CN1395923A - Application of xanthiphenylketamine or its salt in preparing medicines to treat cardiovascalar disease - Google Patents
Application of xanthiphenylketamine or its salt in preparing medicines to treat cardiovascalar disease Download PDFInfo
- Publication number
- CN1395923A CN1395923A CN 02125316 CN02125316A CN1395923A CN 1395923 A CN1395923 A CN 1395923A CN 02125316 CN02125316 CN 02125316 CN 02125316 A CN02125316 A CN 02125316A CN 1395923 A CN1395923 A CN 1395923A
- Authority
- CN
- China
- Prior art keywords
- peperphentonamine
- administration
- salt
- cardiac
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
An application of the xanthiphenyl ketoamine or its phermacologically acceptable salts in treating myocardial ischemia, heat failure, cardiac insufficiency, etc. is disclosed. Experiments show that it has high curative effect and low toxic by-effect.
Description
Technical field
The present invention relates to the application of Peperphentonamine or its salt, relate in particular to the application of Peperphentonamine and salt thereof as preparation treatment myocardial ischemia, ischemical reperfusion injury or heart failure drugs as preparation treatment cardiovascular disease medicine.
Background technology
Heart failure is cardiovascular diseases's the end stage eventually, the mortality rate height.Myocardial infarction and reperfusion injury of cardiac muscle are the major reasons that causes heart failure.Experimentation both domestic and external represents that calcium antagonist and free radical scavenger have the treatment myocardial infarction and to the effect of anti reperfusion injury.Yet most of calcium antagonists suppress myocardial contraction, reduce cardiac function, and clinical practice is restricted.Free radical scavenger is to not directly influence of cardiac function, and its clinical effectiveness is not identified as yet.
The Therapeutic Principle of heart failure is heart tonifying, expansion blood vessel and diuresis.Cardiac tonic improves heart output by strengthening myocardial contraction, keeps the blood supply of vitals such as the heart, brain, kidney; Expand blood vessel medicine and diuretic by reducing cardiac load, the protection cardiac function.Yet, the toxicity of cardiotonic glycoside, catecholamine, phosphodiesterase inhibitor all types of cardiac tonic such as (PDEI) is bigger, because they are mainly by increasing intracellular calcium concentration, reach the effect that strengthens myocardial contraction, this just easily causes intracellular calcium overload, has arrhythogenic danger.Diuretic Chang Zuowei drug of first choice is used for heart failure, still easily causes side effect such as electrolyte disturbance.The research in modern age represents that angiotensin converting enzyme inhibitor (ACEI) has the treatment congestive heart failure, and to resisting myocardial ischemia and the effect of reperfusion injury, but its long-term effect waits to observe.
In a word, development of effective, toxicity is little, and chemical constitution is novel, and the new drug that can treat the cardiovascular diseases is clinical pressing at present, and can help cardiovascular diseases's pathophysiological mechanism is deepened understanding.
Summary of the invention
The object of the present invention is to provide the application of Peperphentonamine or its salt as preparation treatment cardiovascular disease medicine, described Peperphentonamine hydrochloride or its pharmaceutically acceptable salt are obvious as the application curative effect of preparation treatment cardiovascular disease medicine, toxicity is little, has outstanding effect in similar compound or derivant.
In fact the present invention relates to the application of Peperphentonamine or its salt as preparation treatment myocardial ischemia drug.
The invention still further relates to the application of Peperphentonamine or its salt as preparation treatment ischemical reperfusion injury medicine.
The present invention relates to Peperphentonamine in addition or its salt is used as the application that the cardiac insufficiency medicine is treated in preparation.
Wherein said Xanthiphenyl ketamine salt is pharmaceutically acceptable Xanthiphenyl ketamine salt, comprises one of Peperphentonamine hydrochlorate, Peperphentonamine sulfate, Peperphentonamine phosphate, Peperphentonamine carbonate or Peperphentonamine organic salt, with following general formula:
The Peperphentonamine hydrochlorate (being also referred to as Peperphentonamine hydrochloride) that preferably has following structure:
C
21H
24O
4NCl＝389.5
With the preferred Peperphentonamine hydrochloride of the present invention is example, synthetic method is: be initiation material with the homopiperony lamine, through and the benzaldehyde condensation after, form the N-methyl piperethanamine with dimethyl sulfate reaction again, add HCl/EtOH solution and promptly get N-methyl piperethanamine salt hydrochlorate.With N-methyl piperethanamine salt hydrochlorate and right-hydroxyl benzylideneacetone (hydroxy benzaldehyde under alkali condition and acetone promptly get right-hydroxyl benzylideneacetone through the Claisen-Schmidt condensation reaction), paraformaldehyde in dehydrated alcohol, under acid condition, can obtain the Peperphentonamine hydrochlorate, get the pure product of Peperphentonamine hydrochloride with 95% ethyl alcohol recrystallization through the Mannich reaction.Detailed process is expressed as follows:
Synthetic to the hydroxyl benzylideneacetone:
Synthesizing of N-methyl piperethanamine salt hydrochlorate:
Synthesizing of Peperphentonamine hydrochloride:
During use, Peperphentonamine of the present invention or its pharmaceutically acceptable salt can be made water preparation, powder pin, tablet or capsule etc., adopt intravenous injection, intramuscular injection or oral method respectively.Consumption is 0.1-1.0mg/kg.
The present invention finds by pharmacological research, in the analog or derivant of a series of Peperphentonamines, when Peperphentonamine and pharmaceutically acceptable salt thereof are used as preparation treatment cardiovascular disease medicine, has tangible heart tonifying vasodilative effect, for experimental heart failure, myocardial ischemia and reperfusion injury of cardiac muscle all have good preventive and therapeutic effect.Peperphentonamine can strengthen myocardial contraction, improves cardiac function, does not but increase [Ca in the myocardial cell
2+], even can also resist scarce O
2-multiple O
2Or calcium overload in the myocardial cell due to the reperfusion injury.For the heart of myocardial infarction or ischemia reperfusion injury, Peperphentonamine increases blood supply of cardiac muscle, reduces myocardium oxygen consumption, strengthens oxidation resistance, improves energy metabolism of myocardial, keeps cardiac function.
Research of the present invention shows that from aspects such as heart physiological function, myocardium biochemistry and pathomorphology Peperphentonamine and pharmaceutically acceptable salt thereof are that kind can be to resisting myocardial ischemia; the protection Myocardial Ischemia Reperfusion Injury; can improve the novel heart tonifying extension vascular agent of cardiac function again; it increases the sensitivity of myocardial contraction albumen to calcium, does not but increase [Ca in the myocardial cell
2+], it is difficult for causing arrhythmia, helps multiple cardiovascular diseases's treatment.It is again the noval chemical compound that therapeutic effect is good, toxicity is lower simultaneously, and its mechanism of action is different from known cardiovascular disease treating medicine, and curative effect is better than known cardiovascular disease treating medicine.
Peperphentonamine is pharmaceutically acceptable water-soluble in addition, and its derivant is insoluble in water, help drug absorption, therefore in analog or derivant at a series of Peperphentonamines, Peperphentonamine and pharmaceutically acceptable salt thereof might develop into the treatment heart failure, to resisting myocardial ischemia and the new drug of reperfusion injury.
In addition, the synthetic route of Peperphentonamine of the present invention or its pharmaceutically acceptable salt is reasonable in design, and synthesis technique is easy and simple to handle, and raw material is easy to get, and each goes on foot stable reaction conditions, and yield is stable and do not have a serious three-waste pollution.Waste reaction solution mostly is acid, aqueous slkali can discharge through simple process, is fit to industrial production requirement fully.
Describe the present invention in detail below in conjunction with the drawings and specific embodiments
Description of drawings
Fig. 1. Peperphentonamine hydrochloride antagonism KCl causes the Canis familiaris L. coronary artery and shrinks amount-effect curve;
Fig. 2. Peperphentonamine hydrochloride antagonism 5-HT causes the Canis familiaris L. basilar artery and shrinks amount-effect curve;
Fig. 3. Peperphentonamine antagonism CaCl
2Cause the Canis familiaris L. Mesenteric artery and shrink amount-effect curve;
Fig. 4. Peperphentonamine (PKA) and the influence of milrinone (Mil) to myocardial contraction albumen calcium sensitivity, compare with matched group: * * P＜0.01 * * * P＜0.001;
Fig. 5. Peperphentonamine (PKA) and MCI-154 are to myocardium striping sarcostyle Ca
2+, Mg
2+The influence of-atpase activity is compared with no medicine matched group: * * * P＜0.001;
Accompanying drawing 6 is high pressure liquid chromatography figure of the synthetic Peperphentonamine hydrochloride of method of the present invention;
Accompanying drawing 7 is high pressure liquid chromatography figure of the synthetic Peperphentonamine hydrochloride of comparative example method of the present invention.
The specific embodiment
Below be concrete enforcement of the present invention, described experimental example is used to describe the present invention, rather than restriction the present invention.
Experimental example 1
Present embodiment relates to the experiment of the heart tonifying vasodilative effect of Peperphentonamine hydrochloride.1. to the influence of isolated myocardium physiological property
The experiment of adopting isolated rat heart to prepare the SCREENED COMPOUND pharmacologically active is found: Peperphentonamine hydrochloride and pharmaceutically acceptable salt thereof have the enhancing myocardial contraction, the effect of coronary artery dilating and decreased heart rate.For understanding its influence to myocardium physiologically active, adopt guinea pig in vitro papillary muscles and heart muscle specimen, measure cardiac muscular tension and action potential, observe the influence of Peperphentonamine to myocardial contractility, self-disciplining, refractoriness and action potential.Specific as follows: the A. contractility:
Contractility before Cavia porcellus right ventricle papillary muscles of this research and the flesh administration of left room is respectively 54.4 ± 16.8mg and 372 ± 186mg.Promptly produce positive inotropic action in the 1min behind the adding Peperphentonamine hydrochloride, 15min reaches peak value after the administration, acts on more than the lasting 30min, and along with the increase of drug level, peak time shortens, and the persistent period prolongs.In concentration was 1 μ mol/L～100 μ mol/L scopes, Peperphentonamine hydrochloride dose dependent ground increased the contractility of papillary muscles and left room flesh, its ED
50Be respectively 18.4 μ mol/L and 9.2 μ mo1/L.
The positive inotropic action intensity of Peperphentonamine hydrochloride and PDEI class cardiac tonic milrinone (Milrinone) are approximate, and the latter increases the ED of papillary muscles and left room contractility
50Be respectively 6.2 μ mol/L and 4.6 μ mol/L.Yet when the two reached close positive inotropic action intensity, Peperphentonamine hydrochloride made and shrinks the 195 ± 11ms of time-histories before the administration and extend to 211 ± 10ms, (increasing by 8.5 ± 4.7%, P＜0.001); Milrinone then makes and shrinks time-histories minimizing 14 ± 8% (P＜0.01), and the difference between two groups is (P＜0.001) very obviously.B. self-disciplining:
The Peperphentonamine hydrochloride dose dependent ground spontaneous frequency in right room that slows down, milrinone then increases frequency, and when drug level was 100 μ mol/L, the former made right room frequency reduce by 25 ± 11% (P＜0.001), and the latter then makes it to increase by 33 ± 8% (P＜0.001).
