WO2005030202A1 - Use of angiotensin ii receptor antagonists for treating cerebrovascular disorders - Google Patents

Use of angiotensin ii receptor antagonists for treating cerebrovascular disorders Download PDF

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WO2005030202A1
WO2005030202A1 PCT/EP2004/010745 EP2004010745W WO2005030202A1 WO 2005030202 A1 WO2005030202 A1 WO 2005030202A1 EP 2004010745 W EP2004010745 W EP 2004010745W WO 2005030202 A1 WO2005030202 A1 WO 2005030202A1
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cerebral
blocker
infarction
angiotensin
mbp
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PCT/EP2004/010745
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French (fr)
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Hiroaki Iwakuma
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Novartis Ag
Novartis Pharma Gmbh
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention is dealing with the use of antihypertensive agents for the prevention and treatment of insufficient blood flow and cerebral functional disorders.
  • Antihypertensive agents include notably Angiotensin II receptor antagonists, Alpha- adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors.
  • Hypertension as one of cause of arteriosclerosis, activates tissue rennin - angiotensin system (RAS) deteriorating BP fluctuation in the long time and concurrence of complication.
  • RAS tissue rennin - angiotensin system
  • ATII angiotensin ⁇
  • ATII angiotensin ⁇
  • the sympathetic nerve is rather controllable in the elderly hypertension.
  • the enzyme cascade of the renin-angiotensin system comprises a series of biochemical sequences and, as is known, there are different approaches for opening up possibilities for the treatment of, for example, hypertension by regulatory intervention.
  • the RAS is the physiological adjustment factor to CBF- autoregulation together with the sympathetic nervous system.
  • ACE-I and ARB with the direct action to control RAS, decrease collagen content of cerebral artery which is formulated by AT ⁇ through AT1 receptor and improve the exhibition of the cerebral artery wall.
  • ARB blocks the action of ATI! at the final stage and controls the action of ATE more produced by the other enzymes except ACE.
  • ARB indirectly but eventually stimulates AT2 receptor giving opposite action to the hypertrophy and fibrous change and the adjustment of CBF (dual effects).
  • Angiotensinogen a oc2-macroglycoprotein
  • renin enzyme a oc2-macroglycoprotein
  • angiotensin I which itself is biologically only very weakly active.
  • the next step in the cascade is the removal of a further two amino acids by the action of the angiotensin-converting enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin II. This latter is held to be one of the strongest natural vasoconstrictors.
  • ACE angiotensin-converting enzyme
  • angiotensin II The vasoconstrictive effects of angiotensin II are produced by its action on the non-striated muscle cells, the stimulation of the formation of the adrenergenic hormones epinephrine and norepinephrine as well as by the increase of the activity of the sympathetic nervous system as a result of the formation of norepinephrine.
  • Angiotensin II also has an influence on the electrolytic balance, produces e.g. antinatriuretic and anitdiurectic effects in the kidney and accordingly promotes the release of, on the one hand, the vasopressin peptide from the pituitary gland and, on the other hand, of aldosterone from the adrenal glomerulosa. These influences all play an important part in the regulation of blood pressure.
  • Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes which are termed e.g. AT and AT 2 -receptors. Great efforts have been made lately to identify substances that bind to AT -receptors. Such active ingredients are often termed angiotensin II antagonists. Because of the inhibition of the AT receptor such antagonists can be used e.g. as antihypertensives or for the treatment of congestive heart failure.
  • Angiotensin II antagonists are understood to mean those active ingredients which bind to the AT receptor subtype. These include compounds having different structural features. Compounds to be mentioned are, for example, those cited in the compound claims of EP-443983, the subject matter of which is herewith incorporated by reference in this application.
  • valsartan (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'(1H- tetrazol-5-yl)biphenyl-4-yl-methyl]amine
  • angiotensin II receptor antagonists is valsartan.
  • a compound to be highlighted is that of the following formula and the pharmaceutically acceptable salts thereof.
  • a compound to be highlighted is that of the following formula and the pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of valsartan are typically acid addition salts. These acid addition salts are formed, for example, with strong inorganic acids, typically mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, typically with C ⁇ C ⁇ alkanecarboxylic acids which may be substituted, e.g.
  • halogen typically acetic acid, for example with dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, for example with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, for example with amino acids, such as aspartic acid or glutaminic acid, or e.g. benzoic acid, or with organic sulfonic acids, for example with C ⁇ C ⁇ alkanesu ⁇ fonic acids or arylsulfonic acids which may be substituted, e.g.
  • dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid
  • hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid
  • Suitable salts with bases are typically metal salts, such as alkali metal salts or alkaline earth metal salts, typically sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, typically ethylamine, tert-butylamine, diethylamine, diisoopropylamine, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or trihydroxy-lower alkylamine, typically mono-, di- or triethanolamine.
  • Corresponding internal salts can also be used.
  • Alpha-adrenergic antagonist ⁇ also called alpha blocker, alpha-adrenergic blocker, alpha adrenergic blocking agent, alpha blocker
  • alpha-adrenergic antagonists are known in the art.
  • alpha- adrenergic antagonists useful for the invention are preferably Doxazosin, terazosin disclosed in US4026894 and metazosin disclosed in US 4775673 and moxonidine disclosed in US 4323570.
  • the structure of the active agents identified by generic names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. (LifeCycle) Patents International (e.g. IMS world Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties e.g. in standard test models, both in vitro and in vivo.
  • Beta-blockers are known in the art.
  • a beta blocker preferably is a representative selected from the group consisting of a selective ⁇ 1 -blocker, such as atenolol, betaxolol, bisoprolol (especially the fumarate thereof), metoprolol (especially the hemi-(R,R)fumarate orfumarate thereof), furthermore, acebutolol (especially the hydrochloride thereof), esmolol (especially the hydrochloride thereof), celiproplol (especially the hydrochloride thereof), taliprolol, or acebutolol (especially the hydrochloride thereof), a non-selective ⁇ -blocker, such as oxprenolol (especially the hydrochloride thereof), pindolol, furthermore, propanolol (especially the hydrochloride thereof), bupranolol (especially the hydrochloride thereof), penbutolol (
  • beta-blockers useful for the salts of the invention are especially beta- blockers that have been marketed preferably carvedilol, oxprenolol, propanolol and metoprolol. More preferred are metoprolol and oxprenolol. Most preferred is oxprenolol.
  • the class of calcium channel blockers essentially comprises dihydropyridinrs (DHPs) and non DHPs such as diltiazem-type and verapamil-type CCBs.
  • DHPs dihydropyridinrs
  • a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, benidipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil,
  • CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
  • Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
  • a preferred DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof.
  • a preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
  • the class of ACE inhibitors comprises compounds having differing structural features.
  • Preferred ACE inhibitors are those agents which have been marketed, most preferred are benazepril and enalapril. Most preferred is benazepril It has been surprisingly found that antihypertensive agents can be used in therapeutically effective amount for the prevention and treatment of insufficient blood flow and cerebral functional disorders.
  • treatment refers to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of mammal including man, patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.
