CN105153125A - Compound for preparing medicine for treating myocardial ischemia and preparation method and application thereof - Google Patents

Compound for preparing medicine for treating myocardial ischemia and preparation method and application thereof Download PDF

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Publication number
CN105153125A
CN105153125A CN201510631560.1A CN201510631560A CN105153125A CN 105153125 A CN105153125 A CN 105153125A CN 201510631560 A CN201510631560 A CN 201510631560A CN 105153125 A CN105153125 A CN 105153125A
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China
Prior art keywords
myocardial ischemia
compound
formula
heart
preparation
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CN201510631560.1A
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Chinese (zh)
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不公告发明人
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Qingdao You Cheng New And High Technology Co Ltd
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Qingdao You Cheng New And High Technology Co Ltd
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Priority to CN201510631560.1A priority Critical patent/CN105153125A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a compound for preparing medicine for treating myocardial ischemia and a preparation method and application thereof. Pharmacological experiments prove that the compound basically has no influence on the livers, the lungs, the spleens and the kidneys, has the advantage of being little in toxic and side effect, can be used for treating cardiovascular diseases and has the wide application prospect on the aspect of treating the acute myocardial ischemia and the obvious effect on treating the myocardial ischemia.

Description

A kind ofly can be used for compound preparing Ischemic myocardium medicine and preparation method thereof, purposes
Technical field
The present invention relates to the pharmaceutical field relevant to Cardiovarscular.Specifically, the present invention relates to the compound of a kind of cinnamic acid skeletal myocardial ischemia being had to provide protection, its preparation method and the pharmaceutical composition containing them.
Background technology
Cardiovascular and cerebrovascular diseases is exactly that cardiovascular and cerebrovascular disease are referred to as, and makes a general reference because ischemia or hemorrhagic diseases occur for the heart that hyperlipidaemia, blood are sticky, atherosclerosis, hypertension etc. cause, brain and body tissue.A kind of serious threat mankind, the common disease that particularly more than 50 years old the elderly is healthy, even if apply treatment means most advanced, perfect at present, the cerebrovascular accident survivor of more than 50% still can be had to live can not take care of oneself completely, the number of cardiovascular and cerebrovascular diseases is died from every year up to 1,500 ten thousand people in the whole world, occupies the various cause of the death the first.
Wherein myocardial ischemia is very common a kind of cardiovascular and cerebrovascular diseases, and myocardial ischemia refers to that the hemoperfusion of heart reduces, and cause the oxygen supply of heart to reduce, energy metabolism of myocardial is abnormal, can not support a kind of pathological state of normal heart action.Coronary heart disease causes main, the modal cause of disease of myocardial ischemia.Along with the raising of living standards of the people, current myocardial ischemia is the trend risen year by year in the morbidity of China.Myocardial ischemia is common disease and the frequently-occurring disease of the elderly.
The common reason of myocardial ischemia is coronary atherosclerosis, secondly also has inflammation (rheumatic, syphilis, mucocutaneous lymphnode syndrome and thromboangitis obliterans etc.), spasm, embolism, connective tissue disease, wound and congenital abnormality etc. multiple.Epidemiological study finds, the important risk factor relevant to atherosclerosis is hyperlipidaemia, essential hypertension, diabetes, smoking, obesity, homocysteine increases, physical exertion is few, advanced age and the male sex etc.
Blood pressure reduction, aorta blood supply minimizing, coronary occlusion, can directly cause heart blood supply to reduce; The change of valvulopathy, blood viscosity, myocardium pathology own also can make heart blood supply reduce.Also have a kind of situation, heart blood supply does not reduce, but heart oxygen demand adds, and this is a kind of myocardial ischemia relatively.To the blood vessel of heart blood supply coronary artery, opening is in aorta ascendens.Clinical display: causing main, the modal cause of disease of myocardial ischemia, is coronary stricture.And the major cause of coronary stricture is atherosclerosis.The heart trouble caused because of coronary atherosclerosis is exactly the coronary heart disease that the large daily life of a family is said.So coronary heart disease is myocardial ischemia " arch-criminal ".