The experiment of bringing out the guinea pig papillary muscle self-disciplining with epinephrine shows: Peperphentonamine hydrochloride dose dependent ground increases the threshold concentration that epinephrine brings out self-disciplining, when drug level was 10 μ mol/L, Peperphentonamine hydrochloride made 39 ± 27 μ mol/Ls of adrenergic threshold concentration before the administration be increased to 204 ± 96 μ mol/L (P＜0.001); 48 ± 21 μ mol/L that milrinone then makes it before the administration are reduced to 8.2 ± 8.5 μ mol/L (P＜0.001).Show that Peperphentonamine reduces myocardium self-disciplining, milrinone then makes it to improve, and the result is referring to table 1.
Table 1. Peperphentonamine hydrochloride and milrinone are to the influence of guinea pig papillary muscle self-disciplining
Drug level epinephrine threshold concentration μ mol/L
After the preceding administration of μ mol/L sample number administration
Peperphentonamine hydrochloride
3?????????????4?????????38.3±25.9???????54.0±20.8
6???????????4??????????40.5±22.6??????180.0±72.0***
10??????????6??????????39.0±26.5??????204.0±95.7***
Milrinone
10??????????3??????????48.0±20.8??????8.2±8.5***
With before the administration relatively: * * * P＜0.001C. irritability:
With time-result that the intensity curve method is measured myocardial excitability shows that Peperphentonamine hydrochloride does not influence myocardial excitability.D. refractoriness:
The research of adopting continuously two stimulus methods to survey left room refractory stage is represented: Peperphentonamine and pharmaceutically acceptable salt dose dependent ground prolong the function refractory stage, milrinone then makes it shortening.When drug level was 10 μ mol/L, the former made function prolonged refractory period 6.3 ± 2.9% (P＜0.001), and the latter then makes it to shorten 9.8 ± 2.6% (P＜0.001), and the result is referring to table 2.
Table 2. Peperphentonamine and milrinone are to the influence of guinea pig myocardium refractoriness
Change after the drug level function refractory stage ms administration
% after the administration before the administration of μ mol/L sample number
Peperphentonamine hydrochloride
10?????????????????8???????????196.3±11.9???208.8±12.2????6.3±2.9***
50?????????????????8???????????203.8±9.5????227.5±15.1*???11.8±3.4***
100????????????????9???????????197.2±11.5???238.9±12.7***?21.3±6.8***
Peperphentonamine
10?????????????????8???????????195.1±11.7???206.8±13.2????6.0±3.2***
The Peperphentonamine hydrobromate
50?????????????????8???????????201.8±9.4????217.6±13.5*???7.8±1.4*
The Peperphentonamine succinate
50?????????????????8???????????210.6±8.5????219.3±14.6*???4.0±2.4
The Peperphentonamine maleate
50?????????????????8???????????209.5±10.5???215.8±12.2*???3.0±1.4
Milrinone
10?????????????????4???????????198.8±13.1???178.8±11.1*???-9.8±2.6***
With before the administration relatively: * P＜0.05, * * * P＜0.001
With before the administration relatively: * P＜0.05, * * * P＜0.001E. action potential:
Measuring the experiment of papillary muscles action potential represents: when the adding Peperphentonamine hydrochloride reaches 10 μ mol/L and 100 μ mol/L in the perfusate, and action potential duration, APD APD
90Respectively than prolonging 13 ± 12% (P＜0.01) and 21 ± 16% (P＜0.001) .APD before the administration
50Also slightly prolong.Peperphentonamine hydrochloride does not influence action potential amplitude (APA), makes maximum depolarization speed (Vmax) during high concentration than reducing by 17 ± 21% (P＜0.05) before the administration.Milrinone then obviously lowers APD
50, APD
90And APA, Vmax there is not influence.Show that Peperphentonamine hydrochloride is different from PDEI class milrinone to the influence of action potential, the result is referring to table 3.
Table 3. Peperphentonamine and milrinone are to the influence of Cavia porcellus right ventricle papillary muscles action potential
Drug level
The preceding 10 μ mol/L of parameter administration 100 μ mol/L
Measured value changes the % measured value and changes % Peperphentonamine (N=12) APA mv 103 ± 10 109 ± 11 6 ± 9 101 ± 12-1 ± 7Vmax v/s 144 ± 38 138 ± 56-2 ± 33 121 ± 34-17 ± 21*APD
50Ms 188 ± 26 203 ± 27 7 ± 7** 204 ± 29 8 ± 12APD
90Ms 222 ± 28 249 ± 29*, 13 ± 12**, 267 ± 37***, 21 ± 16*** Peperphentonamine hydrochloride (N=12) APA mv, 101 ± 10 110 ± 11 8 ± 7 105 ± 10-2 ± 6Vmax v/s, 142 ± 36 139 ± 53-3 ± 30 119 ± 32-15 ± 19*APD
50Ms 185 ± 24 206 ± 25 9 ± 7** 202 ± 27 7 ± 10APD
90Ms 219 ± 27 253 ± 26*, 15 ± 10**, 259 ± 35***, 20 ± 14*** Peperphentonamine succinate (N=12) APA mv, 107 ± 12 109 ± 11 5 ± 8 103 ± 11-1 ± 5Vmax v/s, 140 ± 28 136 ± 56-3 ± 28 119 ± 33-15 ± 18*APD
50Ms 184 ± 22 201 ± 23 6 ± 9* 201 ± 25 7 ± 14APD
90Ms 218 ± 25 254 ± 27*, 14 ± 8*, 247 ± 35**, 15 ± 14** milrinone (N=6) APA mv, 103 ± 10 92 ± 12-11 ± 7**, 93 ± 15-10 ± 8*Vmax v/s, 139 ± 44 162 ± 48 20 ± 33 153 ± 45 12 ± 22APD
50Ms 223 ± 39 186 ± 41-17 ± 10**, 176 ± 43-22 ± 11***APD
90Ms 256 ± 40 221 ± 38-14 ± 6***, 212 ± 40-18 ± 7***
The APA action potential amplitude, the maximum depolarization speed of Vmax,
APD
50The time-histories of action potential multipole 50%, APD
90The time-histories of action potential multipole 90%
With before the administration relatively: * P＜0.05, * * P＜0.01, * * * P＜0.0012. is to the tensile influence of myocardium vessel
Adopt the stripped coronary artery of Canis familiaris L., basilar artery and Mesenteric artery preparation, with potassium chloride (KCl), calcium chloride (CaCl
2) and the increase of 5-hydroxy tryptamine (5-HT) hyperamization pipe tension force, make amount-effect curve, in order to observe the antagonism of medicine.The result represents: Peperphentonamine and pharmaceutically the above-mentioned agonist of acceptable salt 1 μ mol/L～50 μ mol/L noncompetitive ground antagonism cause coronary artery, the contraction of basilar artery and Mesenteric artery moves to right the amount-effect curve of agonist, maximum reaction reduces.It is close with phosphodiesterase inhibitor (PDEI) class heart tonifying expansion blood vessel medicine milrinone that its antagonism KCl causes the action intensity that the Canis familiaris L. coronary artery shrinks, pD
2' be respectively 4.32 and 4.37 μ mol/L; It is approaching that antagonism 5-HT causes action intensity and papaverine that the Canis familiaris L. Mesenteric artery shrinks, pD
2' be respectively 5.36 and 4.98 μ mol/L.From antagonism CaCl
2The vasodilative effect that causes the reaction and display Peperphentonamine hydrochloride of Canis familiaris L. basilar artery contraction is weaker than the calcium antagonist verapamil, its pD
2' be respectively 5.28 and 6.15 μ mol/L.Show that Peperphentonamine hydrochloride has the lax vascular smooth muscle effect of moderate strength.Referring to Fig. 1～3.
Can demonstrate Peperphentonamine and acceptable salt noncompetitive ground antagonism KCl pharmaceutically thereof, 5-HT, CaCl from above isolated experiment
2Cause the Canis familiaris L. coronary artery Deng agonist, the contraction of basilar artery and Mesenteric artery shows that it has the lax vascular smooth muscle effect of moderate strength.
Peperphentonamine and pharmaceutically acceptable salt increase myocardial contraction, prolong and shrink time-histories, the spontaneous frequency in right room that slows down lowers myocardium self-disciplining, prolongs function refractory stage and action potential duration, APD, and the irritability of cardiac muscle is not had obvious influence.Its positive inotropic action intensity is close with PDEI class cardiac tonic milrinone.Yet in contrast, milrinone shortens the contraction time-histories, increases myocardium spontaneous frequency and self-disciplining; Shorten function refractory stage and action potential duration, APD.
The mechanism of action studies show that Peperphentonamine and pharmaceutically the positive inotropic action of acceptable salt mainly be by increasing the sensitivity of myocardial contraction albumen to calcium, it does not increase [Ca in the myocardial cell
2+], even can also be to the intracellular calcium overload due to anti-hypoxia-reoxygenation.Hold itself out to be a kind of novel inotropic agent, also be difficult for causing the low experimental basis that provides of arrhythmia and toxicity for it.
Experimental example 2
Present embodiment relates to Peperphentonamine and the pharmaceutically experiment of the influence of acceptable salt pair whole animal cardiac hemodynamic and myocardium oxygen metabolism thereof.
