TW200523257A - Use of organic compounds - Google Patents

Abstract

Antihypertensive agents selected from the group of Angiotensin II receptor antagonists (especially the compound (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'(1H-tetra-zol-5-yl) biphenyl-4-yl-methyl] amine (valsartan) of formula, ), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof, can be used for the prevention and treatment of insufficient blood flow and cerebral functional disorders.

Description

200523257 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to the use of antihypertensive agents for the prevention and treatment of insufficient blood flow and brain function diseases. [Prior art] Antihypertensive agents include, inter alia, angiotensin II receptor antagonists, ... adrenaline knot inhibitors, / 3-blockers, dance channel blockers (CCB), and ACE inhibitors. Hypertension activation, which is one of the causes of arteriosclerosis, has long aggravated BP fluctuations and tissue hypertensive protease-angiotensin system (RAS) in the onset of onset. In hypertension, jk tuberculin II (AT II), which causes remodeling and stimulates sympathetic nerves as a major factor in reducing cerebral blood vessel diameter and norepinephrine, generally increases. But sympathetic nerves are quite manageable in elderly hypertension. The enzyme cascade of the hypertensive protease-angiotensin system (RAS) contains a series of biochemical sequences, and we know that there are different ways to achieve the possibility of treating hypertension, such as by regulating intervention. RAS, together with the sympathetic nervous system, are physiological regulators of CBF-autoregulation. ACE-1 and ARB, which directly control RAS, reduce the collagen content of cerebral arteries determined by AT II via ATI receptors, and improve the performance of cerebral arterial walls. ARB blocks the effects of AT II in the final stage and controls the effects of AT II produced by most enzymes other than ACE. In addition, ARB indirectly but ultimately stimulates AT2 receptors to provide opposite effects on overgrowth and fibrotic changes and a regulatory effect on CBF (dual effects). 95730.doc 200523257 Angiotensinogen (an α2-macroglycoprotein) is cleaved by the protease protease to decapeptide A-tubulin I, which itself has only very weak biological activity. The next step in this system is the action of angiotensin-converting enzyme (ACE), which is mainly bound to the endothelium, to remove the other two amino acids, while forming angiotensin π. The latter is considered to be one of the strongest natural vasoconstrictors. Angiotensin II acts on non-striated muscle cells, stimulates the formation of the adrenaline hormones epinephrine and norepinephrine, and increases the activity of the sympathetic nervous system due to the formation of norepinephrine. This produces the vasoconstrictor effect of angiotensin IX. A-tubulin also has an effect on electrolytic balance, which produces (for example) anti-urinary excretion and anti-diuretic effects in the kidney and therefore, on the one hand promotes the release of anti-diuretic hormone peptides from the pituitary gland and on the other hand promotes aldehyde Sterols are released from adrenal filaments. These effects all play an important role in regulating blood pressure. Hemagglutinin II interacts with specific receptors on the surface of the target cells. It has been possible to identify a receptor subtype known as, for example, the AT1 & ATr receptor. Recently, we have made great efforts to identify substances that bind to the AT1_ receptor. Active ingredients such as hydrazone are often called angiotensin π antagonists. Owing to their inhibitory effect on Attilinus, these antagonists can be used, for example, as antihypertensive agents or for the treatment of congestive heart failure. [Summary of the Invention] It should be understood that angiotensin II antagonists mean their active ingredients that bind to the ATi receptor subtype. These ingredients include compounds with different structural characteristics. The compounds to be mentioned are, for example, compounds of Ep_443983 which are cited in the scope of patent application 95730.doc 200523257, the subject matter of which is incorporated herein by reference. '倂 To be strong, Zhou's compound is the following formula described in Example 16 of European Patent Application No. Ling ch2

Soil ... T | _prop-1-yl) _N_pentyl_n_ [2, (1h tetrawa-5yl) biphenyl.methyl] amine (hereinafter referred to as valprosartan) or trisalt (Preferred for its pharmaceutically acceptable salt. The preferred agent is valsartan. Compounds in European Patent Application No. Ep_2533i0: Compounds cited in the scope of application. By reference.

A compound to be emphasized ^ is a compound of the formula \ A JT1 ^ 0H

And its pharmaceutically acceptable salts. 95730.doc 200523257 In addition, the European Patent Publication No. EP-403159 ^ ^ "The compound in the case of the eye" The compound cited in the scope of the patent application is incorporated into the present application by the referenced formula. T stomach The compound to be emphasized is a compound of the formula

And its pharmaceutically acceptable salts. In addition, the compounds cited in the patent application scope of PCT patent application wo 91/1 are also included in this application with reference to this document. The compound to be emphasized is a compound of the following formula

Compounds and their pharmaceutically acceptable salts. In addition, the compounds of the European Patent Application with the publication number EP-420 237 The compounds cited in the scope of the patent application are incorporated herein by reference; in the application. A compound to be emphasized is a compound of the formula 95730.doc 200523257

And its pharmaceutically acceptable salts. In addition, the compounds of European Patent Application No. EP-502314 have been incorporated into this application by reference. A compound to be emphasized is a compound of the formula

In addition, the male tongue refers to the compounds cited in the scope of the European Patent Application No. EP-459136 of the European Patent Application for Mozambique: the compounds in the case. Formula is incorporated into this application. A compound to be emphasized is a compound of the formula 95730.doc 200523257

And its pharmaceutically acceptable salts. In addition, the compounds of European Patent Application Publication No. EP-504888 are incorporated by reference into the present application. The compound to be emphasized is a compound of the following formula

And its pharmaceutically acceptable salts. In addition, the European Patent Publication No. EP-5i4i98 is composed of the compounds cited in the scope of the patent application of the compound of the 4th "Shishi" case in the cited case. The compound incorporated in this application to be emphasized is the following formula: Compound 95730.doc -10-200523257

And its pharmaceutically acceptable salts. In addition, the compounds of European Patent Application Publication No. EP-475206 are incorporated in the present application by reference.

