CN103405438B - Trapidil or the application of its pharmaceutically acceptable salt in preparation control pulmonary hypertension medicine - Google Patents
Trapidil or the application of its pharmaceutically acceptable salt in preparation control pulmonary hypertension medicine Download PDFInfo
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- CN103405438B CN103405438B CN201310302758.6A CN201310302758A CN103405438B CN 103405438 B CN103405438 B CN 103405438B CN 201310302758 A CN201310302758 A CN 201310302758A CN 103405438 B CN103405438 B CN 103405438B
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Abstract
The invention discloses trapidil (5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine) or the application of its pharmaceutically acceptable salt in preparation control pulmonary hypertension medicine.The invention belongs to biomedicine field.By research, the present invention finds that trapidil (formula I shown in) tool is significantly improved pulmonary hypertension animal lung vascular remodeling, alleviate right ventricle plumpness and right heart failure, improve the life quality (improving feed, inflow) of pulmonary hypertension animal, improve the effect of the survival rate of pulmonary hypertension animal.Therefore, proposition of the present invention will make trapidil have broad application prospects in control pulmonary hypertension disease.
Description
Technical field
The present invention relates to trapidil (Trapidil, N, N-diethyl-5-methyl-[1,2,4] Triazolo [1,5-a] pyrimidin-7-amine) a kind of novelty teabag, be specifically related to the purposes of trapidil in control pulmonary hypertension disease.The invention belongs to biomedicine field.
Background technology
Pulmonary hypertension refers to that the pulmonary artery pressure persistency caused by a variety of causes increases.Early stage modal symptom is dyspnea, along with increasing the weight of of the state of an illness, can occur damaged heart valve and right heart failure.Patients with pulmonary hypertension 75% patient dies from 5 years after diagnosis, and after symptom occurs, mean survival time (MST) is 1.9 years; Have right heart failure shower, the mean survival time is less than 1 year.Pulmonary hypertension endangers one of the most serious cardiovascular disease clinically.The clinical medicine for pulmonary hypertension mainly comprises at present: prostacyclin and analog, 5 type phosphodiesterase inhibitors, endothelin-receptor antagonists, immunosuppressant etc.There is the shortcomings such as price is high, medication is inconvenient (some needs intravenously administrable), curative effect is not high in these medicines, needs the medicine of the control pulmonary hypertension of development of new badly.
Trapidil (5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine, N, N-diethyl-5-methyl-[1,2,4] Triazolo [1,5-a] pyrimidin-7-amine) be coronary dilation agent, for coronary heart disease, angina pectoris attacks and myocardial infarction.The present inventor finds that trapidil significantly can improve pulmonary hypertension animal lung vascular remodeling, alleviate right ventricle plumpness and right heart failure, improve the life quality (improving feed, inflow) of pulmonary hypertension animal, improve the survival rate of pulmonary hypertension animal, on this basis, the present invention proposes the medicine that trapidil and analog thereof can be used as the novel control pulmonary hypertension of a class, for preventing and treating pulmonary hypertension.
Summary of the invention
An object of the present invention is to provide trapidil (Trapidil, 5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine, N, N-diethyl-5-methyl-[1,2,4] Triazolo [1,5-a] pyrimidin-7-amine) in the application preventing and treating pulmonary hypertension disease;
Two of object of the present invention is to provide trapidil (Trapidil, N, N-diethyl-5-methyl-[1,2,4] Triazolo [1,5-a] pyrimidin-7-amine) its pharmaceutically acceptable salt or carry out improved based on it, still there is the application of analog in preparation control pulmonary hypertension medicine of control pulmonary hypertension effect.
Following technological means is present invention employs in order to reach above object:
1, pulmonary hypertension disease rat model is built: in one particular embodiment of the present invention, described pulmonary hypertension disease model induced by monocrotaline (Monocrotaline).