For understanding the Peperphentonamine and the heart tonifying vasodilative effect of acceptable salt pair whole animal pharmaceutically thereof, observe it to the dirty hemodynamics of anesthesia Cor Canitis, the influence of coronary circulation and myocardium oxygen metabolism.The result represents quiet notes Peperphentonamine, the Peperphentonamine hydrochlorate, the Peperphentonamine hydrobromate, the Peperphentonamine oxalates, the Peperphentonamine succinate, Peperphentonamine maleate 0.5mg/kg～4mg/kg causes that the following parameter dose dependent ground changes: heart rate (HR) slightly slows down, blood pressure (mean pressure MAP, systolic pressure SP, diastolic pressure DP) obviously reduces, cardiac index (CI) increases with the index (SI) of whenever fighting is slight, whenever the work done (SW) of fighting obviously reduces with left chamber work done (LVW), coronary flow (CBF) increases, and coronary resistance (CVR) reduces with total peripheral vascular resistance (SVR).Peperphentonamine and pharmaceutically acceptable salt obviously reduce the myocardium keto consumption parameter (tension time index TTI=HR * MAP), the result who directly measures CS-O2 represent that it can obviously reduce myocardium oxygen uptake rate and zmount of oxygen consumption.These variations show that Peperphentonamine can increase blood supply of cardiac muscle, reduce cardiac load, reduce myocardium oxygen consumption, help improving the demand balance of myocardium oxygen, and this is the treatment myocardial ischemia, the important experimental basis of protection myocardial damage.With the Peperphentonamine hydrochloride is example, and concrete outcome sees Table 4,5
Table 4. Peperphentonamine is to the influence of anesthesia Cor Canitis rate and blood pressure
Peperphentonamine hydrochloride mg/kg
0.5????????????1???????????2?????????????4
N＝4 N＝7 N＝6 N＝6 HRbpm 157±31 187±21 172±35 175±31％-2±3-2±4-6±3*-11±7** MAPmmHg 107±15 109±18 96±10 98±15％-3±5-10±19-16±9**-28±12*** SPmmHg 129±20 141±20 123±17 137±22％-2±4-12±21-18±13*-25±13** DPmmHg 94±13 92±12 86±12 83±15％-1±3-8±19-18±10**-29±9** TTIbpm.mmHg／100 1715±486 2113±566 1667±464 1752±492％-2±6-11±17-19±6***-33±8***。
With before the administration relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Table 5. Peperphentonamine is to the dirty pumping function of anesthesia Cor Canitis, the influence of coronary flow and myocardium oxygen metabolism
Peperphentonamine mg/kg
0.5???????????????1??????????2?????????????4
N＝4??????????????N＝6???????N＝5??????????N＝6
1/min/m before the cardiac index CI administration
21.3 change % 9 ± 3* 6 ± 8 12 ± 10* 16 ± 6*** after ± 0.5 1.6 ± 0.3 1.3 ± 0.5 1.3 ± 0.2 administration
Whenever the preceding ml/beat/m of the index SI administration of fighting
28.9 change % 13 ± 1*** 5 ± 4* 5 ± 13 12 ± 10* after ± 2.7 8.7 ± 1.7 5.5 ± 3.3 7.8 ± 1.2 administrations
Whenever change % 13 ± 7*-12 ± 21-21 ± 1 3*-25 ± 20* after the preceding g.m/beat 92 of the work done SW administration of fighting ± 29 88 ± 27 68 ± 20 68 ± 14 administrations
Change % 15 ± 4**-15 ± 23-28 ± 15**-32 ± 16** after kg.m/min 14 ± 6 17 ± 6 12 ± 5 12 ± 3 administrations before the left side chamber work done LVW administration
Change %-11 ± 4*-13 ± 11*-10 ± 7*-25 ± 8*** after mmHg/l/min/kg 6.9 ± 0.8 7.3 ± 2.4 8.3 ± 4.7 8.1 ± 2.7 administrations before total peripheral vascular resistance SVR administration
Change % 17 ± 7* 13 ± 13* 46 ± 29** 21 ± 10** after ml/min/100g 67 before the coronary flow CBF administration ± 34 64 ± 18 59 ± 17 53 ± 9 administrations
Change %-7 ± 3**-16 ± 10**-28 ± 9***-22 ± 9*** after mmHg/ml/min/100g 1.9 before the coronary resistance CVR administration ± 0.7 1.8 ± 0.4 1.7 ± 0.3 1.9 ± 0.5 administrations
Change %-26 ± 32-31 ± 9***-9 ± 7**-6 ± 4** after % 40 ± 13 57 ± 17 59 ± 12 66 ± 12 administrations before the administration of cardiac muscle oxygen uptake rate
Change %-28 ± 30-33 ± 12***-31 ± 19**-41 ± 10*** after ml/min/100g 3.9 ± 0.3 5.5 ± 2.6 5.3 ± 1.9 4.7 ± 1.6 administrations before the administration of cardiac muscle zmount of oxygen consumption
With before the administration relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Studies show that in that systemic heart is hemodynamic: heart rate slightly slows down behind the quiet notes Peperphentonamine hydrochloride of anesthesia Canis familiaris L., and blood pressure and vascular resistance obviously reduce, cardiac output and coronary flow increase, cardiac work attenuating.Its obvious coronary artery dilator reduces myocardium oxygen uptake rate and zmount of oxygen consumption.Show that Peperphentonamine hydrochloride can increase blood supply of cardiac muscle, reduce cardiac load, help improving the demand balance of myocardium oxygen, this is the treatment myocardial ischemia, the important experimental basis of protection myocardial damage.
Experimental example 3
Present embodiment relates to Peperphentonamine and the pharmaceutically therapeutical effect experiment of acceptable salt pair heart failure thereof.
Expand the therapeutical effect of blood vessel new drug Peperphentonamine to heart failure for understanding heart tonifying, form pentobarbital sodium and cause Cavia porcellus, the pathological model of cat and Cor Canitis force failure is observed from the cardiac hemodynamic aspect, and compares with all kinds of known medicines.
1. heart failure Cavia porcellus
When heart failure forms, the heart rate of animal, blood pressure, left ventricular systolic pressure (LVSP) and rate of pressure change (± dP/dt max) are all than reducing by more than 50 before the heart failure, quiet notes Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 3mg/kg or 6mg/kg, parameters is obviously increased, and strengthen with drug dose.With of the relatively expression of maximal effective dose/AD: Peperphentonamine the and pharmaceutically effect and the PDEI class cardiac tonic milrinone of acceptable salt is approaching as therapeutic index, yet milrinone is prone to ventricular arrhythmia, Peperphentonamine and pharmaceutically acceptable salt then do not cause the rapidity ventricular arrhythmia, show that it more helps the treatment of heart failure.With the Peperphentonamine hydrochloride is example, and concrete outcome sees Table 6.
Table 6. Peperphentonamine hydrochloride and milrinone cause heart failure Cavia porcellus heart rate, the influence of blood pressure and left constant pressure to pentobarbital sodium
Contrast Peperphentonamine milrinone
3mg/kg?????????6mg/kg?????????50μg/kg
N=6 N=6 N=7 N=6 heart rate HR
Bpm 132 before the administration ± 61 172 ± 40 162 ± 49 151 ± 31
Change %-4 ± 7-20 ± 10***##-20 ± 18*#, 12 ± 21 mean arterial pressure MAP after the administration
MmHg 15 before the administration ± 6 17 ± 9 14 ± 4 15 ± 3
Change %-10 ± 10 22 ± 14**#, 52 ± 29***##, 59 ± 35**## left ventricular systolic pressure LVSP after the administration
MmHg 18 before the administration ± 9 18 ± 9 17 ± 3 20 ± 7
Change %-8 ± 15 52 ± 47*, 73 ± 56**#, 82 ± 60*# left ventricular pressure rate of climb+dP/dt max after the administration
MmHg/s 138 before the administration ± 79 195 ± 109 125 ± 30 167 ± 28
Change %-20 ± 2***, 63 ± 45**#, 168 ± 132*#, 365 ± 251**## left ventricular pressure decrease speed-dP/dt max after the administration
MmHg/s 80 before the administration ± 50 110 ± 71 73 ± 14 73 ± 15
Change %-19 ± 6**, 93 ± 72*#, 148 ± 118*#, 412 ± 396*# after the administration
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with matched group: #P＜0.05 ##P＜0.01 ###P＜0.0012. heart failure cat
The result who the open chest anesthetized cat is observed continuously 4h represents: during heart failure 1h, and HR, MAP, than reducing by 59%, 71% and 67% before the heart failure, ± dP/dt max and myocardial contraction (CF) descend 85% to LVSP respectively, 85% and 58%, common carotid artery blood flow (CCBF) descends 71%.Continuity in time more than changes and further increases the weight of.Quiet notes Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 1mg/kg～8mg/kg dose dependent ground obviously increase heart failure animal MAP, CF, contractility pace of change (± dT/dt max), LVSP, ± dP/dtmax and CCBF, with the Peperphentonamine hydrochloride is example, and concrete outcome sees Table 7.
All kinds of known cardiac tonic show all that at this experimental heart failure model it improves the effect of cardiac function.When reaching close cardiotonic effect, Peperphentonamine and acceptable salt increased blood pressure that the heart failure cat is reduced pharmaceutically thereof, cardiotonic glycoside desacetyldigilanide C (Deslanoside) and catecholamines isoproterenol (Isoproterenol, be called for short: different third kidney) do not influence blood pressure, PDEI class cardiac tonic milrinone and calcium sensitizer MCI-154 make blood pressure continue to reduce.Different third kidney, milrinone and MCI-154 cause that HR continues to increase, and easily cause arrhythmia, are unfavorable for treatment, Peperphentonamine and pharmaceutically acceptable salt is then less to the influence of HR, and proarrhythmia not.
Table 7. Peperphentonamine causes the influence of heart failure cat cardiac hemodynamic to pentobarbital sodium
10% propylene glycol Peperphentonamine mg/kg
2ml/kg?????????1?????????2???????????4?????????????8
N＝10??????????N＝6??????N＝9????????N＝9??????????N＝6
Change %-3 ± 4-9 ± 4-6 ± 10 13 ± 10**###, 29 ± 27*## after bpm 57 before the heart rate HR administration ± 19 62 ± 20 68 ± 23 65 ± 16 61 ± 11 administrations
Change %-1 ± 66 ± 5*#, 25 ± 22**##, 34 ± 18***###, 53 ± 38**### after mmHg 30 before the mean arterial pressure MAP administration ± 7 53 ± 22 34 ± 9 32 ± 7 25 ± 7 administrations
Change % 6 ± 9 14 ± 4***#, 33 ± 21***##, 45 ± 28***###, 80 ± 39***### after mmHg 41 before the left ventricular systolic pressure LVSP administration ± 8 49 ± 9 47 ± 7 44 ± 7 42 ± 9 administrations
Change % 2 ± 10** 30 ± 25*# 83 ± 66**## 98 ± 71***## 185 ± 128**### after mmHg/s 700 before the left ventricular pressure rate of climb+dP/dt max administration ± 283 908 ± 427 855 ± 179 928 ± 248 775 ± 135 administrations
Change % 3 ± 21 27 ± 21*#, 65 ± 59**##, 82 ± 52***###, 159 ± 80***### after mmHg/s 345 before left ventricular pressure decrease speed-dP/dt max administration ± 142 470 ± 262 400 ± 127 433 ± 149 392 ± 127 administrations
Change % 2 ± 10 32 ± 26*##, 97 ± 94**##, 95 ± 53***###, 108 ± 77*## after g 25 before the myocardial contraction administration ± 14 43 ± 32 31 ± 20 31 ± 25 51 ± 27 administrations
Change % 6 ± 13 19 ± 7***, 87 ± 66**##, 121 ± 86**##, 136 ± 94**## after g/s 109 ± 46 154 ± 58 128 ± 50 128 ± 63 186 ± 148 administrations before cardiac muscle maximal velocity of contraction+dT/dt max administration
Change % 1 ± 13 13 ± 9*, 31 ± 13***##, 54 ± 27***##, 61 ± 35***### after ml/min 5 before the common carotid artery flow CCBF administration ± 48 ± 47 ± 47 ± 46 ± 2 administrations
MmHg/ml/min before the common carotid artery vascular resistance CCVR administration
Change %-6 ± 7-11 ± 4***-5 ± 11-25 ± 13***-18 ± 11** after 9 ± 4 6.8 ± 1.7 6.4 ± 4.4 6.2 ± 3.4 4.9 ± 2.2 administrations
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with matched group: #P＜0.05 ##P＜0.01 ###P＜0.0013. heart failure Canis familiaris L.