A compound to be emphasized is a compound of the formula

And its pharmaceutically acceptable salts. In addition, compounds cited in the scope of the patent application for compounds of PCT patent application WO 93/208 16 are included in this application by reference. A compound to be emphasized is a compound of the formula 95730.doc -11-200523257

And its pharmaceutically acceptable salts,

For example, the pharmaceutically acceptable salt of ' valsartan is usually an acid addition salt. For example, these acid addition salts are formed from the following: strong inorganic acids, usually inorganic acids such as sulfuric acid, phosphoric acid, or hydrogen dentate; strong organic carboxylic acids, usually Ci_C4, which can be substituted with, for example, halogens Alkane carboxylic acids, typically acetic acid; for example, may be unsaturated dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or terephthalic acid; for example, Lactic acid, such as ascorbic acid, glycolic acid, lactic acid, picobolic acid, tartaric acid, or citric acid; for example, amino acids such as aspartic acid or ammonium acid, or (for example) stearic acid; or organic acid ,

5 As low as 夂 1 歹 j, for example, CVC4 ^ 1㈣ ㈣, which may be substituted by, for example, halogen, such as methylpyridine or p-p-monobenzylic acid. A suitable basic salt is usually a metal salt (usually a sodium salt, a clock, a green ring, or an isocyanate) or a helium salt, such as a metal test salt or an alkaline earth metal salt, or such as morpholine, thiomorpholine , Hexahydropyridine, pyrrolidine, glutamate, bis- or tri-low-carbon alkylamine organic amines, usually ethylamine, tertiary-butylamine, propylamine, triethylamine, or dimethylamine Propylpropylamine, or mono-, di-, or alkoxy-low-carbon alkylamine, usually mono-, di, or = A-ethanolamine. Corresponding internal salts can also be used. 95730.doc -12 · 200523257… adrenaline antagonists (also known as Of blockers, α-adrenaline blockers, & adrenaline blockers, α blockers) have been human in this technology Know. Examples of alpha-adrenergic antagonists suitable for use in the present invention are preferably Doxazosin, terazosin disclosed in US 4026894, and metazosin disclosed in Us 4775673. Dagger) and moxonidine (moxondine) as disclosed in US 43235 70. The structure of the active agent identified by the generic name can be obtained from the standard summary "Merck Index", the current version or from a lean repository such as (LifeCycle) international patents (such as the IMS World Publication). The corresponding content is cited by reference The method is incorporated herein. Anyone skilled in the art can fully identify these active agents and based on these references, can also manufacture and test medical conditions and properties, for example, in standard test models in vitro and in vivo. Exhaust-blockers are known in the art. 0 Blockers are preferably selected from the group consisting of: selective " blockers, such as' attenol Atenolol, betaxolol, bisoprolol (especially for its fumarate), metoprolol (especially for its semi- (r, R) fumaric acid) Salt or fumarate), in addition, there are acebutolol (especially its hydrochloride), esmolol (especially its hydrochloride), and ceprol. pl〇1) (especially its hydrochloride salt), taprolol or acebutrolol (Especially its hydrochloride) 'non-selective / 3-blockers, such as oxprenolol (especially its hydrochloride), pindolol (01) There are propanolol (especially its hydrochloride), bupranolol (especially its hydrochloride), penbutolol (especially 95730.doc, 13- 200523257 which are its sulfates), mepindolol (especially its sulfates), carteolol (especially its hydrochloride) or nadolol; and / 3-blocker with a-blocking activity, such as carvedilol; or a pharmaceutically acceptable salt in each case. IS-blockers suitable for the salts of the present invention Preferred examples of weaning agents are, in particular, marketed exhaustion-blocking agents, preferably carvedilol, oxenolol, propranolol, and metoprolol. Metoprolol and oxygen are more preferred. Enolol. The best is oxenolol. Calcium channel blockers (CCBs) basically contain dihydrogen. Dipyridines (DHP) and non-DHPs, such as diltiazem and verapamil Type CC B. The CCB suitable for this combination is preferably a representative of DHP, which is selected from the group consisting of: amlodipine, benidipine, felodipine, and Rio Austin (Ryosidine), isradipine, lac i dipine, nicardipine, nifedipine, niguldipine, niludipine, niridine Mordipine, nisoldipine, nitrendipine, and nivaldipine; and preferably non-DHP representatives, which are selected from the group consisting of: Flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, teapapa Tiapamil and verapamil; and pharmaceutically acceptable salts under various conditions. All of these CCBs are used in the treatment of, for example, antihypertensive drugs, antianginal drugs or antiarrhythmic drugs. Preferred CCBs include amlodipine, diltiazem, irradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, for example, depending on the particular CCB, Its pharmaceutically acceptable salt. A preferred DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially its besylate salt. A preferred non-DHP representative is verapamil or a pharmaceutically acceptable salt thereof, especially its hydrochloride. Qi ACE inhibitors include compounds having different structural characteristics. For example, the compounds mentioned are selected from the group consisting of: apripril, benazepril, benazeprilat, captopril, Ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, u meters Imidapril, lisinopril, mototopril, perindopril, quniapril, ramipril, lopupril Spirapril, temocapril and trandolapdl, or pharmaceutically acceptable salts thereof under various conditions. The better ACE inhibitors are their marketed agents, more preferably benazepril and enalapril. The best is benazepril. I have surprisingly found that therapeutically effective amounts of antihypertensive agents can be used to prevent and treat insufficient blood flow and brain function disorders. In this specification, the term "treatment (noun)" or "treatment (verb)" refers to both prevention and treatment of disease 95730.doc -15- 200523257, both curative or disease-modulating treatment, and includes treatment Mammals (including humans), patients at risk of or suspected exposure to the disease, and patients who have been diagnosed with the disease or medical condition. For example, the following experimental procedures can be used to demonstrate the beneficial effects of therapeutically effective amounts of antihypertensive agents for the prevention and treatment of insufficient blood flow and brain function disorders: Materials and methods Those skilled in the relevant art are fully capable of selecting relevant test models to prove The efficacy of the antihypertensive agents of the invention in the therapeutic conditions disclosed elsewhere and below. The relationship between the ε product bed for hypertension treatment and brain function as measured by an electroencephalogram (EEG) is reported below. Based on the effects of high pressure agents on the mean blood pressure (mBp) and EEG in elderly patients with hypertension, the practicability and characteristics of hypertension agents were studied. These experiments are relevant to all generations of patients with hypertension. After 60 years of age, both mBP and EEG have started to change significantly and are of clinical importance for elderly patients with hypertension. The subjects were 139 untreated elderly hypertensive patients (61 males, 78 females) over 60 years of age, and two random systolic blood pressure (SBP) were measured in a sitting position on different days ^ 140 mmHg and / or diastolic blood pressure (DBP) > 90 mmHg. The subjects were divided into 6 patients who did not use antihypertensive agents (control group) and 123 patients who used antihypertensive agents (treatment group), of which the treatment group was used by 18 patients Patients (α1 _ blockers), 30 patients using selective-blockers (no blockers), 24 patients using blood 95730.doc -16- 200523257 tube shrinkin converting enzyme inhibitors Patients (ACEq), 24 patients with angiotensin 11 receptor blockers (fiber), and 27 patients with Ca • antagonists (Ca-antagonists). There were no differences in mean age, male / female ratio, and values (Table 1). Administer the α1-blocker doxazosin pmg / day) and bisoprolol (5 mg / day) and betaxolol (ι〇mg / day) as blocking agents once a day for one year every year for one year. , ACE-I quinapril (10 mg / day) and Medapril (mg / day), ARB valsartan (80 mg / day), and Ca_ antagonist nirendipine (10 mg / day) Days) and Benidipine (4 mg / day), and the same dose was administered during the study period. After the random mBP measurement, the EEG was recorded according to the 10-20 international system with both eyes closed but still at rest. With Nihon Kohden Model EEG 7314 (Nishiochiai,