2, by after lumbar injection trapidil, the situation such as fur, diet, spirit, activity, death of Rats of Pulmonary Hypertension model is observed.
3, research finds, trapidil significantly can improve the reconstruct of monocrotaline-induced pulmonary hypertension Pulmonary Vessels in Rats, alleviate right ventricle plumpness and right heart failure, improve the life quality (improving feed, inflow) of pulmonary hypertension animal, improve the survival rate of pulmonary hypertension animal, namely by research, the present invention has found that trapidil (Trapidil) has the effect of control pulmonary hypertension disease.
Therefore, on the basis of this research, the present invention proposes trapidil (5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine, N, N-diethyl-5-methyl-[1,2,4] Triazolo [1,5-a] pyrimidin-7-amine) or the application of its pharmaceutically acceptable salt in preparation control pulmonary hypertension medicine, and carry out improved based on it, still there is the application of analog in preparation control pulmonary hypertension medicine of control pulmonary hypertension effect;
Wherein the chemical structural formula of trapidil (Trapidil) is such as formula shown in I:
Formula I
Further, the invention allows for a kind of pharmaceutical composition for preventing and treating pulmonary hypertension, it is characterized in that its effective ingredient comprises trapidil or its pharmaceutically acceptable salt or carries out improved based on it, still there is the analog of control pulmonary hypertension effect.
Further, the invention allows for described pharmaceutical composition in the application in preparation control pulmonary hypertension medicine.
Accompanying drawing explanation
Fig. 1 is the survival rate of matched group, monocrotaline model group and the animal of trapidil treatment group when different number of days, illustrates that trapidil can improve the survival rate of pulmonary hypertension animal;
Fig. 2 is the plump situation of matched group, monocrotaline model group and the trapidil treatment group rat right ventricular when different number of days, illustrates that trapidil can significantly suppress Rats of Pulmonary Hypertension right ventricle plump;
Fig. 3 is matched group, monocrotaline model group and trapidil treatment group rats eating amount, inflow and body weight change figure when different number of days, illustrate that monocrotaline causes rats eating, inflow declines gradually, significantly weight loss be can suppress after trapidil medication treatment, feed and the inflow of rat increased;
Fig. 4 is matched group, monocrotaline model group and trapidil treatment group Rats of Pulmonary Hypertension right ventricular pressure compare, and illustrates that trapidil can reduce Rats of Pulmonary Hypertension right ventricular pressure;
* P<0.01vs matched group; ##P<0.01vs monocrotaline model group
Fig. 5 is the typical lung tissue photo of matched group, monocrotaline model group and trapidil treatment group, shows that trapidil significantly can improve Rats of Pulmonary Hypertension pulmonary venous pleonaemia symptom.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiments are only exemplary, do not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
Embodiment 1
1. animal and experiment reagent:
Rat (strain: SD, laboratory animal Technology Co., Ltd. of system in Beijing Jing dimension tonneau China buys), monocrotaline (Monocrotaline, Hui Cheng bio tech ltd, Shanghai buys).
2. experimental technique:
The foundation of monocrotaline-induced pulmonary hypertension model:
Healthy SD male rat 45 (body weight 250-300 gram) is divided into 3 groups at random according to body weight homeostatic principle, and experimental group A, experimental group B, matched group, all raise in standard sterile feeding environment.Experimental group lumbar injection monocrotaline 60mg/kg, after 24 days, divides 2 groups more at random by body weight, be respectively model group (MCT group, with the isopyknic normal saline of model medication group, lumbar injection) and model medication group (trapidil, 30mg/kg/ days, lumbar injection).Observe the situations such as fur, diet, spirit, activity, death.
Dirty and left lung of coring carries out 4% paraformaldehyde to be fixed, and all the other lobes of the lung carry out frozen process.Fixing heart and lung carry out pathological staining.
