CN106038542A - Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs - Google Patents
Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs Download PDFInfo
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- CN106038542A CN106038542A CN201610404545.8A CN201610404545A CN106038542A CN 106038542 A CN106038542 A CN 106038542A CN 201610404545 A CN201610404545 A CN 201610404545A CN 106038542 A CN106038542 A CN 106038542A
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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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 relates to the fields of organic synthesis and pharmaceutical chemistry, in particular to composition, a preparation method and an application of the composition in preparation of acute renal failure resistant drugs. The invention discloses the composition and the preparation method thereof. Pharmacological experiments indicate that the composition has an acute renal failure resistant function and has the value in development of the acute renal failure resistant drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) is the clinical syndrome caused by many reasons,
Being found in clinical departments patient, sickness rate 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 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.Causing the principal element of acute renal failure is the drastically minimizing of renal blood flow, and owing to nephridial tissue ischemia draws
The oxidative stress risen and cell injury, 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 acidosis and arranging
Executing and improve symptom, the later stage also needs to maintain body function by hemodialysis.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 obtaining
The potential drug of high-efficiency low-toxicity most has important value.
The compound I that the present invention relates to be one within 2011, deliver (Antonella Maggio et al.,
2011.Artalbic acid,a sesquiterpene with an unusual skeleton from Artemisia
Alba (Asteraceae) from Sicily.Tetrahedron Letters, 52 (2011) 4,543 4545) compound, I
Compound I has been carried out structural modification, it is thus achieved that two new derivant i.e. compound III and compound IV, and use chemical combination
Thing III and compound IV is prepared for compositions and acute renal failure activity anti-to said composition 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, said composition
The mass percent of middle compound III and compound IV is respectively 45% and 55%.
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 renal failure
The purposes of 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 by concrete real
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Artalbic acid
The document that the preparation method of compound Artalbic acid (I) is delivered with reference to Antonella Maggio et al.
(Antonella Maggio et al.,2011.Artalbic acid,a sesquiterpene with an unusual
skeleton from Artemisia alba(Asteraceae)from Sicily.Tetrahedron Letters,52
(2011) 4,543 4545) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2Artalbic acid
Compound I (266mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB)
(0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 6mL.Mixture is Celsius 40
Degree stirring 16h.After 16h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.So
Washing organic phase solution 5 times with water and saturated aqueous common salt successively afterwards, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed
Solvent obtains product crude product.Product crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v),
Collect brown concentrate elution band and fling to solvent and i.e. obtain the brown ceramic powder (272mg, 73%) of compound II.
1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),6.06(s,1H),5.76(s,1H),4.99(s,1H),
4.71(s,1H),4.56(s,1H),3.86(s,2H),3.54(s,2H),2.65(s,1H),2.43(s,2H),2.33(s,2H),
2.10(s,1H),1.64(s,3H),1.54(s,1H),1.44(s,2H),0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05
(s),109.43(s),81.86(s),70.27(s),57.68(s),41.26(s),39.07(s),38.86(s),35.69(s),
33.36(s),30.72(s),20.44(s),18.42(s).
HRMS(ESI)m/z[M+H]+calcd for C17H26BrO4:373.1014；found 373.1017.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3Artalbic acid
Compound II (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg, 10mmol), mixture is heated to reflux 2h.Reaction
After end, reactant liquor is poured in frozen water, extract 2 times with equivalent dichloromethane, merge organic facies.Successively with water and saturated common salt
Organic facies after water washing merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates elution band, concentrate
I.e. obtain the brown solid (80.0mg, 39%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 16.65 (s, 1H), 8.22 (s, 1H), 7.61 (d, J=25.0Hz, 2H),
7.25(s,1H),7.16(s,1H),6.05(s,1H),5.76(s,1H),4.90(s,1H),4.67(s,1H),4.58(s,1H),
4.12(s,1H),4.00(s,1H),3.85(s,2H),2.63(s,1H),2.43(s,2H),2.35(s,2H),1.95(s,1H),
1.61(s,3H),1.52(s,2H),1.37(s,1H),0.94(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.70(s),175.59(s),149.00(s),147.93(s),146.20
(s),139.75(s),133.40(s),123.95(s),123.48(s),118.46(s),116.84(s),110.97(s),
109.08(s),81.62(s),67.86(s),57.36(s),44.96(s),41.15(s),38.72(s),38.62(s),
35.56(s),30.41(s),20.19(s),18.28(s).