The result that the open chest anesthetized Canis familiaris L. is observed continuously represents: after heart failure formed, the major parameter that influences cardiac function all reduced by more than 50, and these change more than the lasting 3h.Quiet notes Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 1mg/kg～6mg/kg dose dependent ground obviously increase the heart failure animal blood pressure, LVSP, ± dP/dt max, myocardial contraction, contractility pace of change (± dT/dt max), cardiac index (CI), the index (SI) of whenever fighting, whenever fight work done (SW) and left chamber work done (LVW).Peperphentonamine and pharmaceutically acceptable salt obviously increase arteria coronaria and femoral artery flow, do not influence coronary resistance (CVR) and total peripheral vascular resistance (SVR).This research further support Peperphentonamine and pharmaceutically acceptable salt improve the effect of cardiac function, and demonstrate it to vasoactive selectivity in a organized way.
Peperphentonamine hydrochloride 3mg/kg increases heart failure Cor Canitis output (CI, SI), the degree and the milrinone 30 μ g/kg of the left ventricular pressure rate of climb (+dP/dt max) and myocardium maximal velocity of contraction (+dT/dt max) are approaching, but the latter is less to the influence of cardiac diastolic function (dP/dt max with-dT/dt max), and Peperphentonamine then makes it obvious improvement.Milrinone slightly increases HR, further reduces MAP and the SVR of heart failure Canis familiaris L., and in contrast, the Peperphentonamine HR that slows down increases MAP, does not influence SVR.It is more favourable to the treatment of heart failure to express Peperphentonamine, referring to table 8,9 result displayed.
Table 8. Peperphentonamine hydrochloride causes heart failure Cor Canitis rate, the influence of blood pressure and left constant pressure to pentobarbital sodium
Solvent Peperphentonamine mg/kg milrinone
0.6ml/kg?????1?????????????????3??????????6???????????30μg/kg
N＝6?????????N＝8??????????????N＝7???????N＝4????????N＝5
Change % 2 ± 3-12 ± 5***###-13 ± 9-12 ± 7*#, 9 ± 5**## after bpm 69 before the heart rate HR administration ± 16 98 ± 17 85 ± 15 79 ± 14 63 ± 14 administrations
Change % 6 ± 5* 11 ± 9** 34 ± 17***# 46 ± 19**###-6 ± 9# after mmHg 58 before the mean arterial pressure MAP administration ± 15 52 ± 20 54 ± 17 55 ± 12 65 ± 19 administrations
Change % 2 ± 76 ± 7*, 43 ± 33**#, 64 ± 39*##, 16 ± 14* after mmHg 71 before the left ventricular systolic pressure LVSP administration ± 13 65 ± 19 67 ± 17 65 ± 14 82 ± 18 administrations
Change % 1 ± 10 9 ± 15 53 ± 37**##, 125 ± 88*##, 64 ± 17***### after mmHg/s 100 before the left ventricular pressure rate of climb+dP/dt max administration ± 252 137 ± 377 1100 ± 351 1025 ± 179 1017 ± 517 administrations
Change % 4 ± 8 35 ± 40*, 28 ± 16***##, 117 ± 83*# 2 ± 15 after mmHg/s 983 before left ventricular pressure decrease speed-dP/dt max administration ± 177 837 ± 500 786 ± 365 813 ± 74 1070 ± 240 administrations
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with matched group: #P＜0.05 ##P＜0.01 ###P＜0.001 table 9. Peperphentonamine hydrochloride causes the dirty pumping function of heart failure Cor Canitis, the influence of blood flow and vascular resistance to pentobarbital sodium
Solvent Peperphentonamine mg/kg milrinone
0.6ml/kg??????1??????????3?????????????6?????????????30μg/kg
N＝6??????????N＝8???????N＝7??????????N＝4??????????N＝5
Change % 3 ± 10 24 ± 18**#, 94 ± 63**##, 58 ± 24**## 26 ± 26 after g 52 before the myocardial contraction administration ± 26 42 ± 22 41 ± 32 46 ± 26 58 ± 27 administrations
Change % 1 ± 9-3 ± 11 77 ± 21**###, 170 ± 67*##, 62 ± 14***### after g/s 63 ± 25 107 ± 57 40 ± 8 37 ± 9 51 ± 7 administrations before cardiac muscle maximal velocity of contraction+dT/dt max administration
Change % 2 ± 10 13 ± 22 31 ± 21#, 42 ± 24*#, 12 ± 1***## after g/s 95 ± 56 108 ± 48 110 ± 53 70 ± 23 96 ± 49 administrations before the maximum diastolic velocity of cardiac muscle-dT/dt max administration
1/min/m before the cardiac index CI administration
21.2 change % 3 ± 49 ± 7*#, 18 ± 11*#, 46 ± 31*##, 21 ± 7***### after ± 0.5 1.5 ± 0.3 1.5 ± 0.6 1.3 ± 0.5 1.4 ± 0.4 administration
Whenever the preceding ml/beat/m of the index SI administration of fighting
2Change % 2 ± 6 23 ± 6***###, 19 ± 11*# 34 ± 53 15 ± 9**# after 17 ± 7 15 ± 5 21 ± 8 18 ± 8 24 ± 9 administrations
Whenever change % 8 ± 9 27 ± 17**#, 69 ± 23**###, 73 ± 40*## 15 ± 20 after the preceding g.m 7.0 of the work done SW administration of fighting ± 4.0 6.2 ± 1.5 9.1 ± 3.2 7.3 ± 3.7 10.4 ± 5.3 administrations
Change % 26 ± 94-4 ± 11 26 ± 14*, 22 ± 17*-18 ± 3*** after mmHg/l/min/kg 5.7 ± 1.0 5.7 ± 2.9 6.0 ± 1.7 4.8 ± 1.0 6.3 ± 0.8 administrations before total peripheral vascular resistance SVR administration
Change % 9 ± 9* 3 ± 11 49 ± 12**## 61 ± 10***### after ml/min 9 before the femoral artery blood flow FBF administration ± 49 ± 17 ± 3 10 ± 2 administrations
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with matched group: #P＜0.05 ##P＜0.01 ###P＜0.001
Above-mentioned experiment demonstrates the Cavia porcellus of Peperphentonamine hydrochloride to experimental heart failure, and cat and Canis familiaris L. all have the good curing effect, can obviously strengthen myocardial contraction, lowers cardiac load, improves cardiac function.And express it and be better than all kinds of known cardiac tonic, be hopeful to develop into the newtype drug of treatment heart failure.
Experimental example 4
Present embodiment relates to Peperphentonamine and the pharmaceutically experiment that resists myocardial ischemia of acceptable salt thereof, and is specific as follows:
Peperphentonamine and pharmaceutically acceptable salt antagonism isoproterenol cause the therapeutical effect of rat heart muscle necrosis:
For understanding the Peperphentonamine and the therapeutical effect of acceptable salt pair myocardial ischemic injury pharmaceutically thereof, form different third kidney and cause rat heart muscle ischemic necrosis model, from myocardium biochemical indicator and morphology aspect evaluate efficacy.The cardiac enlargement when result represents to damage, myocardium creatine phosphokinase (CPK) is active to be reduced, and lipid peroxidation end-product malonaldehyde (MDA) content increases, and serum glutaminic acid aminotransferase (GOT) activity increases.Pathomorphism shows that ventricular muscles is dispersed in the lamellar necrosis, and saturating wall involves under the endocardium 1/2, ring week 1/2～2/3; The myocardial cell dissolving disappears inflammatory cell infiltration, granulation tissue hyperplasia.Lumbar injection Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 1mg/kg～6mg/kg obviously alleviate above-mentioned variation.Show that Peperphentonamine and pharmaceutically acceptable salt thereof have the effect of protection myocardial damage, referring to table 10 demonstration is the result of example with the Peperphentonamine hydrochloride.
Table 10. Peperphentonamine hydrochloride influences group number of animals heart coefficient cardiac muscle serum pathomorphism to what isoproterenol caused the rat heart muscle ischemic necrosis
CPK MDA GOT damages rank
Different third injury of kidney damage of U/mg pro nmol/mg pro Kamen normal control 11 2.86 ± 0.17** 4.4 ± 0.8** 11.4 ± 2.1* 148 ± 21** 0 ± 0*** contrast 12 3.81 ± 0.40 3.1 ± 0.6 15.2 ± 4.6 219 ± 60 3.3 ± 0.7 Peperphentonamine hydrochlorides
2mg/kg????????6?????????3.40±0.78??????2.8±1.2?????11.1±3.7??????166±42
4mg/kg????????10????????3.69±0.25??????3.4±0.9?????13.1±2.4??????155±10**??????2.6±0.5
8mg/kg 6 3.42 ± 0.27* 3.8 ± 0.8* 9.2 ± 3.4* 144 ± 15** 2.3 ± 0.5* Propranolol
4mg/kg????????11????????3.99±0.38??????3.4±0.8?????12.1±4.1??????70±33*????????2.3±1.0
Compare with the different third injury of kidney matched group: * P＜0.05 * * P＜0.01 * * * P＜0.001
2. Peperphentonamine and the pharmaceutically influence of acceptable salt pair myocardial infarction cat cardiac function
Preparation blocking-up branch of coronary artery causes the pathological model of cat acute myocardial infarction, is the effect of index observing medicine with the cardiac hemodynamic.Reduce by 47 ± 25% before the myocardial contraction force rate infarction when result represents myocardial infarction, cardiac output and cardiac work reduce by 30%～40% approximately, and blood pressure and left ventricular systolic pressure also moderate reduce, and show that cardiac function is obviously impaired.Quiet respectively notes Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate behind the heart infarction, bring high blood pressure down Peperphentonamine maleate 1mg/kg～8mg/kg dose dependent, vascular resistance and tension time index (TTI), it is to myocardial contraction, and the influence of cardiac output and cardiac work is less.The expression Peperphentonamine is by reducing cardiac load and myocardium keto consumption, reach the effect that improves cardiac function and protection myocardial ischemia, and wherein the effect of Peperphentonamine hydrochloride is best.Referring to table 11,12 demonstrations is the example result with the Peperphentonamine hydrochloride.