Myocardial ischemia all may bring many disadvantageous effects to heart and whole body.Oxygen is the movable requisite material of myocardial cell, and oxygen by blood transport to cell.Heart does not have " oxygen warehouse ", relies on myocardial blood flow completely, so once ischemic, can cause anoxic at once.The direct result of anoxic is that myocardial cell's aerobic metabolism weakens, and production capacity reduces, and energy required when making cardiomotility is under-supply, causes stenocardia, irregular pulse, heart function to decline.Meanwhile, the refuse of metabolism can not effectively be removed in time, easily has a negative impact.Ischemic, anoxic, scarce energy, finally can affect the contractile function of heart.If there is the cardiac muscle of 20% ~ 25% to stop shrinking, usually there will be left chamber function exhaustion; If there is the cardiac muscle of more than 40% not shrink, just have the exhaustion of severe cardiac pump function.If this situation occurs suddenly, just there will be breakneck cardiogenic shock.Acute myocardial infarction is just normal relevant to this situation.Myocardial ischemia also can damage diastolic function.Shrink bad and diastole is bad combines, easily cause ventricular filling pressure to raise, cause pulmonary congestion, also can cause complicated substance metabolism disorder and myocardial electrical activity not normal.Therefore, once there is myocardial ischemia, cause of disease symptomatic treatment should be found accurately, just can avoid potential serious consequence.
The invention discloses a kind of compound of cinnamic acid skeletal, can be used for preparing the medicine of Cardiovarscular especially Ischemic myocardium.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, a kind of formula I that can be used in preparing Cardiovarscular medicine is provided.
Another object of the present invention is to provide the method for the compound of preparation formula I.
Another object of the present invention is to provide the compound containing formula I and is jointly used for the treatment of cardiovascular disorder as the medicinal compositions of effective constituent and one or more pharmaceutically acceptable carrier, vehicle or thinners.
The Compound I that the present invention has formula I structure has following structural formula:
Formula I of the present invention is synthesized by following steps:
Compd A carries out esterification, obtains compd B, and the process of compd B bromide reagent obtains Compound C, and C is obtained by reacting Compound D with tetrazole in the presence of a base, and D obtains Compound I through amidate action.
The present invention by every test determination such as formula the activity of I to cardiovascular disorder.The results showed, the compound of formula I structure for the preparation of the medicine of Cardiovarscular, can have good development prospect.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Accompanying drawing explanation
Fig. 1 is the structural formula of the Compound I that the present invention prepares.
The reaction equation of the Compound I that the present invention of Fig. 2 position prepares.
Embodiment
Embodiment 1:
12mmol formic acid and 15mmol phosphorus oxychloride are joined in 20mL ether, stir 30 minutes at 50 DEG C, after add 10mmol compd A, 3mmolDCC be stirred in 60 DEG C at stir 30 minutes, reaction 10h after, by in reaction mixture impouring 100mL frozen water, stir, pH=6 is regulated with concentrated hydrochloric acid, extract with the ethylene dichloride of 50mL × 3, merge extraction phase, salt water washing once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain resistates, then column chromatography purification, obtain the sterling of B, ESI-MS, m/z=294.11 ([M+NH 4] +).
8mmol compd B is dissolved in 20mL toluene, slowly stirs, slowly drip 2.71g (10mmol) PBr under ice-water bath cooling 3the solution that the methylene dichloride being dissolved in 2mL drying is made, dropwising rear reaction mixture at room temperature stirs after half an hour in impouring 100mL frozen water, stirs, extracts with the ethylene dichloride of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains resistates in salt water washing, then column chromatography purification, obtain the sterling of C, ESI-MS, m/z=356.03 ([M+H] +).
6mmol Compound C and 8mmol tetrazole are dissolved in 10mLDMF, stir, add 3.32g (24mmol) K 2cO 3, continue at 100 DEG C to stir until raw material consumption complete (10 hours).In reaction mixture impouring 100mL frozen water, stir, regulate pH=2 with concentrated hydrochloric acid, extract with the ethylene dichloride of 50mL × 3, merge extraction phase, once, anhydrous sodium sulfate drying, boils off solvent at Rotary Evaporators and obtains resistates in salt water washing, then column chromatography purification, obtain the sterling of D, ESI-MS, m/z=346.13 ([M-H] -).
Be dissolved in 20mL toluene by 5mmol Compound D and 8mmol thionyl chloride, stirred at ambient temperature reacts 30 minutes, after add 3mmolTEA and 5mmol compd E and at room temperature stirring reaction 5 hours.In reaction mixture impouring 100mL frozen water, stir, extract with the ethylene dichloride of 50mL × 3, merge extraction phase, salt water washing once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain resistates, then column chromatography purification, obtain the sterling of I, ESI-MS, m/z=461.18 ([M-H] -).
