CN106822107A - The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for anti-acute renal failure - Google Patents
The imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions are used for anti-acute renal failure Download PDFInfo
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- CN106822107A CN106822107A CN201611191304.6A CN201611191304A CN106822107A CN 106822107 A CN106822107 A CN 106822107A CN 201611191304 A CN201611191304 A CN 201611191304A CN 106822107 A CN106822107 A CN 106822107A
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
Imidazole radicals and two hydroxyethylamine derivative compositions the invention discloses Psiguadial A are used for anti-acute renal failure, a kind of O (imidazole radicals) ethyls of Psiguadial A and application of the composition of O (two hydroxyethylamines) ethyl derivative in anti-acute renal failure medicine, the present invention relates to organic synthesis and medicinal chemistry art, and in particular to the imidazole radicals of Psiguadial A and two hydroxyethylamine derivative compositions, preparation method and its purposes on anti-acute renal failure medicine is prepared.Imidazole radicals and two hydroxyethylamine derivative compositions the invention discloses a kind of Psiguadial A and preparation method thereof.Pharmacological experiment shows, the imidazole radicals of Psiguadial A of the invention and two hydroxyethylamine derivative compositions have the effect of anti-acute renal failure, with the value for developing anti-acute renal failure medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, and in particular to composition, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) is the clinical syndrome caused by many reasons,
Clinical departments patient is found in, the incidence of disease is high and often has serious consequences, its feature is (a few hours 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 discharge and produce obstacle, occur azotemia, water and electrolyte, disturbance of acid-base balance rapidly, and cause each system of whole body
Corresponding function is lacked of proper care.The principal element for causing acute renal failure is the drastically reduction of renal blood flow, and because nephridial tissue ischemic draws
The oxidative stress and cellular damage for rising, ultimately result in renal tissue structural damage and the deterioration of 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 acid poisoning and arranging
Improvement symptom is applied, 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.
Compound or lead compound are found from natural products and structural modification is carried out and obtains its derivative, so as to obtain
The potential drug of high-efficiency low-toxicity most has important value.
Compound I of the present invention is one and delivers within 2011 (Meng Shao et al., 2010.Psiguadials
A and B,Two Novel Meroterpenoids with Unusual Skeletons from the Leaves of
Psidium guajava.Organic Letters 12 (2010) 5040-5043) compound, we are carried out to compound I
Structural modification, obtains two new derivatives i.e. compound III and compound IV, and with compound III and compound IV
It is prepared for composition and the anti-acute renal failure activity of said composition is evaluated, it has anti-acute renal failure activity.
The content of the invention
The invention discloses a new composition, 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 20% and 80%.
Composition disclosed by the invention can be made pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is used to treat the purposes of acute renal failure it is an object of the invention to provide composition, i.e., for preparing treatment acute renal failure
The purposes of medicine.
Composition of the invention has obvious therapeutic action to acute renal failure disease.
Find that composition 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 by specific real
Any limitation of example is applied, but is defined in the claims.
Specific embodiment
The preparation of the compound Psiguadial A of embodiment 1
Document (the Meng Shao that the preparation method of compound Psiguadial A (I) is delivered with reference to Meng Shao et al.
et al.,2010.Psiguadials A and B,Two Novel Meroterpenoids with Unusual
Skeletons from the Leaves of Psidium guajava.Organic Letters 12(2010)5040–
5043) method.
The synthesis of O- bromoethyls derivative (II) of the Psiguadial A of embodiment 2
Compound I (474mg, 1.00mmol) is dissolved in 20mL benzene, to addition TBAB (TBAB) in solution
50% sodium hydroxide solution of (0.16g), 1,2- Bromofume (7.520g, 40.00mmol) and 12mL.Mixture is Celsius 35
Degree stirring 8h.Reaction solution is poured into frozen water after 8h, is extracted twice with dichloromethane immediately, merge organic phase solution.Then
To organic phase solution successively with water and saturated common salt water washing 3 times, then with anhydrous sodium sulfate drying, the removal that is finally concentrated under reduced pressure is molten
Agent obtains product crude product.(mobile phase is the purifying of product crude product silica gel column chromatography:Petroleum ether/acetone=100:0.5, v/v), receive
Collection brown concentrates elution band and flings to the brown ceramic powder (502mg, 73%) that solvent obtains compound II.