  • mBP mean blood pressure
  • EEG EEG
  • hypertensive agents were investigated based on influences on mean blood pressure (mBP) and EEG in elderly hypertensive patients. These experiments are relevant to hypertensive patients of all generations. Both mBP and EEG begin to change after 60 years old remarkably, and are clinically important for elderly hypertensive patients.
  • the subjects were 139 untreated elderly hypertensive patients (61 males, 78 females), over 60 years old and the casual systolic blood pressure (SBP) ⁇ 140 mmHg and/or diastolic blood pressure (DBP) ⁇ 90mmHg determined twice in the sitting position on different days.
  • SBP casual systolic blood pressure
  • DBP diastolic blood pressure
  • the EEG according to the 10-20 international system was recorded at resting state with eyes closed but alert.
  • the EEG derived from the 12 electrodes (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1 and O2) was analyzed by the Nihon Kohden Model EEG 7314 (Nishiochiai, Shinjyuku-ku Tokyo, Japan) with ATAMAPE .
  • the Nihon Kohden Model is a Topographic Electroencephalographic System, which permits assess cerebral function through quantitative and objective analysis of EEG. These data input were done to computer and underwent Fast Fourier Transformation . Fourier analysis is to dismantle complicated frequencies as the sum of a sine wave with serial different frequency and amplitude.
  • FFT is one of frequency analysis method with a high-speed operation by microcomputer. for the steady sampling epochs of 16 seconds, and spectral analysis of EEG was performed with separation into 9 frequency bands of delta (2-4Hz), theta (4-8Hz), slow (2-8Hz), alphal (8-10Hz), alpha2 (10-13Hz), alpha (8-13Hz), betal (13-20Hz), beta2 (20-30 Hz) and fast (13- 30 Hz) wave.
  • a classification of EEG frequency is generally divided into 6 frequency bands of delta (2- 4Hz), theta (4-8Hz), alphal (8-10Hz), alpha2 (10-13Hz), betal (13-20Hz), beta2 (20-30 Hz) wave.
  • EEG is often discussed by using 3 frequencies of slow (delta + theta), alpha (alphal + alpha2) and fast (betal + beta2) wave.
  • Normal EEG at rest is mainly constituted by alpha wave.
  • a superior EEG frequency is never slow wave, and delta wave is not recognized. Slow wave comes to develop in pathological condition such as abnormalities of cerebral circulation and function. Thus 9 frequency bands were used.
  • the % power of EEG expressing the proportion of each frequency band to all frequency bands was calculated. From the power spectrum obtained by FFT, the equivalent potential which is square root of power was calculated in each frequency band. The % power means the ratio of equivalent potential of a frequency band in the total equivalent potential of all frequency bands. The % power is available to evaluate the scalp distribution of EEGs quantitatively.
  • Average mBP of the treated group was decreased from 114 ⁇ 11 mmHg to 101 ⁇ 12 mmHg (p ⁇ 0.001).
  • Change in mBP ( lmBP) of the control group was -1.4 ⁇ 11.3 mmHg.
  • lmBP of treated group was -13.0 ⁇ 13.5 mmHg (p ⁇ 0.01) and was significant difference in comparison with control group (Figurel).
  • % power of delta in control group was increased from 22.6 ⁇ 13.3 % to 27.3 ⁇ 15.8 % (p ⁇ 0.05). % power of other waves were not changed significantly.
  • % power of delta and betal wave of treated group tended to decrease from 23.5 ⁇ 12.0 % to 21.9 ⁇ 11.2 % (p ⁇ 0.10), and tended to increase from 11.2 ⁇ 4.6 % to 11.7 ⁇ 5.3 % (p ⁇ 0.10), respectively ( Figure 2).
  • Treated group showed the reduction in ⁇ ddelta by -1.6 ⁇ 10.4 % (p ⁇ 0.01), Zlslow by -1.3 ⁇ 12.8 % (p ⁇ 0.05), and observed increasing tendency of lalphal by 1.2 ⁇ 11.8 % (p ⁇ 0.10) in average compared to control group ( Figure 3).
  • delta wave meaning sever cerebral hypofunction or CBF insufficiency
  • Treated hypertensive patients with antihypertensive agent can receive the decrease in delta wave and slow wave developing in pathological condition.
  • the reduction of Zldelta and Zlslow for treated patients means that treatment with antihypertensive agents can restore or improve cerebral function and CBF.
  • Average mBP of ⁇ 1 -blocker tended to decrease from 111 ⁇ 6 mmHg to 102 ⁇ 15 mmHg
  • ZlmBP of ⁇ -blocker by -12 ⁇ 12 mmHg (p ⁇ 0.05), ACE-I by -13 ⁇ 12 mmHg (p ⁇ 0.05), ARB by -14 ⁇ 15 mmHg (p ⁇ 0.05) and Ca-antagonist by -17 ⁇ 11 mmHg (p ⁇ 0.01) were significant difference than ZlmBP of control group ( Figure 5).
  • Respective % power of alpha2, beta2 and fast of ⁇ l -blocker tended to decrease from 13.3 ⁇ 7.8 % to 11.6 ⁇ 5.5 % (p ⁇ 0.10), increased from 11.6 ⁇ 5.3 % to 13.2 ⁇ 6.4 % (p ⁇ 0.05) and tended to increase from 18.6 ⁇ 8.0 % to 20.4 ⁇ 8.8 % (p ⁇ 0.10).
  • % power of delta and alphal wave of ARB tended to decrease from 21.9 ⁇ 12.1 % to 18.3 ⁇ 9.3 % (p ⁇ 0.10) and to increase from 25.8 ⁇ 14.0 % to 31.6 ⁇ 17.1 % (p ⁇ 0.10), These results show that the background EEG by ARB is changed from slow wave to alpha wave. Considering that desirable EEG consists of alpha wave mainly and has a few slow wave as possible, ARB can give good influence for cerebral function or CBF.
  • % power of beta2 was decreased from 7.2 ⁇ 3.2 % to 5.8 ⁇ 3.0 % (p ⁇ 0.05) % power of EEG of ⁇ 1 -blocker, ACE-I and Ca-antagonist were not changed significantly These results show that ⁇ 1 -blocker, ACE-I and Ca-antagonist have no influence on EEG. In control group, ⁇ 1-blocker, ⁇ l-blocker, ACE-I, ARB and Ca-antagonist, % power of alphal was not statistically significant in comparison with delta and theta, and was higher than alpha2, betal and beta2.
  • Zlalphal of ARB was increased by 5.8 ⁇ 15.4 % (p ⁇ 0.05). These result show that in comparison with control group, ARB can increase alphal wave.
  • ZJalpha2 of ⁇ -blocker tended to decrease by -1.7 ⁇ 5.3 % (p ⁇ 0.10).
  • Zlalpha of ARB tended to increase by 4.7 ⁇ 14.7 % (p ⁇ 0.10)
  • the brain has a system to keep constant CBF at the BP variation.
  • This CBF-autoregulation works between the lower limit of range of mBP with 50-70 mmHg and the upper limit of range of mBP with 150 mmHg.
  • the lower limit of CBF-autoregulation shifts to higher range of mBP with 110-120 mmHg resulting from the middle membrane hypertrophy of arteries (reduction in internal diameter) and the change in the arrangement of smooth muscle cell (remodeling , reduction in external diameter) of cerebral arteriole by the continuous high BP.
