CN104887682A - Application of terazosin type medicines - Google Patents

Application of terazosin type medicines Download PDF

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CN104887682A
CN104887682A CN201510340653.9A CN201510340653A CN104887682A CN 104887682 A CN104887682 A CN 104887682A CN 201510340653 A CN201510340653 A CN 201510340653A CN 104887682 A CN104887682 A CN 104887682A
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terazosin
pharmaceutical applications
aging
age
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刘磊
赵春月
李宇红
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a new medicinal application of terazosin type medicines, in particular to an application of the terazosin type medicines in the aspects of anti-aging and body metabolism regulation functions. The terazosin type medicines are compounds shown in the formula I or pharmaceutical salt of the compounds or solvates of the compounds, wherein substituent groups are shown in the specification.

Description

The purposes of azoles piperazine class medicine
Technical field
The invention belongs to medical art, relate to the purposes of a class azoles piperazine class medicine, particularly relate to them at defying age and regulate purposes in organism metabolism.
Background technology
Terazosin (Terazosin) is used for clinical with its hydrochlorate usually, and the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg etc.Terazosin hydrochloride can be used for treat benign prostate hyperplasia, also can be used for treat hypertension, can be used alone or with other antihypertensive drug as diuretic or Alpha 1 adrenergic blocking agent share.For existing clinical indication, terazosin is 1 ~ 10mg for the daily dose usual range of being grown up.Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, benign prostate hyperplasia shape alleviates that to improve the smooth muscle loosening caused by blocking with the alpha 1 adrenergic receptor in neck of bladder and prostate with urine flow velocity relevant.Because there is relatively few alpha 1 adrenergic receptor in body of bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.In addition, terazosin is by reducing Total peripheral vascular resistance thus making blood pressure reduce.Vasodilation, the blood pressure reducing effect of terazosin seem mainly caused by alpha 1 adrenergic receptor blocks.
Terazosin chemistry (4-(4-amido-6,7-dimethoxy quinazoline-2-base) piperazine-1-base) (oxolane-2-base) ketone by name, molecular formula is C 19h 25n 5o 4, chemical structural formula is with following formula I:
Terazosin (Terazosin can replace with TZ in this article) is used for clinical with its hydrochlorate usually, and the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg.Terazosin hydrochloride can be used for treating benign prostatic hyperplasia, also can be used for treating hypertension, can be used alone or with other antihypertensive drug as diuretic or Alpha 1 adrenergic blocking agent conbined usage (Wilde MI, Fitton A, Sorkin EM (1993) Terazosin.A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in benign prostatic hyperplasia.Drugs & aging 3:258-277; Achari R, Hosmane B, Bonacci E, O'Dea R (2000) The relationship between terazosin dose and blood pressure response in hypertensive patients.Journal of clinical pharmacology 40:1166-1172; Zusman RM (2000) The role of alpha 1-blockers in combination therapy for hypertension.International journal of clinical practice 54:36-40).Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, benign prostate hyperplasia shape alleviates that to improve the smooth muscle loosening caused by blocking with the alpha 1 adrenergic receptor in neck of bladder and prostate with urine flow velocity relevant.Because there is relatively few alpha 1 adrenergic receptor in body of bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect contraction (the Wilt TJ of bladder, Howe RW, Rutks IR, MacDonald R (2002) Terazosin for benign prostatic hyperplasia.The Cochrane database of systematic reviews CD003851).In addition, terazosin is by reducing Total peripheral vascular resistance thus making blood pressure reduce.The vasodilation of terazosin, blood pressure reducing effect are mainly caused by alpha 1 adrenergic receptor blocks.
Vascular ageing has played extremely important effect (Oakley R, Tharakan B (2014) Vascular hyperpermeability and aging.Aging and disease 5:114-125) in whole Individual senescence.With advancing age, body is at cell, tissue, these varying levels of organ all have accumulated increasing damage, different piece (the endotheliocyte of blood vessel, smooth muscle cell etc.) experience damage too, blood flow rate is caused to slow down, blood fat, cholesterolemia concentration increases, atherosclerosis is shown as time serious, these pathological changes add the probability that multiple cardiovascular disease occurs, (Orlandi A such as such as myocardial infarction and apoplexy etc., Bochaton-Piallat ML, Gabbiani G, Spagnoli LG (2006) Aging, smooth muscle cells and vascular pathobiology:implications for atherosclerosis.Atherosclerosis 188:221-230, Liu Y, Chen KJ (2012) Atherosclerosis, vascular aging and therapeutic strategies.Chinese journal of integrative medicine 18:83-87, Oakley R, Tharakan B (2014) Vascular hyperpermeability and aging.Aging and disease 5:114-125).And at present clinically, do not have a kind of medicine by protection blood vessel, blood vessel normal function can be maintained and reach to antidotal object.
