CN106074534A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-acute renal failure medicine - Google Patents

The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-acute renal failure medicine Download PDF

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Publication number
CN106074534A
CN106074534A CN201610347870.5A CN201610347870A CN106074534A CN 106074534 A CN106074534 A CN 106074534A CN 201610347870 A CN201610347870 A CN 201610347870A CN 106074534 A CN106074534 A CN 106074534A
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composition
renal failure
acute renal
acid
compound
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丁秋菊
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Nanjing Haiaosi Biological Pharmaceutical Co Ltd
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Nanjing Haiaosi Biological Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41921,2,3-Triazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/041,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04Five-membered rings

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the application in anti-acute renal failure medicine of the composition of O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid and O (1H tetrazole base) ethyl derivative, the present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O (triazolyl) ethyl of Ah draw'sing Bick acid i.e. Artalbic acid and the composition of O (1H tetrazole base) ethyl derivative, preparation method and in the purposes prepared on anti-acute renal failure medicine.The invention discloses O (triazolyl) ethyl of a kind of Ah draw'sing Bick acid i.e. Artalbic acid and composition of O (1H tetrazole base) ethyl derivative and preparation method thereof.Pharmacological experiment shows, O (triazolyl) ethyl of Ah draw'sing Bick acid i.e. Artalbic acid of the present invention has the effect of anti-acute renal failure with the composition of O (1H tetrazole base) ethyl derivative, has the value developing anti-acute renal failure medicine.

Description

The composition of Ah draw'sing Bick acid triazolyl and 1H-tetrazole radical derivative is for preparing Anti-acute renal failure medicine
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to composition, preparation method and its usage.
Background technology
Acute renal failure (Acute Renal Failure, ARF) is the clinical syndrome being caused by many reasons, Being found in clinical departments patient, the incidence of disease 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 oliguresis (urine volume < 400mLPd) or anuria (urine volume < 100mLPd), internal nitrogen matter generation Thank to product and discharge generation obstacle, azotemia, water and electrolyte, disturbance of acid-base balance occur rapidly, and causes each system of whole body Corresponding function is lacked of proper care.Cause the drastically minimizing that the principal element of acute renal failure is renal blood flow, and owing to nephridial tissue ischemic draws The oxidative stress rising and cellular damage, 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 acid poisoning and arranging Executing and improving symptom, 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.
Find compound or lead compound and carry out structural modification and obtain its derivative from natural products, thus obtaining The potential drug of high-efficiency low-toxicity has important value most.
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 Structural modification has been carried out to compound I, it is thus achieved that two new derivative i.e. compound III and compound IV, and use chemical combination Thing III and compound IV is prepared for composition and is evaluated said composition anti-acute renal failure activity, and it has anti-acute Renal failure activity.
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 40% and 60%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
It is an object of the invention to provide composition for treating the purposes of acute renal failure, be i.e. used for preparing treatment acute renal failure The purposes of medicine.
The composition of the present invention has obvious therapeutic action to acute renal failure disease.
Research discovery composition by us can improve the function of kidney.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by specifically in fact 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 derivative (II) of embodiment 2 Artalbic acid
Compound I (266mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds TBAB (TBAB) (0.08g), 1,2-Bromofume (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 being dried with anhydrous sodium sulfate, last reduced pressure concentration is removed Solvent obtains product crude product.Product crude product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), Collect brown concentrate elution band and fling to the brown ceramic powder (272mg, 73%) that solvent i.e. obtains 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-(triazolyl) ethyl derivative (III) of embodiment 3 Artalbic acid
Be dissolved in compound II (187mg, 0.5mmol) in the middle of 25mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg, 2.5mmol), KI (84mg, 0.5mmol) and 1,2,3-triazoles (2760mg, 40mmol), mixture is heated to reflux 3h. Reaction after terminating is poured reactant liquor in frozen water into, extracts three times with equivalent dichloromethane, merges organic phase.Use water and saturated successively Organic phase after brine It merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Produce Thing crude product silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects faint yellow concentration and elutes Band i.e. obtains the faint yellow colloidal solid (124.5mg, 69%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 16.23 (s, 1H), 7.99 (d, J=29.4Hz, 2H), 6.11 (s, 1H), (5.82 s, 1H), 4.76 (d, J=17.3Hz, 2H), 4.62 (s, 1H), 4.24 (s, 1H), 4.18 (s, 1H), 3.84 (s, 2H), 2.70 (s, 1H), 2.52 (d, J=16.3Hz, 4H), 2.02 (s, 1H), 1.69 (s, 3H), 1.62 (s, 2H), 1.51 (s, 1H), 1.02(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.95(s),149.17(s),148.18(s),136.99 (s),120.76(s),117.09(s),109.44(s),81.89(s),65.54(s),57.72(s),46.43(s),41.30 (s),39.08(s),38.89(s),35.71(s),30.77(s),20.46(s),18.43(s).
HRMS(ESI):m/z[M+H]+calcd for C19H28N3O4:362.2080;found:362.2085.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative of embodiment 4 Artalbic acid
Be dissolved in compound II (187mg, 0.5mmol) in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg, 2.5mmol), KI (84mg, 0.5mmol) and 1H-tetrazole (1401mg, 20mmol), mixture is heated to reflux 5h.Reaction After end pour reactant liquor in frozen water into, extract three times with equivalent dichloromethane, merge organic phase.Use water and saturated common salt successively Organic phase after water washing merging, then be dried with anhydrous sodium sulfate, reduced pressure concentration is removed solvent and is obtained product crude product.Because mutually Become isomerization, 1H-tetrazole base and two kinds of substitution products of 2H-tetrazole base can be generated at reaction conditions.Product crude product is used Silica gel column chromatography purifies (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects yellow and concentrates elution band, then will wash-out Band concentrates, and is purified (flowing is mutually: petroleum ether/acetone=100:0.5, v/v) by silica gel column chromatography, and collection two is faint yellow successively Elution band, concentrate front 1 elution band and i.e. obtain the faint yellow solid (41.6mg, 23%) of compound IV.
1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),10.04(s,1H),6.07(s,1H),5.78(s,1H), 4.69 (d, J=11.0Hz, 2H), 4.58 (s, 1H), 4.22 (s, 1H), 4.15 (s, 1H), 3.84 (s, 2H), 2.66 (s, 1H), 2.52 (s, 2H), 2.45 (s, 2H), 2.20 (s, 1H), 1.65 (d, J=8.0Hz, 5H), 1.44 (s, 1H), 0.98 (s, 3H).
13C NMR(125MHz,DMSO-d6)δ201.92(s),175.93(s),149.14(s),148.15(s),145.18 (s),117.08(s),109.40(s),81.85(s),65.53(s),57.68(s),46.71(s),41.29(s),39.04 (s),38.85(s),35.70(s),30.73(s),20.42(s),18.42(s).
HRMS(ESI):m/z[M+H]+calcd for C18H27N4O4:363.2032;found:363.2029.
The therapeutic action to acute renal failure rat for embodiment 5 composition
(1) experimental technique
The preparation of composition: the powder of the 40mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding The powder of the 60mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg composition with the mixing of turbine stirring instrument, Dissolve, with water, the solution that the composition of this 100mg obtains composition during use.
Intramuscular injection glycerine is used to cause Acute Renal Failure Rats animal model.Select the healthy male SD of 180~220g Rat 30, is randomly divided into 5 groups: sham-operation group (intramuscular injection physiological saline);Model group (intramuscular injection glycerine);It is administered and intervene Group (composition, compound III or compound IV 0.6mg/Kg, intramuscular injection glycerine), each group rat is vertical after glycerine 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 physiological 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 CBF after treatment, averages As single animal renal blood flow;Take blood and prepare serum, measure blood BUN and Cre (all by the operation of kit specification).
(3) experimental result
1. composition can increase acute renal failure Mouse Kidney CBF
Composition can dramatically increase acute renal failure Mouse Kidney CBF, and compound III and compound IV acts on without this.
The impact on acute renal failure Mouse Kidney CBF for table 1 composition
* P < 0.05vs acute renal failure model group
2. composition has protective effect to acute renal failure Mouse Kidney function
Acute renal failure rat intravenous injection physiological saline is after 24 hours, and serum BUN and Cre is shown in Table 2.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 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: 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 embodiment 7 composition tablet involved in the present invention
Taking 2 grams of compositions, the customary adjuvant 18 grams of tablet is prepared in addition, mixes, and conventional tablet presses makes 100.
The preparation of embodiment 8 composition capsule involved in the present invention
Taking 2 grams of compositions, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixes, encapsulated makes 100.