  • the change of such morphology makes possible to cause decrease CBF by insufficient cerebrovascular dilatation at the time of the excessive BP reduction.
  • the CBF-autoregulation is strong, but in case, the insufficient CBF breaks out easily even only a little reduction of BP.
  • EEG EEG
  • the alpha wave is a basis of the basic rhythm.
  • CBF autoregulation of elderly hypertension is often disturbed resulting from intimal thickening and remodeling of cerebral arteries. They prevent the decrease in CBF by the maximal autoregulatory vasodilatation and shift the lower limit of CBF autoregulation to higher range of mBP. They cannot furthermore dilate cerebral arteries for mBP reduction, and have deviation of original CBF autoregulatory range. Systemic mBP reduction by hypertensive agents promotes cerebral ischemia easily. This abnormality of CBF and cerebral functional state is observed on EEG. Especially slowing EEG, showing the increase of slow wave and decrease of alpha wave, is observed in early stage of these damages. In normal elderly over 60 years old, the incidence of slow wave, alpha wave and fast wave were about 15%, 60% and 25%, respectively (Gibbs). Alpha wave can be considered to be a basis of the basic rhythm.
  • Treated patients can improve EEG (decrease delta wave) in spite of mBP reduction.
  • hypertensive patients who can improve the residual ability of cerebral artery by treatment with antihypertensive agents.
  • antihypertensive agent can be used in the prevention and treatment of insufficient blood flow and cerebral functional disorders.
  • Antihypertensive agents are possible to give benefits, which are prevention of complications by lowering mBP and maintenance or recovery of cerebral function and CBF. Some antihypertensive agents may be applied to normotensive patients with disorders of CBF or cerebral function.
  • 100 mmHg as well as SBP 130 mmHg and DBP 85 mmHg can be useful and desirable even in the elderly hypertensive patients.
  • EEG of ACE-I and ARB may be affected by the decrease of AT E which acts cerebrovascular endothelial cell and contracting the cerebral artery.
  • AT E acts cerebrovascular endothelial cell and contracting the cerebral artery.
  • the more desirable change of EEG in ARB, showing decrease in delta wave, increase in alphal wave and the appearance of alphal wave as basic rhythm may be explained that ARB is able to control RA system more certainly in comparison with ACE-I.
  • Ca antagonist showed no influences on EEG. The reason is that Ca antagonist can not restrain the sympathetic nerve system and RA system even if there is some difference of degree.
  • /?1 -blocker, ACE-I and ARB controlling the rennin activity showed the good response both in mBP and EEG.
  • the minimum and maximum change in mBP for ⁇ -blocker was around by -12 mmHg and ARB by -14 mmHg respectively.
  • antihypertensive agent which can bring baseline EEG close to desirable EEG are ⁇ -blocker, ACE-I and ARB.
  • ARB brings baseline EEG more close to normal EEG.
  • the deterioration of original cerebral vasodilatation is mainly due to angiotensin II (AT E ).
  • ARB decreases collagen content of cerebral artery which is formulated by AT H through AT1 receptor, and improves the cerebrovascular dilatation (the residual ability of cerebral artery).
  • Average reduction of mBP is from -12 mmHg to -14 mmHg (around -13 mmHg) and has no difference in each agent.
  • the conditions for which the instant invention is useful include, without limitation, stroke and cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia and hypertensive encephalopathy.
  • stroke and cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia and hypertensive encephalopathy.
  • a cerebral infarction consists in the formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction).
  • hemisphere i.e., left vs. right
  • lobe e.g., frontal lobe infarction
  • arterial distribution e.g., infarction, anterior cerebral artery
  • etiology e.g., embolic infarction
  • Cerebral infarction is an interruption of the blood supply to any part of the brain, resulting in damaged brain tissue.
  • Cerebral infarction is commonly considered to be either atherothrombotic, cardioembolic or lacunar.
  • Cardioembolic infarction occurs together with arrhythmias, especially atrial fibrillation.
  • Atherothrombotic infarction occurs together with atherosclerosis.
  • a lacuna is a small area of cerebral ischemic infarction, resulting from occlusion of the small distal branches of the middle cerebral artery, posterior cerebral artery, or basilar artery.
  • Lacunae are associated with hypertension and arteriosclerosis.
  • TIA transient ischemic attack
  • TIA disappear within an hour, although they may persist for up to 24 hours.
  • Symptoms can include: numbness or weakness in the face, arm, or leg, especially on one side of the body; confusion or difficulty in talking or understanding speech; trouble seeing in one or both eyes; and difficulty with walking, dizziness, or loss of balance and coordination.
  • Cerebral apoplexy A sudden loss of consciousness resulting when the rupture or occlusion of a blood vessel leads to oxygen lack in the brain. Cerebrovascular dementia:
  • Hypertensive encephalopathy is defined by brain dysfunction or damage resulting from malignant hypertension, usually associated with a diastolic blood pressure in excess of 125 mmHg.
  • Clinical manifestations include headache, nausea, emesis, seizures, altered mental status (in some cases progressing to coma), papilledema, and retinal hemorrhage.
  • Focal neurologic signs may develop. Pathologically, this condition may be associated with the formation of ischemic lesions in the brain (brain ischemia).
  • the present invention relates to an agent for preventing recurrence of cerebrovascular disorder comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof as an active ingredient, as well as an agent for ameliorating troubles following cerebrovascular disorder and inhibiting progress thereof comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof as an active ingredient.
  • cerebrovascular disorder is classified into asymptomatic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, and hypertensive encephalopathy.
  • TIA transient ischemic attack
  • cerebral apoplexy cerebral hemorrhage, subarachnoid hemorrhage, cranial hemorrhage accompanying a malformation in cerebral arteries and veins, and cerebral infarction.
  • Cerebral infarction is classified into atherothrombotic cerebral infarction, lacuna infarction, and cardiogenic cerebral infarction.
  • the most dangerous factor for cerebrovascular disorder is hypertension
  • the dangerous factors for cerebral infarction include an abnormality of sugar resistance and an abnormality in electrocardiogram
  • the dangerous factors for cerebral hemorrhage include an abnormality in electrocardiogram, an abnormality in eye ground and drinking, and the like.
  • antihypertensive therapy is applied not only to prevention of occurrence of cerebrovascular disorder (primary prevention) but also to prevention of recurrence thereof (secondary prevention).
  • the invention also relates to the use an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebral functional disorders (or cerebrovascular disorders) including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy in mammal (including man).
  • Angiotensin II receptor antagonists especially valsartan
  • Alpha-adrenergic antagonists especially valsartan
  • Beta-blockers calcium channel blockers
  • ACE inhibitors or of a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebral functional disorders
  • the invention also relates to a process for the prevention and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , which process comprises administering a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
  • Angiotensin II receptor antagonists especially valsartan
  • Alpha-adrenergic antagonists especially valsartan
  • Beta-blockers calcium channel blockers (CCBs) and ACE inhibitors
  • ACE inhibitors or of a pharmaceutical salt thereof.