Therefore, this area still expects can have the anti-senescence function even medicine of other beneficial functions for providing clinically.
Summary of the invention
The object of the invention is to for providing a kind of have the anti-senescence function even medicine of other beneficial functions clinically.The present invention finds, terazosin and analog thereof can reduce cellular level and mice, nematicide in the aging of body level, correct the many undesirable elements (body weight, blood glucose, insulin level etc.) supervened in aging course, further, other azoles piperazine compounds with terazosin with close structural also have similar function.This discovery, for treatment/reduction cardiovascular and cerebrovascular disease provides important scheme.The present invention is based on this find and be accomplished.
For this reason, the invention provides the pharmaceutical applications with compounds of Formula I or its pharmaceutical salts or its solvate, for the preparation of the medicine delaying mammals age, or for the preparation of improving the medicine of organism metabolism age of sucking:
Wherein R1 is hydrogen or methoxyl group, and R2 is selected from following group:
Below respectively represent in the group of R2, the key in atom N is connected to the R2 place of formula I.
According to pharmaceutical applications of the present invention, wherein said formula I is selected from: terazosin, doxazosin, prazosin, bunazosin, alfuzosin, trimazosin and pharmaceutical salts thereof or its solvate.
According to pharmaceutical applications of the present invention, wherein said pharmaceutical salts is such as hydrochlorate, phosphate, benzene sulfonate, mesylate, sulfate, the nitrate of described compound.
According to pharmaceutical applications of the present invention, wherein said solvate is the hydrate of described compound or pharmaceutically acceptable salt thereof, such as monohydrate, dihydrate etc.
In concrete test herein, when using terazosin, as do not illustrated especially in addition, its hydrochloride dihydrate is used to carry out testing.
According to pharmaceutical applications of the present invention, wherein said aging is the aging relevant with vascular endothelial cell.
According to pharmaceutical applications of the present invention, wherein said slow down aging is the health status maintaining the compact siro spinning technology of body in aging course between endotheliocyte thus maintain blood vessel, thus delays mammals age.
According to pharmaceutical applications of the present invention, wherein said slow down aging is the minimizing of mammal blood vessel Mottling formation.Such as, described slow down aging is the Mottling formation reducing blood vessel caused by atherosclerosis.
According to pharmaceutical applications of the present invention, wherein said slow down aging is the aging delaying animal economy level.
According to pharmaceutical applications of the present invention, the wherein said age of sucking organism metabolism of improving refers to and improves the metabolism relevant with aspects such as its body weight, blood glucose, insulin levels of body age of sucking.
According to pharmaceutical applications of the present invention, wherein said improve age of sucking organism metabolism refer to reduce hypercholesterolemia body weight, blood glucose, the insulin level of atherogenic body.
According to pharmaceutical applications of the present invention, wherein said improve age of sucking organism metabolism refer to improve hypercholesterolemia the food ration of atherogenic body, particularly increase hypercholesterolemia the food ration of atherogenic body.
In the present invention, typically, terazosin (Terazosin), its chemistry (4-(4-amino-6 by name, 7-dimethoxyquinazoline-2-base) piperazine-1-base) (oxolane-2-base) ketone, molecular formula is C19H25N5O4, and structural formula is:
Typically, doxazosin (Doxazosin), particularly Carclura, its chemical name is: [1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-(Isosorbide-5-Nitrae-benzodioxan-2-supports carbonyl)] piperazine methanesulfonate, molecular formula: C23H25N5O5CH3SO3H, molecular weight: 547.59, chemical structural formula is:
Doxazosin is usually used in clinically: 1. Original light-middling hypertension.The patient controlling blood pressure is difficult to for independent medication, can share with diuretic, beta-blocker, calcium antagonist or angiotensin-convertion enzyme inhibitor (ACEI); 2. the symptomatic treatment of benign prostatic hyperplasia.