Claims (6)

1. a composition, 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 40% and 60%,
2. the preparation method of composition as claimed in claim 1, is characterized by: by powder and the compound IV of compound III Powder be respectively 40% and 60% according to mass percent and be sufficiently mixed.
3. a composition as claimed in claim 1 application in treatment acute renal failure medicine.
4. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes The reduction of kind renal blood flow amount caused by acute renal failure.
5. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes The rising of the serum BUN that kind acute renal failure causes.
6. application in treatment acute renal failure medicine for the composition as claimed in claim 3, is characterized by: described composition changes The rising of change of serum C re that kind acute renal failure causes.
CN201610347870.5A 2016-05-24 2016-05-24 The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-acute renal failure medicine Pending CN106074534A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105193793A (en) * 2015-07-16 2015-12-30 南京海澳斯生物医药科技有限公司 Composition and application thereof in anti-ARF (Acute Renal Failure) drugs
CN105287585A (en) * 2015-11-05 2016-02-03 南京海澳斯生物医药科技有限公司 Composition and application of composition in medicine for resisting acute renal failure
CN105343082A (en) * 2015-12-07 2016-02-24 南京海澳斯生物医药科技有限公司 Composition and application of composition in medicines for resisting acute renal failure

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105193793A (en) * 2015-07-16 2015-12-30 南京海澳斯生物医药科技有限公司 Composition and application thereof in anti-ARF (Acute Renal Failure) drugs
CN105287585A (en) * 2015-11-05 2016-02-03 南京海澳斯生物医药科技有限公司 Composition and application of composition in medicine for resisting acute renal failure
CN105343082A (en) * 2015-12-07 2016-02-24 南京海澳斯生物医药科技有限公司 Composition and application of composition in medicines for resisting acute renal failure

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《TETRAHEDRON LETTERS》: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 *

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