Shinjyuku-ku Tokyo, Japan) was used to analyze EEG obtained from 12 electrodes (ρρΐ, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, 01, and 02). Nihon Keden model is a local anatomic EEG scan

(Topographic Electroencephalographic) system, which analyzes brain function through quantitative and objective analysis of EEG. Enter this information into a computer and perform a Fast Fourier Transformation. Fourier analysis is used to decompose complex frequencies into sine waves with successively different frequencies and amplitudes. FFT is a frequency analysis method running at high speed via a microcomputer. Under a stable 16-second sampling time, the EEG spectrum is decomposed into 9 frequency bands (δ wave (2-4 Hz), 0 wave (4-8 Hz), slow wave (2-8 Hz), 〇 ^ 1 wave (8-10 Hz), 12 waves (10-13 Hz), 0! Wave (8-13 Hz), / 51 wave 95730.doc -17- 200523257 (13-20 Hz), / 32 wave (20- 30 Hz) and fast wave (13-30 Hz)) for EEG spectral analysis. EEG frequency classification is usually divided into 6 frequency bands: δ wave (2-4 Hz), 0, pico (4-8 Hz), 0 ^ 1 wave (8-10 Hz), 0; 2 wave (10-13 Hz) , 131 waves (13 20 Hz), and no 2 waves (20-30 Hz). Eeg is usually discussed using three frequency waves: slow wave (δ + 0), ye, pico (al + o: 2) and fast wave (/ 51 + / 32). Normal EEG at rest energy consists mainly of alpha waves. High Eeg frequencies are by no means slow waves, and delta and skin are not recognized. Slow waves appear in pathological conditions such as cerebral circulation and dysfunction. Therefore 9 frequency bands are used. Calculate the power of EEG%, which represents the ratio of each frequency band to all frequency bands. The power spectrum obtained by the free FFT calculates the equivalent potential (square root of power) in each frequency band. ''% Power '' means the ratio of the equivalent electric charge of one frequency band to the total equivalent potential of all frequency bands. The% power can be used to quantitatively evaluate the scalp distribution of EEG. Statistical analysis The lean material table is not the mean ± standard deviation. Comparison of mBP and EEG% power results before and after one year of treatment. The t_ test (Student's t-test) or Welchb test (while heart t seven) and the Newman-Keulus's test (Newman-Keulus's test) are used for multiple comparisons. p &lt; 〇 〇5 is defined as statistically significant. In the presence or absence of discrete, Student t_ test or Welchb test are commonly used to compare the average between two individuals. The Newman-Cole test is a multiple comparison method and is widely used to compare the average values between 95730.doc 200523257 groups. Results One year after the control group and the treatment group, the average mBP of the control group has not changed significantly. 109 ± 12 mmHg changed to 107 ± 9 mmHg. Untreated hypertensive patients maintained high mBP. No significant decrease in mBP indicated that the change in DBP reduction over the year was greater than the increase in SBP. The average mBP in the treatment group was from 114 μH. The 11 mmHg decreased to 101 to 12 mmHg (ρ &lt; 0.001). The mBP change in the control group (mBP) was -1.4 to 11.3 mmHg. The ZmBP of the treatment group was -13.0 ± 13.5 mmHg (p &lt; 0.0i) and was significantly different from the control group (Figure 1). These data indicate that elderly hypertensive patients can reduce some mBP by antihypertensive agents. One year later, the% power of δ in the control group increased from 22.6 ± 13.3% to 27.3 ± 15.8% (<0.05). The% power of other waves did not change significantly. The% power of the delta wave / 31 wave of the treatment group tended to decrease from 23.5 to 12.0% to 21.9 to 11.2ο / 〇 (ρ &lt; 0.10) and to increase from 11.2 to 4.6% to 11.7 to 5.3%, respectively. (&Lt; 0.10) (Figure 2). One year later,% power change of 3 (『3),% power change of 0 (Z 0),% power change of slow wave (” slow wave ”),% power change of α1 (ζΐαΐ), and 2% power Change ("α2),"% power change ("〇〇,% power change of / 51,% power change of / 32 ("%), and% power change of fast wave (Z fast wave) are respectively 4. 7 ± 7 · 8%, -0.6 soil 4_0%, 4.0 soil 8.5%, -3.8 soil 9.6%, 1.0 ± 2.9%, -2 · 8 ± 10 · 3%, -0.6 soil 3.7%, -0.7 soil 3.2 % And -1.3 ± 6.30 / 〇. Compared with the control group, the treatment 95730.doc -19- 200523257 group showed a reduction of -1.6 ± 10.4% (ρ &lt; 0.001), a decrease in Z slow wave -1 · 3 ± 12.8% (ρ &lt; 0.05), and an average observable trend of zicd increased by 1.2 ± 11.8% (ρ &lt; 0 · 10) (Figure 3). For patients with untreated hypertension In terms of meaning, it means that the five waves of severe brain dysfunction or insufficient CBF are increased. Hypertensive patients treated with antihypertensive agents can obtain a reduction of 5 waves and slow waves that appear under pathological conditions. Treated patients "( The reduction of 5 waves and slow waves means that treatment with antihypertensive agents can recover or Good brain function and CBF. Differences among antihypertensive agents The average mBP of αΐ-blockers tends to decrease from 111 ± 6 mmHg to 102 ± 15 mmHg (p &lt; 0.10). / 51-blocker, The average mBP of ACE-I, ARB, and Ca-antagonists decreased from 115 ± 12 mmHg to 103 ± 10 mmHg (ρ &lt; 0.001), from 115 ± 13 mmHg to 102 ± 12 mmHg (p &lt; 0.001), From 115 to 11 mmHg to 101 ± 16 mmHg (p &lt; 0_001), and from 113 to 9 mmHg to 96 ± 9 mmHg (ρ &lt; 0 · 001) (Figure 4). These data show that in addition to cd- Antihypertensive agents other than blockers can control mBP. Cd-blockers _8 · 4 ± 18 · 7 "mBP is not significantly different. These data show that the decrease in mBP caused by α 阻断 -blockers is comparable to that of the control group. The mBP changes are not significant. The reason may be that the mBP changes caused by -blockers have a large floating range (standard deviation). -12 ± 12 mmHg (p &lt; 0.05) / 51-blockers zmBP, -13 soil 12 mmHg (p &lt; 0.05) of ACE-1 '' mBP, -14 soil 15 mmHg (p &lt; 0.05) of ARB ZlmBP and -17 ± 11 mmHg (p &lt; 0.01) Ca_ antagonist Compared with 95730.doc -20 · 200523257 ZmBP The group "mBP have significant differences (Figure 5). These data show that / 51-blockers, ACE-I, ARB and Ca-antagonists reduce mBP. The degree of mBP reduction varies from reagent to reagent. Ca-antagonists are the strongest. ARB is the strongest and is located between ACE-1 and Ca-antagonist. The% power of the / 51 -blocker wave, / 52 wave and fast wave decreased from 13.3 to 7.8% to 11.6 ± 5.5% ^ &lt; 0.10), and increased from 11.6 to 5.3% to 13.2 ± 6.4%. (ρ &lt; 0.05) and tend to increase from 18.6 to 8.0% to 20.4 to 8.8% (ρ &lt; 0.10). The 5 waves of ARB and the α wave. / 〇 Power tends to decrease from 21 · 9 ± 12.1% to 18.3 ± 9 · 3ο / 〇 (ρ &lt; 0.10) and increase from 25.8 ± 14.0% to 31.6 ± 17.1% (ρ &lt; 0 · 10) ° These results show that ARB causes the background EEG to change from a slow wave to a wave. Considering that the desired EEG is mainly composed of alpha waves and has as few slow waves as possible, ARB can provide beneficial effects on brain function or CBF. The power of% 2 was reduced from 7.2 ± 3.2% to 5.8 ± 3.0% (ρ &lt; 〇β〇5). There was no significant change in EEGi% power of α-blockers, ACE-1, and Ca-antagonists. These results show that αΐ-blockers, ACE-1 and Ca-antagonists have no effect on EEG. In the control group, the% power of 1 wave of cd-blocker, / 51-blocker, ACE-I, ARB, and Ca_ antagonist was not statistically significant compared to δ wave and 0 wave, and Above α2 wave, make 1 wave reach | 82 wave. These results show that at the baseline EEG of 0: 1-blocker, / 31-blocker, ACE-I, ARB, and Ca-antagonist, the basic rhythm showing the strongest effect is not an alpha wave. In addition, there were no differences in the occurrence rates of δ, 0, and cd waves. 95730.doc -21-200523257 One year later, the αΐ-blocker, / 31-blocker, ACE-I, and Ca-cumulant maintained the same od wave distribution in the control group. These results show that 0? 