Typically, prazosin (Prazosin), particularly minipress, its chemical name is: 1-(amino-6, the 7-dimethoxy-2-quinazolyls of 4-)-4-(2-furoyl) piperazine hydrochloride, and chemical structural formula is:
Prazosin is usually used in gently clinically, moderate hypertension.It can reduce the forward and backward load of heart, is also used for the treatment of cardiac insufficiency.
Typically, bunazosin (Bunazosin), particularly E-643, its chemistry is by name: 1-[4-(4-amino-6, 7-dimethoxyquinazoline-2-base)-1, 4-Diazesuberane-1-base] fourth-1-keto hydrochloride, English name: 1-Butanone, 1-[4-(4-amino-6, 7-dimethoxy-2-quinazolinyl) hexahydro-1H-1, 4-diazepin-1-yl]-, hydrochloride (1:1), CAS No.:52712-76-2, molecular formula: C19H27N5O3.HCl, molecular weight: 409.91, chemical structural formula is:
Bunazosin is usually used in the hypertension etc. that essential hypertension, renal hypertension and pheochromocytoma cause clinically.
Typically, alfuzosin (Alfuzosin), such as alfuzosin hydrochloride, its chemical name: N-[3-[(4-amino-6,7-dimethoxy-2-quinazolyl)-methylamino] propyl group] tetrahydrochysene-2-furoyl amine hydrochlorate, molecular formula: C19H27N5O4HCI, molecular weight: 425.91, chemical structural formula is:
Alfuzosin is usually used in alleviating benign prostate hyperplasia shape clinically.
Typically, trimazosin (Trimazosin), its chemical structural formula is:
Trimazosin is usually used in reducing blood pressure clinically, can be used for hypertension.
Accompanying drawing explanation
Fig. 1 describes the cell ageing impact that terazosin causes etoposide, the cell ageing that display terazosin causes Asia dead concentration (2uM) etoposide, the impact of old and feeble label p16, p21 transcriptional level is (in figure, vertical coordinate fold change represents that multiple changes, abscissa ctrl represents contrast, Etoposide represents etoposide, and TZ0.1uM represents the terazosin of 0.1uM, hereafter has during similar terms and all has same implication).
Fig. 2 and Fig. 3 describes the cell ageing impact that terazosin causes hydrogen peroxide.Fig. 2 shows the cell ageing using sub-dead concentration (50uM) hydrogen peroxide to cause, and simultaneously with terazosin process cell, detects the impact of old and feeble label p16, p21 transcriptional level.
Fig. 2 and Fig. 3: describe the cell ageing impact that terazosin causes hydrogen peroxide, Fig. 3 shows the cell ageing caused with sub-dead concentration (50uM) hydrogen peroxide, simultaneously with terazosin process cell, detect SA-β-Gal dye and add up (in figure, vertical coordinate positive/% represents increases percent).
Fig. 4: describe terazosin stimulates the VE cadherin phosphorylation level caused impact on aging, result shows, the phosphorylation level of VE cadherin can be caused to increase thus cause aging with etoposide (2uM) and hydrogen peroxide (50uM), and when adding terazosin, terazosin can suppress the phosphorylation level of VE cadherin to increase, thus slow down aging.
Fig. 5: describe the impact of terazosin on atherosclerosis Mouse Blood inside pipe wall speckle; Mouse systemic was fixed by perfusion paraformaldehyde mode after 12 weeks by high-cholesterol diet of feeding, and took out blood vessel and did oil red O stain and statistical result; Vertical coordinate " lesion area " expression " damaged area " in figure.
Fig. 6: describe the impact of terazosin on the C. Elegans Automatic Screening life-span; Terazosin is added, statistics nematode survival in normal C. Elegans Automatic Screening food (escherichia coli) of raising; Vertical coordinate " survival " expression " survival rate " in figure, abscissa " days " express time natural law.
Fig. 7: describe the impact of terazosin on atherosclerosis Mouse Weight; Give ApoE KO mice high cholesterol diet to feed, and give mouse peritoneal injection terazosin (0.08mg/kg) every day, add up feeding/drug treating Mouse Weight change in 12 weeks; Vertical coordinate " body weight increase " expression " body weight increase " in figure, abscissa " Normal diet " expression " normal diet ", " High cholesterol " expression " hypercholesterolemia ".