Table 11. Peperphentonamine hydrochloride is to myocardial infarction cat heart rate, the influence of blood pressure and left constant pressure
Solvent control Peperphentonamine hydrochloride mg/kg
1????????????2??????????????4???????????????8
N＝10?????????N＝5?????????N＝6???????????N＝6????????????N＝7
Change % 2 ± 3-12 ± 7*###-13 ± 6***###-14 ± 3***###-23 ± 10***### after bpm 106 before the mean arterial pressure MAP administration ± 29 108 ± 25 103 ± 24 96 ± 24 91 ± 33 administrations
MmHg.bpm/10 before the tension time index TTI administration
Change % 2 ± 5-13 ± 10*##-15 ± 7***###-17 ± 6***###-26 ± 9***### after 1396 ± 540 1469 ± 492 1402 ± 481 1310 ± 539 1171 ± 701 administrations
Change % 2 ± 5-5 ± 2 7-8 ± 13-11 ± 8## 12 ± 54 after mmHg/s 4622 before the left ventricular pressure rate of climb+dP/dt max administration ± 1,085 6620 ± 3,024 6700 ± 3,603 6367 ± 2,812 5286 ± 2931 administrations
Change % 6 ± 18 0 ± 26-18 ± 15*#-3 ± 16-1 ± 19 after mmHg/s 1756 before left ventricular pressure decrease speed-dP/dt max administration ± 440 2560 ± 771 2667 ± 618 2608 ± 1,242 2521 ± 1673 administrations
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with the solvent control group: #P＜0.05 ##P＜0.01 ###P＜0.001
Table 12. Peperphentonamine hydrochloride is to the influence of myocardial infarction cat cardiac systolic function and vascular resistance
Solvent control Peperphentonamine hydrochloride mg/kg
1?????????????2?????????????4?????????????8
N＝10???????????N＝4??????????N＝6??????????N＝6??????????N＝6
Change % 6 ± 10 10 ± 12 19 ± 1 6*, 28 ± 22*#, 22 ± 17* after g 65 before the myocardial contraction administration ± 17 34 ± 13 37 ± 14 44 ± 27 45 ± 33 administrations
L/min/m before the cardiac index CI administration
2
0.89 change % 10 ± 11 11 ± 5**, 15 ± 8***, 30 ± 14***##, 27 ± 16**# after ± 0.41 1.07 ± 0.34 1.04 ± 0.34 1.10 ± 0.38 1.15 ± 0.44 administration
Whenever the preceding ml/beat/m of the index SI administration of fighting
2
7.51 change % 9 ± 12* 11 ± 2*** 2 ± 6*** 31 ± 14***## 39 ± 28**# after ± 1.91 8.01 ± 2.05 8.01 ± 2.05 8.71 ± 2.26 10.26 ± 4.65 administrations
Whenever change % 11 ± 13** 1 ± 86 ± 16 14 ± 12* 13 ± 19 after the preceding g.m 26 of the work done SW administration of fighting ± 14 30 ± 9 28 ± 10 29 ± 9 33 ± 12 administrations
Change % 12 ± 21-12 ± 20 0 ± 10 6 ± 13 8 ± 26 after kg.m/min 3.5 ± 2.2 3.4 ± 1.9 3.7 ± 1.3 3.8 ± 1.7 4.1 ± 2.3 administrations before the left side chamber work done LVW administration
Change % 21 ± 19* 8 ± 13 15 ± 11* 27 ± 7*** 25 ± 22* after ml/min 21 before the common carotid artery flow CCBF administration ± 11 9 ± 49 ± 39 ± 49 ± 4 administrations
MmHg/ml/min before the common carotid artery vascular resistance CCVR administration
8.8 change %-14 ± 13*-17 ± 10*-21 ± 10**-33 ± 6***#-34 ± 10***# after ± 5.3 16.6 ± 10.7 12.3 ± 3.2 11.2 ± 3.3 11.3 ± 2.9 administrations
MmHg/l/min/kg before total peripheral vascular resistance SVR administration
Change %-6 ± 10-18 ± 6***-23 ± 9***##-32 ± 9***###-40 ± 9***### after 159 ± 34 129 ± 27 115 ± 29 106 ± 27 105 ± 36 administrations
With before the heart failure relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with the solvent control group: #P＜0.05 ##P＜0.01
Represent that from the research of myocardium biochemical indicator and morphology aspect Peperphentonamine antagonism isoproterenol causes the rat heart muscle ischemic necrosis.
Cause the cat of acute myocardial infarction for the blocking-up branch of coronary artery, bring high blood pressure down Peperphentonamine and pharmaceutically acceptable salt dose dependent thereof, vascular resistance and tension time index (TTI), it is to myocardial contraction, and the influence of cardiac output and cardiac work is less.Represent this medicine by reducing cardiac load and myocardium keto consumption, can reach the effect that keeps cardiac function and protection myocardial ischemia, wherein the effect of Peperphentonamine hydrochloride is best.
Experimental example 5
Present embodiment relates to Peperphentonamine and pharmaceutically acceptable salt is tested the protective effect of Myocardial Ischemia Reperfusion Injury
1. Peperphentonamine and pharmaceutically acceptable salt thereof are to the protective effect of isolated heart reperfusion injury
1. Peperphentonamine and pharmaceutically acceptable salt thereof are to arteria coronaria blocking-up-irritate the again protective effect with anoxia-reoxygenation
Adopt the Mus heart preparation of exsomatizing, being blocked branch of coronary artery causes regional myocardial ischemia-reperfusion injury or forms the pathological model of anoxia-reoxygenation whole-heartedly, from incidence of arrhythmia, the drug effect of Peperphentonamine and pharmaceutically acceptable salt thereof is observed in the release of myocardium enzyme and lipid peroxidation aspect.The result represents: the ventricular fibrillation incidence rate when Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 1 μ mol/L and 3 μ mol/L make ischemia-reperfusion obviously is reduced to 12.5% and 9.1% (P＜0.01) from 85% of contrast; Myocardium CPK and LDH that it reduces due to the damage discharge.For ischemia-again irritate or anoxia-reoxygenation due to myocardium MDA content increase, Peperphentonamine and pharmaceutically acceptable salt thereof all have tangible antagonism, even make it remain on normal level, SOD of heart tissue activity due to what anoxia-reoxygenation is reduced, Peperphentonamine and pharmaceutically acceptable salt thereof also have certain antagonism, and be best with the Peperphentonamine hydrochloride effect especially.This studies show that Peperphentonamine and pharmaceutically acceptable salt thereof have protective effect to reperfusion injury, and referring to table 13 demonstration is the experimental result of example with the Peperphentonamine hydrochloride.
Table 13. Peperphentonamine hydrochloride is to the influence of isolated rat heart anoxia-reoxygenation or arteria coronaria blocking-up-reperfusion injury
Anoxia-reoxygenation arteria coronaria blocking-up-irritate again
Medicine MDA SOD CPK LDH MDA (μ mol/L) nmol/g U/mg pro U/g/min U/g/min nmol/100mg pro normal control 175 ± 27*** 94 ± 18*** 0.07 ± 0.02** 2.3 ± 0.3*** 61 ± 14*** damage contrast 279 ± 58 61 ± 23 0.35 ± 0.14 12.0 ± 3.9 158 ± 82 damage+Peperphentonamine hydrochlorides
1?????????????161±64***?????80±19???????0.12±0.05**?????7.6±2.3**?????60±14**
3?????????????0.07±0.02***??6.8±3.4**???99±30*
10????????????164±24***?????80±21
Compare with the damage matched group: * * * P＜0.001
2. Peperphentonamine and pharmaceutically acceptable salt thereof stop myocardial ischemia to irritate-protective effect of filling again
For further understanding the protective effect of Peperphentonamine and pharmaceutically acceptable salt thereof to Myocardial Ischemia Reperfusion Injury; the preparation of employing isolated rat heart; stopped irritating 40min-and irritated 30min again; cause the reperfusion injury model; from cardiac function; cardiac muscle is observed the drug effect of Peperphentonamine, Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 1～10 μ mol/L with aspects such as mitochondrion biochemistry and forms, and inquires into its mechanism of action.The result represents: myocardial contraction is very weak when irritating again, than reducing by 79 ± 26% before stopping irritating, reduces 43 ± 15% before the coronary flow ratio stops irritating, and the 60 ± 23U/L of the CPK activity of arteria coronaria effluent before the administration is elevated to 317 ± 195U/L.Give the heart of Peperphentonamine 10 μ mol/L, the myocardial contraction when irritating again and coronary flow reduce by 16 ± 82% and 22 ± 19% than before stopping irritating respectively, and the CPK activity remains on stops irritating preceding level (55 ± 41U/L), comparing with the damage matched group all has significant difference.
Peperphentonamine and pharmaceutically acceptable salt 1～10 μ mol/L thereof obviously increase cardiac muscle and mitochondrial oxidation resistance, the myocardium superoxide dismutase (SOD) that its antagonism stops irritating-answering due to irritating reduces with glutathion peroxidase (GSH-px) is active, make mitochondrion malonaldehyde (MDA), glutathion (GSH) remains on normal level with GSH-px.(table 17)
Myocardium adenosine triphosphate (ATP) due to the dose dependent ground antagonism damage of Peperphentonamine and pharmaceutically acceptable salt thereof, phosphagen (PCr) content reduces, and makes it to remain on normal level.And resist and stop irritating-answering the mitochondrial calcium overload of irritating due to damaging, increase mitochondrial membrane flowability and atpase activity, make structure of mitochondria keep more completely, referring to table 14,15 demonstrations is the experimental result of example with the Peperphentonamine hydrochloride.。
Table 14. Peperphentonamine hydrochloride is irritated-multiple filling cardiac muscle and mitochondrion MDA, SOD, GSH, the influence of GSH-px stopping
Myocardial mitochondria
Normal 44 ± 8***, the 35 ± 7*** of group SOD GSH-px MDA GSH GSH-px (μ mol/L) nmol/mg pro. U/mg pro nmol/mg pro U/mg pro U/mg pro 17 ± 2*** 19 ± 1*** 16.8 ± 2.9*** stops irritating-multiple the filling
1????????????36±5**?????????28±5**????????22±1??????????16±1????????7.4±1.1
3????????????39±5***????????28±6***???????21±1*?????????19±1***?????8.5±1.4*
10???????????42±6***????????29±5***???????18±1***???????19±1***?????22.6±7.6***
N=6 and stops irritate-irritating again matched group relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Table 15. Peperphentonamine hydrochloride is to stopping irritate-irritating again the rat heart muscle energy metabolism, the influence of mitochondrial membrane flowability and calcium content
Normal 43 ± 19***, the 127 ± 15*** of the mobile calcium μ mol/L μ mol/g μ mol/g nmoi Pi/mg pro η nmol/mg pro of myocardial mitochondria medicine ATP PCr ATP enzyme membrane 247 ± 24*** 1.06 ± 0.23** 6 ± 2*** stops filling with-multiple contrast 17 ± 5 59 ± 27 171 ± 10 1.57 ± 0.29 118 ± 15 Peperphentonamine hydrochlorides of filling with
1?????????26±9*????????????95±59?????????177±17??????????1.29±0.18????????114±12
3?????????31±12*???????????95±14*????????187±11*?????????1.10±0.13**??????51±19***
10 51 ± 18***, 176 ± 80***, 261 ± 37***, 1.05 ± 0.31*, 27 ± 18*** verapamil
3??????????27±3***???????117±23***???????198±16***????1.23±0.19?????36±8***
With stop irritate-irritating again matched group relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
This research expression Peperphentonamine hydrochloride obviously improves and stops irritating-irritate the physiological function of heart again, alleviate biochemical variation of cardiac muscle due to the damage, and keep the integrity of structure of mitochondria, its mechanism of action is relevant with the enhancing oxidation resistance.
2. Peperphentonamine and pharmaceutically acceptable salt thereof are to the protective effect in the systemic heart reperfusion injury
1. Peperphentonamine and pharmaceutically acceptable salt thereof are to the rat heart reperfusion injury
Employing is poured into the pathological model of 30min again at body rat heart arteria coronaria blocking-up 10min, and from electrocardiogram, drug influence is observed in aspects such as cardiac muscle biochemistry and Change of Ultrastructure.The result show before the ischemia or during ischemia quiet notes Peperphentonamine, Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 0.1mg/kg～1mg/kg obviously alleviate arrhythmia; reducing myocardium CPK and LDH discharges; reduce myocardium MDA and produce and blood plasma free fatty acid (FFA) content, the protection myocardial ultrastructure.This result shows Peperphentonamine in the systemic heart Myocardial Ischemia Reperfusion Injury significant protective effect being arranged, and it is the experimental result of example that table 16 has been listed with the Peperphentonamine hydrochloride.