1 -Blockers, / 51-blockers, ACE-1 and Ca-antagonists cannot form the basic rhythm of the cd wave. Only the% power of the 0: 1 wave in ARB is higher than any other wave (Figure 6). These results show that ARB can replace the basic rhythm with cd waves. Only ARB produces a normal basic rhythm. Compared to the control group, the δ of the cd-blocker tends to decrease by -0.8 ± 10 ·% (ρ &lt; 0 · 10), and the δ of the 1-blocker, ACE-1, and ARB decreases- 2.4 soil 10.4% (卩 &lt; 0.05), 丄 5 ± 8.3% (? &Lt; 0.05) and _3.6 ± 10.0% (ρ &lt; 0.01). These results show that the / 31-blocker, ACE-1 and ARB can reduce the delta wave, but the Ca-antagonist cannot reduce the delta wave like the control group. The 8-foot-3 / slow wave tends to decrease by -2.7 to 14.7% (卩 <0.10). These results show that compared with the control group, ARB has a slow wave reduction trend. "Eight 1 ^ of" 〇: 1 reduced by 5.8 ± 15.40 / 〇 (? <0.05). These results show that ARB can increase the cd wave compared to the control group. "/ 31-blocker" (^ 2 tends to decrease -1.77 ± 5.3% (卩 &lt; 0.10). Eighty ^^ tends to increase by 4.7 ± 14.7% (ρ &lt; 〇 · ι〇). These results show that compared with the control group, the / 51-blocker has a decreasing trend of α2 waves. The ARB has a trend of increasing ce waves. The increase of / 51-blockers. Each of the antihypertensive agents is 0, zl / 32 And "fast wave is not statistically significant (Figure 7). These results show that / 51 -blocker increases / 51 wave compared to the control group. 95730.doc • 22- 200523257 All hypertension agents and control group There is no change in Θ wave, / 32 wave, and fast wave. Antihypertensive agents have no effect on Θ wave, / 32 wave, and fast wave. The brain has a system that maintains a constant CBF in the change of BP. This CBF-self-regulating effect is from 50 to The lower mBP range of 70 mmHg and the upper mBP range of 150 mmHg play a role. In high blood pressure, the continuous high bp causes excessive growth of the arterial intermediary membrane (reduced inner diameter) and changes in the smooth muscle cell arrangement of cerebral arterioles (remodeling , The outer diameter decreases), which causes the lower limit of CBF-self-regulation to move to a higher mBP range of 110 to 120 mmHg. This morphological change may be in CBF decreases due to insufficient cerebral vasodilatation when excessive BP is reduced. CBF-self-regulation is strong, but if there is only a small reduction in BP, CBF deficiency can easily occur. Refer to EEG, because when CBF is reduced and brain function is reduced With the aging, the slow wave increases and the alpha wave decreases. This slowing EEG is observed before the irreversible damage of neurons. The basis of the basic rhythm of the alpha wave. The brain has a mechanism to maintain a constant CBF for blood pressure changes (CBF self-regulating effect). The CBF self-regulating effect of senile hypertension is often disturbed by the intimal thickening and remodeling of cerebral arteries. It prevents the decrease of CBF by maximizing self-regulating vasodilation and moves the lower limit of CBF self-regulating effect to mBp High range. In addition, it can not dilate the cerebral arteries to reduce mBp, and there is a deviation in the original CBF self-regulating range. Systemic mBP reduction caused by hypertension agents can easily promote cerebral ischemia. Observe on EEG and brain function status This anomaly. EEG showing particularly slower increases in slow waves and reduction in 0: waves can be observed in the early stages of these injuries. Normally older than 60 years old Among young people, the incidences of slow wave, skin and fast wave are about 15%, 60%, and 25% (Gibbs). The wave can be considered as the basis of the basic rhythm. 95730.doc -23- 200523257 It has been shown that The incidence of slow waves in patients with dementia (high scores on the Hasegawa scaie) or gait disorders is higher than in patients without these symptoms. The incidence of slow waves and includes brain function and gait capacity The quality of life (QOL) is closely related. Patients with high blood pressure without antihypertensive agents In this study, patients with hypertension without antihypertensive agents showed small changes in mBp and a final mBP value of about 107 mmHg. However, the delta wave has a significant increase in strength. These 4 results show that in elderly with high gray pressure, hypertension that persists for one year exacerbates EEG (5-wave increase). Patients treated with anti-hypertensive agents for one year Patients treated with antihypertensive agents for one year showed a decrease in mBp, which had a trend of δ wave reduction and / 51 wave increase. Compared with the control group, it shows the decreasing change of mBP, delta wave and slow wave and the increasing change trend of wave. This specific result shows a reduction in CBF usually attributed to a reduction in mBP. Treated patients can also improve EEG (reduced exhaustion) despite reduced mBP. Hypertensive patients treated with antihypertensive agents can improve the remaining capacity of the cerebral arteries. These results also indicate that antihypertensive agents can be used to prevent and treat insufficient blood flow and brain function disorders. Anti-hypertensive agents may provide the following benefits: prevention of dysentery by reducing mBp 'and maintenance or restoration of brain function and CBF. Certain antihypertensive agents can be used in patients with normal hypertension who have a CBF disorder or a brain function disorder. Reduction of mBP by antihypertensive agents does not worsen baseline EEG, and the use of antihypertensive agents produces good results for EEG. 95730.doc -24-200523257 In terms of brain function, mBP reduction of -13 mmHg to about 100 mmHg and SBP 130 mmHg and DBP 85 mmHg are useful and even desirable in elderly hypertensive patients. These results show that mBP calculated from SBP 130 mmHg and DBP 85 mmHg is equal to 100 mmHg, which is the hypertension value used in JNC VI. SBP 130 mmHg and DBP 85 mmHg are different from mBP 100 mmHg. Therefore, considering EEG, it is more practical to use mBP 100 mmHg. Among the various antihypertensive agents, the mBP of / 31-blocker, ACE-I, ARB, and Ca-antagonist decreased, the delta wave of / 31-blocker, ACE-1 and ARB decreased, and the alpha wave of ARB Both the increase and the increase of the / 31-blocker's / η wave were statistically significant. These results show that the degree of mBP reduction does not vary with / 31-blockers, ACE-I, ARB, and Ca-antagonists, but each agent has a different effect on EEG. Although αΐ-blockers tend to reduce βBP and usually have a weak catecholamine effect on cerebral arteries and are not associated with sympathetic nerves for CBF at rest ', 0: 1 -blockers do not show changes in EEG. The decrease in AT II can affect the effects of ACE-1 and ARB on EEG, where the AT II acts on cerebral vascular endothelial cells and constricts cerebral arteries. The more desirable changes in EEG in ARB (showing a decrease in δ waves, an increase in cd waves, and the appearance of waves as a basic rhythm) can be explained as compared to ACE-I, ARB can control the RA system more surely. Ca-antagonists have shown no effect on rrg. The reason is that Ca-antagonists cannot inhibit the sympathetic nervous system and the RA system even if there are differences to some extent. The / 31-blocker, 95730.doc -25- 200523257 ACE-1, and ARB, which control hypertensive protease activity, show good responses to both mBP and EEG. The minimum and maximum changes of / 51-blocker and ARB in mBP are about -12 mmHg and -14 mmHg, respectively. This result shows that the antihypertensive agent that can make the baseline EEG close to the desired EEG is / 51-blocker, ACE-1 and ARB. ARB especially brings the baseline EEG closer to normal EEG. The deterioration of primitive cerebral vasodilation is mainly due to angiotensin II (AT II). ARB reduces the collagen content of cerebral blood vessels determined by AT II via the AT1 receptor and improves cerebral vasodilation (remaining capacity of the cerebral arteries). The average