromide (3.760g, 20.00mmol) and 6ml.Mixture is Celsius 35
Degree stirring 6h.After 6h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Successively water and saturated common salt water washing 3 times are used to organic phase solution, then uses anhydrous sodium sulfate drying, last concentrating under reduced pressure removal is molten
Agent obtains product crude product.Product crude product silica gel column chromatography purification (mobile phase is: petroleum ether/acetone=100:1.0, v/v), receives
Collection brown is concentrated elution band and is flung to the yellow powder (309mg, 74%) that solvent obtains compound ii.
1h nmr(500mhz,dmso-d6)δ9.86(s,1h),5.23(s,1h),4.87(s,1h),4.83(s,1h),
4.39 (s, 1h), 4.00 (s, 2h), 3.91 (s, 1h), 3.58 (s, 2h), 3.01 (s, 1h), 2.27 (s, 1h), 2.15 (d, j=
6.3hz, 2h), 2.09 2.00 (m, 5h), 1.78 (dd, j=35.2,19.2hz, 2h), 1.71 1.65 (m, 1h), 1.41 (s,
2h),0.99(s,3h).
13c nmr(125mhz,dmso-d6)δ208.55(s),203.16(s),150.94(s),125.16(s),111.66
(s),78.63(s),71.39(s),57.77(s),47.73(s),40.79(s),34.58(s),33.01(s),32.69(s),
29.25(s),29.34(s),26.52(s),24.23(s),22.30(s),20.64(s).
hrms(esi)m/z[m+h]+calcd for c22h28bro3:419.1222；found 419.1226.
The synthesis of the o- (nafoxidine base) ethyl derivative (iii) of embodiment 3 atropurpuran
Compound ii (209mg, 0.5mmol) is dissolved in the middle of 18ml acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture is heated to reflux 2h.Reaction knot
After bundle, reactant liquor is poured in frozen water, extracted 2 times with equivalent dichloromethane, merge organic faciess.Use water and saturated aqueous common salt successively
Washing merge after organic faciess, then use anhydrous sodium sulfate drying, concentrating under reduced pressure removal solvent obtain product crude product.Product crude product
Purified (mobile phase is: petroleum ether/acetone=100:1.0, v/v) with silica gel column chromatography, collect brown and concentrate elution band, concentration is
Obtain the brown solid (125mg, 61%) of compound iii.
1H nmr (500mhz, dmso-d6) δ 9.78 (s, 1h), 5.15 (s, 1h), 4.61 (d, j=10.5hz, 2h),
4.45(s,1h),3.83(s,1h),3.53(s,2h),2.94(s,1h),2.62(s,2h),2.46(s,4h),2.20(s,1h),
2.08 (d, j=6.0hz, 2h), 2.00 1.91 (m, 3h), 1.75 (d, j=2.1hz, 2h), 1.69 (s, 2h), 1.62 (d, j=
5.5hz,5h),1.30(s,2h),0.91(s,3h).
13c nmr(125mhz,dmso-d6)δ208.65(s),203.36(s),151.04(s),125.36(s),111.76
(s), 78.83 (s), 67.20 (s), 57.97 (s), 54.33 (d, j=17.1hz), 47.82 (s), 41.00 (s), 34.67 (s),
32.79(s),29.45(s),29.22(s),26.61(s),25.14(s),24.43(s),22.40(s),20.84(s).
hrms(esi):m/z[m+h]+calcd for c26h36no3:410.2695；found:410.2699.
The synthesis of o- (the 1h- tetrazole base) ethyl derivative of embodiment 4 atropurpuran
Compound ii (209mg, 0.5mmol) is dissolved in the middle of 15ml acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and 1h- tetrazole (1401mg, 20mmol), mixture is heated to reflux 4h.Reaction
After end, reactant liquor is poured in 20ml frozen water, extracted 3 times with equivalent dichloromethane, merge organic faciess.Use water and saturation successively
Brine It merge after organic faciess, then use anhydrous sodium sulfate drying, concentrating under reduced pressure removal solvent obtain 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 purification (mobile phase is: petroleum ether/acetone=100:0.8, v/v), collects yellow and concentrates elution band, then will
Elution band concentrates, and is purified (mobile phase is: petroleum ether/acetone=100:0.4, v/v) with silica gel column chromatography, and collection two is light successively
The elution band of yellow, concentrates the yellow powder (83.6mg, 41%) that front 1 elution band obtains compound iv.
