CN103027912A - Application of N-[2-[3-(1-piperazine methyl) imidazo [2, 1-B] thiazole-6-yl] phenyl]-2-quinoxaline formamide in preparation of medicament for prevention and treatment of high blood pressure - Google Patents
Application of N-[2-[3-(1-piperazine methyl) imidazo [2, 1-B] thiazole-6-yl] phenyl]-2-quinoxaline formamide in preparation of medicament for prevention and treatment of high blood pressure Download PDFInfo
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Abstract
The invention discloses an application of N-[2-[3-(1- piperazine methyl) imidazo [2, 1-B] thiazole-6-base] phenyl]-2-quinoxaline formamide in preparation of a medicament for prevention and treatment of high blood pressure. The experiment research proves that the N-[2-[3-(1- piperazine methyl) imidazo [2, 1-B] thiazole-6-yl] phenyl]-2-quinoxaline formamide can greatly reduce the tail arterial blood pressure, central aortic systolic blood pressure, central aortic diastolic blood pressure, center average arterial pressure and pulse wave velocity of hypertension rats, can improve the artery elastic function, and can reduce the middle thickness of aorta and the vessel wall collagen fiber, increases the blood vessel diameter, and has a favorable effect of prevention and treatment of high blood pressure; and even no significant adverse reactions appear in the experiment process, the medicament is expected to be developed into a new generation safe and effective medicament for prevention and treatment of high blood pressure.
Description
Technical field
The present invention relates to N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline benzamide compound, be particularly related to N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-the new clinical application of 2-quinoxaline Methanamide in preparation control hypertension drug.
Background technology
Hypertension is modal chronic disease, has become the main public health problem in the whole world.According to studies show that of WHO 2004, the annual number by hypertension death in the whole world is 7,500,000 examples, and the permanent disability that it causes is adjusted the loss of year in life-span and come the 5th.In the past few decades, the hypertensive prevalence of China increases fast, and especially since the reform and opening-up, along with the variation of people life style and the acceleration of aging process, the Prevalence of Hypertension growth rate is accelerated.The hypertension number of estimating among China adult from 3,000 ten thousand of nineteen sixty be increased to 1980 5,900 ten thousand, then be increased to again 1991 9,400 ten thousand and 2004 1.6 hundred million, annual newly-increased hyperpietic more than 1,000 ten thousand.162 monitoring points that Chinese chronic disease monitoring in 2010 covers in National Diseases Surveillance Spots system (dsp system), investigated altogether 98548 inhabitants more than 18 years old, found that, hypertensive prevalence is 38%, estimate that accordingly China has 3.3 hundred million adults to suffer from hypertension at present." world health statistics in 2012 " data show of WHO issue, the whole world 1/3rd adults suffer from hypertension, the hypertensive prevalence of China adult has been higher than global average level, and these numerals show that China becomes one of the most serious country of in the world hypertension harm.Hypertension is the most important independent hazard factors of cardiovascular and cerebrovascular disease such as present apoplexy of generally acknowledging, coronary heart disease.The long-term chronic Pressure Overload-induced will cause the change of heart, blood vessel structure and function.Present antihypertensive medicine is more, but mostly has larger untoward reaction, and needs long-term prescription.
N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide, molecular formula is C
25H
23N
7OS; English full name is: N-(2-(3-(piperazin-1-ylmethyl) imidazo[2; 1-b] thiazol-6-yl) phenyl) quinoxaline-2-carboxamide; be a kind of new chemical entities medicine by the exploitation of GlaxoSmithKline PLC company, belong to the activator of nicotinamide adenine dinucleotide (NAD+) dependency deacetylase SIRT1.
Bibliographical information N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide can enhances skeletal flesh, the oxidative metabolism process in liver and the brown adipose tissue and promote its fat consumption, can be used for treating the insulin resistant under obesity, type 2 diabetes mellitus and the high fat diet state, but it does not also study report to hypertensive therapeutical effect.
Summary of the invention
Goal of the invention: the objective of the invention is in order to overcome the deficiencies in the prior art, at N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-the former powerful basis of 2-quinoxaline Methanamide on, develop its new clinical application, N-[2-[3-(1-piperazinyl methyl) imidazo [2 is provided, 1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preventing and treating hypertension, experimental result shows, it has the effect that well prevents and treats hypertension and relevant disease thereof, and have no adverse reaction, safe and effective.
Technical scheme: in order to realize above purpose, N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide (hereinafter to be referred as SRT1720), its structural formula is:
The present invention shows by lot of experiments, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide has the hypertensive effect of good control, can be used for preparing the application in the control hypertension drug.