reduction of mBP was -12 mmHg to -14 mmHg (about -13 mmHg) and there was no difference in each drug. This study shows that reducing BP with antihypertensive agents, especially ARBs with some control over RAS, is suitable for elderly patients with hypertension. In terms of brain function, the reductions in mBP of about 100 mmHg and -13 mmHg obtained from this study can be used as one of the guidelines for the treatment of elderly hypertension. An object of the present invention is to provide a pharmaceutical composition for use in a therapeutically effective amount to prevent and treat insufficient blood flow and brain function disorders in mammals (including humans). The conditions (non-limiting) applicable to the present invention include stroke and cerebrovascular disorders, which include asymptomatic cerebral infarction, atherosclerotic thrombotic cerebral infarction, lacunar infarction, cardiac cerebral infarction, transient ischemia Seizures (TIA), stroke, cerebrovascular dementia and hypertensive encephalopathy. Cerebral infarction: Cerebral infarction is an area of gangrene formed in the brain due to insufficient arterial or venous blood flow. Cerebral infarction is usually classified by hemisphere (meaning left-to-right), lobe (for example, frontal 95730.doc -26- 200523257 lobe infarction), arterial distribution (for example, anterior cerebral infarction), and pathogen (for example, embolic infarction). Cerebral infarction (stroke) is the interruption of blood supply to any part of the brain, which results in damaged brain tissue. Cerebral infarction is generally considered to be one of atherogenic thrombosis, psychogenic or lacunar. Cardiac infarction occurs with arrhythmias, especially with atrial fibrillation. Athematous thrombotic infarction occurs in conjunction with atherosclerosis. Lacunar space is a small area of cerebral infarction caused by occlusion of small peripheral branches of the middle cerebral artery, posterior cerebral artery, or basilar artery. Transient ischemic attack Transient ischemic attack (TIA) is a transient stroke that lasts only a few minutes. It occurs when the blood supply to the brain is temporarily interrupted. Sudden symptoms of TIA are usually similar to those of their stroke but do not last as long. Symptoms can last up to 24 hours, but most TIA symptoms disappear within an hour. Symptoms may include: numbness or weakness in the face, arms, or legs (especially one side of the body); confusion or difficulty in talking or understanding the conversation; difficulty in seeing with one or both eyes; difficulty in walking, dizziness or loss of balance and coordination . Stroke A sudden loss of consciousness caused by hypoxia in the brain due to ruptured or occluded blood. ..., Cerebrovascular dementia: The effect of a cerebrovascular disease is dementia. About 10% of dementia is due to repetitive small blockages of arterial branches caused by atherosclerosis, while 95730.doc 200523257 brain tissue is gradually destroyed due to lack of sufficient blood. Hypertensive encephalopathy: Southern blood pressure encephalopathy is defined as abnormal or impaired brain function caused by malignant high pressure, which is usually related to diastolic blood pressure in excess of 125 mmHg. Clinical manifestations include headache, nausea, vomiting, seizures, altered mental state (in some cases developing into a coma), optic nerve papillary edema, and retinal hemorrhage. Focal neurological symptoms can develop. Pathologically, this condition is related to the formation of cerebral ischemic disease (cerebral ischemia). The invention relates to a medicament for preventing the recurrence of cerebrovascular diseases, which contains as an active ingredient a compound having angiotensin π antagonistic activity, a prodrug or a salt thereof; and also relates to a method for improving the sequelae of cerebrovascular diseases and inhibiting their development. A medicament comprising, as an active ingredient, a compound having an angiotensin π antagonistic activity, a prodrug thereof, or a salt thereof. According to the third edition of the National Institute of Neurological Disorders and Stroke (MINDS) (MINDS-III, Stroke 21: 637-676, 1990), cerebrovascular disorders are classified into asymptomatic cerebral infarction and transient ischemia Seizures (TIA), stroke, cerebrovascular dementia and hypertensive encephalopathy. Types of stroke include cerebral hemorrhage, subarachnoid hemorrhage, cranial hemorrhage with cerebral arterial and venous malformations, and cerebral infarction. Cerebral infarction is divided into atherosclerotic gold embolism cerebral infarction, lacunar cerebral infarction and cardiogenic cerebral infarction. The risk factors for vascular disease are hypertension, and the risk factors for cerebral infarction include abnormal glucose resistance and abnormal electrocardiogram, and the risk factors of cerebral hemorrhage include abnormal electrocardiogram, fundus and drinking water. It has been pointed out that hypertension, heart 95730.doc • 28- 200523257 visceral diseases, Ding IA, diabetes, etc. are risk factors for the recurrence of cerebrovascular diseases' and that antihypertensive agents can be used not only to prevent cerebrovascular diseases (primary prevention) It can also be used to prevent its recurrence (secondary prevention). The invention also relates to a compound selected from angiotensin II receptor antagonists (especially valsartan), alpha-adrenergic antagonists, heart blockers, calcium channel blockers (CCB), and ACE inhibitors or Antihypertensive agents of salt for medicine for use in the preparation of pharmaceutical compositions for the prevention and treatment of insufficient blood flow and cerebral function diseases (or cerebrovascular disorders) in mammals (including humans), wherein these disorders include Asymptomatic cerebral infarction, atherosclerotic thrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebrovascular dementia, and hypertensive encephalopathy. The present invention also relates to a method for preventing and treating insufficient blood flow and cerebral function diseases or cerebrovascular disorders, wherein the disorders include asymptomatic cerebral infarct base, atherosclerotic thrombotic cerebral infarction, lacunar Infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebrovascular dementia and hypertensive encephalopathy, the method comprises administering a therapeutically effective amount of an angiotensin II receptor antagonist ( In particular, valsartan), ~ adrenaline antagonists, / 3-blockers, calcium channel blockers ((: :( :) 5), and the inhibitors or their pharmaceutical salts Hypertensive agent. The present invention also relates to a method for preventing, delaying development and treating insufficient blood flow and cerebral function diseases or cerebrovascular disorders, wherein the disorders include asymptomatic cerebral infarction, atherosclerotic thrombotic cerebral infarction , Lacunar infarct, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebral hemorrhagic dementia, and hypertensive encephalopathy, the method includes administering a therapeutically effective amount of 95730.doc -29- 200523257 from the blood Antihypertensive effects of contractin η receptor antagonists (especially valsartan), ... adrenaline antagonists, A blockers, calcium channel blockers (CCB), and ace inhibitors or their medicinal salts The present invention also relates to a compound selected from the group consisting of angiotensin π receptor antagonists (especially valproin'ytan), alpha-adrenergic antagonists, &amp; blockers, calcium channel blockers (CCB). And anti-hypertensive agents of the group of ACE inhibitors or a group of medicinal salts thereof for the prevention and treatment of insufficient blood flow and cerebral functional or cerebrovascular disorders in mammals (including humans) Symptomatic cerebral infarction, atherogenic thrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebrovascular dementia, and hypertensive encephalopathy.