  • the invention also relates to a method of prevention, delay of progression and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , which process comprises administering a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
  • Angiotensin II receptor antagonists especially valsartan
  • Alpha-adrenergic antagonists especially valsartan
  • Beta-blockers calcium channel blockers (CCBs) and ACE inhibitors
  • ACE inhibitors or of a pharmaceutical salt thereof.
  • the invention also relates to the use of an antihypertensive agent selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the prevention and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy in mammal (including man).
  • an antihypertensive agent selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the prevention and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular
  • Said pharmaceutical compositions are those for enteral, such as oral, and also rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being present on its own or together with the usual pharmaceutical excipients.
  • the pharmaceutical compositions contain, for example, from about 0.1 % to 100 %, preferably from about 1 % to about 80 %, of the active ingredient.
  • Pharmaceutical compositions for enteral or parenteral and also for ocular administration are typically those in unit dose forms, such as dragees, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilising methods.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to give tablets or dragee cores.
  • Suitable carriers are preferably fillers, typically sugars, such as lactose, saccharose, mannitol or sorbitol, cellulose compositions and/or calcium phosphates, e.g. tricalcium phosphate or calciumhydrogen phosphate, furthermore binders, such as starch paste, typically using e.g. corn starch, wheat starch, rice starch or potato starch, gelatin, traga- canth gum, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrants, such as the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, typically sodium alginate.
  • sugars such as lactose, saccharose, mannitol or sorbitol
  • cellulose compositions and/or calcium phosphates e.g. tricalcium phosphate or calciumhydrogen phosphate
  • Excipients are primarily flow regulators and lubricants, typically silica gel, talcum, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose compositions, typically acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourants or pigments may be added to the tablets or dragee coatings, for example to identify or indicate different doses of active ingredient.
  • compositions for oral administration are dry-filled gelatin capsules as well as soft closed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of granules, typically in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talcum or magnesium stearate.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilisers can also be added.
  • Suitable pharmaceutical compositions for rectal administration are typically suppositories consisting of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons and higher alkanols.
  • gelatin rectal capsules containing a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • compositions for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, typically a water-soluble salt, and also suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
  • suitable lipophilic solvents or vehicles typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides
  • viscosity-increasing substances e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
  • unit dosage forms for oral administration are preferred, typically tablets or capsules and, in acute treatments, i.v. application forms.
  • the dose of the active ingredient can depend of various factors, e.g. mode of application, species of warm-blooded animal, age and/or individual state.
  • the estimated normal dose for oral administration to a patient weighing about 75 kg is an approximate dose of about 10 mg to about 250 mg of AT receptor antagonist.
  • compositions comprising valsartan are used.
  • the daily dose for oral administration of AT •] -antagonist valsartan in a unit dose form is preferably about 20 mg to about 160 mg, more preferably about 40 mg or about 80 mg.
  • a hard gelatin capsule comprising as active ingredient e.g. (S)-N-(1-carboxy-2-methylprop- 1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine, can be formulated, for example, as follows: Composition: (1) valsartan 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidone K30 45.2 mg (4) sodium lauryl sulfate 1.2 mg (5) crospovidone 26.0 mg (6) magnesium stearate 2.6 mg
  • Components (1 ) and (2) are granulated with a solution of components (3) and (4) in water.
  • the components (5) and (6) are added to the dry granulate and the mixture is filled into size 1 hard gelatin capsules.
  • Figure 1 Changes in average mBP and subtraction between before and after 1 year in mBP (ZlmBP) of control group and treated group. In treated group, average mBP was decreased and ZlmBP was decreased significantly in comparison with control group. Values are mean ⁇ SD. ⁇ : p ⁇ 0.001 versus control group.
  • Figure 2. Changes in % power of frequency bands (delta, theta, alphal , alpha2, betal and beta2) of control group and treated group. Control group showed a significant increase of delta. Treated group showed a decreasing tendency of delta and an increasing tendency of betal .
  • Figure 3 Changes in average mBP and subtraction between before and after 1 year in mBP (ZlmBP) of control group and treated group. In treated group, average mBP was decreased and ZlmBP was decreased significantly in comparison with control group. Values are mean ⁇ SD. ⁇ : p ⁇ 0.001 versus control group.
  • Figure 2. Changes in % power of frequency bands (delta, theta, alphal
  • mBP ZimBP of ⁇ 1-blocker, ACE-I, ARB and Ca antagonist were decreased significantly in comparison with control group, f: p ⁇ 0.10, *: p ⁇ 0.05, **: p ⁇ 0.01 versus control group.
  • ARB shifting a baseline EEG to a more normal EEG may restore cerebral circulation and function.
  • ⁇ 1 -blocker showed a decreasing tendency of Zldelta.
  • ⁇ -blocker showed a decrease of Zldelta and Z)alpha2 and an increase of
  • ACE-I showed a decrease of Zldelta.
  • ARB showed a decrease of Zldelta, a decreasing tendency of Zlslow, an increase of Zalphal and an increasing tendency of
  • Zalpha Values are mean (SD). f: p ⁇ 0.10, *: p ⁇ 0.05, **: p ⁇ 0.01 versus control group.

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Abstract

Antihypertensive agents selected from the group of Angiotensin II receptor antagonists (especially the compound (S)-­N-(l -carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl) biphenyl-4-yl-methyl] amine (valsartan) of formula (I), 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

USE OF ANGIOTENSIN II RECEPTOR ANTAGONISTS FOR TREATING CEREBROVASCULAR DISORDERS
Use of Organic Compounds
The invention is dealing with the use of antihypertensive agents for the prevention and treatment of insufficient blood flow and cerebral functional disorders.
Antihypertensive agents include notably Angiotensin II receptor antagonists, Alpha- adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors.
Hypertension, as one of cause of arteriosclerosis, activates tissue rennin - angiotensin system (RAS) deteriorating BP fluctuation in the long time and concurrence of complication. In hypertension, angiotensin π (ATII), causing remodeling as a major factor for reduction in cerebrovascular diameter and norepinephrine, stimulating sympathetic nerve are often going up. But the sympathetic nerve is rather controllable in the elderly hypertension.
The enzyme cascade of the renin-angiotensin system (RAS) comprises a series of biochemical sequences and, as is known, there are different approaches for opening up possibilities for the treatment of, for example, hypertension by regulatory intervention. The RAS is the physiological adjustment factor to CBF- autoregulation together with the sympathetic nervous system. ACE-I and ARB with the direct action to control RAS, decrease collagen content of cerebral artery which is formulated by ATπ through AT1 receptor and improve the exhibition of the cerebral artery wall. ARB blocks the action of ATI! at the final stage and controls the action of ATE more produced by the other enzymes except ACE. In addition, ARB indirectly but eventually stimulates AT2 receptor giving opposite action to the hypertrophy and fibrous change and the adjustment of CBF (dual effects).
