WO2016202099A1 - Use of terazosin drugs - Google Patents

Abstract

The invention relates to a new pharmaceutical use of terazosin drugs, in particular to the use of the terazosin drugs in terms of anti-aging and body metabolism regulation. The terazosin drugs are compounds of formula I or pharmaceutically acceptable salts thereof or solvates thereof, wherein each substituent is as shown in the description.

Description

Use of azozolines Technical field

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.

Background technique

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. For existing clinical indications, 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 α1-adrenergic receptors.

The chemical name of terazosin is (4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone, the molecular formula is C ₁₉ H ₂₅ N ₅ O ₄ , the 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. 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 are mainly caused by the blockade of α1-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.

Therefore, the art still expects to be clinically available with anti-aging functions and even other beneficial functions.

Summary of the invention

It is an object of the present invention to provide a clinically useful drug having anti-aging and even other beneficial functions. The present inventors have found that 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.

To this end, 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:

Wherein R1 is hydrogen or methoxy, and R2 is a group selected from the group consisting of:

In the above groups each representing R2, the bond at the N atom is bonded to R2 of the formula I.

Pharmaceutical use according to the invention, wherein 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.

Pharmaceutical use according to the invention, 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.

In the specific test herein, when terazosin was used, it was tested using its hydrochloride dihydrate, unless otherwise specifically stated.

Pharmaceutical use according to the invention wherein the aging is aging associated with vascular endothelial cells.

According to the pharmaceutical use of the present invention, 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.

According to the pharmaceutical use of the present invention, the delayed aging is a reduction in plaque formation in the blood vessel wall of a mammal. For example, the delaying of aging is to reduce plaque formation in the inner wall of blood vessels caused by atherosclerosis.

According to the pharmaceutical use of the present invention, the delaying of aging is to delay the aging of the body as a whole.

According to the pharmaceutical use of the present invention, 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.

According to the pharmaceutical use of the present invention, 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.

According to the pharmaceutical use of the present invention, 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.

In the present invention, typical, Terazosin, whose chemical name is (4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl ) (tetrahydrofuran-2-yl)methanone, the molecular formula is C19H25N5O4, the structural formula is:

Typically, 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.

Typically, Prazosin, especially 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.

Typically, Bunazosin, especially 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.

Typically, alfuzosin, such as 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.

Typically, Trimazosin has a chemical structural formula of:

Tramadrazine is commonly used clinically to lower blood pressure and can be used for hypertension.

DRAWINGS

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-β- 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.

detailed description

The invention is further described by the following examples, however, the scope of the invention is not limited to the embodiments described below. A person skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope of the invention. The present invention provides a general and/or specific description of the materials and test methods used in the tests. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. The following examples further illustrate the invention and are not intended to limit the invention. Any equivalent transformations that are made in accordance with the inventive concept only as a form rather than a substantial one are considered to be within the scope of the invention.

Example 1: Study of terazosin inhibition (vascular endothelial cell) cell senescence

Test 1a:

In this experiment, DNA damage was induced by using a low concentration of etoposide (2 μM) that did not cause cell death (for specific experimental methods, see: Meresse P, Dechaux E, Monneret C, Bertounesque E (2004) Etoposide: discovery and medicinal chemistry. Current medicinal chemistry 11:2443-2466) induced HUVEC (human umbilical cord vascular endothelial cells) senescence, extracted RNA 24 hours later, reversed into cDNA, and detected transcript level aging markers p16, p21 by Real-time PCR (specific experiment See, for example, Herbig U, 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). The results showed that etoposide treatment induced cell senescence, resulting in increased levels of aging markers p16 and p21, and terazosin significantly reduced etoposide-induced increases in senescence markers p16 and p21 (with etoposide group). See Figure 1 for specific results compared to p < 0.01).

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).

Test 1b:

In a similar test of the present invention, cell senescence was also induced by a non-lethal concentration of hydrogen peroxide (i.e., H ₂ O ₂ , 50 μM) (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.

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.

Test 1c:

Further, in addition to detecting the transcription levels of p16 and p21, the present invention also detects cell senescence using a method of β-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). The results showed that hydrogen peroxide (50 μM) also induced cell senescence, resulting in increased β-Gal staining; at the addition of terazosin 0.1 uM, terazosin significantly reduced the β-Gal staining signal caused by aging stimulation (and The hydrogen peroxide group was compared with p<0.01), and the statistical results are shown in Figure 3 below.

Figure 3 shows cell senescence induced by sub-death concentration (50 uM) of hydrogen peroxide, while cells were treated with terazosin, and SA-β-Gal staining was detected and counted (in the figure, ordinate positive/% indicates an increase percentage).

Test 1d:

Under normal physiological conditions, 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). During aging, 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).

In this example, the inventors detected the phosphorylated VE cadherin levels by western blot. As shown in Figure 4, non-lethal concentrations of etoposide (2 μM) and hydrogen peroxide (50 μM) 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. 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

In the development of atherosclerosis, the lining of the blood vessels produces "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. After 12 weeks of high cholesterol feeding to ApoE KO mice, after total systemic perfusion fixation, the aortic arch was dissected along with the thoracic segment and stained with Oil Red O (for specific test methods, 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 CD36 expression And HDL.Arteriosclerosis, thrombosis, and vascular biology 21:372-377). The results showed that high cholesterol feeding caused plaque formation and showed positive fat staining. The plaques injected into the terazosin group were significantly reduced (p<0.01 compared with the ApoE KO group). The statistical results are shown in Fig. 5.

