CN105998002A - Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs - Google Patents
Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs Download PDFInfo
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- CN105998002A CN105998002A CN201610256270.8A CN201610256270A CN105998002A CN 105998002 A CN105998002 A CN 105998002A CN 201610256270 A CN201610256270 A CN 201610256270A CN 105998002 A CN105998002 A CN 105998002A
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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
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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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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Abstract
The invention discloses an application of a composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs, relates to the fields of organic synthesis and medicinal chemistry, and particularly relates to the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives, and a preparation method and the application thereof in preparation of the anti-acute renal failure drugs. Provided are the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives and the preparation method thereof. Pharmacological experiments indicate that the composition has an anti-acute renal failure effect and has the value for development of the anti-acute renal failure drugs.
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 2011, deliver (Ayumi Ohsaki et al., 2011.
Salviskinone A,a diterpene with a new skeleton from Salvia przewalskii.Tetrahedron
Letters 52 (2011) 1,375 1377) compound, we have carried out structural modification to compound I, it is thus achieved that
Two new derivants i.e. compound III and compound IV, and be prepared for compound III and compound IV
Compositions acute renal failure activity anti-to said composition are 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 50% and 50%.
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 Salviskinone A
The document that the preparation method of compound Salviskinone A (I) is delivered with reference to Ayumi Ohsaki et al.
(Ayumi Ohsaki et al.,2011.Salviskinone A,a diterpene with a new skeleton from
Salvia przewalskii.Tetrahedron Letters 52 (2011) 1,375 1377) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Salviskinone A
Compound I (312mg, 1.00mmol) is dissolved in 15mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 12h at 35 degrees Celsius.After 12h, 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
Saline washs 4 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects brown collection
Middle elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (327mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),
3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,
3H),1.08(s,6H),0.99(s,6H).
13C NMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),
140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49
(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),
22.65(s).
HRMS(ESI)m/z[M+H]+calcd for C22H28BrO3:419.1222；found 419.1220.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg,
10mmol), mixture is heated to reflux 5h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts three 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 brown and concentrate elution band, concentrate and i.e. obtain
The brown solid (215mg, 43%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 8.15 (s, 1H), 7.54 (d, J=25.0Hz, 2H), 7.15 (s,
1H), 7.06 (s, 1H), 6.33 (d, J=84.1Hz, 1H), 6.26 (s, 1H), 5.66 (s, 1H), 4.38 (d, J=
15.8Hz,4H),3.57(s,1H),1.96(s,1H),1.90(s,1H),1.77(s,1H),1.51(s,1H),1.20
(s,3H),0.99(s,6H),0.81(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.51(s),154.17(s),147.37(s),
146.27(s),139.98(s),139.63(s),136.22(s),134.51(s),133.48(s),131.05(s),
128.18 (s), 123.93 (s), 123.35 (s), 118.56 (d, J=9.6Hz), 110.85 (s), and 68.55 (s), 45.29
(s),44.74(s),37.34(s),33.36(s),25.96(s),24.94(s),24.46(s),23.32(s),22.96(s),
22.42(s).
HRMS(ESI):m/z[M+H]+calcd for C29H33N2O3:457.2491；found:457.2493.
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4 Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 30mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (690mg, 5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg,
10mmol), mixture is heated to reflux 9h.Reactant liquor is poured in 25mL frozen water after terminating by reaction, with etc.
Amount dichloromethane extracts 2 times, merges organic facies.Successively with water and saturated aqueous common salt washing merge after organic
Phase, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silicagel column
Chromatography purification (flowing is mutually: petroleum ether/acetone=100:0.5, v/v), collects yellow and concentrates elution band and fling to
Solvent i.e. obtain O-(two hydroxyethylamines) ethyl derivative of Salviskinone A faint yellow solid (159.5mg,
72%).
1H NMR(500MHz,DMSO-d6)δ6.52(s,1H),6.40(s,1H),5.71(s,1H),4.15(s,
2H),3.70(s,1H),3.37(s,4H),3.00(s,2H),2.50(s,4H),2.07(s,1H),1.96(s,1H),
1.83 (s, 1H), 1.57 (d, J=1.4Hz, 3H), 1.30 (s, 3H), 0.99 (s, 6H), 0.90 (s, 6H).