Angiotensinogen, a oc2-macroglycoprotein, is split by the renin enzyme into the decapeptide angiotensin I, which itself is biologically only very weakly active. The next step in the cascade is the removal of a further two amino acids by the action of the angiotensin-converting enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin II. This latter is held to be one of the strongest natural vasoconstrictors. The vasoconstrictive effects of angiotensin II are produced by its action on the non-striated muscle cells, the stimulation of the formation of the adrenergenic hormones epinephrine and norepinephrine as well as by the increase of the activity of the sympathetic nervous system as a result of the formation of norepinephrine. Angiotensin II also has an influence on the electrolytic balance, produces e.g. antinatriuretic and anitdiurectic effects in the kidney and accordingly promotes the release of, on the one hand, the vasopressin peptide from the pituitary gland and, on the other hand, of aldosterone from the adrenal glomerulosa. These influences all play an important part in the regulation of blood pressure.
Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes which are termed e.g. AT and AT2-receptors. Great efforts have been made lately to identify substances that bind to AT -receptors. Such active ingredients are often termed angiotensin II antagonists. Because of the inhibition of the AT receptor such antagonists can be used e.g. as antihypertensives or for the treatment of congestive heart failure.
Angiotensin II antagonists are understood to mean those active ingredients which bind to the AT receptor subtype. These include compounds having different structural features. Compounds to be mentioned are, for example, those cited in the compound claims of EP-443983, the subject matter of which is herewith incorporated by reference in this application.
A compound to be highlighted is (S)-N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'(1H- tetrazol-5-yl)biphenyl-4-yl-methyl]amine (hereinafter termed valsartan) of formula
Figure imgf000003_0001
cited in European patent application having the publication no. EP-443983, Example 16, or a salt thereof, preferably a pharmaceutically acceptable salt thereof. Preferred angiotensin II receptor antagonists is valsartan.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-253310 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000004_0001
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-403159 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000004_0002
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of PCT patent application WO 91/14679 are, with reference to this literature, herewith also included in this application. A compound to be highlighted is that of the following formula
Figure imgf000005_0001
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-420 237 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000005_0002
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-502314 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000006_0001
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-459136 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000006_0002
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-504888 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000007_0001
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-514198 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000007_0002
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of European patent application having the publication no. EP-475206 are incorporated by reference in this application.
A compound to be highlighted is that of the following formula
Figure imgf000008_0001
and the pharmaceutically acceptable salts thereof.
Furthermore, the compounds cited in the compound claims of PCT patent application WO 93/20816 are incorporated by reference included in this application.
A compound to be highlighted is that of the following formula
Figure imgf000008_0002
and the pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of valsartan, for example, are typically acid addition salts. These acid addition salts are formed, for example, with strong inorganic acids, typically mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, typically with C^C^alkanecarboxylic acids which may be substituted, e.g. by halogen, typically acetic acid, for example with dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, for example with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, for example with amino acids, such as aspartic acid or glutaminic acid, or e.g. benzoic acid, or with organic sulfonic acids, for example with C^C^alkanesuϊfonic acids or arylsulfonic acids which may be substituted, e.g. by halogen, for example with methane- or p-toluenesulfonic acid. Suitable salts with bases are typically metal salts, such as alkali metal salts or alkaline earth metal salts, typically sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, typically ethylamine, tert-butylamine, diethylamine, diisoopropylamine, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or trihydroxy-lower alkylamine, typically mono-, di- or triethanolamine. Corresponding internal salts can also be used.
Alpha-adrenergic antagonist^ also called alpha blocker, alpha-adrenergic blocker, alpha adrenergic blocking agent, alpha blocker) are known in the art. Examples of alpha- adrenergic antagonists useful for the invention are preferably Doxazosin, terazosin disclosed in US4026894 and metazosin disclosed in US 4775673 and moxonidine disclosed in US 4323570.
The structure of the active agents identified by generic names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. (LifeCycle) Patents International (e.g. IMS world Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties e.g. in standard test models, both in vitro and in vivo.
Beta-blockers are known in the art. A beta blocker preferably is a representative selected from the group consisting of a selective β1 -blocker, such as atenolol, betaxolol, bisoprolol (especially the fumarate thereof), metoprolol (especially the hemi-(R,R)fumarate orfumarate thereof), furthermore, acebutolol (especially the hydrochloride thereof), esmolol (especially the hydrochloride thereof), celiproplol (especially the hydrochloride thereof), taliprolol, or acebutolol (especially the hydrochloride thereof), a non-selective β-blocker, such as oxprenolol (especially the hydrochloride thereof), pindolol, furthermore, propanolol (especially the hydrochloride thereof), bupranolol (especially the hydrochloride thereof), penbutolol (especially the sulphate thereof), mepindolol (especially the sulphate thereof), carteolol (especially the hydrochloride thereof) or nadolol, and a β-blocker with α-blocking activity such as carvedilol; or in each case, a pharmaceutically acceptable salt thereof. Preferred examples of beta-blockers useful for the salts of the invention are especially beta- blockers that have been marketed preferably carvedilol, oxprenolol, propanolol and metoprolol. More preferred are metoprolol and oxprenolol. Most preferred is oxprenolol.
The class of calcium channel blockers (CCBs) essentially comprises dihydropyridinrs (DHPs) and non DHPs such as diltiazem-type and verapamil-type CCBs. A CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, benidipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, a pharmaceutically acceptable salt thereof. All these CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs. Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof. A preferred DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof. A preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
The class of ACE inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or, in each case, a pharmaceutically acceptable salt thereof.
Preferred ACE inhibitors are those agents which have been marketed, most preferred are benazepril and enalapril. Most preferred is benazepril It has been surprisingly found that antihypertensive agents can be used in therapeutically effective amount for the prevention and treatment of insufficient blood flow and cerebral functional disorders.
In the present description the terms "treatment" or "treat" refer to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of mammal including man, patients at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.
The favourable effect of antihypertensive agents that can be used in therapeutically effective amount for the prevention and treatment of insufficient blood flow and cerebral functional disorders, can be manifested, for example, by the following experimental procedure:
MATERIALS AND METHODS
The person skilled in the pertinent art is fully enabled to select a relevant test model to prove the efficacy of the antihypertensive agents of the present invention in the hereinbefore and hereinafter indicated therapeutic indications.
Clinical relations between treatment of hypertension and cerebral function measured by electroencephalogram (EEG) are reported below.
Usefulness and characteristics of hypertensive agents were investigated based on influences on mean blood pressure (mBP) and EEG in elderly hypertensive patients. These experiments are relevant to hypertensive patients of all generations. Both mBP and EEG begin to change after 60 years old remarkably, and are clinically important for elderly hypertensive patients.
The subjects were 139 untreated elderly hypertensive patients (61 males, 78 females), over 60 years old and the casual systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90mmHg determined twice in the sitting position on different days. They were classified into 16 patients without an antihypertensive agent (control group) and 123 patients with an antihypertensive agent (treated group) who consist of 8 with o - blocker (σ1 -blocker), 30 with selective β -blocker (?1 -blocker), 24 with angiotensin converting enzyme inhibitor (ACE-I), 24 with angiotensin E receptor blocker (ARB) and 27 with Ca antagonist (Ca-antagonist). There was not a difference in the average age, the ratio of male / female and the value of mBP (Table 1 ).