Table 16. Peperphentonamine hydrochloride is to the influence of rat in the systemic heart Myocardial Ischemia Reperfusion Injury
Cardiac muscle medicament chamber CPK LDH MDA pathology damage mg/kg incidence % U/mg pro U/mg pro nmol/100mg pro rank sham-operation 5** 9.8 ± 0.8*** 7.4 ± 1.8*** 70 ± 9*** 0.17 ± 0.24*** transient ischemia/reperfusion damage contrast 52 5.2 ± 0.6 10.9 ± 2.3 136 ± 10 1.55 ± 0.91 Peperphentonamine hydrochlorides that quiver
0.1????????25???????????6.5±0.8***?????8.2±0.6*????????100±15***??????????1.25±0.51
0.5????????0*???????????9.3±1.0***?????7.2±0.6**???????74±6***????????????0.65±0.45***
1.0 17 10.9 ± 0.8***, 6.3 ± 0.5***, 60 ± 6***, 0.33 ± 0.40*** verapamil
1.0????????22???????????9.2±1.5***?????7.2±2.0**???????61±20***
Compare with the damage matched group: * P＜0.05 * * P＜0.01 * * * P＜0.001
2. Peperphentonamine and pharmaceutically acceptable salt thereof are to the reperfusion injury of cat heart
For further determining the protective effect of Peperphentonamine and pharmaceutically acceptable salt thereof to reperfusion injury; be formed on the pathological model of body cat heart reperfusion injury, blocked arteria coronaria 30min, irritate 60min again; from cardiac hemodynamic, aspects such as blood biochemical and energy metabolism of myocardial are observed.The result represents quiet notes Peperphentonamine Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, the Peperphentonamine maleate 2mg/kg-8mg/kg dose dependent ground HR that obviously slows down, and reduces MAP and myocardium keto consumption parameter TTI; It does not have influence to cardiac output (CI), the slight increase index (SI) of whenever fighting; It reduces cardiac work (SW and LVW) and peripheral vascular resistance (SVR).Show that Peperphentonamine has the damaged heart of reduction load, the effect of protection cardiac function, it is the experimental result of example that table 17 has been listed with the Peperphentonamine hydrochloride.
Table 17. Peperphentonamine is to myocardial ischemia-pour into the again influence of cat cardiac hemodynamic
Change % after the administration
Damage contrast Peperphentonamine hydrochloride mg/kg verapamil
2.0?????????4.2??????????????8.4?????????????1.3mg/kg
N=8 N=5 N=5 N=8 N=3 heart rate HR
Ischemic stage-3 ± 4*-10 ± 7*#-20 ± 6***###-22 ± 5***###-43 ± 2***###
Irritate phase-10 ± 6***-19 ± 10**-26 ± 10**#-30 ± 9***###-35 ± 5***### mean arterial pressure MAP again
Ischemic stage-4 ± 3***-14 ± 15-41 ± 19**###-32 ± 10***###-40 ± 6***###
Irritate phase-11 ± 10**-7 ± 10-28 ± 7***###-26 ± 12***##-20 ± 4**## tension time index TTI again
Ischemic stage-8 ± 4***-23 ± 17*-50 ± 19***###-43 ± 11***###-65 ± 4***###
Irritate phase-17 ± 5***-23 ± 17*-46 ± 12***###-47 ± 16***###-49 ± 2***### cardiac index CI again
Ischemic stage-9 ± 9*-7 ± 17-16 ± 11*-16 ± 13**-29 ± 9**##
Irritate phase-16 ± 12**-15 ± 15-6 ± 91 ± 22 12 ± 6# index SI that whenever fights again
Ischemic stage-2 ± 11-3 ± 27 7 ± 5*# 7 ± 16 43 ± 4***###
Irritate phase-10 ± 13 18 ± 28 26 ± 18*, 33 ± 31*#, 66 ± 9***### work done SW that whenever fights again
Ischemic stage-10 ± 13*-9 ± 27-42 ± 21**##-28 ± 12***##-26 ± 13*
Irritate phase-18 ± 14**-9 ± 26-17 ± 5***, 7 ± 25#-40 ± 19*## left side chamber work done LVW again
Ischemic stage-9 ± 14-19 ± 22-51 ± 21***###-40 ± 12***##-57 ± 8***###
Irritate phase-22 ± 16-22 ± 19-34 ± 9***-29 ± 21**, 15 ± 8 total peripheral vascular resistance SVR again
Ischemic stage-9 ± 14-5 ± 17-27 ± 17*#-27 ± 10***###-27 ± 1***##
Irritate phase-22 ± 16 1 ± 15-20 ± 12*#-17 ± 15**##-25 ± 12*# again
With the ischemia previous crops is 100%, calculates the variation percentage value of each parameter.
With before the ischemia relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with the damage matched group: #P＜0.05 ##P＜0.01 ###P＜0.001
Serum biochemistry measure to show that the lipid peroxidation end-product MDA content due to the Peperphentonamine dose dependent ground antagonism ischemia-reperfusion increases, reduction serum CPK and GOT activity, make it with ischemia before relatively do not have significant difference.The research of energy metabolism represents that ischemic region myocardial ATP and PCr content that Peperphentonamine obviously resists due to the damage reduce; make it to remain on normal level; show that Peperphentonamine obviously improves the energy metabolism of myocardial obstacle; this may be a major reason of its protection reperfusion injury, and table 18 has been listed experimental result.
Table 18. Peperphentonamine hydrochloride is to myocardial ischemia-pour into the cat serum MDA again, CPK, GOT and myocardial ATP, the influence of PCr
Damage contrast Peperphentonamine hydrochloride mg/kg verapamil
2.0???????????4.2??????????????8.4???????????1.3mg/kg
N=8 N=5 N=5 N=6 N=3 serum MDA nmol/L
Ischemia preceding 78 ± 21 50 ± 10 61 ± 17 77 ± 39 54 ± 5
Ischemic stage 99 ± 31 58 ± 26#, 58 ± 18# 80 ± 40 54 ± 4#
Ischemia preceding 128 ± 79 136 ± 21 146 ± 60 151 ± 42 115 ± 17
Ischemic stage 197 ± 83 206 ± 21** 174 ± 62 200 ± 71 181 ± 17**
Irritate phase 263 ± 88** 324 ± 82** 250 ± 84 216 ± 63 263 ± 14*** serum GOT U/L again
Ischemia preceding 57 ± 21 46 ± 10 73 ± 24 71 ± 33 76 ± 15
Ischemic stage 96 ± 72 63 ± 12 59 ± 28 75 ± 27 76 ± 19
Irritate phase 122 ± 73* 90 ± 44 81 ± 21 100 ± 28 92 ± 25 myocardial ATP μ mol/g again
Non-ischemic region 41 ± 8 36 ± 5 47 ± 11 55 ± 10 36 ± 2
Ischemic region 16 ± 6** 15 ± 2*** 33 ± 8*## 55 ± 4### 33 ± 1## cardiac muscle PCr μ mol/g
Non-ischemic region 48 ± 8 43 ± 8 57 ± 17 69 ± 12# 50 ± 8
Ischemic region 31 ± 5** 28 ± 6* 49 ± 15# 69 ± 8### 48 ± 20
With before the ischemia or non-ischemic region relatively: * P＜0.05 * * P＜0.01 * * * P＜0.001
Compare with the damage matched group: #P＜0.05 ##P＜0.01 ###P＜0.001
By adopt exsomatize with at the multiple myocardial ischemia of systemic heart-reperfusion injury pathological model, from the heart physiological function, cardiac muscle changes with mitochondrion is biochemical, aspects such as PATHOMORPHOLOGICAL OBSERVATION OF PULLORUM demonstrate Peperphentonamine has significant protective effect to reperfusion injury.It keeps cardiac function, strengthens myocardium oxidation resistance, improves energy metabolism, and the antagonism intracellular calcium overload alleviates Ultrastructural damage.Show also simultaneously that its mechanism of action is relevant with the oxidation resistance that strengthens cell.
Experimental example 6
Present embodiment relates to Peperphentonamine and pharmaceutically acceptable salt thereof to the experiment 1. of myocardium positive inotropic action and the relation of intracellular Ca2+:
Observe various antagonisies to myocardial contraction sex research represent: the positive inotropic action of Peperphentonamine and pharmaceutically acceptable salt thereof and α, β and H
2Receptor does not have obvious relation, not by activating the approach of cAMP yet.Biochemical measurement represents that it does not increase myocardium cAMP, does not also suppress Na
+, K
+-ATP enzyme and phosphodiesterase (cAMP-PDE, cGMP-PDE).The positive inotropic action mechanism that shows Peperphentonamine and pharmaceutically acceptable salt thereof is different from cardiotonic glycoside, and catecholamine and PDEI class cardiac tonic point out it main if it were not for the approach by the increase intracellular Ca2+.For this reason, separate the ventricular muscle cell of the Cavia porcellus that grows up, adopt fluorescent probe Fura-2 to measure free calcium ion concentration in the myocardial cell, the result represents: in the positive inotropic action concentration range, Peperphentonamine does not increase [Ca in the guinea pig myocardium cell
2+], even can also be to the intracellular calcium overload due to anti-hypoxia-reoxygenation, it is the experimental result of example that table 19,20 has been listed respectively with the Peperphentonamine hydrochloride.
Table 19. Peperphentonamine hydrochloride and ouabain are to the influence of free calcium in the myocyte of guinea-pig ventricular
[Ca in the cell
2+] nmol/L
Contrast Peperphentonamine hydrochloride μ mol/L ouabain nmol/L
124 ± 16 125 ± 19 121 ± 19 162 ± 24** changes % 9 ± 78 ± 9-5 ± 8##, 59 ± 15### after preceding 112 ± 14 116 ± 15 125 ± 15 102 ± 12 administrations of 1 10 50 administrations
With before the administration relatively: * * P＜0.01.Compare with matched group: ##P＜0.01, ###P＜0.001
Table 20. Peperphentonamine hydrochloride is to the influence of the guinea pig myocardium intracellular free calcium of anoxia-reoxygenation injury
[Ca in the cell
2+] nmol/L
Normal cell damage contrast Peperphentonamine hydrochloride μ mol/L
1?????????????5?????????????10
N＝10?????????????????N＝12??????????N＝7??????????N＝8??????????N＝10
100±9***?????????????246±26????????237±45???????189±8***?????114±11***
Compare with damage: * * * P＜0.0012. and myocardial contraction albumen are to the relation of calcium sensitivity:
The myocardium striping sarcostyle of preparation Canis familiaris L. is measured Ca
2+, Mg
2+-ATp enzymatic activity is with Ca in enzymatic activity and the reactant liquor
2+Concentration (log mol/L) relation (pCa) evaluation contractile protein is to the sensitivity of calcium, and the result represents: in pCa 8.0～4.5 scopes, and striping sarcostyle Ca
2+, Mg
2+-atpase activity is with Ca
2+Concentration increases and raises, and obtains the pCa of matched group from relation curve
50=7.408.Peperphentonamine, Peperphentonamine hydrochlorate, Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate 50 μ mol/L move up curve left, pCa
50=7.879, with the close (pCa of effect of known calcium sensitizer MCI-154 100 μ mol/L
50=7.993), with matched group significant difference is arranged more all, it is the experimental result of example that Fig. 4 has provided with the Peperphentonamine hydrochlorate.Select pCa=7.0, the observation during drug level 3～100 μ mol/L shows that Peperphentonamine increases striping sarcostyle Ca
2+, Mg
2+The effect of-atpase activity is dose dependent, and it is the experimental result of example that Fig. 5 has provided with the Peperphentonamine hydrochlorate.
