WO2016202099A1 - Utilisation de médicaments de térazosine - Google Patents

Utilisation de médicaments de térazosine Download PDF

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Publication number
WO2016202099A1
WO2016202099A1 PCT/CN2016/080466 CN2016080466W WO2016202099A1 WO 2016202099 A1 WO2016202099 A1 WO 2016202099A1 CN 2016080466 W CN2016080466 W CN 2016080466W WO 2016202099 A1 WO2016202099 A1 WO 2016202099A1
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aging
terazosin
pharmaceutical use
use according
metabolism
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PCT/CN2016/080466
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English (en)
Chinese (zh)
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刘磊
赵春月
李宇红
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刘磊
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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

Definitions

  • the invention belongs to the technical field of medicine and relates to the use of a class of azoles, in particular to their use in anti-aging and regulation of body metabolism.
  • Terazosin is usually used in clinical practice with its hydrochloride salt, and the specifications of the marketed tablets or capsules are 1 mg, 2 mg, and 5 mg.
  • Terazosin hydrochloride can be used to treat benign prostatic hyperplasia and can also be used to treat hypertension. It can be used alone or in combination with other antihypertensive drugs such as diuretics or alpha 1-adrenergic blockers.
  • the daily dose of terazosin for adults is usually in the range of 1 to 10 mg.
  • Terazosin is used to treat benign prostatic hyperplasia (BPH), and the reduction in benign prostatic hyperplasia and improvement in urinary flow rate after administration are associated with smooth muscle relaxation caused by alpha1-adrenergic receptor blockade in the bladder neck and prostate. Because there are relatively few alpha 1-adrenergic receptors in the bladder, terazosin can reduce blockage of the bladder outlet without affecting bladder contraction. In addition, terazosin lowers blood pressure by reducing total peripheral vascular resistance. The vasodilation and blood pressure lowering effects of terazosin appear to be mainly caused by blockade of ⁇ 1-adrenergic receptors.
  • terazosin (4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone
  • molecular formula is C 19 H 25 N 5 O 4
  • chemical structural formula is the following formula I:
  • Terazosin (which can be replaced by TZ herein) is usually used clinically as its hydrochloride salt, and the specifications of the marketed tablets or capsules are 1 mg, 2 mg and 5 mg.
  • Terazosin hydrochloride can be used to treat benign prostatic hyperplasia and can also be used to treat hypertension. It can be used alone or in combination with other antihypertensive drugs such as diuretics or alpha 1-adrenergic blockers.
  • Terazosin is used to treat benign prostatic hyperplasia (BPH), and the reduction in benign prostatic hyperplasia and improvement in urinary flow rate after administration are associated with smooth muscle relaxation caused by alpha1-adrenergic receptor blockade in the bladder neck and prostate.
  • terazosin can reduce blockage of the bladder outlet without affecting bladder contraction.
  • terazosin lowers blood pressure by reducing total peripheral vascular resistance.
  • the vasodilation and blood pressure lowering effects of terazosin are mainly caused by the blockade of ⁇ 1-adrenergic receptors.
  • Vascular aging plays an extremely important role in the aging of individuals. With the increase of age, the body has accumulated more and more damage at different levels of cells, tissues and organs. Different parts of the blood vessels (endothelial cells, smooth muscle cells, etc.) also experience damage. It causes slowing of blood flow, increase of blood lipids and blood cholesterol, and severe atherosclerosis. These lesions increase the possibility of various cardiovascular diseases, such as myocardial infarction and stroke. At present, no clinical drug can achieve the purpose of resisting aging by protecting blood vessels and maintaining the normal function of blood vessels.
  • terazosin and its analogues can reduce cell level and aging of mice and nematodes at the body level, and correct many adverse factors (body weight, blood sugar, insulin levels, etc.) accompanying aging, and Other azozoazines with similar structures of terazosin have similar functions. This finding provides an important solution for the treatment/reduction of cardiovascular and cerebrovascular diseases. The present invention has been completed based on this finding.
  • the present invention provides a pharmaceutical use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a medicament for delaying aging in a mammal, or for the preparation of a medicament for improving metabolism during lactation:
  • R1 is hydrogen or methoxy
  • R2 is a group selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of: terazosin, doxazosin, prazosin, bunazosin, alfuzosin, tramazosin and pharmaceutically acceptable salts thereof Its solvate.
  • compositions wherein the pharmaceutically acceptable salt is, for example, the hydrochloride, phosphate, benzenesulfonate, methanesulfonate, sulfate, nitrate of the compound.
  • a pharmaceutical use according to the present invention wherein the solvate is a hydrate of the compound or a pharmaceutically acceptable salt thereof, such as a monohydrate, Dihydrate and the like.
  • aging is aging associated with vascular endothelial cells.
  • the delaying of aging is to maintain a tight connection between endothelial cells of the body during aging to maintain the health of the blood vessel, thereby delaying aging of the mammal.
  • the delayed aging is a reduction in plaque formation in the blood vessel wall of a mammal.
  • the delaying of aging is to reduce plaque formation in the inner wall of blood vessels caused by atherosclerosis.
  • the delaying of aging is to delay the aging of the body as a whole.
  • the improving metabolism during lactation refers to improving the metabolism of the body during lactation in relation to its body weight, blood sugar, insulin level and the like.
  • the improvement of body metabolism during lactation refers to a reduction in body weight, blood sugar, and insulin levels of a body having high cholesterol-induced atherosclerosis.
  • the improvement of body metabolism during lactation refers to an improvement in the food intake of a body having high cholesterol-induced atherosclerosis, particularly an increase in the food intake of a body having high cholesterol-induced atherosclerosis.
  • doxazosin especially doxazosin mesylate, has the chemical name: [1-(4-amino-6,7-dimethoxy-2-quinazolinyl) 4-(1,4-benzodioxan-2-butanylcarbonyl)]piperazine methanesulfonate, molecular formula: C23H25N5O5 ⁇ CH3SO3H, molecular weight: 547.59, chemical structural formula:
  • Doxazosin is commonly used in clinical practice: 1. Primary mild to moderate hypertension. For patients who have difficulty controlling blood pressure by medication alone, Diuretics, beta blockers, calcium antagonists or angiotensin converting enzyme inhibitors (ACEI); 2. Symptomatic treatment of benign prostatic hyperplasia.
  • Prazosin especially prazosin hydrochloride
  • Prazosin hydrochloride has the chemical name: 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2 - furoyl) piperazine hydrochloride, the chemical structural formula is:
  • Prazosin is commonly used in clinical practice for mild to moderate hypertension. It can reduce the front and back load of the heart and is also used to treat cardiac insufficiency.
  • Bunazosin especially bunazosin hydrochloride
  • Bunazosin hydrochloride has the chemical name: 1-[4-(4-amino-6,7-dimethoxyquinazolin-2-yl) -1,4-diazepan-1-yl]butan-1-one 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:
  • Bunazosin is commonly used clinically for essential hypertension, renal hypertension, and hypertension caused by pheochromocytoma.
  • alfuzosin such as alfuzosin hydrochloride
  • alfuzosin hydrochloride has the chemical name: N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)- Methylamino]propyl]tetrahydro-2-furancarboxamide hydrochloride, molecular formula: C19H27N5O4 ⁇ HCI, molecular weight: 425.91, chemical structural formula:
  • Alfuzosin is often used clinically to relieve symptoms of benign prostatic hyperplasia.
  • Trimazosin has a chemical structural formula of:
  • Tramadrazine is commonly used clinically to lower blood pressure and can be used for hypertension.
  • Figure 1 depicts the effect of terazosin on cell senescence induced by etoposide, showing the effect of terazosin on sub-death concentration (2uM) of etoposide-induced cellular senescence, aging markers p16, p21 transcription (Figure In the middle, the fold change indicates a fold change, the abscissa ctrl indicates a control, Etoposide indicates etoposide, and TZ0.1uM indicates 0.1 uM terazosin, which has the same meaning when similar terms are used below).
  • Figures 2 and 3 depict the effect of terazosin on cellular senescence induced by hydrogen peroxide.
  • Figure 2 shows cell senescence induced by sub-death concentration (50 uM) of hydrogen peroxide, while cells were treated with terazosin to examine the effects of senescence markers p16, p21 transcription levels.
  • Figure 2 and Figure 3 Describe the effect of terazosin on cellular senescence induced by hydrogen peroxide.
  • Figure 3 shows cell senescence induced by sub-death concentration (50 uM) of hydrogen peroxide, while treating cells with terazosin to detect SA- ⁇ - Gal staining and statistics (in the figure, the ordinate positive/% indicates an increase percentage).
