CN106074522A - The compositions of Artalbic acid derivant is used for preparing cardiotonic agents - Google Patents
The compositions of Artalbic acid derivant is used for preparing cardiotonic agents Download PDFInfo
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- CN106074522A CN106074522A CN201610405040.3A CN201610405040A CN106074522A CN 106074522 A CN106074522 A CN 106074522A CN 201610405040 A CN201610405040 A CN 201610405040A CN 106074522 A CN106074522 A CN 106074522A
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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 present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions and in the purposes preparing on cardiotonic agents.The invention discloses a kind of compositions and preparation method thereof.Pharmacological experiment shows, the compositions of the present invention has anti-heart failure effect, 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 compositions, 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, anemia, gestation, childbirth, cardiac arrhythmia, pulmonary infarction, hyperthyroidism, diabetes, suppression heart medicine induction increase the weight of
HF.Pathogeny 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.
At present for the treatment of heart failure, not having specific medicament clinically, major part medicine is while alleviating symptoms of heart failure
There is inevitable toxic and side effects, from natural product, find compound or lead compound and carry out structural modification and obtain it
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 (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 heart failure activity anti-to said composition is evaluated, and it has anti-heart failure and lives
Property.
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 70% and 30%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositions 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 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 2 Artalbic 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 3 Artalbic 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 4 Artalbic 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 anti-heart failure activity
(1) experimental example: the compositions therapeutical effect to dog acute heart failure
1 material: animal--healthy adult dog body weight 12.5～13.5kg.Pentobarbital sodium (Sigma, import subpackage, 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 compositions: the powder that will cross the 70mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 30mg 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.
2 test methods and result
Dog is randomly divided into NS group (waiting capacity solvent), gastric infusion compositions 1.0mg/kg group, compound III
1.0mg/kg group and compound IV 1.0mg/kg group, often group 6.After fasting 12 hours, intravenous injection pentobarbital sodium 40mg/
Kg anaesthetizes, tracheal intubation, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram.Breast 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 ascending aorta blood flow.Using ascending aorta 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 pentobarbital sodium (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 of table 1 compositions
Compare with NS group,@p<0.05
The impact (n=6) on heart failure canine cardiac work of table 2 compositions
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 1,2, and compositions can dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt (with model group matched 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 compositions impact kinemic on heart failure canine (n=6)
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 3, compositions 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: compositions 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) the experimental example compositions impact on chronic heart failure rat
Test method and result
Rat 50, male and female half and half.10 are only used as Normal group.40 lumbar injection doxorubicin hydrochloride 2mg/kg, often
Week 1 time, totally 6 weeks, when the 5th week, it 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 trachea and intubate, the total tremulous pulse 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), intraventricular pressure maximum climbing speed (+dp/dtmax), 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
Doxorubicin hydrochloride, 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 of table 4 compositions
Compare with NS group,Δ: p < 0.05
Table 4 result of the test shows that compositions 2.5mg/kg can significantly raise the Heart Failure Wistar Rats that caused by doxorubicin hydrochloride
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 caused by doxorubicin hydrochloridemax,-dp/dtmaxWith
The reduction of Vpm.
Conclusion: compositions has significantly treatment or the effect of 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 significantly treatment or the effect of preventing chronic heart failure, it is not possible to
It is used for preparing treatment or the medicine of preventing chronic heart failure.
The preparation of embodiment 6 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 7 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 (10)
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 70% and 30%,
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 70% and 30%.
A kind of compositions the most as claimed in claim 1 application in cardiotonic agents.
4. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure is the acute heart
Decline.
5. compositions application in cardiotonic agents as claimed in claim 4, it is characterised in that: described compositions can increase
The heart acting of extra urgaent dispatch heart failure.
A kind of compositions the most as claimed in claim 4 application in cardiotonic agents, it is characterised in that: described compositions can
To increase the cardiac output of acute heart failure.
7. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure is the chronic heart
Decline.
8. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions can increase
Add the left ventricular systolic pressure of chronic heart failure.
9. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions can increase
Add the intraventricular pressure maximum climbing speed of chronic heart failure.
10. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described compositions is permissible
Increase the myocardium maximal velocity of contraction of chronic heart failure.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610405040.3A CN106074522A (en) | 2016-06-08 | 2016-06-08 | The compositions of Artalbic acid derivant is used for preparing cardiotonic agents |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610405040.3A CN106074522A (en) | 2016-06-08 | 2016-06-08 | The compositions of Artalbic acid derivant is used for preparing cardiotonic agents |
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| CN106074522A true CN106074522A (en) | 2016-11-09 |
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| CN201610405040.3A Pending CN106074522A (en) | 2016-06-08 | 2016-06-08 | The compositions of Artalbic acid derivant is used for preparing cardiotonic agents |
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2016
- 2016-06-08 CN CN201610405040.3A patent/CN106074522A/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》 * |
| 文宏: "双氢青蒿素对肺动脉高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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