Doxazosin (2mg/day) as α -blocker, bisoprolol (5mg/day), betaxolol (10mg/day) asβl- blocker, quinapril (10mg/day) and imidapril (10mg/day) as ACE-I, valsartan (80mg/day) as ARB, and nitrendipine (10mg/day) and benidipine (4mg/day) as Ca-antagonist was administered once daily in the morning for 1 year, and was the same dosage during the study period.
After casual mBP measurement, the EEG according to the 10-20 international system was recorded at resting state with eyes closed but alert. The EEG derived from the 12 electrodes (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1 and O2) was analyzed by the Nihon Kohden Model EEG 7314 (Nishiochiai, Shinjyuku-ku Tokyo, Japan) with ATAMAPE . The Nihon Kohden Model is a Topographic Electroencephalographic System, which permits assess cerebral function through quantitative and objective analysis of EEG. These data input were done to computer and underwent Fast Fourier Transformation . Fourier analysis is to dismantle complicated frequencies as the sum of a sine wave with serial different frequency and amplitude. FFT is one of frequency analysis method with a high-speed operation by microcomputer. for the steady sampling epochs of 16 seconds, and spectral analysis of EEG was performed with separation into 9 frequency bands of delta (2-4Hz), theta (4-8Hz), slow (2-8Hz), alphal (8-10Hz), alpha2 (10-13Hz), alpha (8-13Hz), betal (13-20Hz), beta2 (20-30 Hz) and fast (13- 30 Hz) wave.
A classification of EEG frequency is generally divided into 6 frequency bands of delta (2- 4Hz), theta (4-8Hz), alphal (8-10Hz), alpha2 (10-13Hz), betal (13-20Hz), beta2 (20-30 Hz) wave. EEG is often discussed by using 3 frequencies of slow (delta + theta), alpha (alphal + alpha2) and fast (betal + beta2) wave. Normal EEG at rest is mainly constituted by alpha wave. A superior EEG frequency is never slow wave, and delta wave is not recognized. Slow wave comes to develop in pathological condition such as abnormalities of cerebral circulation and function. Thus 9 frequency bands were used.
The % power of EEG expressing the proportion of each frequency band to all frequency bands was calculated. From the power spectrum obtained by FFT, the equivalent potential which is square root of power was calculated in each frequency band. The % power means the ratio of equivalent potential of a frequency band in the total equivalent potential of all frequency bands. The % power is available to evaluate the scalp distribution of EEGs quantitatively. Statistical analysis
Data were expressed as the mean ± standard deviation. Results of mBP and % power of EEG were compared before and 1 year after treatment. The t-test (Student's t-test or Welch's t-test) , and Newman-Keulus's test for multiple comparison were used. The differences at p<0.05 were defined as statistically significant.
From presence or absence of dispersion, Student's t-test or Welch's t-test is used properly in comparison of mean value between two independence, respectively. Newman-Keulus's test is one of multiplex comparison method and used broadly for comparison between averages of many groups. RESULTS
The control group and the treated group
After 1 year, average mBP of control group was not changed significantly from 109 ± 12 mmHg to 107 ± 9 mmHg. Untreated hypertensive patients remain high mBP. The presence of insignificant decrease of mBP suggests that the change of DBP decrease is more than that of SBP increase in one year.
Average mBP of the treated group was decreased from 114 ± 11 mmHg to 101 ± 12 mmHg (p<0.001). Change in mBP ( lmBP) of the control group was -1.4 ± 11.3 mmHg. lmBP of treated group was -13.0 ± 13.5 mmHg (p<0.01) and was significant difference in comparison with control group (Figurel).
These data show that elderly hypertensive patients can receive the definite mBP reduction by antihypertensive agents.
After 1 year, % power of delta in control group was increased from 22.6 ± 13.3 % to 27.3 ± 15.8 % (p<0.05). % power of other waves were not changed significantly. % power of delta and betal wave of treated group tended to decrease from 23.5 ± 12.0 % to 21.9 ± 11.2 % (p<0.10), and tended to increase from 11.2 ± 4.6 % to 11.7 ± 5.3 % (p<0.10), respectively (Figure 2). After 1 year, changes in % power of delta ( ldelta), theta (Zltheta), slow ( lslow), alphal ( lalphal), alpha2 (Zlalpha2), alpha ( lalpha), betal (Zlbetal), beta2 (Zlbeta2) and fast (Zlfast) wave were 4.7 ± 7.8 %, -0.6 ± 4.0 %, 4.0 ± 8.5 %, -3.8 ± 9.6 %, 1.0 ± 2.9 %, -2.8 ± 10.3 %, -0.6 ± 3.7 %, -0.7 ± 3.2 % and -1.3 ± 6.3 %, respectively. Treated group showed the reduction in ^ddelta by -1.6 ± 10.4 % (p<0.01), Zlslow by -1.3 ± 12.8 % (p<0.05), and observed increasing tendency of lalphal by 1.2 ± 11.8 % (p<0.10) in average compared to control group (Figure 3). For untreated hypertensive patients, delta wave, meaning sever cerebral hypofunction or CBF insufficiency, is increased. Treated hypertensive patients with antihypertensive agent can receive the decrease in delta wave and slow wave developing in pathological condition. The reduction of Zldelta and Zlslow for treated patients means that treatment with antihypertensive agents can restore or improve cerebral function and CBF.
Difference each antihypertensive agent
Average mBP of σ1 -blocker tended to decrease from 111 ± 6 mmHg to 102 ± 15 mmHg
(p<0.10). Average mBP of 1 -blocker, ACE-I, ARB and Ca-antagonist were decreased from
115 ± 12 mmHg to 103 ± 10 mmHg (pθ.001), from 115 ± 13 mmHg to 102 ± 12 mmHg
(p<0.001), from 115 ± 11 mmHg to 101 ± 16 mmHg (p< 0.001), and from 113 ± 9 mmHg to
96 ± 9 mmHg (p<0.001 ) respectively (Figure 4)
These data show that antihypertensive agents, except σ1 -blocker, can control mBP.
ZlmBP of σ1 -blocker by -8.4 ± 18.7 mmHg was not different significantly
These data show that mBP reduction by σ1 -blocker was insignificant as well as mBP change of control group. One reason may be that mBP change by σ1 -blocker has large drifting width
(standard deviation).)
ZlmBP of β\ -blocker by -12 ± 12 mmHg (p<0.05), ACE-I by -13 ± 12 mmHg (p<0.05), ARB by -14 ± 15 mmHg (p<0.05) and Ca-antagonist by -17 ± 11 mmHg (p<0.01) were significant difference than ZlmBP of control group (Figure 5).
These data show that β\ -blocker, ACE-I, ARB and Ca-antagonist lower mBP. Degree of mBP lowering is different of each agent. Ca-antagonist is the strongest. ARB is secondly strong and located between ACE-I and Ca-antagonist.
Respective % power of alpha2, beta2 and fast of βl -blocker tended to decrease from 13.3 ± 7.8 % to 11.6 ± 5.5 % (p<0.10), increased from 11.6 ± 5.3 % to 13.2 ± 6.4 % (p<0.05) and tended to increase from 18.6 ± 8.0 % to 20.4 ± 8.8 % (p<0.10).