3, result
3.1 trapidils improve the survival rate of pulmonary hypertension animal
After monocrotaline injects 24 days, carry out trapidil therapeutic administratp, count 0 day with this time point for each group, the survival rate (P=0.0003) of different number of days pulmonary hypertension animal after the administration of Log-rank (Mantel-Cox) inspection display trapidil.
Found by research, the pulmonary hypertension animal that monocrotaline is brought out, extend with feeding time and occur death successively, to injection monocrotaline after 60 days, model group mortality rate reaches 80%, and model medication group (trapidil, 30mg/kg/ days, lumbar injection) mortality rate is only 30%, and illustrate that trapidil can improve the survival rate of pulmonary hypertension animal, result is as shown in Figure 1.
It is plump that 3.2 trapidils significantly can suppress to alleviate Rats of Pulmonary Hypertension right ventricle
Research finds, the Rats of Pulmonary Hypertension that monocrotaline is brought out is dead gradually, the rat of death is drawn materials, found that the remarkable right ventricular hypertrophy of the Animal performance of drawing materials, right heart index (right heart weight/interventricular septum+Zuo Xinchong) significantly increases, and the right heart index increased after trapidil medication treatment significantly suppresses, result as shown in Figure 2.Illustrate that trapidil significantly can suppress to alleviate Rats of Pulmonary Hypertension right ventricle plump, can right heart failure be corrected.
3.3 trapidils significantly can improve the life quality of Rats of Pulmonary Hypertension
Research finds, monocrotaline brings out Pulmonary Hypertension, not only occurs death successively with feeding time prolong rats, and rat body weight in feeding process declines gradually, and feed, inflow also decline gradually.Significantly can suppress weight loss after trapidil medication treatment, significantly increase feed and the inflow of rat, result as shown in Figure 3.
3.4 trapidils can significantly reduce Rats of Pulmonary Hypertension right ventricular pressure
The visible right ventricular pressure of monocrotaline-induced pulmonary hypertension model significantly increases.Trapidil treatment group compares monocrotaline model group, and right ventricular pressure increases situation and significantly improves, and result as shown in Figure 4.
3.5 trapidils significantly can improve Rats of Pulmonary Hypertension pulmonary venous pleonaemia symptom
Fig. 5 is each group of typical lung tissue photo, as can be seen from the figure the visible significantly pulmonary venous pleonaemia symptom of monocrotaline-induced pulmonary hypertension model, and organize dark red, and trapidil treatment group compares pulmonary hypertension model group, congestion symptom is significantly improved.Illustrate that trapidil significantly can improve Rats of Pulmonary Hypertension pulmonary venous pleonaemia symptom.
Found out as seen by above result, trapidil significantly can improve the reconstruct of monocrotaline-induced pulmonary hypertension Pulmonary Vessels in Rats, alleviate right ventricle plumpness and right heart failure, improve the life quality (improving feed, inflow) of pulmonary hypertension animal, improve the survival rate of pulmonary hypertension animal, therefore, there is the effect of control pulmonary hypertension disease.
Claims (1)
1. trapidil (5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine) or its pharmaceutically acceptable salt alleviate in preparation the application that the right ventricle of pulmonary hypertension animal is plump or alleviate in the right heart failure medicine of pulmonary hypertension animal; Wherein the chemical structural formula of trapidil (5-methyl-7-diethylin-1,2,4-triazol [1,5-a] pyrimidine) is such as formula shown in I:
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| CN201310302758.6A CN103405438B (en) | 2013-07-18 | 2013-07-18 | Trapidil or the application of its pharmaceutically acceptable salt in preparation control pulmonary hypertension medicine |
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| CN103405438B true CN103405438B (en) | 2016-01-20 |
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- 2013-07-18 CN CN201310302758.6A patent/CN103405438B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Modification of pulmonary hypertension in patients with chronic obstructive lung diseases by trapidil(Rocornal)in an acute trial;Schauer J.et al;《Z Erkr Atmungsorgane》;19911231;第177卷(第3期);第204-206页 * |
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