CN106074509A - The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing cardiotonic agents - Google Patents
The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing cardiotonic agents Download PDFInfo
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- CN106074509A CN106074509A CN201610347901.7A CN201610347901A CN106074509A CN 106074509 A CN106074509 A CN 106074509A CN 201610347901 A CN201610347901 A CN 201610347901A CN 106074509 A CN106074509 A CN 106074509A
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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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- 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
- A61K31/4192—1,2,3-Triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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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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Abstract
The invention discloses the application in cardiotonic agents 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 and in the purposes preparing on cardiotonic agents.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 anti-heart failure effect with the composition of O (1H tetrazole base) ethyl derivative, has the value of exploitation cardiotonic agents.
Description
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
Heart failure (hear failure, HF) refers to that cardiac function is abnormal and causes heart pump blood volume can not meet tissue metabolism's need
A kind of pathological and physiological condition wanted.The cause of disease is that cardiac overload, myocardium diastole own are limited, and any reason cause initial
Myocardial damage；And infect, anaemia, gestation, childbirth, arrhythmia, pulmonary embolism, hyperthyroidism, diabetes, suppression heart medicine induction increase the weight of
HF.Pathogenesis is it is considered that the mechanism that HF occurs development is abnormal hemodynamics；The later stage eighties 20th century recognizes god
The activation of warp-endocrine hormone plays an important role (sympathetic ↑ NE ↑ RAS ↑ wait activation)；" cardiac muscle weight is gradually specify that after the nineties
Mould " (remodelling) be cause heart failure occur development fundamental mechanism.Heart failure is divided into again acute heart failure and chronic heart failure.
Treatment for heart failure at present, does not has specific medicament clinically, and major part medicine is while alleviating symptoms of heart failure
There is inevitable toxic and side effect, from natural products, find compound or lead compound and carry out structural modification and obtain it
Derivative, thus the potential drug obtaining 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-heart failure activity, and it has anti-heart failure and lives
Property.
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 65% and 35%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the composition of the present invention has preferable anti-heart failure effect.The present invention pharmaceutically can connect
The salt being subject to has same drug effect.
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 2Artalbic 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 3Artalbic 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 4Artalbic 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.
Embodiment 7 composition anti-heart failure activity
(1) experimental example: the therapeutic action to dog acute heart failure for the composition
1 material: animal--healthy adult dog body weight 12.5～13.5kg.(Sigma, import dispenses yellow Jackets, rule
Lattice: 25g)；Instrument U.S. BIC16 leads physiograph (production of BIC Corp. of the U.S.)；Electromagnetic flowmeter (MFV-3200 type): day
This photoelectricity company produces.
The preparation of composition: the powder of the 65mg compound III that will cross 200 mesh nets after grinding crosses 200 after grinding
The powder of the 35mg 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.
2 test methods and result
Dog is randomly divided into NS group (waiting capacity solvent), gastric infusion composition 1.0mg/kg group, compound III
1.0mg/kg group and compound IV 1.0mg/kg group, often organize 6.After fasting 12 hours, intravenous injection yellow Jackets 40mg/
Kg anaesthetizes, trachea cannula, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram.Chest is opened in left side, plugs in conduit to left room from the apex of the heart
Pressure and rate of pressure change (± dp/dt thereofmax).Waltan-Brodie strain bow is implanted left ventricle antetheca, measures cardiac muscle and receive
Contracting power.With electromagnetic flowmeter determination aorta ascendens CBF.Using aorta ascendens flow as cardiac output (CO), calculate heart and refer to
Number (CI), index (SI) of often fighting, work done (SW) of often fighting, left heart work done (LVW).Parameters record and BIC physiograph.Art
Half an hour after, parameters reaches stable.From femoral vein constant speed gasing injection yellow Jackets (0.5mL/kg min), with ± dp/
dtmaxDropping to about 1000mHg/s is that leading indicator forms acute heart failure.After acute heart failure model stability, each treated animal
Duodenum gives relative medicine.Between group, T inspection, carries out statistical procedures.
The impact (n=6) on heart failure canine dp/dt for table 1 composition
Compare with NS group,@p<0.05
The impact (n=6) on heart failure canine cardiac work for table 2 composition
Compare before being administered*p<0.05；Compare with NS group@p<0.05
Result is as shown in table the 1st, 2, and composition can dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt (with model group control group
Relatively, p < 0.05).Compound III and compound IV can not dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt.