Fig. 8: describe the impact of terazosin on atherosclerosis mouse blood sugar; Respectively mice be satiated with food and fasting measure mouse blood sugar after 16 hours; The level of vertical coordinate " Glucose " expression " glucose " in figure.
Fig. 9: describe the impact of terazosin on atherosclerosis mouse blood insulin level; Respectively mice hypercholesterolemia feed and fasting get after 16 hours hematometry mouse islets element; In figure, vertical coordinate " Insulin " is " insulin level "; Abscissa " ApoE KO " expression " hypercholesterolemia is fed ", ctrl represents the insulin level testing front 2 treated animals; " Fasting insulin " expression " fasting group insulin level " in figure, " Normal insulin " expression " normal group insulin level ".
Figure 10: describe the impact of terazosin on atherosclerosis mice food ration; Take weekly mouse chow weight and add up.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.Any conceive according to the present invention done be only pro forma but not substantial equivalent transformation and all should be considered as technical scheme category of the present invention.
embodiment 1: terazosin suppresses the research of (blood vessel endothelium) cell ageing
test 1a:
In this experiment, use can not cause the low concentration etoposide of cell death (2 μMs), and by causing DNA damage, (specific experiment method is see Meresse P, Dechaux E, Monneret C, Bertounesque E (2004) Etoposide:discovery and medicinal chemistry.Current medicinal chemistry 11:2443-2466) and induce HUVEC (human umbilical endothelial cell) old and feeble, RNA is extracted after 24 hours, after being inverted to cDNA, the old and feeble label p16 of transcriptional level is detected with Real-time PCR, (specific experiment method is see Herbig U for p21, Sedivy JM (2006) Regulation of growth arrest in senescence:telomere damage is not the end of the story.Mechanisms of ageing and development 127:16-24) change.Result shows, etoposide process can Induction of Cellular senescence, old and feeble label p16, p21 transcriptional level is caused to increase, terazosin can reduce the increase (compared with etoposide group p<0.01) of old and feeble label p16, p21 that etoposide causes significantly, and concrete outcome is see Fig. 1.
Fig. 1 describes the cell ageing impact that terazosin causes etoposide, the cell ageing that display terazosin causes Asia dead concentration (2uM) etoposide, the impact of old and feeble label p16, p21 transcriptional level is (in figure, vertical coordinate fold change represents that multiple changes, abscissa ctrl represents contrast, Etoposide represents etoposide, and TZ0.1uM represents the terazosin of 0.1uM, hereafter has during similar terms and all has same implication).
test 1b:
In the test that the present invention is similar, same, with hydrogen peroxide (the i.e. H of Sublethal concentration 2o 250 μMs) also can Induction of Cellular senescence (specific experiment method is see Vigneron A, Vousden KH (2010) p53, ROS and senescence in the control of aging.Aging2:471-474), cause the increase of old and feeble label p16, p21; When additional terazosin, terazosin can reduce their increase (compared with hydrogen peroxide group p<0.05); Concrete outcome is see Fig. 2.
Fig. 2 shows the cell ageing using sub-dead concentration (50uM) hydrogen peroxide to cause, and simultaneously with terazosin process cell, detects the impact of old and feeble label p16, p21 transcriptional level.
test 1c:
Further, except detecting p16, p21 transcriptional level, method that the present invention also uses β-Gal to dye to detect cell ageing, and (specific experiment method is see Sikora E, Arendt T, Bennett M, Narita M (2011) Impact of cellular senescence signature on ageing research.Ageing research reviews 10:146-152).Result shows, and hydrogen peroxide (50 μMs) also can Induction of Cellular senescence, and causing β-Gal to dye increases; When additional terazosin 0.1uM, terazosin can reduce the old and feeble β-Gal staining signals caused that stimulates significantly and increase (compared with hydrogen peroxide group p<0.01), statistical result See Figure 3.