As preferred version, N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control essential hypertension medicine.
As another preferred version, N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide prevents and treats application in the secondary hypertension medicine in preparation.
As preferred version, N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control hypertension drug, with N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide and pharmaceutically acceptable carrier make the medicine of capsule, granule, spray, injectable powder, injection, microcapsule, tablet, ointment or skin-permeable and control-released plaster dosage form.
N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-when 2-quinoxaline Methanamide is made capsule N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide and carrier lactose or corn starch mix homogeneously, granulate, the then encapsulated capsule of making.
With N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-when 2-quinoxaline Methanamide is made tablet, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide and lactose or corn starch, add magnesium stearate lubricant when needing, mix homogeneously, then tabletting is made tablet.
N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-during the agent of 2-quinoxaline Methanamide granulation, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide and diluent lactose or corn starch mix homogeneously, granulate, drying, the granulation agent.
N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-when 2-quinoxaline Methanamide is made injection, get N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide adds physiological saline solution and then adds activated carbon, stir, 80 ℃ were heated 30 minutes, filter, regulate pH value, be filtered to clear and bright with sintered glass funnel or other filter, fill was made injection in 30 minutes 100 to 115 ℃ of sterilizations.
N-[2-[3-provided by the invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide depyrogenation after, through aseptic filtration, lyophilization obtains powder ampoule agent for injection.
Beneficial effect: the present invention is at N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-carry out new purposes exploitation on the former powerful basis of 2-quinoxaline Methanamide, experimentation shows N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide has obvious reduction rat tail artery blood pressure, the center systolic arterial pressure, the effect of center auterial diastole pressure and center tremulous pulse mean blood pressure, and can improve the trunk stiffness index, reduce pulse wave velocity, it is loose to suppress vascular smooth muscle cell, reduce the aorta intima-media thickness, enlarge vessel diameter, has the hypertensive effect of good control, all has an extraordinary prevention effect to constitutional and secondary hypertension and hypertension thereof are diseases related, and in the experimentation, do not show the untoward reaction such as side effect, being expected to exploitation, to become a new generation safe and effective, is used for preventing and treating hypertensive medicine.
The specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, should understand these embodiment only is used for explanation the present invention and is not used in and limits the scope of the invention, after having read the present invention, those skilled in the art all fall within the application's claims limited range to the modification of the various equivalent form of values of the present invention.
Embodiment 1:N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-hypotensive effect of 2-quinoxaline Methanamide Dichlorodiphenyl Acetate desoxycortone-salt Hypertensive Rats
One, experimental technique
1, animal model preparation and experiment grouping: the foundation of animal model and grouping: 13 all SD rats in age (220-250g), lumbar injection pentobarbital (40mg/Kg BW) anesthesia, the abdominal part median incision, behind separation and ligation left side renal artery, renal veins and the ureter, row left kidney excision, and successively close abdominal cavity, 1 week of post-operative recovery.Test 23 of the rats that survive after the left nephrectomy, be divided at random 3 groups, matched group (n=7): the drink tap water; Model group (n=8) and N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide (SRT1720) treatment group (n=8): the rubber medium that 200mg/Kg desoxycorticosterone acetate (DOCA) (DOCA) and silica gel are made is placed on subcutaneous between the scapula of rat both sides, and gives 1%NaCl drinking-water; The SRT1720 treatment group gives 100mgKg
-1D
-1, and the model group rat gives the distilled water gavage of equivalent, 1 times/day, and totally 4 weeks.
2, the rat systolic pressure is measured: adopt the arteria caudalis manometry, survey weekly systolic pressure (SBP) once, every rat is surveyed 3 times, averages.
3, rat center arterial pressure and pulse wave velocity (PWV) are measured: after modeling was finished, rat was fixed on 37 ° of C temperature-constant plates to keep body temperature through pentobarbital (40mg/KgBW) intraperitoneal injection of anesthesia.Insert respectively 1.4Fr Millar pressure transducer in left carotid artery and left side femoral artery, catheter tip (sensor) places respectively descending aorta and top, abdominal aortic bifurcation place, record simultaneously 2 tremulous pulse internal pressure curves, adopt the Foot-to-Foot method to determine respectively the diastolic pressure (blood pressure minimum) at descending aorta and ventral aorta place, calculate the propagation time (T) of pulse wave between bright spot.After data acquisition is finished, put to death rat, open the abdominal cavity, silk thread is placed on the aorta of two catheter tips, directly measure the distance (D) of point-to-point transmission.PWV=D/T（m/s）。Get data behind the intubate 20min, gather 10-20 cardiac cycle, draw mean P WV, process in order to follow-up data.Intraarterial pressure curve record center systolic arterial pressure (cSBP) and center auterial diastole with the descending aorta place are pressed (cDBP), and calculate center average pulse pressure (cPP, cPP=cSBP-cDBP) and center mean blood pressure (cMBP, cMBP=cDBP+cPP/3).