Originally studies show that Peperphentonamine and pharmaceutically acceptable salt thereof obviously increase the sensitivity of myocardial contraction albumen to calcium, represent that it is a kind of to increase the novel cardiac tonic of myocardial contraction albumen to the sensitivity of calcium, for this medicine is difficult for causing the low experimental basis that proposes of arrhythmia and toxic reaction.
Embodiment 1 adopts the synthetic N-methyl piperethanamine salt hydrochlorate of following method:
1.09mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.96mol benzaldehyde are placed flask at the bottom of the 1000ml garden, mix homogeneously, emit a large amount of heat, add 300ml dehydrated alcohol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 18 hours, concentrating under reduced pressure is removed ethanol, and reuse oil pump concentrating under reduced pressure is removed unreacted benzaldehyde, gets rufous grease, behind the cool to room temperature, add 200ml toluene and 1.09mol dimethyl sulfate again, outer temperature is maintained at about 120 ℃ of reactions 30 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 300ml, back flow reaction is 30 minutes again, gets dark brownish red opaque liquid.Adding distil water 10ml, shake up the back under stirring, use water pump to remove ethanol, toluene and water equal solvent under reduced pressure, reuse oil pump concentrating under reduced pressure is removed benzaldehyde, get the opaque thickness grease of dark brownish red, in the extremely thick thing of gained, add saturated substantially HCl/ ethanol solution to PH=3, separate out a large amount of N-methyl piperethanamine salt hydrochlorate solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, subalbous solid 89g, yield: 38%, mp:186～188 ℃ (dec.).R
f=0.23 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Obtain the hydroxyl benzylideneacetone through the Claisen-Schmidt condensation reaction with acetone under alkali condition by hydroxy benzaldehyde.
21.5g (0.1mol) N-methyl piperethanamine salt hydrochlorate and 30g (1mol) paraformaldehyde are placed the 500ml round-bottomed bottle, add 240ml dehydrated alcohol and 2ml concentrated hydrochloric acid, make solution be acid, outer temperature remains in the 90-100 ℃ of oil bath and heats, after being stirred to solid and all dissolving, reheat stirred about 30 minutes, cold slightly, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 8.0 hours of backflow stirring reaction, slowly separate out solid in the course of reaction, in reaction bulb, all solidify.Detect R with TLC
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly with refrigerative dehydrated alcohol, drying.Get faint yellow solid 27.3g.This solid is with 95% ethanol heated and stirred, the very fast whole dissolvings of solid are lurid settled solution, and reuse 3g activated carbon decolorizing gets lurid settled solution, put and slowly separate out the white powder solid after cold, and then put the refrigerator cooling, and filter, get subalbous Peperphentonamine hydrochloride pulverulent solids, wash with dehydrated alcohol, vacuum drying, heavy 22g, yield: 69%.mp：168～170℃。R
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), elementary analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 99.3%, referring to Fig. 6.Results of elemental analyses:
| Element | ????C(％) | ????H(％) | ????N(％) | ????Cl(％) |
| Value of calculation | ????64.69 | ????6.16 | ????3.59 | ????9.114 |
| Measured value | ????64.57 | ????6.19 | ????3.69 | ????9.01 |
| ????64.78 | ????6.04 | ????3.44 | ????9.14 |
Mass spectrum: m/s 218,135.Infrared absorption spectroscopy (IR) testing result sees Table 1:
Table 20
Proton nmr spectra (DMSO-d
6, TMS) the results are shown in Table 2 structural formulas:
| Absworption peak (cm -1) | Oscillatory type | Group | Absorption peak strength |
| ????3080 ????2960 | ??vas??C-H | Phenyl ring CH 2 | ????S ????M |
| ????1684 | ??vas??C＝O | The unsaturated C=O of α β | ????M |
| ????1655 ????1593 ????1514 | ??vas??C＝C | Phenyl ring connects the phenyl ring of carbonyl | Weak S M |
| ????1284 ????1242 ????1192 ????1111 ????1032 ????970 ????924 | ??vas?C-OH | The phenolic hydroxyl group phenyl ring | ? ????M ? ? ????M |
| ????1192，1169 ? | ??vas ??c-o-c-o-c | On the phenyl ring | ????M |
| ????823 | ??vas??C-H | Phenyl ring (1,4-two replaces) | ????M |
Table 21 Peperphentonamine hydrochloride
1H-NMR composes resolution table
6.3.4 carbon-13 nmr spectra and carbon, the relevant spectrum of hydrogenation displacement study see Table 3:
| Sequence number | Chemical shift (δ) | The peak type | Proton number | Corresponding proton |
| ????21 | ????2.796 | ????s | ????3H | ????N-CH 3 |
| ????13 | ????2.910 | ????br.t | ????2H | ????-CH 2 |
| ????11 | ????3.281 | ????br.m | ????2H | ????-CH 2 |
| ????10 | ????3.320 | ????br.t | ????2H | ????-CH 2 |
| ????12 | ????3.421 | ????br.m | ????2H | ????-CH 2 |
| ????20 | ????5.896 | ????s | ????2H | ????-OCH 2O- |
| ????8 | ????6.659 | ????d，J＝16.5Hz | ????1H | ????-C-H |
| ????19 | ????6.746 | ????dd，J＝8.0Hz ????J＝1.50Hz | ????1H | ????-C-H |
| ????18 | ????6.80 | ????d，J＝8.0Hz | ????1H | ????-C-H |
| ????2，6 | ????6.823 | ????A 2B 2，d，J＝9.0Hz | ????2H | ????-C-H |
| ????15 | ????6.861 | ????d，J＝1.50Hz | ????1H | ????-C-H |
| ????3，5 | ????7.533 | ????A 2B 2，d，J＝9.0Hz | ????2H | ????-C-H |
| ????7 | ????7.582 | ????d，J＝16.5Hz | ????1H | ????-C-H |
| ????1 | ????10.195 | ????Br.s?D 2The O exchange | ????1H | ????-C-O0H |
Table 22. Peperphentonamine hydrochloride
13C-NMR composes resolution table
| The carbon sequence number | Chemical shift (δ) | The carbon sequence number | Chemical shift (δ) |
| ??? C-1 | ??160.260 | ??C-13 | ??29.109 |
| ????C-2，6 | ??115.939 | ??C-14 | ??130.630 |
| ????C-4 | ??125.020 | ??C-15 | ??109.129 |
| ????C-3，5 | ??130.555 | ??C-16 | ??146.009 |
| ????C-7 | ??143.714 | ??C-17 | ??147.361 |
| ????C-8 | ??122.551 | ??C-18 | ??108.318 |
| ????C-9 | ??196.187 | ??C-19 | ??121.805 |
| ????C-10 | ??33.886 | ??C-20 | ??100.839 |
| ????C-11 | ??55.959 | ??C-21 | ??39.384 |
| ????C-12 | ??50.236 |
Embodiment 2
17.2g (0.08mol) N-methyl piperethanamine salt hydrochlorate and 24g (0.8mol) paraformaldehyde are placed the 500ml round-bottomed bottle, add 200ml dehydrated alcohol and 1.5ml concentrated hydrochloric acid, make PH be about 3-4,100 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring about 20 minutes, cold slightly, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 6.0 hours of backflow stirring reaction, slowly separate out solid in the course of reaction, in reaction bulb, all solidify.Detect R with TLC
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly with dehydrated alcohol, drying.Get faint yellow solid.This solid 95% ethyl alcohol recrystallization obtains pale yellow powder shape solid, cools off then, filters, and uses absolute ethanol washing, gets subalbous Peperphentonamine hydrochloride pulverulent solids, vacuum drying, heavy 15.58g, yield: 60.1%.mp：167～169℃。R
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), elementary analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.6%.
Embodiment 3
25.8g (0.12mol) N-methyl piperethanamine salt hydrochlorate and 36g (1.2mol) paraformaldehyde are placed the 500ml round-bottomed bottle, add 320ml dehydrated alcohol and 2.0mol concentrated hydrochloric acid, make PH be about 4,90 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring 10 minutes, cold slightly, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 9.5 hours of backflow stirring reaction, slowly separate out solid in the course of reaction, in reaction bulb, all solidify.Detect R with TLC
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid is washed repeatedly, is dried with dehydrated alcohol, gets faint yellow solid.This solid ethyl alcohol recrystallization obtains faint yellow Peperphentonamine hydrochloride pulverulent solids, cools off then, filters, and uses absolute ethanol washing, gets subalbous pulverulent solids, vacuum drying, yield: 62%.mp：167～169℃。R
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), elementary analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.8%.
Embodiment 4
43.0g (0.2mol) N-methyl piperethanamine salt hydrochlorate and 45g (1.5mol) paraformaldehyde are placed the 1000ml round-bottomed bottle, add 400ml dehydrated alcohol and concentrated hydrochloric acid, make PH be about 3-4,95 ℃ of oil bath temperatures are after heated and stirred to solid all dissolves, reheat, stirring 25 minutes, cold slightly, add hydroxyl benzylideneacetone 24.3g ((0.15mol), about 7 hours of backflow stirring reaction, slowly separate out solid in the course of reaction, in reaction bulb, all solidify.Detect R with TLC
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter, solid with dehydrated alcohol wash repeatedly, drying, faint yellow solid.This solid ethyl alcohol recrystallization obtains pale yellow powder shape solid, cools off then, filters, and uses absolute ethanol washing, gets subalbous Peperphentonamine hydrochloride pulverulent solids, vacuum drying, yield: 56.4%.mp：167～169℃。R
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), elementary analysis is near theoretical value, and high pressure liquid chromatography detects, and purity is about 98.5%.