1h nmr(500mhz,dmso-d6)δ10.51(s,1h),9.74(s,1h),5.05(s,1h),4.61–4.48(m,
3h),4.19(s,1h),4.12(s,1h),3.80(s,2h),3.75(s,1h),2.86(s,1h),2.08(s,1h),1.97(d,
J=2.9hz, 2h), 1.90 1.81 (m, 3h), 1.69 1.57 (m, 4h), 1.54 (s, 1h), 1.25 (s, 2h), 0.80 (s,
3h).
13c nmr(125mhz,dmso-d6)δ208.46(s),203.17(s),150.83(s),144.83(s),125.18
(s),111.56(s),78.65(s),66.57(s),57.79(s),47.63(s),46.37(s),40.80(s),34.49(s),
32.59(s),29.27(s),29.02(s),26.43(s),24.24(s),22.21(s),20.67(s).
hrms(esi):m/z[m+h]+calcd for c23h29n4o3:409.2240；found:409.2244.
The therapeutical effect to acute renal failure rat for embodiment 5 compositionss
(1) experimental technique
The preparation of compositionss: cross the powder of the 55mg compound iii of 200 mesh nets after grinding and cross 200 after grinding
The powder of the 45mg compound iv of mesh net loads in tubule with cover and obtains 100mg compositionss with the mixing of turbine stirring instrument,
Obtain the solution of compositionss with the compositionss of this 100mg of water dissolution during use.
Acute Renal Failure Rats animal model is caused using intramuscular injection glycerol.From 180～220g health male sd
Rat 30, is randomly divided into 5 groups: sham operated rats (intramuscular injection normal saline)；Model group (intramuscular injection glycerol)；Administration is intervened
Group (compositionss, compound iii or compound iv 0.6mg/kg, intramuscular injection glycerol), each group rat is vertical after glycerol modeling
I.e. tail vein injection saline or treat reagent thing, is administered once after 12 and 24 hours again.
(2) observation index
Put into metabolic cage after rat last dose or normal saline and collect twenty-four-hour urine, stay urine to be hydrated chlorine with 4% in latter 6 hours
Aldehyde intraperitoneal injection of anesthesia, using laser Doppler flowmetry measure modeling after and treatment after bilateral renal blood flow, average
As single animal renal blood flow；Take blood to prepare serum, measure blood bun and cre (all operating by kit specification).
(3) experimental result
1. compositionss can increase acute renal failure mice renal blood flow
Compositionss can dramatically increase acute renal failure mice renal blood flow, and compound iii and compound iv no this effect.
The impact to acute renal failure mice renal blood flow for table 1 compositionss
* p < 0.05vs acute renal failure model group
2. compositionss have protective effect to acute renal failure mice renal function
After 24 hours, serum bun and cre is shown in Table 2 to acute renal failure rat intravenous injection normal saline.Acute renal failure model group
Apparently higher than sham operated rats, illustrate that model group animal renal function injury is serious.Compositionss can improve the kidney work(of acute renal failure rat
Energy (p < 0.05), and compound iii and compound iv no this effect.It is shown 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: compositionss 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
Take 2 grams of compositionss, 18 grams of the customary adjuvant of tablet is prepared in addition, mix, conventional tablet presses make 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Take 2 grams of compositionss, customary adjuvant such as 18 grams of the starch of capsule is prepared in addition, mix, encapsulated make 100.
Claims (6)
1. a kind of compositionss, it is characterized by 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 compositionss as claimed in claim 1, it is characterized by: by the powder of compound iii and compound iv
Powder be respectively according to mass percent and 55% and 45% be sufficiently mixed.
3. application in treatment acute renal failure medicine for a kind of compositionss as claimed in claim 1.
4. application in treatment acute renal failure medicine for the compositionss as claimed in claim 3, it is characterized by: described compositionss change
The reduction of the renal blood flow amount caused by kind acute renal failure.
5. application in treatment acute renal failure medicine for the compositionss as claimed in claim 3, it is characterized by: described compositionss change
The rising of the serum bun that kind acute renal failure causes.
6. application in treatment acute renal failure medicine for the compositionss as claimed in claim 3, it is characterized by: described compositionss change
The rising of the serum cre that kind acute renal failure causes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610616896.5A CN106344571A (en) | 2016-07-29 | 2016-07-29 | Application of Atropurpuran derivative composition in medicine resistant to acute renal failure |
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|---|---|---|---|
| CN201610616896.5A CN106344571A (en) | 2016-07-29 | 2016-07-29 | Application of Atropurpuran derivative composition in medicine resistant to acute renal failure |
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| CN201610616896.5A Withdrawn CN106344571A (en) | 2016-07-29 | 2016-07-29 | Application of Atropurpuran derivative composition in medicine resistant to acute renal failure |
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Application publication date: 20170125 |