4, pathology detection: the about 2cm of blunt separation thoracic aorta, PBS cleans, and 4% neutral formalin is fixed, and paraffin embedding prepares 5 μ m section, HE dyeing.Observe the morphological change of aorta middle level vascular smooth muscle cell (VSMC), elastic fibers under the light microscopic, and measure aorta intima-media thickness (MT), vessel diameter (LD).
5, statistical method: the result represents with mean ± standard deviation, adopts SPSS 11.5 statistical softwares to carry out statistical analysis.Relatively adopt one factor analysis of variance between group, the relatively employing q check between a plurality of means, P＜0.05 expression difference has statistical significance.
Two, experimental result
1, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is on the impact of DOCA-salt rat tail artery blood pressure
Each organizes rat in the left kidney excision after one week, and the arteria caudalis blood pressure is all in normal range, and the model group rat obviously increases from testing the 2nd week beginning blood pressure, and along with time lengthening, blood pressure raises gradually, to test the 4th when week blood pressure the highest, reach (175.3 ± 15.9) mmHg.Through N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide control after, the treatment group rat blood pressure significantly reduces than model group, concrete experimental result is as shown in table 1.
Table 1 is respectively organized the dynamic change (mmHg) of rat tail artery blood pressure
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
2, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is on the impact of DOCA-salt rat center arterial pressure
When finishing, experiment adopt tremie method to measure rat center arterial pressure, model group center systolic arterial pressure, center auterial diastole are pressed and center tremulous pulse mean blood pressure all significantly raises than matched group, through N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment after, center systolic arterial pressure, center auterial diastole are pressed and center tremulous pulse mean blood pressure all significantly descends, and concrete experimental result is as shown in table 2.
Table 2 is respectively organized the variation (mmHg) of rat center arterial pressure
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
3, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is on the impact of DOCA-salt rat aorta stiffness index: adopts tremie method to measure rat pulse wave velocity (PWV) when experiment finishes and reacts arterial stiffness.Found that model group PWV is significantly higher than matched group, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment can significantly improve aortic stiffness index, and concrete experimental result is as shown in table 3.
Table 3 is respectively organized the variation of rat pulse wave velocity, aorta intima-media thickness and vessel diameter
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
4, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is on the impact of DOCA-salt rat aorta intima-media thickness: gets respectively and respectively organizes rat chest aorta slice row HE dyeing, the morphological change of observing aorta middle level vascular smooth muscle cell and elastic fibers.The result shows, the model group rat smooth muscle cells is obviously loose and thicken with elastic fibers, and the aorta intima-media thickness significantly thickens, and vessel diameter then obviously descends.N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment after the vascular smooth muscle cell hypertrophy be subject to obvious inhibition, the aorta intima-media thickness significantly descends, and vessel diameter obviously increases, and concrete experimental result is as shown in table 3.
Desoxycorticosterone acetate (DOCA) (DOCA)-salt hypertension is a kind of secondary hypertension model, similar with the primary aldosteronism in the human hypertension, take large artery trunks and the obvious hypertrophy plumpness of the little blood vessel of resistance as feature, show as vascular smooth muscle cell hypertrophy and fibrous connective tissue hypertrophy, media thickness significantly increases, and vessel diameter reduces.Above experimental result shows, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide can be loose by suppressing vascular smooth muscle cell, reduce the aorta intima-media thickness, thereby expansion vessel diameter, reduce rat tail artery blood pressure, center systolic arterial pressure, center auterial diastole pressure and center tremulous pulse mean blood pressure, have good antihypertensive effect.
Embodiment 2 N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is to the hypotensive effect of spontaneous hypertensive rat
One, experimental technique
1, laboratory animal grouping: 16 (16 ages in week of male spontaneous hypertensive rat (SHR), body weight 280-320g), be divided at random 2 groups, every group 8, be respectively SHR matched group and N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment group.8 with the age consubstantiality heavy healthy male Wistar-Kyoto(WKY) rat is the normal arterial pressure matched group.N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment group gives 100mgKg
-1D
-1, gavage, SHR matched group and WKY normal arterial pressure matched group give commensurability distilled water gavage every day simultaneously, and 1 times/day, continuous 8 weeks.