  • Figure 4 depicts the effect of terazosin on VE cadherin phosphorylation induced by senescence stimulation. The results show that etoposide (2uM) and hydrogen peroxide (50uM) cause an increase in the phosphorylation level of VE cadherin, causing aging. When terazosin is added, terazosin can inhibit the increase of phosphorylation of VE cadherin and delay aging.
  • Figure 5 Describes the effect of terazosin on vascular plaques in atherosclerotic mice; after 12 weeks of feeding high cholesterol foods, mice were fixed by perfusion of paraformaldehyde, and blood vessels were removed for oil red O staining. And statistical results; the ordinate "lesion area” in the figure means "damage area”.
  • Figure 6 depicts the effect of terazosin on the lifespan of C. elegans; the addition of terazosin to normal nematode food (E. coli), statistical nematode survival; the ordinate “survival” in the figure means “survival rate” The abscissa "days” indicates the number of days.
  • Figure 7 Describes the effect of terazosin on the body weight of atherosclerotic mice; ApoE KO mice were fed a high cholesterol diet, and mice were given daily intraperitoneal injection of terazosin (0.08 mg/kg). Feed/drug treatment changes in body weight at 12 weeks; in the figure, the ordinate "body weight increase” means “weight gain”, the abscissa “Normal diet” means “normal diet”, and "High cholesterol” means "high cholesterol”.
  • Figure 8 depicts the effect of terazosin on blood glucose in atherosclerotic mice; small in mice after 16 hours of fasting and fasting Rat blood glucose; the ordinate "Glucose” in the figure indicates the level of "glucose”.
  • Figure 9 Describes the effect of terazosin on blood insulin levels in atherosclerotic mice; blood was measured in mice after high cholesterol feeding and fasting for 16 hours; in the figure, the ordinate “Insulin “It is the “insulin level”; the abscissa “ApoE KO” means "high cholesterol feeding”, ctrl indicates the insulin levels of the two groups before the test; “Fasting insulin” means “fasting insulin level”, “Normal insulin” “Expresses "normal insulin levels”.
  • Figure 10 depicts the effect of terazosin on food intake in atherosclerotic mice; mouse food weights were weighed weekly and counted.
  • Example 1 Study of terazosin inhibition (vascular endothelial cell) cell senescence
  • Figure 1 depicts the effect of terazosin on cell senescence induced by etoposide, showing the effect of terazosin on sub-death concentration (2uM) of etoposide-induced cellular senescence, aging markers p16, p21 transcription (Figure In the middle, the fold change indicates a fold change, the abscissa ctrl indicates a control, Etoposide indicates etoposide, and TZ0.1uM indicates 0.1 uM terazosin, which has the same meaning when similar terms are used below).
  • cell senescence was also induced by a non-lethal concentration of hydrogen peroxide (i.e., H 2 O 2 , 50 ⁇ M) (for specific experimental methods, see: Vigneron A, Vousden KH (2010) p53, ROS and senescence. In the control of aging. Aging 2: 471-474), causing an increase in aging markers p16, p21; terazosin was able to reduce their increase in the addition of terazosin (p ⁇ 0.05 compared to the hydrogen peroxide group) See Figure 2 for specific results.
  • H 2 O 2 a non-lethal concentration of hydrogen peroxide
  • Figure 2 shows cell senescence caused by sub-death concentration (50 uM) of hydrogen peroxide, while treating cells with terazosin to detect aging The effect of transcription levels of p16 and p21.
  • the present invention also detects cell senescence using a method of ⁇ -Gal staining (for specific experimental methods, see: Sikora E, Arendt T, Bennett M, Narita M (2011) Impact of cellular senescence signature on Ageing research.Ageing research reviews 10:146-152).
  • Figure 3 shows cell senescence induced by sub-death concentration (50 uM) of hydrogen peroxide, while cells were treated with terazosin, and SA- ⁇ -Gal staining was detected and counted (in the figure, ordinate positive/% indicates an increase percentage).
  • VE cadherin protein forms a homodimer on the surface of vascular endothelial cells, and VE cadherin between adjacent cells maintains tight junctions between smooth muscle cells through direct interaction, thereby maintaining vascular stability (see: Dejana E, Orsenigo F (2013) Endothelial adherens junctions at a glance. Journal of cell science 126:2545-2549).
  • VE cadherin is first phosphorylated in the intracellular region and then indented into cells, and then the intercellular interaction gradually weakens to disappear, and the vascular endothelial cell gap becomes larger, increasing vascular permeability (see: Quadri SK) (2012) Cross talk between focal adhesion kinase and cadherins: role in regulating endothelial barrier function. Microvascular research 83: 3-11).
  • the inventors detected the phosphorylated VE cadherin levels by western blot.