Its physical properties:
1H-NMR:δH(DMSO):0.96(t,3H),1.33(t,2H),1.71(t,2H),2.08(s,3H),3.94(s,2H),6.67(d,1H),6.8(d,1H),6.9(d,1H),7.58(d,1H),7.72(d,1H),7.82(d,1H),8.0(s,1H),8.20(s,1H),8.23(s,1H),8.92(s,1H),12.4(s,1H)。
Ultimate analysis: theoretical value: C:59.86, H:5.02, O:13.87;
Measured value: C:59.78, H:5.01, O:13.89.
Embodiment 2:
The pharmacological evaluation of formula I of the present invention and result
1, maximum tolerance test:
Getting the mouse 40 of body weight 20 ± 2g, male and female half and half, is the suspension of 100mg/ml by 0.8mg/20g gavage such as formula the concentration of I, the death condition of animal in Continuous Observation 30 days, result, in 30 days, all animal feeding activities are normal, do not have death, LD do not detected 50, think that it is nontoxic.
2, Pituitrin is caused to the provide protection of myocardial ischemia:
Get healthy rat 36, male and female half and half, body weight 180-220g, random point three groups, give three groups of rats the urethane anesthesia of 25% respectively, face upward position and fix, be separated femoral vein, connect electrocardiograph, record II lead electrocardiogram, abnormal then be discarded.First group of i.v. injection of compounds I dosage is 1mg/kg, second group of intravenous injection physiological saline 1mg/kg, inject latter 2 minutes, vena femoralis injection Pituitrin 72 μ/kg, within 8 seconds, injected, injection each recording ecg rear 0-30 second, 60 seconds, 90 seconds, 120 seconds, 180 seconds, 240 seconds, 300 seconds, 420 seconds, 600 seconds and 900 seconds once.
After giving Pituitrin, ECG Change divides the second phase:
The first phase: inject 5-30 second afterwards, T ripple increases, and ST section raises >0.1mV.
The second phase: inject latter 30 seconds to several points, low flat, the two-phase of T ripple, inversion, heart rate are slack-off, P-R, Q-T interval prolongation.
Effect judges: not occur that the above-mentioned first phase or second phase ischemia change person is as feminine gender.
Number of animals/total number of animals of myocardial ischemia negative rate=do not occur myocardial ischemia.
Table 1 experimental group and control group negative rate comparison sheet
Group Dosage (mg/kg) Myocardial ischemia negative rate
Formula I 1 7/12±
Pannonit 1 9/12±±
Physiological saline 1ml 1/12
P<0.05 ± ± P<0.01 is compared with physiological saline
Can be found out by above-mentioned experiment, formula I structural compounds has provide protection to Acute Myocardial Ischemia in Rats, action intensity compared with pannonit without difference.
3, formula I is to the provide protection of myocardial ischemia-reperfusion injury:
Get healthy Wistar rat 45, male and female dual-purpose, body weight 180-220g, respectively by three groups of rats with 25% urethane press 0.6ml/100g anesthesia, face upward position and fix, expose organ T-shaped and cut, connect animal respirator, be separated carotid artery.Be inserted into the carotid artery of separation with heparin flush plastics tubing, connect channel polygraph, recording blood pressure and heart rate, be separated femoral vein stand-by.At rats with left 4-5 intercostal incision, cut off 4,5 ribs, expose pericardium, tear pericardium, gently press from offside with finger, heart is released.Be separated ligation 5 minutes (ligation rises at once respectively by above-mentioned dose intravenous administration) near coronary artery (LCA) initial part, then decontrol Reperfu-sion 60 minutes.Occur that any exception does not deal with, to observe its nature evolution.Before test, open chest, ligation LCA at once, 2,5,15,30,60 minutes, synchronous recording electrocardiogram(ECG, systolic arterial pressure, mean pressure and diastolic pressure.Experiment monitored over time.All take left room flesh sample for each group, do the inspection of myocardium electron microscopic morphology.
Control group heart disorder accounts for 100%, wherein 6 death, only a Self recovery rhythm, and formula I structural compounds group irregular pulse only accounts for 25%, and without dead, equal Self recovery rhythm, pannonit group irregular pulse accounts for 60%, dead 3, all the other Self recovery rhythms.Formula I structural compounds can reduce Reperfu-sion room and to quiver incidence, and two groups are compared with control group, have significant difference.
More myocardium left room pressure, formula I structural compounds group is compared with pannonit group, the latter is starkly lower than formula I structural compounds group on left room is pressed and held time, and point out two groups can maintain heart function at myocardial ischemia in perfusion fashion, and myocardial ischemia-reperfusion group is better than pannonit group.
Shown by above-described embodiment, formula I of the present invention is a kind of novel cpd, safer, can life-time service, and toxicity is lower, and side effect is less, can the damage that brings of available protecting myocardial ischemia, is applicable to Cardiovarscular.