Fig. 3 shows the cell ageing caused with sub-dead concentration (50uM) hydrogen peroxide, simultaneously with terazosin process cell, detects SA-β-Gal and dyes and add up (in figure, vertical coordinate positive/% represents increases percent).
test 1d:
Under normal physiological conditions, vascular endothelial cell surface of cell membrane VE cadherin albumen forms homodimer, and the VE cadherin between flanking cell is by the compact siro spinning technology kept between smooth muscle cell that directly interacts, thus the stability of maintenance blood vessel (see: Dejana E, Orsenigo F (2013) Endothelial adherens junctions at a glance.Journal of cell science 126:2545-2549).In aging course, first VE cadherin is phosphorylated at intracellular region, then in indentation cell, then cell-cell interaction weakens gradually to disappearance, vascular endothelial cell gap becomes large, make vascular permeability increase (see: Quadri SK (2012) Cross talk between focal adhesion kinase and cadherins:role in regulating endothelial barrier function.Microvascular research83:3-11).
In the present embodiment, the present inventor detects the VE cadherin level of phosphorylation by western blot method, as Fig. 4 display, the etoposide (2 μMs) of Sublethal concentration and hydrogen peroxide (50 μMs) can cause the phosphorylation level of VE cadherin to increase; When additional terazosin 0.1uM, terazosin can reduce it and increase.This result means that terazosin can maintain the compact siro spinning technology in aging course between endotheliocyte thus maintain the health status of blood vessel.
Fig. 4 describes terazosin stimulates the VE cadherin phosphorylation level caused impact on aging, result shows, the phosphorylation level of VE cadherin can be caused to increase thus cause aging with etoposide (2uM) and hydrogen peroxide (50uM), and when adding terazosin, terazosin can suppress the phosphorylation level of VE cadherin to increase, thus slow down aging.
embodiment 2: terazosin reduces the test of the Mottling formation of atherosclerosis mouse model medium vessels inwall
During atherosclerosis develops, blood vessel can produce to be piled up " speckle " that produce by old and feeble/dead endotheliocyte, vascular smooth muscle cell, macrophage, lipid, calcium ion etc., the formation of speckle gently then causes blood vessel hard, and serious directly may cause blood vessel blockage.Hypercholesterolemia fed ApoE KO mice after 12 weeks, after total body perfusion is fixing, aortic arch is dissected together with breast section, with oil red O stain, (concrete test method is see Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N (2001) Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice:pleiotropic effects on CD36expression and HDL.Arteriosclerosis, thrombosis, and vascular biology 21:372-377).Result shows, and hypercholesterolemia is fed and can be caused Mottling formation, presents the fat stains positive, and injection terazosin group speckle reduces (compared with ApoE KO group p<0.01) significantly, and Fig. 5 is shown in statistical result.
Fig. 5: describe the impact of terazosin on atherosclerosis Mouse Blood inside pipe wall speckle.Mouse systemic was fixed by perfusion paraformaldehyde mode after 12 weeks by high-cholesterol diet of feeding, and took out blood vessel and did oil red O stain and statistical result.Vertical coordinate " lesion area " expression " damaged area " in figure.
embodiment 3: terazosin can extend the life-span of C. Elegans Automatic Screening
Vascular ageing has played important effect in normal physiological aging.The present invention has demonstrated the aging that terazosin can suppress vascular endothelial cell, does is further query: terazosin can affect the aging in integral level? for this reason, the present inventor adds terazosin in the nematode feeds escherichia coli OP50 normally fed, then the survival of every two days record nematicides.Result shows, and terazosin can improve the average life of nematicide, and concrete outcome is shown in Fig. 6.In body, prove that the result of terazosin anti-aging effects is coincide with this paper, this result demonstrates the antidotal effect of terazosin from external.
Fig. 6: describe the impact of terazosin on the C. Elegans Automatic Screening life-span.Terazosin is added, statistics nematode survival in normal C. Elegans Automatic Screening food (escherichia coli) of raising.Vertical coordinate " survival " expression " survival rate " in figure, abscissa " days " express time natural law.