  • non-lethal concentrations of etoposide (2 ⁇ M) and hydrogen peroxide (50 ⁇ M) caused phosphorylation of VE cadherin.
  • Increase; terazosin can reduce its increase when additional terazosin 0.1uM is added. This result means that terazosin can maintain a tight junction between endothelial cells during aging to maintain the health of the blood vessels.
  • Figure 4 depicts the effect of terazosin on the phosphorylation of VE cadherin induced by senescence stimulation.
  • the results show that etoposide (2uM) and hydrogen peroxide (50uM) cause an increase in the phosphorylation level of VE cadherin, which causes aging.
  • etoposide (2uM) and hydrogen peroxide (50uM) cause an increase in the phosphorylation level of VE cadherin, which causes aging.
  • terazosin When terazosin is added, terazosin inhibits the increase in phosphorylation of VE cadherin, thereby delaying aging.
  • Example 2 Triazosin reduces plaque formation in the vascular wall of a mouse model of atherosclerosis
  • plaques caused by the accumulation of aging/dead endothelial cells, vascular smooth muscle cells, macrophages, lipids, calcium ions, etc., and the formation of plaques causes blood vessels. Hard, severe may directly cause vascular blockage.
  • Figure 5 depicts the effect of terazosin on vascular plaques in atherosclerotic mice. After 12 weeks of feeding high-cholesterol food, the mice were fixed by perfusion of paraformaldehyde, and blood vessels were taken out for oil red O staining and statistical results were obtained. In the figure, the ordinate "lesion area” means "damage area”.
  • Example 3 Terazosin can prolong the lifespan of C. elegans
  • terazosin can inhibit the senescence of vascular endothelial cells. Further question is: Can terazosin affect aging at the overall level? To this end, the inventors added terazosin to the normally fed nematode food E. coli OP50, and then recorded the survival of the nematode every two days. The results show that terazosin can increase the average lifespan of nematodes, the specific results are shown in Figure 6. This article is consistent with the results of in vivo proof of the anti-aging effect of terazosin, which demonstrates the anti-aging effect of terazosin in vitro.
  • Figure 6 depicts the effect of terazosin on the lifespan of C. elegans. Trazosin was added to normal nematode food (E. coli) and the nematode was counted for survival.
  • the ordinate “survival” means “survival rate”
  • the abscissa “days” means time days.
  • Example 4 Terazosin reduces body weight, blood glucose, and insulin levels in an animal model of atherosclerosis caused by high cholesterol
  • APOE Apolipoprotein E
  • VLDLs very low density lipoproteins
  • ApoE knockout mice are prone to hypercholesterolemia, and then immune cells such as macrophages are more likely to be "captured", eventually forming damage plaques formed by lipids, calcium, cell debris, immune cells, etc. on the inner wall of blood vessels.
  • Normal function of the blood vessels resulting in slower blood flow, blocked supply, and direct vascular occlusion (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 reports 1:101-107).
  • Figure 7 depicts the effect of terazosin on body weight in atherosclerotic mice.
  • ApoE KO mice were fed with high cholesterol diet, and mice were intraperitoneally injected with terazosin (0.08 mg/kg) daily, and the body weight of the mice fed for 12 weeks was counted.
  • the ordinate "body weight increase” means "weight gain”
  • the abscissa "Normal diet” means "normal diet”
  • “High cholesterol” means "high cholesterol”.
  • Figure 8 depicts the effect of terazosin on blood glucose in atherosclerotic mice. Mouse blood glucose was measured after the mice were fed and fasted for 16 hours. In the figure, the ordinate "Glucose” indicates the level of "glucose”.
  • Figure 9 depicts the effect of terazosin on blood insulin levels in atherosclerotic mice.
  • Mouse insulin was measured by taking blood in mice after high cholesterol feeding and fasting for 16 hours.
  • the ordinate "Insulin” is “insulin level”
  • the abscissa "ApoE KO” means "high cholesterol feeding”
  • ctrl indicates the insulin levels of the two groups before the test;
  • “Fasting insulin” in the figure means “fasting group”
  • Normal insulin means "normal insulin level”.
  • Figure 10 depicts the effect of terazosin on food intake in atherosclerotic mice. Mouse food weights were weighed weekly and counted.
  • the terazosin was changed to an equimolar amount of doxazosin (tested with methanesulfonic acid) and prazosin (prazosin).
  • Bunazosin tested with its hydrochloride salt
  • alfuzosin Alfuzosin, tested with its hydrochloride
  • Trimazosin Trimazosin, tested with its hydrochloride
  • the present invention provides a novel pharmaceutical use of terazosin or an analogue thereof that provides a new option for the treatment of clinically relevant diseases.