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

Vascular aging plays an important role in normal physiological aging. The present invention has demonstrated that 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. In the figure, the ordinate "survival" means "survival rate", and 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

Maintaining normal concentrations of cholesterol in the blood is extremely important for maintaining heart and vascular function, and can prevent cardiovascular diseases such as heart disease and stroke to a certain extent (Rosendorff C (2002) Effects of LDL cholesterol on vascular function. Journal of human Hypertension 16 Suppl 1: S26-28). APOE (Apolipoprotein E) is an important component of very low density lipoproteins (VLDLs) that transfer excess cholesterol from the blood to the liver for degradation (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). 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).

In the present invention, ApoE KO mice were fed with high cholesterol diet for 12 weeks, and 0.08 mg/kg terazosin was intraperitoneally administered per day according to body weight, and the body weight change of the mice was recorded every day. The results showed that high cholesterol feeding caused a significant increase in body weight in mice, while the body weight of mice treated with terazosin was significantly lower than that in the high cholesterol feeding group (p<0.05 compared with the animals in the high cholesterol feeding group). ), the specific results are shown in Figure 7.

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. In the figure, the ordinate "body weight increase" means "weight gain", the abscissa "Normal diet" means "normal diet", and "High cholesterol" means "high cholesterol".

In addition, during the above-mentioned feeding of high cholesterol diet, the blood glucose changes of the mice were measured and fasted for 16 hours. The results are shown in Figure 8. The results showed that high cholesterol feeding caused an increase in blood glucose (PBG) in the satiety state of mice, and terazosin significantly reduced the blood in the mouth. Glucose increased (p = 0.012); however, terazosin did not cause changes in blood glucose (FBG) in mice under fasting conditions.

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".

Further, during the above-mentioned feeding of the high cholesterol diet, the changes in insulin levels in the mice were measured and fasted for 16 hours. The results are shown in Figure 9. The results showed that high cholesterol feeding caused an increase in insulin levels under normal conditions, and when given terazosin, it significantly reduced the above-mentioned increase in insulin (compared with high cholesterol-fed animals without terazosin) Ratio, p < 0.05), but terazosin did not cause changes in insulin levels under fasting conditions.

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. In the figure, 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" "Insulin level", "Normal insulin" means "normal insulin level".

Example 5: Triazolazine-induced increase in food intake in mice

In the present invention, ApoE KO mice were fed with high cholesterol diet for 12 weeks, and 0.08 mg/kg of terazosin was intraperitoneally administered per day according to body weight, and the food intake of the mice was recorded every day. The results showed that for high cholesterol-fed mice, the food intake of terazosin was 1.1 times higher than that given to the terazosin group, indicating an increase in food intake after injection of terazosin. 10.

Figure 10: depicts the effect of terazosin on food intake in atherosclerotic mice. Mouse food weights were weighed weekly and counted.

Referring to the methods of Examples 1-5 above, 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), or Trimazosin (Trimazosin, tested with its hydrochloride), The results showed that they all exhibited similar effects to terazosin in each of the above examples, that is, they all had anti-vascular endothelial cell senescence, decreased body weight in a mouse model of atherosclerosis, increased blood sugar and insulin, and caused an increase in diet. It can reduce the formation of plaque in the vascular wall and prolong the lifespan of nematodes in the mouse model of atherosclerosis.

Industrial applicability

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.

Claims (10)

1. 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:

   

   Wherein R1 is hydrogen or methoxy, and R2 is a group selected from the group consisting of:

   
2. A pharmaceutical use according to claim 1 wherein said compound of formula I is selected from the group consisting of terazosin, doxazosin, prazosin, bunazosin, alfuzosin, trimazolazine and pharmaceutically acceptable salts thereof Or a solvate thereof.
3. A pharmaceutical use according to claim 1 wherein said pharmaceutically acceptable salt is, for example, the hydrochloride, phosphate, benzenesulfonate, methanesulfonate, sulfate, nitrate of said compound.
4. A pharmaceutical use according to claim 1, wherein the solvate is a hydrate of the compound or a pharmaceutically acceptable salt thereof, such as a monohydrate, a dihydrate or the like.
5. The pharmaceutical use according to claim 1, wherein said aging is aging associated with vascular endothelial cells.
6. The pharmaceutical use according to claim 1, wherein said delaying 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.
7. The pharmaceutical use according to claim 1, wherein said delaying aging is a reduction in plaque formation in the blood vessel wall of a mammal. For example, the delaying of aging is to reduce plaque formation in the inner wall of blood vessels caused by atherosclerosis.
8. The pharmaceutical use according to claim 1, wherein said delaying aging is aging which delays the overall level of the body.
9. A pharmaceutical use according to the present invention, wherein the improving the metabolism of the body during lactation means improving the metabolism of the body during lactation in relation to its body weight, blood sugar, insulin level and the like.
10. The pharmaceutical use according to claim 1 wherein:

    The improving lactation metabolism refers to reducing the body weight, blood sugar and insulin levels of the body caused by high cholesterol-induced atherosclerosis; and/or

    The improvement of body metabolism during lactation refers to an improvement in the food intake of an atherosclerotic body caused by high cholesterol, in particular, an increase in the food intake of an atherosclerotic body caused by high cholesterol.

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