13C NMR(125MHz,DMSO-d6)δ188.01(s),183.52(s),154.08(s),147.15(s),
140.11(s),136.23(s),134.42(s),130.84(s),128.31(s),118.62(s),68.93(s),58.73
(s),56.61(s),53.94(s),45.20(s),37.13(s),33.49(s),25.96(s),24.84(s),24.26(s),
23.43(s),22.97(s),22.33(s).
HRMS(ESI):m/z[M+H]+calcd for C26H38NO5:444.2750；found:444.2746.
The synthesis of O-(bischloroethylamines base) ethyl derivative of embodiment 5 Salviskinone A
O-(two hydroxyethylamines) ethyl derivative of Salviskinone A prepared by embodiment 4 (0.222g,
0.5mmol) being dissolved in 6mL chloroform, be added dropwise over thionyl chloride (0.238g, 2mmol), reactant heats
Backflow 1h.Reactant is cooled to room temperature, and the thionyl chloride of dropping Methanol Decomposition excess, concentrating under reduced pressure removes
Solvent.Product, through silica gel column chromatography purification (petroleum ether/acetone 100:0.3, v/v), obtains Salviskinone A
The faint yellow solid (170.0mg, 71%) of O-(bischloroethylamines base) ethyl derivative.
1H NMR(500MHz,Chloroform-d1)δ6.51(s,1H),6.22(s,1H),5.72(s,1H),4.16
(s,1H),3.66(s,1H),3.44(s,4H),3.01(s,2H),2.80(s,2H),2.64(s,2H),2.04(s,1H),
1.98(s,1H),1.85(s,1H),1.59(s,1H),1.28(s,3H),0.97(s,6H),0.93(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.41(s),153.97(s),147.04(s),
140.00(s),136.12(s),134.31(s),130.73(s),128.20(s),118.51(s),68.82(s),55.57
(s),53.94(s),45.20(s),39.10(s),37.02(s),33.39(s),25.87(s),24.76(s),24.19(s),
23.33(s),22.88(s),22.25(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36Cl2NO3:480.2072；found:480.2070.
The synthesis of O-(two (2-methylmercaptoethyl) amido) ethyl derivative of embodiment 6 Salviskinone A
O-(bischloroethylamines base) ethyl derivative of Salviskinone A prepared by embodiment 5 (0.240g, 0.5
Mmol) being dissolved in 15mL ethanol, add sodium methyl mercaptide (0.21g, 3mmol) under room temperature, reactant heats
Backflow 1h.Concentrating under reduced pressure removes solvent, and products therefrom silica gel column chromatography is purified (petroleum ether/acetone
100:0.5, v/v), obtain yellow solid, i.e. compound IV (0.169g, 67%).
1H NMR(500MHz,Chloroform-d1)δ6.48(s,1H),6.41(s,1H),5.65(s,1H),4.12
(s, 2H), 3.99 (s, 1H), 2.94 (s, 2H), 2.53 (d, J=15.4Hz, 8H), 1.99 (s, 1H), 1.94 (s, 6H),
1.90(s,1H),1.77(s,1H),1.51(s,1H),1.23(s,3H),0.92(s,6H),0.83(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.81(s),183.42(s),154.08(s),147.28(s),
139.90(s),136.12(s),134.44(s),130.96(s),128.09(s),118.53(s),68.94(s),53.83
(s),52.15(s),45.21(s),37.24(s),33.29(s),31.87(s),25.85(s),24.86(s),24.38(s),
23.21(s),22.88(s),22.34(s),14.38(s).
HRMS(ESI):m/z[M+H]+calcd for C28H42NO3S2:504.2606；found:504.2603.
Embodiment 7 compositions therapeutical effect to acute renal failure rat
(1) experimental technique
The preparation of compositions: powder and the grinding of the 50mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 50mg 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 9 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 10 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 50% and 50%,
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 50% and 50%.
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.
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| CN201610256270.8A CN105998002A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs |
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| CN201610256270.8A CN105998002A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs |
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| CN105998002A true CN105998002A (en) | 2016-10-12 |
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| CN201610256270.8A Pending CN105998002A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-acute renal failure drugs |
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2016
- 2016-04-22 CN CN201610256270.8A patent/CN105998002A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| AYUMI OHSAKI等: "salviskinone A, a diterpene with a new skeleton from salvia przewalskii", 《TETRAHEDRON LETTERS》 * |
| 曹译心等: "丹参酮IIA对急性肾功能衰竭大鼠肾脏的保护作用", 《四川解剖学杂志》 * |
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