2, the rat systolic pressure is measured: adopt the arteria caudalis manometry, survey weekly systolic pressure (SBP) once, every rat is surveyed 3 times, averages.
3, rat center arterial pressure and pulse wave velocity (PWV) are measured: after modeling was finished, rat was fixed on 37 ° of C temperature-constant plates to keep body temperature through pentobarbital (40mg/KgBW) intraperitoneal injection of anesthesia.Insert respectively 1.4Fr Millar pressure transducer in left carotid artery and left side femoral artery, catheter tip (sensor) places respectively descending aorta and top, abdominal aortic bifurcation place, record simultaneously 2 tremulous pulse internal pressure curves, adopt the Foot-to-Foot method to determine respectively the diastolic pressure (blood pressure minimum) at descending aorta and ventral aorta place, calculate the propagation time (T) of pulse wave between bright spot.After data acquisition is finished, put to death rat, open the abdominal cavity, silk thread is placed on the aorta of two catheter tips, directly measure the distance (D) of point-to-point transmission.PWV=D/T（m/s）。Get data behind the intubate 20min, gather 10-20 cardiac cycle, draw mean P WV, process in order to follow-up data.Intraarterial pressure curve record center systolic arterial pressure (cSBP) and center auterial diastole with the descending aorta place are pressed (cDBP), and calculate center average pulse pressure (cPP, cPP=cSBP-cDBP) and center mean blood pressure (cMBP, cMBP=cDBP+cPP/3).
4, pathology detection: the about 2cm of blunt separation thoracic aorta, PBS cleans, and 4% neutral formalin is fixed, and paraffin embedding prepares 5 μ m section, HE dyeing.Observe the morphological change of aorta middle level vascular smooth muscle cell (VSMC), elastic fibers under the light microscopic, and measure aorta intima-media thickness (MT), vessel diameter (LD).
5, the aortic collagen fiber area is measured: section is through the trichroism improved method dyeing of Masson, and collagen fiber are blackish green under the light microscopic, and muscle fiber takes on a red color.Adopt Motic 6.0 Digital image analysis systems to carry out graphical analysis, measure vascular collagen fiber area percentage ratio, each specimen is measured 5 cross sections, gets its average.
6, statistical method: the result represents with mean ± standard deviation, adopts SPSS 11.5 statistical softwares to carry out statistical analysis.Relatively adopt one factor analysis of variance between group, the relatively employing q check between a plurality of means, P＜0.05 expression difference has statistical significance.
Two, experimental result
1, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide (SRT1720) is on the impact of spontaneous hypertensive rat arteria caudalis blood pressure
Experimental result shows, the front two groups of SHR rat tail artery blood pressures of administration are without significant difference, and all is higher than the WKY Normal group; N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment group rat tail artery blood pressure all significantly reduces than model group, and concrete experimental result is as shown in table 4.
Table 4 is respectively organized the dynamic change (mmHg) of rat tail artery blood pressure
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
2, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide (SRT1720) is on the impact of spontaneous hypertensive rat center arterial pressure: when finishing, experiment adopt tremie method to measure rat center arterial pressure, the result shows SHR matched group center systolic arterial pressure, the center auterial diastole is pressed and center tremulous pulse mean blood pressure all significantly raises than the WKY matched group, and through N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment after, the center systolic arterial pressure, the center auterial diastole is pressed and center tremulous pulse mean blood pressure all obviously descends, compare with model group and to have statistical significance, concrete experimental result is as shown in table 5.
Table 5 is respectively organized the variation (mmHg) of rat center arterial pressure
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
3, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is on the impact of (SRT1720) spontaneous hypertensive rat arterial stiffness: adopts tremie method to measure rat pulse wave velocity (PWV) when experiment finishes and reacts arterial stiffness.Found that compare with the WKY matched group, each is organized SHR P of Rats WV and all significantly speeds.Compare with the SHR matched group, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide can significantly reduce SHR P of Rats WV value, show N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide can improve aortic stiffness index, and concrete experimental result is as shown in table 6.
Table 6 is respectively organized the variation of rat pulse wave velocity, aorta intima-media thickness and vessel diameter
Compare with matched group,
*P＜0.05; Compare with model group,
◆P＜0.05.
4, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide (SRT1720) is on the impact of DOCA-salt rat aorta intima-media thickness: gets respectively and respectively organizes rat chest aorta slice row HE dyeing, the morphological change of observing aorta middle level vascular smooth muscle cell and elastic fibers.The result shows, compares with the WKY rat, and the SHR rat smooth muscle cells is obviously loose and thicken with elastic fibers, and the aorta intima-media thickness significantly thickens, and the blood vessel wall collagen contents significantly increases, and vessel diameter then significantly descends.And through N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide treatment after the vascular smooth muscle cell hypertrophy be significantly inhibited, aorta intima-media thickness and blood vessel wall collagen contents significantly descend, and vessel diameter obviously increases, show the hypertensive effect of good control, relapse rate is low.
Spontaneous hypertensive rat (SHR) be generally acknowledge in the world at present close to the animal model of human essential hypertension, this rat 3-4 week blood pressure after giving birth to begins to raise, 12-24 peaked during week.The SHR rat in 16 ages in week is selected in this research, has dynamically observed N-[2-[3-(1-piperazinyl methyl) imidazo [2, the 1-B] thiazole of various dose-6-yl] phenyl]-2-quinoxaline Methanamide is to the hypotensive effect of SHR rat.The result shows, SHR rat tail artery blood pressure, center systolic arterial pressure, center auterial diastole are pressed and center tremulous pulse mean pressure all significantly raises, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-arteria caudalis blood pressure, center systolic arterial pressure, center auterial diastole that 2-quinoxaline Methanamide can significantly reduce the SHR rat press and center tremulous pulse mean pressure.
Arterial elasticity goes down, the stiffness index increase is the independent hazard factor of the following cardiovascular disease event of hyperpietic, and improving arterial elasticity is one of target of present resisting hypertension control.Arterial elasticity descends during hypertension, even blood pressure is controlled after the control, its danger does not effectively reduce yet.Pulse wave velocity (PWV) has become the optimum prediction index of cardiovascular disease prognosis, is the important prognostic indicator of the various diseases such as cerebrovascular disease, diabetes and hypertension.This research is found, SHR P of Rats WV significantly increases than the WKY rat, prompting SHR rat artery spring function goes down, and through N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide control can significantly reduce SHR P of Rats WV, improve arterial elasticity, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide is prevented and treated the aorta posterior intima-media thickness and the blood vessel wall collagen contents significantly descends, and vessel diameter obviously increases, can change the ratio of arterial wall elasticin and collagen, increase arterial compliance.
Above experimental result shows, N-[2-[3-of the present invention (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide has the effect of good control constitutional and secondary hypertension and relevant disease thereof, cure rate is high, and chemical constituent is clear, untoward reaction is low, is expected to be developed to new antihypertensive effect.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (4)
- (1.N-[2-[3-1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control hypertension drug.
- 2. N-[2-[3-according to claim 1 (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control hypertension drug, it is characterized in that, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control essential hypertension medicine.
- 3. N-[2-[3-according to claim 2 (1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control hypertension drug, it is characterized in that, N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide prevents and treats application in the secondary hypertension medicine in preparation.
- 4. according to claim 1 to 3 each described N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-application of 2-quinoxaline Methanamide in preparation control hypertension drug, it is characterized in that, with N-[2-[3-(1-piperazinyl methyl) imidazo [2,1-B] thiazole-6-yl] phenyl]-2-quinoxaline Methanamide and pharmaceutically acceptable carrier make the medicine of capsule, granule, spray, injection, microcapsule, tablet, ointment or skin-permeable and control-released plaster dosage form.
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| CN2012105299400A Pending CN103027912A (en) | 2012-12-11 | 2012-12-11 | Application of N-[2-[3-(1-piperazine methyl) imidazo [2, 1-B] thiazole-6-yl] phenyl]-2-quinoxaline formamide in preparation of medicament for prevention and treatment of high blood pressure |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019346A1 (en) * | 2005-08-04 | 2007-02-15 | Sirtris Pharmaceuticals, Inc. | Benzothiazoles and thiazolopyridines as sirtuin modulators |
| CN102283841A (en) * | 2011-07-05 | 2011-12-21 | 张爱华 | Application of N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide in preparation of medicine for treating kidney disease |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019346A1 (en) * | 2005-08-04 | 2007-02-15 | Sirtris Pharmaceuticals, Inc. | Benzothiazoles and thiazolopyridines as sirtuin modulators |
| CN102283841A (en) * | 2011-07-05 | 2011-12-21 | 张爱华 | Application of N-(2-(3-(piperazin-1-ylmethyl)imidazo[2,1-b]thiazol-6-yl)phenyl)quinoxaline-2-carboxamide in preparation of medicine for treating kidney disease |
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Application publication date: 20130410 |