1H NMR(500MHz,DMSO-d6) δ 10.44 (s, 2H), 7.24 (s, 2H), 7.20 (d, J=10.0Hz, 3H),
4.31(s,4H),3.89(s,1H),3.74(s,4H),2.30(s,1H),2.12(s,1H),2.02(s,1H),1.92(s,1H),
1.79 (s, 1H), 1.73 (s, 1H), 1.51 (d, J=19.8Hz, 3H), 0.99 (s, 3H), 0.95 (d, J=4.7Hz, 7H),
0.85(s,3H),0.53(s,1H),0.43(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.69(s),170.54(s),165.42(s),163.38(s),142.72
(s),129.71(s),127.96(s),127.08(s),118.00(s),116.82(s),114.82(s),72.73(s),
40.19(s),34.75(s),34.32(s),31.75(s),30.93(s),28.09(s),26.43(s),24.48(s),23.74
(s),21.18(s),20.77(s),19.99(s),14.39(s).
HRMS(ESI)m/z[M+H]+calcd for C34H41Br2O5:689.1300;found 689.1303.
The synthesis of O- (imidazole radicals) ethyl derivative (III) of embodiment 3Psiguadial A
Compound II (344mg, 0.5mmol) is dissolved in the middle of 25mL acetonitriles, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), KI (168mg, 1.0mmol) and imidazoles (3480mg, 40mmol), mixture is heated to reflux 2h.Reaction terminates
Reaction solution is poured into 25mL frozen water afterwards, is extracted 2 times with equivalent dichloromethane, merge organic phase.Water and saturated common salt are used successively
Water washing merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Product is thick
(mobile phase is the purifying of product silica gel column chromatography:Petroleum ether/acetone=100:0.4, v/v) yellow, is collected to concentrate elution band and wave
Solvent is gone to obtain the yellow powder (235.0mg, 71%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 10.38 (s, 2H), 7.80 (s, 2H), 7.17 (s, 2H), 7.11 (d, J=
10.0Hz,3H),7.07(s,2H),6.66(s,2H),4.47(s,4H),4.37(s,4H),3.91(s,1H),2.03(s,1H),
1.86-1.77 (m, 3H), 1.64 (s, 1H), 1.60 (s, 1H), 1.35 (d, J=4.6Hz, 3H), 1.15 (s, 1H), 0.89 (s,
3H),0.87–0.64(m,9H),0.43(s,1H),0.17(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.52(s),170.35(s),165.17(s),163.13(s),142.49
(s),139.47(s),129.44(s),128.51(s),127.70(s),126.82(s),119.14(s),117.75(s),
116.59(s),114.54(s),69.29(s),43.78(s),39.96(s),34.50(s),34.09(s),30.66(s),
27.84(s),26.18(s),24.25(s),23.46(s),20.92(s),20.51(s),19.76(s),14.20(s).
HRMS(ESI):m/z[M+H]+calcd for C40H47N4O5:663.3546;found:663.3541.
The synthesis of the O- (two oxyethylamines) ethyl derivative (IV) of the Psiguadial A of embodiment 4
Compound II (344mg, 0.5mmol) is dissolved in 18mL acetonitriles, Anhydrous potassium carbonate (0.345g, 2.5mmol) is added,
KI (0.084g, 0.5mmol) and diethanol amine (2.103g, 20mmol), mixture is heated to reflux 2h.Reaction will after terminating
Reaction solution is poured into cold water, is extracted 2 times with dichloromethane, merges organic phase, successively with water and saturated common salt water washing, anhydrous sulphur
Sour sodium is dried, and be concentrated under reduced pressure removal solvent.Product silica gel column chromatography purifies (petroleum ether/acetone 100:0.7, v/v), changed
The Light brown solid (0.254g, 69%) of compound IV.