HRMS(ESI):m/z[M+H]+calcd for C24H31N2O4:411.2284；found:411.2281.
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4Artalbic acid
Compound II (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg, 10mmol), mixture is heated to reflux 1h.Reaction
Reactant liquor is poured in 20mL frozen water after end, extract 3 times with equivalent dichloromethane, merge organic facies.Successively with water and saturated
Organic facies after brine It merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects yellow and concentrates elution band
And fling to solvent and i.e. obtain the faint yellow solid (146.9mg, 74%) of compound IV.
1H NMR(500MHz,DMSO-d6)δ18.72(s,1H),δ6.11(s,1H),5.80(s,1H),5.14(s,1H),
4.73 (s, 1H), 4.63 (s, 1H), 3.57 (s, 2H), 3.45 (s, 4H), 2.70 (d, J=15.6Hz, 3H), 2.60 (s, 4H),
(2.50 s, 2H), 2.46 (s, 2H), 2.33 (s, 1H), 1.88 (s, 2H), 1.68 (s, 3H), 1.62 (d, J=19.9Hz, 3H),
1.02(s,3H).
13C NMR(125MHz,DMSO-d6)δ202.01(s),176.11(s),149.21(s),148.55(s),117.15
(s),109.60(s),81.93(s),67.25(s),59.28(s),57.88(s),56.83(s),53.74(s),41.36(s),
39.24(s),38.93(s),35.88(s),30.82(s),20.61(s),18.49(s).
HRMS(ESI):m/z[M+H]+calcd for C21H36N1O6:398.2543；found:398.2547.
Embodiment 5 compositions therapeutical effect to acute renal failure rat
(1) experimental technique
The preparation of compositions: the powder that will cross the 45mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 55mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg compositions with the mixing of turbine stirring instrument,
Obtain the solution of compositions by the compositions of this 100mg of water dissolution during use.
Intramuscular injection glycerol is used to cause Acute Renal Failure Rats animal model.Select 180～220g healthy male SD
Rat 30, is randomly divided into 5 groups: sham operated rats (intramuscular injection normal saline)；Model group (intramuscular injection glycerol)；It is administered and intervenes
Group (compositions, 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
Rat last is administered or puts into after normal saline metabolic cage and collects twenty-four-hour urine, stays urine to be hydrated chlorine with 4% in latter 6 hours
Aldehyde intraperitoneal injection of anesthesia, uses laser Doppler flowmetry to measure after modeling and bilateral renal blood flow after treatment, averages
As single animal renal blood flow；Take blood and prepare serum, measure blood BUN and Cre (all operating 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 acts on without this.
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, illustrate that model group animal renal function injury is serious.Compositions can improve the kidney merit 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: compositions 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 7 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.
The preparation of embodiment 8 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 makes 100.
Claims (6)
1. a compositions, 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 45% and 55%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be sufficiently mixed according to mass percent respectively 45% and 55%.
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 compositions changes
The reduction of kind renal blood flow amount caused by acute renal failure.
5. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described compositions changes
The rising of the serum BUN that kind acute renal failure causes.
6. the compositions as claimed in claim 3 application in treatment acute renal failure medicine, is characterized by: described compositions changes
The rising of change of serum C re that kind acute renal failure causes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404545.8A CN106038542A (en) | 2016-06-08 | 2016-06-08 | Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404545.8A CN106038542A (en) | 2016-06-08 | 2016-06-08 | Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs |
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| CN106038542A true CN106038542A (en) | 2016-10-26 |
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| CN201610404545.8A Pending CN106038542A (en) | 2016-06-08 | 2016-06-08 | Application of composition of Artalbicacid derivatives in preparation of acute renal failure resistant drugs |
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| CN (1) | CN106038542A (en) |
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2016
- 2016-06-08 CN CN201610404545.8A patent/CN106038542A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO等: "Artalbic acid，a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
| 薛存宽，等: "缬草挥发油成分分析及其含量影响因素探讨", 《中草药》 * |
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