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Abstract

L'invention concerne une nouvelle utilisation pharmaceutique de médicaments de térazosine, en particulier l'utilisation des médicaments de térazosine en termes d'anti-vieillissement et de régulation de métabolisme corporelle. Les médicaments de térazosine sont des composés de formule I ou des sels pharmaceutiquement acceptables de ces derniers ou des solvates de ces derniers, chaque substituant étant tel que présenté dans la description.
PCT/CN2016/080466 2015-06-18 2016-04-28 Utilisation de médicaments de térazosine WO2016202099A1 (fr)

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CN113730413A (zh) * 2021-10-14 2021-12-03 张存泰 特拉唑嗪作为制备降低血管硬度药物的用途
CN116077501A (zh) * 2023-01-17 2023-05-09 上海青颜博识生物技术有限公司 喹唑啉类衍生物在制备抗衰老的产品中的用途

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WEI, JIANRUI ET AL.: "Effects of Terazosin on Plasma Lipid, Glucose and Insulin Metabolism in Patients with Essential Hypertension", CHINA JOURNAL OF HOSPITAL PHARMACY, vol. 19, no. 8, 31 December 1999 (1999-12-31) *
WU, PENG;: "Effect of Doxazosin on Blood Vessel Endothelium and Insulin Action", CHINESE JOURNAL OF ANDROLOGY, vol. 21, no. 6, 31 December 2007 (2007-12-31) *

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