These pharmaceutical compositions are their compositions for enteral (e.g. oral) and rectal or external administration to warm-blooded animals. The pharmacologically active ingredients are present on their own or together with commonly used pharmaceutical excipients. For example, the pharmaceutical composition contains about 0.1% to 100%, preferably about 1% to about 80% of the active ingredient for a pharmaceutical composition for enteral or parenteral administration and also for ocular administration. 4 ί are often pharmaceutical compositions such as sugar-coated pills, lozenges, capsules or suppositories, and early-dose dosage forms. These compositions are prepared from a known jadeite, such as a conventional mixed granule ^ + Μ sugar coating 'dissolution method ^ lyophilization method. Therefore, the mashin composition for oral Λ,, ^, serving can be obtained by granulating 9, and Japanese 榀 &gt; 右, if necessary, granulate the obtained 3 and 3, and if necessary or Bristol, 9+ accept ... After adding suitable excipients, the 3 substances or granules are processed to obtain lozenges or sugar-coated pills kernels. Suitable carriers are preferably bulking agents, dextrose (e.g. lactose, 95730.doc -30-200523257 sugar, mannitol or sorbitol), cellulose compositions and / or calcium phosphates (e.g. acid triphosphates) # 5 或 填 酸 氢 # 5) '· In addition, there are binders, such as; rice flour paste (for example, corn starch, wheat starch, rice starch or potato starch are usually used), gelatin, tragacanth, methyl cellulose and And / or polyethylene σ-pyrrolidone; and if necessary, a decomposing agent, such as the above-mentioned starch; in addition, there are carboxymethyl starch powder, cross-linked polyethylene π-bilopridone, agar, alginic acid or the like Salt (usually sodium alginate). Excipients are mainly flow regulators and lubricants, usually stone gum, talc, stearic acid or a salt thereof (usually magnesium stearate or calcium stearate), and / or polyethylene glycol. The sugar-coated pill core has a suitable coating that is resistant to gastric fluids when necessary, using a concentrated sugar solution containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, as appropriate, in a suitable organic solvent or solvent mixture The coating solution, or a solution of a suitable cellulose composition for the preparation of antigastric fluid coatings, is usually ethyl lisavidin phthalate or ethylmethyl cellulose phthalate. Colorants or pigments may be added to the capsule or sugar-coated pill coatings, for example, to identify or indicate different doses of the active ingredient. / The pharmaceutical composition used for piservium U is dry-filled gelatin capsules and soft closed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Dry-filled capsules may contain the active ingredient in particulate form, which is usually mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or stearate). In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid (e.g., fatty oil, stone-filled oil, or liquid polyethylene glycol) 'and a stabilizer may be added. 95730.doc -31-200523257 ^ The tincture composition for rectal administration is generally a test agent consisting of a living, aliquot, and a tincture composition. Suitable suppository bases are, for example, deciduous autumn or synthetic triglycerides, chain hydrocarbons and higher carbon number alcohols. In addition, ^ gelatin rectal capsules having a combination of active ingredient and base substance. Suitable base materials are, for example, liquid glycerin or paraffin. Ethylene glycol is suitable for parenteral administration of pharmaceutical compositions which are mainly aqueous solutions of the active ingredient in water-soluble form (usually water-soluble salts) and also a suspension of the active ingredient, such as using a suitable lipophilic solvent or vehicle (usually Fatty oils such as sesame oil, or synthetic fatty acid vinegar, usually ethyl oleate or triglyceride ^ Appropriate oily injection suspensions' or containing viscosifying substances (such as sodium methylcellulose sodium, sorbitol and / or glucose Glycan) and optional stabilizers in aqueous injection suspensions. Μ For prophylactic treatment, it is usually in the form of a lozenge or gel. Unit dosage forms for oral administration are preferably in sacs, and in acute The dosage of the active ingredient for intravenous application in the treatment may depend on pure factors such as the mode of application, the type of warm-blooded animal, age and / or individual state. The estimated normal dose for oral administration to patients weighing about 75 kg is Appropriate dosage of about 10 mg to about 25 mg of AT- party antagonist. A preferred embodiment of the present invention uses a pharmaceutically acceptable composition containing valsartan. In unit dose The daily dose of the ATP-antagonist valsartan is preferably about 20 mg to about 160 mg, more preferably about 40 mg or about 80 mg. 95730.doc -32- 200523257 [Embodiments] The following The examples illustrate the above invention, but do not limit its scope in any way. Formulation Example 1: Contains (S) -N- (1-carboxy-2-methylprop-1-yl) pentane as an active ingredient, for example The hard gelatin capsules of fluorenyl-N- [2 '(1H-tetrazol-5-yl) biphenyl-4-yl-methyl] amine are formulated as follows (for example): Components: (1) Prevalsartan 80_0 mg (2) microcrystalline cellulose 110.0 mg (3) povidone K30 45.2 mg (4) sodium lauryl sulfate 1.2 mg (5) cross-linked polyvinyl pyrrolidone 26.0 mg (6) magnesium stearate 2.6 mg Components (1) and (2) are granulated together with a solution of components (3) and (4) in water. Components (5) and (6) are added to the dry granules and the mixture is filled to a size of 1 In hard gelatin capsules. Formulation Example 2: Diovan bond product. Diovan. Diovan. Diovan. Lozenges. Lozenges. Lozenges. 40 mg 80 mg 160 mg 320 mg Ingredients Internal :, _Reading, discussing, discussing, _clicking, discussing, ______________________________________________________________________________________________________________________________________________________________________________________Prevalsartan 40.000 80.000 160.000 320.000 HCTZ — — — — Avicel 27.000 54.000 108.000 216.00 95730.doc -33- 200523257 Cross-linking Polyethylene is different from 7.500 15.000 30.000 60.000 Cab-0-Sil 0.750 1.500 3.000 6.000 magnesium stearate 1.500 3.000 6.000 12.000 external '+ medicine Xinli green magnesium stearate 0.750 1.500 3.000 6.000 weight 77.500 155.000 310.000 620.000 Table 1 Subject characteristics Control group (n = 16) Treatment group (n = 123) cd-blocker (n = 18) jSl-blocker (n = 30) ACE-I (n = 24) ARB ( (n = 24) Ca-antagonist (n = 27) Male: Female 8: 8 53:70 7:11 13:17 9:15 9:15 15:12 Age (years) 75 Tu 7 71 Shi 7 71 Tu 7 68 people 7 71 people 7 71 soil 6 73 soil 7 range (years) 62-85 60-86 60-82 60-81 60-86 60-86 60-86 MBP (mmHg) 109 ± 12 114 soil 11 111 people 6 115 ± 12 115 ± 13 115 ± 11 113 ± 9 Range (mmHg) 89-136 86-139 89-136 86-139 87-138 95-139 95-133 Values are the standard deviation of the number or average. mBP is the mean blood pressure. [Schematic description] Figure 1. Changes in average mBP and decrease in mBP between the control and treatment groups before and after one year ("mBP"). Compared to the control group, the mean mBP decreased and the Z1 mBP decreased significantly in the treatment group. Values are mean ± SD. §: Relative to control group ρ &lt; 0.001. Figure 2. 95730.doc -34- 200523257 The change in the frequency band (δ, 0, cd, α2, Lu1, and / 32)% power of the control group and the treatment group. The control group showed a significant increase in δ. The treatment group showed a decrease in δ and an increase in / 51. Figure 3. Changes in% power of all frequency bands (Z1 δ, ζ 0, slow wave,, 0: 2, Zee, zl / 51, Z / 32, and "fast wave") in the control and treatment groups. Compared with the control group, the treatment group showed a significant decrease in Z δ and J slow waves and an increase in zl αΐ. Values are averages (SD). Relative to the control group, +: ρ &lt; 0.10, *: ρ &lt; 〇 · 〇5, **: ρ &lt; 〇 · 〇ι 〇 These results show that compared with untreated patients, antihypertensive agents do not worsen and May improve baseline EEG. Figure 4. Changes in mean mBP of αΐ-blockers, / blockers, ace-1, ARB, and Ca-antagonists. The mean mBP of w-blockers, ace-1, ARB, and Ca-antagonists was significantly reduced. Values are mean ± SD. Compared to the previous, +: ρ &lt; 0 · 10, §: p &lt; 0.0001 0 These results show that / 31-blockers, ACE-I, ARB, and Ca-antagonists decrease mBP. Figure 5. mBp changes (Z mBp) in the control group and each treatment group treated with α1_blocker, -blocker, Ace-I, ARB, and Ca-antagonist. Compared with the control group, the z] mBP of blockers, ACE-I, ARB, and Ca-antagonists was significantly reduced. Relative to the control group, +: p &lt; 〇1〇, *: p &lt; 〇〇5, **: p &lt; 0_01 〇95730.doc 200523257 These results show / 51-blocker, ACE-I, ARB, and Ca -Antagonists all reduce mBP to varying degrees.