% power of delta and alphal wave of ARB tended to decrease from 21.9 ± 12.1 % to 18.3 ± 9.3 % (p<0.10) and to increase from 25.8 ± 14.0 % to 31.6 ± 17.1 % (p<0.10), These results show that the background EEG by ARB is changed from slow wave to alpha wave. Considering that desirable EEG consists of alpha wave mainly and has a few slow wave as possible, ARB can give good influence for cerebral function or CBF. % power of beta2 was decreased from 7.2 ± 3.2 % to 5.8 ± 3.0 % (p<0.05) % power of EEG of σ1 -blocker, ACE-I and Ca-antagonist were not changed significantly These results show that σ1 -blocker, ACE-I and Ca-antagonist have no influence on EEG. In control group, σ1-blocker, βl-blocker, ACE-I, ARB and Ca-antagonist, % power of alphal was not statistically significant in comparison with delta and theta, and was higher than alpha2, betal and beta2. These result show that on baseline EEGs of σ1 -blocker, β\ -blocker, ACE-I, ARB and Ca- antagonist, basic rhythm showing the most superior action is not alphal wave. In addition, the prevalence of delta wave, theta wave and alphal wave are not different. After 1 year, the same distribution of alphal wave remained in control group, σ1 -blocker, β\- blocker, ACE-I and Ca-antagonist. These results show that σ1 -blocker, β"\ -blocker, ACE-I and Ca-antagonist cannot form basic rhythm of alphal wave.
Only in ARB, % power of alphal was higher than any other waves (Figure 6). These results show that ARB can replace basic rhythm by alphal wave. It is only ARB that makes normal basic rhythm.
In comparison with control group, Zldelta of σ1 -blocker tended to decrease by -0.8 ± 10.0 % (p<0.10), and Zidelta of β -blocker, ACE-I and ARB was decreased by -2.4 ± 10.4 % (p<0.05), by -1.5 ± 8.3 % (p<0.05) and by -3.6 ± 10.0 % (p<0.01) respectively. These results show that β\ -blocker, ACE-I and ARB can decrease delta wave, but Ca- antagonist cannot decrease delta wave as well as control group. Zlslow of ARB tended to decrease by -2.7 ± 14.7 % (p<0.10) These result show that in comparison with control group, ARB has decreasing tendency of slow wave.
Zlalphal of ARB was increased by 5.8 ± 15.4 % (p<0.05). These result show that in comparison with control group, ARB can increase alphal wave.
ZJalpha2 of β\ -blocker tended to decrease by -1.7 ± 5.3 % (p<0.10). Zlalpha of ARB tended to increase by 4.7 ± 14.7 % (p<0.10)
These result show that in comparison with control group, ?1-blocke has decreasing tendency of alpha2 wave. ARB has increasing tendency of alpha wave.
Zlbetal of β\ -blocker was increased by 1.6 ± 3.5 % (p<0.05). Ztheta, Zbeta2 and Zifast of each antihypertensive agent were not statistically significant (Figure 7). These result show that in comparison with control group, β\ -blocker increases betal wave. There is no change of theta, beta2 and fast wave for all hypertensive agents as well as control group. Antihypertensive agents have no influence of theta, beta2 and fast wave.
The brain has a system to keep constant CBF at the BP variation. This CBF-autoregulation works between the lower limit of range of mBP with 50-70 mmHg and the upper limit of range of mBP with 150 mmHg. In hypertension, the lower limit of CBF-autoregulation shifts to higher range of mBP with 110-120 mmHg resulting from the middle membrane hypertrophy of arteries (reduction in internal diameter) and the change in the arrangement of smooth muscle cell (remodeling , reduction in external diameter) of cerebral arteriole by the continuous high BP. The change of such morphology makes possible to cause decrease CBF by insufficient cerebrovascular dilatation at the time of the excessive BP reduction. The CBF-autoregulation is strong, but in case, the insufficient CBF breaks out easily even only a little reduction of BP. Regarding EEG, by the aging at the time of the reduction of CBF and the cerebral hypof unction, slow wave is increased and alpha wave is decreased. This slowing EEG is observed before neuron irreversible damage . The alpha wave is a basis of the basic rhythm.
The brain has the mechanism keeping the constant CBF for blood pressure variation (CBF autoregulation). CBF autoregulation of elderly hypertension is often disturbed resulting from intimal thickening and remodeling of cerebral arteries. They prevent the decrease in CBF by the maximal autoregulatory vasodilatation and shift the lower limit of CBF autoregulation to higher range of mBP. They cannot furthermore dilate cerebral arteries for mBP reduction, and have deviation of original CBF autoregulatory range. Systemic mBP reduction by hypertensive agents promotes cerebral ischemia easily. This abnormality of CBF and cerebral functional state is observed on EEG. Especially slowing EEG, showing the increase of slow wave and decrease of alpha wave, is observed in early stage of these damages. In normal elderly over 60 years old, the incidence of slow wave, alpha wave and fast wave were about 15%, 60% and 25%, respectively (Gibbs). Alpha wave can be considered to be a basis of the basic rhythm.
It has been shown that the incidence of slow wave in patients, with dementia (a high score for Hasegawa scale) or gait inability, is higher than patients without these symptoms. The incidence of slow wave has close relation to the quality of life (QOL) including cerebral function and gait ability.
Hypertensive patients without administration of antihypertensive agent.
In this study the hypertensive patients without administration of antihypertensive agent showed insignificant change in mBP and final value of mBP at about 107 mmHg. But, the delta wave was significantly increased. These results show that in elderly hypertension, continuous high pressure for one year aggravates EEG (the increase in delta wave).
1 year treated patients with antihypertensive agents.
1 year treated patients with antihypertensive agents showed reduction of mBP with a tendency to decrease delta wave and to increase betal wave. In comparison with control group, they showed decreasing changes in mBP, delta and slow wave and increasing tendency of change in alphal wave.
These results show that the decrease CBF due to mBP reduction is generally concerned.
Treated patients can improve EEG (decrease delta wave) in spite of mBP reduction. There are hypertensive patients who can improve the residual ability of cerebral artery by treatment with antihypertensive agents.
These results also indicate that antihypertensive agent can be used in the prevention and treatment of insufficient blood flow and cerebral functional disorders.
Antihypertensive agents are possible to give benefits, which are prevention of complications by lowering mBP and maintenance or recovery of cerebral function and CBF. Some antihypertensive agents may be applied to normotensive patients with disorders of CBF or cerebral function.
The mBP reduction by antihypertensive agents does not deteriorate baseline EEG, and the use of antihypertensive agents produces a good result of EEG.
For the cerebral function, the reduction of mBP by -13 mmHg and reached mBP at about
100 mmHg as well as SBP 130 mmHg and DBP 85 mmHg can be useful and desirable even in the elderly hypertensive patients.
These result show that mBP calculated from SBP 130 mmHg and DBP 85 mmHg, as hypertensive value adopted by JNC VI, is equivalent to 100 mmHg. SBP 130 mmHg and DBP 85 mmHg is different from mBP lOOmmHg. Thus considering EEG, the use of mBP lOOmmHg is more useful.