1H NMR (500MHz, DMSO-d6) δ 10.45 (s, 2H), 7.27 (t, J=15.0Hz, 2H), 7.21 (t, J=
15.0Hz,2H),7.21(s,1H),4.04(s,4H),3.97(s,1H),3.39(s,8H),2.68(s,4H),2.54(s,8H),
2.16(s,1H),2.01(s,1H),1.98–1.90(m,3H),1.68(s,1H),1.62(s,1H),1.45(s,2H),1.40
(s,1H),1.12(s,4H),1.00(s,3H),0.93(s,6H),0.89(s,3H),0.52(s,1H),0.27(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.43(s),170.26(s),165.08(s),163.04(s),142.40
(s),129.34(s),127.61(s),126.73(s),117.67(s),116.49(s),114.46(s),69.16(s),
58.86(s),56.40(s),53.85(s),39.84(s),34.42(s),33.99(s),30.58(s),27.74(s),26.10
(s),24.15(s),23.38(s),20.82(s),20.43(s),19.66(s),14.02(s).
HRMS(ESI):m/z[M+H]+calcd for C42H61N2O9:737.4377;found:737.4374.
Therapeutic action of the composition of embodiment 5 to acute renal failure rat
(1) experimental technique
The preparation of composition:The powder of the 20mg compounds III of 200 mesh nets will be crossed after grinding and 200 will be crossed after grinding
The powder of the 80mg compounds IV of mesh net is fitted into tubule with cover and obtains 100mg compositions with the mixing of turbine stirring instrument,
The solution of composition is obtained when using with the composition of water dissolves this 100mg.
Acute Renal Failure Rats animal model is caused using intramuscular injection glycerine.From 180~220g health males SD
Rat 30, is randomly divided into 5 groups:Sham-operation group (intramuscular injection physiological saline);Model group (intramuscular injection glycerine);Administration is intervened
Group (composition, compound III or compound IV 0.6mg/Kg, intramuscular injection glycerine), each group rat stands after glycerine modeling
Tail vein injection saline or reagent thing is treated, be administered once again after 12 and 24 hours.
(2) observation index
Metabolic cage is put into after rat last dose or physiological saline and collects twenty-four-hour urine, chlorine is hydrated with 4% within 6 hours after staying urine
Aldehyde intraperitoneal injection of anesthesia, using laser Doppler flowmetry determine modeling after and treatment after bilateral renal CBF, average
As single animal renal blood flow;Take blood and prepare serum, determine blood BUN and Cre (being operated by kit specification).
(3) experimental result
1. composition can increase acute renal failure mouse renal blood flow
Composition can dramatically increase acute renal failure mouse renal blood flow, and compound III and compound IV is acted on without this.
Influence of the composition of table 1 to acute renal failure mouse renal blood flow
*P<0.05vs acute renal failure model groups
2. composition has protective effect to acute renal failure mouse renal function
After 24 hours, serum BUN and Cre are shown in Table 2 to acute renal failure rat intravenous injection physiological saline.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
Can (P<0.05), and compound III and compound IV without this act on.It is shown in Table 2.
Each rats in test groups renal function index of table 2 compares
*P<0.05vs acute renal failure model groups
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 the composition tablet involved in the present invention of embodiment 6
2 grams of compositions are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixed, conventional tablet presses are made 100.
The preparation of the composition capsule involved in the present invention of embodiment 7
2 grams of compositions are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixed, it is encapsulated to be made 100.
Claims (6)
1. a kind of composition, 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 20% and 80%,
2. the preparation method of composition as claimed in claim 1, it is characterized by:By the powder of compound III and compound IV
Powder be respectively 20% and 80% according to mass percent and be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in acute renal failure medicine is treated.
4. application of the composition as claimed in claim 3 in acute renal failure medicine is treated, it is characterized by:The composition changes
The reduction of the renal blood flow amount caused by kind acute renal failure.
5. application of the composition as claimed in claim 3 in acute renal failure medicine is treated, it is characterized by:The composition changes
The rising of the serum BUN that kind acute renal failure causes.
6. application of the composition as claimed in claim 3 in acute renal failure medicine is treated, it is characterized by:The composition changes
The rising of the change of serum C re that kind acute renal failure causes.
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CN113712930A (en) * | 2021-09-07 | 2021-11-30 | 山东仁和制药有限公司 | Sitagliptin phosphate tablet and preparation method thereof |
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Application publication date: 20170613 |