Ca-antagonists have the strongest reducing effect. Figure 6. Variations in power of the frequency bands (δ, 0, 0d, α2, / 31, and 2) of αΐ-blockers, / 31-blockers, ACH, ARB, and antagonists. ARB shows a decrease in δ and an increase in αΐ. The basic rhythm becomes d only in Arb. Values are mean ± SD. Relative to the previous, ρ &lt; 0.10. These results indicate that only ARB has an improvement trend in baseline EEG. Moving the baseline EEG to an ARB that is more normal than normal EEG can restore cerebral circulation and function. Figure 7. All frequency bands of blockers, blockers, aCE-I, ARB, and Ca-antagonists (δ, z 0, "slow wave", "α1", "α2", "", "^, "/ 52 and zl fast wave)% power change. Compared to the control group, d_blockers showed a decrease in "δ". The abusive blocker shows a decrease in zeta and α2 and an increase in z / 51. ACE] shows that δ increases. ARB shows a decrease, Z slow wave has a decreasing trend, "od increases, and ζΐ 〇: has an increasing trend. Values are averages (SD). Relative to the control group, +: ρ &lt; 〇 丨 〇, *: ρ &lt; 0.05, **: ρ &lt; 〇 · 〇ι 〇 These results show that αΐ-blockers and Ca-antagonists are as similar as the control group. Significant EEG ^: 化. The desired changes in EEG were observed in elderly patients with ABP treated with ARB, i.e., the slow wave decreased and the αΐ wave increased. 95730.doc -36-