Claims (4)

1. the compound of a formula I structure:
2. synthesize the method for the compound of the formula I structure that claim 1 defines, comprise the following steps:
3. the compound of formula I structure that defines of claim 1 is in the purposes preparing Cardiovarscular medicine.
4. the compound of formula I structure as claimed in claim 4 is in the purposes preparing Cardiovarscular medicine, and it is characterized in that, described cardiovascular disorder is myocardial ischemia.
CN201510631560.1A 2015-09-29 2015-09-29 Compound for preparing medicine for treating myocardial ischemia and preparation method and application thereof Pending CN105153125A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105418527A (en) * 2015-12-28 2016-03-23 青岛友诚高新技术有限公司 Compound with ductal breast cancer prevention activity, and preparation method and use thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312070A (en) * 2000-03-08 2001-09-12 萧湘 Application of cinnamic acid, cinnamate and their derivative in preparing medicine
WO2003049702A2 (en) * 2001-12-10 2003-06-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
CN101213194A (en) * 2004-08-03 2008-07-02 惠氏公司 Indazoles useful in treating cardiovascular diseases
CN101704752A (en) * 2009-07-10 2010-05-12 中国人民解放军第四军医大学 Anti-ischemia/reperfusion injury medicine
WO2015047973A1 (en) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. FACTOR XIa INHIBITORS

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312070A (en) * 2000-03-08 2001-09-12 萧湘 Application of cinnamic acid, cinnamate and their derivative in preparing medicine
WO2003049702A2 (en) * 2001-12-10 2003-06-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
CN101213194A (en) * 2004-08-03 2008-07-02 惠氏公司 Indazoles useful in treating cardiovascular diseases
CN101704752A (en) * 2009-07-10 2010-05-12 中国人民解放军第四军医大学 Anti-ischemia/reperfusion injury medicine
WO2015047973A1 (en) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. FACTOR XIa INHIBITORS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105418527A (en) * 2015-12-28 2016-03-23 青岛友诚高新技术有限公司 Compound with ductal breast cancer prevention activity, and preparation method and use thereof

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