32.25g (0.15mol) N-methyl piperethanamine salt hydrochlorate and 45g (1.5mol) paraformaldehyde are placed the 1000ml round-bottomed bottle, add 350ml dehydrated alcohol and concentrated hydrochloric acid, adjust PH and be about 3-5,100 ℃ of oil bath temperatures, after heated and stirred to solid all dissolves, add hydroxyl benzylideneacetone 16.2g ((0.1mol), about 7.5 hours of backflow stirring reaction, slowly separate out solid in the course of reaction, in reaction bulb, all solidify.Detect R with TLC
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), reaction is complete substantially.Filter out solvent, solid is washed repeatedly with dehydrated alcohol, drying.Get faint yellow solid.This solid is with 95% ethanol heated and stirred, the very fast whole dissolvings of solid are lurid settled solution, reuse 3g activated carbon decolorizing, lurid settled solution, put and slowly separate out the white powder solid after cold, cool off then, filter, get subalbous pulverulent solids, wash vacuum drying with dehydrated alcohol, obtain Peperphentonamine hydrochloride, yield: 58.9%.mp：168～170℃。R
f=0.38 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08), elementary analysis is near theoretical value, and high pressure liquid chromatography detects purity 99.5%
Embodiment 6
1.5g Peperphentonamine hydrochloride, sodium bicarbonate solution (pH=9) that 200ml is saturated and 80 ethyl acetate are mixed, stirring at room three hours, solid dissolve gradually settled solution, the intact R of TLC reaction
f=0.49 (developing solvent: CH
2Cl
2: CH
3OH=10: 0.8), tell the upper strata ethyl acetate solution, wash neutrality with water, use anhydrous sodium sulfate drying, filter, get subalbous pulverulent solids, wash with absolute ether, vacuum drying gets Peperphentonamine pulverulent solids 1.3g, yield: 95.6%.mp：142～143℃。Results of elemental analyses and theoretical value are approaching.
Embodiment 7
It according to mol ratio 1: 1.2 ratio, Peperphentonamine is reacted salify with acid such as hydrobromic acid, oxalic acid, succinic acid or maleic acids respectively under the room temperature in ethyl acetate, the TLC monitoring reaction, to the Peperphentonamine disappearance, wash neutrality with water, use anhydrous sodium sulfate drying, filter, get subalbous pulverulent solids, wash vacuum drying with absolute ether.Obtain Peperphentonamine hydrobromate, Peperphentonamine oxalates, Peperphentonamine succinate, Peperphentonamine maleate salt respectively, results of elemental analyses and theoretical value are approaching.
Experimental example 8
Adopt following method to synthesize N-methyl piperethanamine salt hydrochlorate:
0.8mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.0mol benzaldehyde are placed flask at the bottom of the 1000ml garden, mix homogeneously, emit a large amount of heat, add 200ml absolute methanol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 21 hours, concentrating under reduced pressure is removed methanol, and reuse oil pump concentrating under reduced pressure is removed unreacted benzaldehyde, gets rufous grease, behind the cool to room temperature, add 100ml benzene and 1.0mol dimethyl sulfate again, outer temperature is maintained at about 80 ℃ of reactions 60 minutes, and room temperature leaves standstill cooling, treat the benzene layer that inclines top again after the layering, and then 75% ethanol of adding 200ml, back flow reaction is 40 minutes again, gets dark brownish red opaque liquid.Adding distil water 15ml shakes up the back under stirring, uses water pump to remove ethanol, toluene and water equal solvent under reduced pressure, reuse oil pump concentrating under reduced pressure is removed benzaldehyde, get the opaque thickness grease of dark brownish red, in the extremely thick thing of gained, add saturated substantially HCl/ ethanol solution to PH=4, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, subalbous solid, yield: 35%, mp:186～188 ℃ (dec.).R
f=0.23 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Experimental example 9
1.2mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 1.5mol benzaldehyde are placed flask at the bottom of the 1000ml garden, mix homogeneously, emit a large amount of heat, add the anhydrous THF mixing of 400ml, add zeolite, the heating of electricity consumption hot tap, back flow reaction 15 hours, the water pump concentrating under reduced pressure is removed THF, and reuse oil pump concentrating under reduced pressure is removed unreacted benzaldehyde, gets rufous grease, behind the cool to room temperature, add 200ml toluene and 1.4mol dimethyl sulfate again, outer temperature is maintained at about 130 ℃ of reactions 40 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 400ml, back flow reaction is 50 minutes again, gets dark brownish red opaque liquid.Adding distil water 20ml shakes up the back under stirring, uses water pump to remove ethanol, toluene and water equal solvent under reduced pressure, reuse oil pump concentrating under reduced pressure is removed benzaldehyde, get the opaque thickness grease of dark brownish red, in the extremely thick thing of gained, add saturated substantially HCl/ absolute methanol solution to pH=1-3, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, subalbous solid, yield: 40%, mp:186～188 ℃ (dec.).R
f=0.23 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Experimental example 10
0.4mol homopiperony lamine (intermediate of Northeast Pharmaceutical Factory) and 0.8mol benzaldehyde are placed flask at the bottom of the 1000ml garden, mix homogeneously, emit a large amount of heat, add 150ml dehydrated alcohol mixing, add zeolite, the heating of electricity consumption hot tap, back flow reaction 20 hours, the water pump concentrating under reduced pressure is removed ethanol, and reuse oil pump concentrating under reduced pressure is removed unreacted benzaldehyde, gets rufous grease, behind the cool to room temperature, add 45ml cyclohexane extraction and 0.6mol dimethyl sulfate again, outer temperature is maintained at about 100 ℃ of reactions 20 minutes, and room temperature leaves standstill cooling, treat the top toluene layer that inclines again after the layering, and then 75% ethanol of adding 200ml, back flow reaction is 50 minutes again, gets dark brownish red opaque liquid.Adding distil water 12ml shakes up the back under stirring, uses water pump to remove ethanol, cyclohexane extraction and water equal solvent under reduced pressure, reuse oil pump concentrating under reduced pressure is removed benzaldehyde, get the opaque thickness grease of dark brownish red, in the extremely thick thing of gained, add saturated substantially HCl/ absolute methanol solution to PH=3.5, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, subalbous solid, yield: 380%, mp:186～188 ℃ (dec.).R
f=0.23 (developing solvent: CH
2Cl
2: CH
3OH: HCOOH=10: 0.8: 0.08).
Embodiment 11
Method with reference to embodiment 9, difference is to add saturated substantially oxalic acid/ethanol solution to Ph=2 in the thickness grease that finally obtains, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, get subalbous N-methyl piperethanamine oxalates solid, refer again to the synthetic Peperphentonamine oxalates of method of embodiment 2.
Embodiment 12
Method with reference to embodiment 10, difference is to add saturated substantially succinic acid/ethanol solution to Ph=3 in the thickness grease that finally obtains, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, get subalbous N-methyl piperethanamine succinate solid, refer again to the synthetic Peperphentonamine succinate of method of embodiment 2.
Embodiment 13
Method with reference to embodiment 10, difference is to add saturated substantially maleic acid/ethanol solution to Ph=4 in the thickness grease that finally obtains, separate out a large amount of solids gradually, filter, solid with acetone wash repeatedly, the reuse absolute ether washes, subalbous N-methyl piperethanamine maleate solid.Refer again to the synthetic Peperphentonamine maleate of method of embodiment 2.
Embodiment 14
With reference to the method for embodiment 8, acid/ethanol solution such as that difference is to add is saturated substantially, oxalic acid, succinic acid or maleic acid is to Ph=1-3.
Comparative example
In 100ml ethanol, 0.018mol,, add 5ml 36% formaldehyde and 5ml hydrochloric acid again with 5ml 36% formaldehyde and 0.018mol N-methyl piperethanamine salt hydrochlorate stirring and refluxing 3 hours under PH3-4 to hydroxyl-phenyl-1-butylene-3-ketone, continue reaction 7 hours, be concentrated into solid and occurred, put and be chilled to room temperature, put refrigerator again 2 hours, the solid that sucking filtration is separated out, use the ether washed twice, get the 3.4g white solid, yield 44%.Use the absolute ether recrystallization, obtain Peperphentonamine hydrochloride, fusing point 157-9 ℃.The HPLC spectrogram of product is seen Fig. 7.
Claims (6)
1. Peperphentonamine or its salt are as the application of preparation treatment cardiovascular disease medicine.
2. Peperphentonamine or its salt are as the application of preparation treatment myocardial ischemia drug.
3. Peperphentonamine or its salt are as the application of preparation treatment ischemical reperfusion injury medicine.
4. Peperphentonamine or its salt are as the application of preparation treatment cardiac insufficiency medicine.
5. according to any one described application of claim 1-4, it is characterized in that described Xanthiphenyl ketamine salt is pharmaceutically acceptable Xanthiphenyl ketamine salt, comprise one of Peperphentonamine hydrochlorate, Peperphentonamine sulfate, Peperphentonamine phosphate, Peperphentonamine carbonate or Peperphentonamine organic salt.
6. according to any one described application of claim 1-4, it is characterized in that described Xanthiphenyl ketamine salt is the Peperphentonamine hydrochlorate.
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|---|---|---|---|
| CN 02125316 CN1205928C (en) | 2002-07-24 | 2002-07-24 | Application of xanthiphenylketamine or its salt in preparing medicines to treat cardiovascalar disease |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02125316 CN1205928C (en) | 2002-07-24 | 2002-07-24 | Application of xanthiphenylketamine or its salt in preparing medicines to treat cardiovascalar disease |
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| CN1395923A true CN1395923A (en) | 2003-02-12 |
| CN1205928C CN1205928C (en) | 2005-06-15 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008095328A1 (en) | 2007-01-31 | 2008-08-14 | Guangzhou Zhongwei Biotechnology Ltd | A kind of hydrochloric piperphentonamine freeze-dried powder injection, preparation methods and uses thereof |
| CN101234102B (en) * | 2007-01-31 | 2010-08-18 | 广州市众为生物技术有限公司 | Peperphentonamine hydrochloride freeze-dried injection and preparation and application thereof |
| CN101235027B (en) * | 2007-01-31 | 2010-11-10 | 广州市众为生物技术有限公司 | Xanthiphenylketamine crystal and its preparation method and medical use |
| WO2011035500A1 (en) * | 2009-09-24 | 2011-03-31 | 广州市众为生物技术有限公司 | Use of piperphentonamine or salts thereof in manufacture of medicaments for preventing / treating brain diseases |
-
2002
- 2002-07-24 CN CN 02125316 patent/CN1205928C/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008095328A1 (en) | 2007-01-31 | 2008-08-14 | Guangzhou Zhongwei Biotechnology Ltd | A kind of hydrochloric piperphentonamine freeze-dried powder injection, preparation methods and uses thereof |
| CN101234102B (en) * | 2007-01-31 | 2010-08-18 | 广州市众为生物技术有限公司 | Peperphentonamine hydrochloride freeze-dried injection and preparation and application thereof |
| CN101235027B (en) * | 2007-01-31 | 2010-11-10 | 广州市众为生物技术有限公司 | Xanthiphenylketamine crystal and its preparation method and medical use |
| US8513301B2 (en) | 2007-01-31 | 2013-08-20 | Guangzhou Zhongwei Biotechnology Ltd. | Kind of piperphentonamine hydrochloride lyophilized powder for injection and preparation and use thereof |
| WO2011035500A1 (en) * | 2009-09-24 | 2011-03-31 | 广州市众为生物技术有限公司 | Use of piperphentonamine or salts thereof in manufacture of medicaments for preventing / treating brain diseases |
| US8916607B2 (en) | 2009-09-24 | 2014-12-23 | Guangzhou Municipal Zhongwei Biotechnology Limited Company | Use of piperphentonamine or salts thereof in manufacture of medicaments for treating brain diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1205928C (en) | 2005-06-15 |
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