Table 3 composition kinemic impact (n=6) on heart failure canine
Compare before being administered*p<0.05；Compare with NS group@p<0.05
Result is as shown in table 3, composition can dramatically increase Heart Failure Dogs cardiac output (compare with model control group, p <
0.05).Compound III and compound IV can not dramatically increase the cardiac output of Heart Failure Dogs.
Conclusion: composition can significantly improve acute heart failure, can be used to preparation treatment or the medicine of prevention acute heart failure.
Compound III and compound IV can not significantly improve acute heart failure, should not be used to preparation treatment or the medicine of prevention acute heart failure.
(2) impact on chronic heart failure rat for the experimental example composition
Test method and result
Rat 50, male and female half and half.10 are only used as Normal group.40 lumbar injection ADMh 2mg/kg, often
It week 1 time, totally 6 weeks, when the 5th week, is randomly divided into 4 groups, i.e. normal NS group and 3 gastric infusion 2.5mg/kg groups.Gastric infusion combines
Thing 2.5mg/kg group, compound III 2.5mg/kg group and compound IV 2.5mg/kg group rose at the 5th week and give group respectively every day
Compound, compound III and each group of compound IV gavage, be administered 21 days.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, operation
Peeling off tracheae and intubating, the total artery in right side of simultaneously dissociating, (diameter 1mm is full of 1% liver to insert homemade heart catherization through it
Element), trace blood pressure curve；It is further continued for inserting so that it is enter left ventricle by left arterial lobe, trace intraventricular pressure curve, automatically
Analyzing and processing left ventricular systolic pressure (LVSP), maximum the climbing speed (+dp/dt of intraventricular pressuremax), intraventricular pressure maximum falling speed
(-dp/dtmax) and survey the data such as cardiac muscle maximal velocity of contraction (Vpm).Separately take 10 rats as Normal group, do not give
ADMh, remaining operation is with above-mentioned, and between group, T inspection, carries out statistical procedures.
The impact (n=10) on chronic heart failure Cardiac Function in Rat for table 4 composition
Compare with NS group,△: p < 0.05
Table 4 result of the test shows that composition 2.5mg/kg can significantly raise the Heart Failure Wistar Rats being caused by ADMh
LVSP ,+dp/dtmax,-dp/dtmaxReduction (comparing with NS group, P < 0.05) with Vpm；Compound III 2.5mg/kg and chemical combination
Thing IV 2.5mg/kg can not significantly raise the LVSP ,+dp/dt of the Heart Failure Wistar Rats being caused by ADMhmax,-dp/dtmaxWith
The reduction of Vpm.
Conclusion: composition has the effect of significantly treatment or preventing chronic heart failure, can be used to preparation treatment or prevention
The medicine of chronic heart failure.Compound III and compound IV does not have the effect of significantly treatment or preventing chronic heart failure, it is not possible to
It is used for preparing the medicine for the treatment of or preventing chronic heart failure.
The preparation of embodiment 6 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 7 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 (10)
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 65% and 35%,
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 65% and 35% according to mass percent and be sufficiently mixed.
3. application in cardiotonic agents for a kind of composition as claimed in claim 1.
4. application in cardiotonic agents for the composition as claimed in claim 3, it is characterised in that: described heart failure is the acute heart
Decline.
5. application in cardiotonic agents for the composition as claimed in claim 4, it is characterised in that: described composition can increase
The heart acting of extra urgaent dispatch heart failure.
6. application in cardiotonic agents for a kind of composition as claimed in claim 4, it is characterised in that: described composition can
To increase the cardiac output of acute heart failure.
7. application in cardiotonic agents for the composition as claimed in claim 3, it is characterised in that: described heart failure is the chronic heart
Decline.
8. application in cardiotonic agents for the composition as claimed in claim 7, it is characterised in that: described composition can increase
Add the left ventricular systolic pressure of chronic heart failure.
9. application in cardiotonic agents for the composition as claimed in claim 7, it is characterised in that: described composition can increase
Add the maximum climbing speed of intraventricular pressure of chronic heart failure.
10. application in cardiotonic agents for the composition as claimed in claim 7, it is characterised in that: described composition is permissible
Increase the myocardium maximal velocity of contraction of chronic heart failure.
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| CN201610347901.7A CN106074509A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing cardiotonic agents |
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| CN201610347901.7A CN106074509A (en) | 2016-05-24 | 2016-05-24 | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing cardiotonic agents |
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2016
- 2016-05-24 CN CN201610347901.7A patent/CN106074509A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| ANTONELLA MAGGIO,ET AL: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba(Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 * |
| 文宏: "双氢青蒿素对肺动脉高血压干预作用的实验研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
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Application publication date: 20161109 |