embodiment 4: terazosin reduces body weight, blood glucose, the insulin level of atherosclerosis animal model caused by hypercholesterolemia
The cholesterol maintaining normal concentration in blood for maintenance heart and vascular function of crucial importance, and the cardiovascular system diseases (Rosendorff C (2002) Effects of LDL cholesterol on vascular function.Journal of human hypertension 16Suppl 1:S26-28) of such as heart disease and apoplexy can be prevented to a certain extent.APOE (Apolipoprotein E) is one of important component part of very low density lipoprotein (VLDL) (VLDLs), unnecessary cholesterol in blood can be transferred to liver and make its (van Dijk KW that is degraded by it, Hofker MH, Havekes LM (1999) Dissection of the complex role of apolipoprotein E in lipoprotein metabolism and atherosclerosis using mouse models.Current atherosclerosis reports 1:101-107).And easily there is high-cholesterol disease in ApoE knock out mice, then the immunocyte such as macrophage is more easily " trapped ", finally formed by lipid at blood vessel, calcium, cell debris, the damage speckle that immunocyte etc. are formed, affect blood vessel normal function, light then cause blood flow slack-off, supply is obstructed, heavy then directly cause blood vessel blockage (van Dijk KW, Hofker MH, Havekes LM (1999) Dissection of the complex role of apolipoprotein E in lipoprotein metabolism and atherosclerosis using mouse models.Current atherosclerosis reports1:101-107).
The present invention's high cholesterol diet is fed ApoE KO mouse 12 weeks, and every day gives 0.08mg/kg terazosin lumbar injection according to body weight, records the body weight change of mice every day.Result shows, hypercholesterolemia is fed and Mouse Weight can be caused significantly to increase, and be markedly inferior to hypercholesterolemia through the Mouse Weight of terazosin process and feed treated animal (feeding compared with treated animal with hypercholesterolemia, p<0.05), concrete outcome is shown in Fig. 7.
Fig. 7: describe the impact of terazosin on atherosclerosis Mouse Weight.Give ApoE KO mice high cholesterol diet to feed, and give mouse peritoneal injection terazosin (0.08mg/kg) every day, add up feeding/drug treating Mouse Weight change in 12 weeks.Vertical coordinate " body weight increase " expression " body weight increase " in figure, abscissa " Normal diet " expression " normal diet ", " High cholesterol " expression " hypercholesterolemia ".
In addition, during above-mentioned high cholesterol diet of feeding, choose three weeks detection mices and be satiated with food and the fasting change of blood sugar of 16 hours.The results are shown in Figure 8.Result show, hypercholesterolemia feed and can cause mice fed state under blood glucose (PBG) increase, terazosin significantly can reduce blood glucose of being satiated with food and increase (p=0.012); But terazosin can not cause the change of blood glucose (FBG) under mice fasted conditions.
Fig. 8: describe the impact of terazosin on atherosclerosis mouse blood sugar.Respectively mice be satiated with food and fasting measure mouse blood sugar after 16 hours.The level of vertical coordinate " Glucose " expression " glucose " in figure.
Further, during above-mentioned high cholesterol diet of feeding, choose three weeks detection mices and be satiated with food and the fasting insulin level of 16 hours.The results are shown in Figure 9.Result shows, hypercholesterolemia feed and can cause normal condition under insulin level increase, and when giving terazosin, it significantly can reduce situation that above-mentioned insulin increases and (feed compared with treated animal with not using the hypercholesterolemia of terazosin, p<0.05), but terazosin can not cause the change of insulin level under fasted conditions.
Fig. 9: describe the impact of terazosin on atherosclerosis mouse blood insulin level.Respectively mice hypercholesterolemia feed and fasting get after 16 hours hematometry mouse islets element.In figure, vertical coordinate " Insulin " is " insulin level "; Abscissa " ApoE KO " expression " hypercholesterolemia is fed ", ctrl represents the insulin level testing front 2 treated animals; " Fasting insulin " expression " fasting group insulin level " in figure, " Normal insulin " expression " normal group insulin level ".
embodiment 5: the test that terazosin causes mice food ration to increase
The present invention's high cholesterol diet is fed ApoE KO mouse 12 weeks, every day gives 0.08mg/kg terazosin lumbar injection according to body weight, records mice every day food ration.Result shows, and to feed mice for hypercholesterolemia, the animal ingestion amount simultaneously giving terazosin is 1.1 times that do not give terazosin group, and after showing injection terazosin, mice food ration increases, and Figure 10 is shown in statistical result.
Figure 10: describe the impact of terazosin on atherosclerosis mice food ration.Take weekly mouse chow weight and add up.