Claims (1)

200523257 10. Scope of patent application: 1 A kind selected from angiotensin π receptor antagonist (especially valsartan), ... adrenaline antagonist, / 5-blocker, calcium channel blocker (ccb) &amp; ace inhibition; = 1 antihypertensive agent of the group or its medical salt for the preparation of a pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebrovascular disorders. 'These disorders include no Symptomatic cerebral infarction, atherosclerotic haemostatic cerebral infarction, lacunar infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebrovascular dementia, and hypertensive encephalopathy. 2. Use of an ATi-receptor antagonist according to claim 1, or a pharmaceutically acceptable salt thereof under various conditions, wherein the receptor antagonist is selected from the group consisting of: 95730.doc 200523257 m 95730.doc -2- 200523257 N 95730.doc 200523257 Mouthpieces where these conditions include asymptomatic cerebral infarction, atherosclerotic thrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), stroke, cerebrovascular Dementia and Hypertensive Encephalopathy 'The composition comprises a therapeutically effective amount selected from the group consisting of angiotensin π receptor antagonists (especially valsartan), adrenaline antagonists, heart blockers, calcium channel blockers ( CCB) and ACE inhibitors or antihypertensive agents thereof. 5. A method for preventing and treating insufficient blood flow and cerebrovascular disorders, wherein the disorders include asymptomatic cerebral infarction, atheromatous cerebral infarction, lacunar infarction, cardiogenic cerebral infarction, Transient ischemia 95730.doc 200523257 attack (TIA), stroke, cerebrovascular dementia, and hypertensive encephalopathy, the method comprises administering a therapeutically effective amount of an angiotensin II receptor antagonist (especially propane) Satan), ce-adrenergic antagonists, / 3-blockers, calcium channel blockers (CCB), and anti-hypertensive agents of the group of ACE inhibitors or groups of pharmaceutically acceptable salts thereof. 95730.doc