With reference to the method for above embodiment 1-5, terazosin is wherein used instead the doxazosin (Doxazosin of equimolar amounts, test with its methanesulfonic acid), prazosin (Prazosin, test with its hydrochlorate), bunazosin (Bunazosin, test with its hydrochlorate), Alfuzosin (Alfuzosin, test with its hydrochlorate), or trimazosin (Trimazosin, test with its hydrochlorate) test, result shows them and all presents the effect similar to terazosin in the various embodiments described above, namely they all have anti-vascular endothelial cell aging, reduce body weight in atherosclerosis mouse model to increase, blood glucose and insulin increase, dietary amount is caused to increase, reduce atherosclerosis mouse model medium vessels inwall Mottling formation, extend the effects such as nematicide life-span.
industrial applicability
The invention provides the new pharmaceutical applications of a kind of terazosin or its analog, this new pharmaceutical applications can provide new selection scheme for the treatment of clinical relevant disease.

Claims (10)

1. with the pharmaceutical applications of compounds of Formula I or its pharmaceutical salts or its solvate, for the preparation of the medicine delaying mammals age, or for the preparation of improving the medicine of organism metabolism age of sucking:
Wherein R1 is hydrogen or methoxyl group, and R2 is selected from following group:
2. pharmaceutical applications according to claim 1, wherein said formula I is selected from: terazosin, doxazosin, prazosin, bunazosin, alfuzosin, trimazosin and pharmaceutical salts thereof or its solvate.
3. pharmaceutical applications according to claim 1, wherein said pharmaceutical salts is such as hydrochlorate, phosphate, benzene sulfonate, mesylate, sulfate, the nitrate of described compound.
4. pharmaceutical applications according to claim 1, wherein said solvate is the hydrate of described compound or pharmaceutically acceptable salt thereof, such as monohydrate, dihydrate etc.
5. pharmaceutical applications according to claim 1, wherein said aging is the aging relevant with vascular endothelial cell.
6. pharmaceutical applications according to claim 1, wherein said slow down aging is the health status maintaining the compact siro spinning technology of body in aging course between endotheliocyte thus maintain blood vessel, thus delays mammals age.
7. pharmaceutical applications according to claim 1, wherein said slow down aging is the minimizing of mammal blood vessel Mottling formation.Such as, described slow down aging is the Mottling formation reducing blood vessel caused by atherosclerosis.
8. pharmaceutical applications according to claim 1, wherein said slow down aging is the aging delaying animal economy level.
9. pharmaceutical applications according to claim 1, according to pharmaceutical applications of the present invention, the wherein said age of sucking organism metabolism of improving refers to and improves the metabolism relevant with aspects such as its body weight, blood glucose, insulin levels of body age of sucking.
10. pharmaceutical applications according to claim 1, wherein:
Described improve age of sucking organism metabolism refer to reduce hypercholesterolemia body weight, blood glucose, the insulin level of atherogenic body; And/or
Described improve age of sucking organism metabolism refer to improve hypercholesterolemia the food ration of atherogenic body, particularly increase hypercholesterolemia the food ration of atherogenic body.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113730413A (en) * 2021-10-14 2021-12-03 张存泰 Application of terazosin in preparation of medicines for reducing blood vessel hardness
CN116077501A (en) * 2023-01-17 2023-05-09 上海青颜博识生物技术有限公司 Application of quinazoline derivative in preparation of anti-aging products

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532110A (en) * 2010-12-22 2012-07-04 刘磊 Quinazoline derivative and application of serving as cell apoptosis inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532110A (en) * 2010-12-22 2012-07-04 刘磊 Quinazoline derivative and application of serving as cell apoptosis inhibitor
CN102526057A (en) * 2010-12-22 2012-07-04 刘磊 Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
RYAN OAKLEY等: "Vascular Hyperpermeability and Aging", 《AGING AND DISEASE》 *
医学部: "北京大学衰老研究中心成立十周年暨学术研讨会成功举办", 《网址：HTTP://PKUNEWS.PKU.EDU.CN/XYWH/2015-06/12/CONTENT_289308.HTM》 *
曹雪滨 等: "消旋多沙唑嗪及其两种光学异构体长期给药对老龄小鼠血脂水平的影响", 《第四军医大学学报》 *
朱九群 等: "甲磺酸多沙唑嗪控释片的临床应用研究进展", 《中国新药杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113730413A (en) * 2021-10-14 2021-12-03 张存泰 Application of terazosin in preparation of medicines for reducing blood vessel hardness
CN116077501A (en) * 2023-01-17 2023-05-09 上海青颜博识生物技术有限公司 Application of quinazoline derivative in preparation of anti-aging products

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