In each antihypertensive agent, the decrease in mBP of /?1 -blocker, ACE-I, ARB and Ca- antagonist, the decrease delta wave of ?1 -blocker, ACE-I and ARB, the increase in alphal wave of ARB and the increase betal wave of β\ -blocker were statistically significant. These results show that the degree of mBP reduction is not different by ?1 -blocker, ACE-I, ARB and Ca-antagonist, but each agent has different influence on EEG. σ1 -blocker showed no changes on EEG, though σ1 -blocker tended to decrease mBP and generally has weak action of catecholamine to the cerebral artery but no relation to sympathetic nerve for CBF at rest.
The influences on EEG of ACE-I and ARB may be affected by the decrease of AT E which acts cerebrovascular endothelial cell and contracting the cerebral artery. The more desirable change of EEG in ARB, showing decrease in delta wave, increase in alphal wave and the appearance of alphal wave as basic rhythm may be explained that ARB is able to control RA system more certainly in comparison with ACE-I. Ca antagonist showed no influences on EEG. The reason is that Ca antagonist can not restrain the sympathetic nerve system and RA system even if there is some difference of degree. /?1 -blocker, ACE-I and ARB controlling the rennin activity showed the good response both in mBP and EEG. The minimum and maximum change in mBP for β\ -blocker was around by -12 mmHg and ARB by -14 mmHg respectively.
This result show that antihypertensive agent which can bring baseline EEG close to desirable EEG are β -blocker, ACE-I and ARB. Above all, ARB brings baseline EEG more close to normal EEG. The deterioration of original cerebral vasodilatation is mainly due to angiotensin II (AT E ). ARB decreases collagen content of cerebral artery which is formulated by AT H through AT1 receptor, and improves the cerebrovascular dilatation (the residual ability of cerebral artery). Average reduction of mBP is from -12 mmHg to -14 mmHg (around -13 mmHg) and has no difference in each agent.
This study shows that the BP lowering by the antihypertensive agent, especially ARB with the certain control of RAS is useful in the elderly hypertensive patients. For the cerebral function, the mBP at around 100 mmHg and the reduction in mBP by around -13 mmHg obtained from this study may be useful as one of guidelines for the treatment of elderly hypertension.
It is the object of this invention to provide pharmaceutical compositions for use in therapeutically effective amount for the prevention and treatment of insufficient blood flow and cerebral functional disorders ( or cerebral disorders) in mammal (including man).
The conditions for which the instant invention is useful include, without limitation, stroke and cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia and hypertensive encephalopathy.
Cerebral infarction:
A cerebral infarction consists in the formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction).
Cerebral infarction (stroke) is an interruption of the blood supply to any part of the brain, resulting in damaged brain tissue.
Cerebral infarction is commonly considered to be either atherothrombotic, cardioembolic or lacunar.
Cardioembolic infarction occurs together with arrhythmias, especially atrial fibrillation.
Atherothrombotic infarction occurs together with atherosclerosis.
A lacuna is a small area of cerebral ischemic infarction, resulting from occlusion of the small distal branches of the middle cerebral artery, posterior cerebral artery, or basilar artery.
Lacunae are associated with hypertension and arteriosclerosis.
Transient Ischemic Attack
A transient ischemic attack (TIA) is a transient stroke that lasts only a few minutes. It occurs when the blood supply to part of the brain is briefly interrupted. TIA symptoms, which usually occur suddenly, are similar to those of stroke but do not last as long. Most symptoms of a
TIA disappear within an hour, although they may persist for up to 24 hours. Symptoms can include: numbness or weakness in the face, arm, or leg, especially on one side of the body; confusion or difficulty in talking or understanding speech; trouble seeing in one or both eyes; and difficulty with walking, dizziness, or loss of balance and coordination. Cerebral apoplexy A sudden loss of consciousness resulting when the rupture or occlusion of a blood vessel leads to oxygen lack in the brain. Cerebrovascular dementia:
An effect of cerebrovascular disease is dementia. About 10% of cases of dementia are due to small, repeated blockages of arterial branches by atherosclerosis, with progressive overall destruction of brain tissue because it is being deprived of enough blood. Hypertensive encephalopathy:
Hypertensive encephalopathy is defined by brain dysfunction or damage resulting from malignant hypertension, usually associated with a diastolic blood pressure in excess of 125 mmHg. Clinical manifestations include headache, nausea, emesis, seizures, altered mental status (in some cases progressing to coma), papilledema, and retinal hemorrhage. Focal neurologic signs may develop. Pathologically, this condition may be associated with the formation of ischemic lesions in the brain (brain ischemia).
The present invention relates to an agent for preventing recurrence of cerebrovascular disorder comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof as an active ingredient, as well as an agent for ameliorating troubles following cerebrovascular disorder and inhibiting progress thereof comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof as an active ingredient.
According to the classification of cerebrovascular disorder, 3rd edition (MINDS-MI, Stroke
21:637-676, 1990), National Institute of Neurological Disorders and Stroke (MINDS), cerebrovascular disorder is classified into asymptomatic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, and hypertensive encephalopathy. The type of cerebral apoplexy includes cerebral hemorrhage, subarachnoid hemorrhage, cranial hemorrhage accompanying a malformation in cerebral arteries and veins, and cerebral infarction.
Cerebral infarction is classified into atherothrombotic cerebral infarction, lacuna infarction, and cardiogenic cerebral infarction.
The most dangerous factor for cerebrovascular disorder is hypertension, while the dangerous factors for cerebral infarction include an abnormality of sugar resistance and an abnormality in electrocardiogram, and the dangerous factors for cerebral hemorrhage include an abnormality in electrocardiogram, an abnormality in eye ground and drinking, and the like. As the dangerous factors for recurrence of cerebrovascular disorder, hypertension, cardiac disorders, TIA, diabetes, etc. are pointed out, and it can be considered that antihypertensive therapy is applied not only to prevention of occurrence of cerebrovascular disorder (primary prevention) but also to prevention of recurrence thereof (secondary prevention).
The invention also relates to the use an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebral functional disorders (or cerebrovascular disorders) including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy in mammal (including man).
The invention also relates to a process for the prevention and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , which process comprises administering a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
The invention also relates to a method of prevention, delay of progression and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , which process comprises administering a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
The invention also relates to the use of an antihypertensive agent selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the prevention and treatment of insufficient blood flow and cerebral functional disorders or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy in mammal (including man).
Said pharmaceutical compositions are those for enteral, such as oral, and also rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being present on its own or together with the usual pharmaceutical excipients. The pharmaceutical compositions contain, for example, from about 0.1 % to 100 %, preferably from about 1 % to about 80 %, of the active ingredient. Pharmaceutical compositions for enteral or parenteral and also for ocular administration are typically those in unit dose forms, such as dragees, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilising methods. Accordingly, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to give tablets or dragee cores.
Suitable carriers are preferably fillers, typically sugars, such as lactose, saccharose, mannitol or sorbitol, cellulose compositions and/or calcium phosphates, e.g. tricalcium phosphate or calciumhydrogen phosphate, furthermore binders, such as starch paste, typically using e.g. corn starch, wheat starch, rice starch or potato starch, gelatin, traga- canth gum, methylcellulose and/or polyvinylpyrrolidone and, if desired, disintegrants, such as the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, typically sodium alginate. Excipients are primarily flow regulators and lubricants, typically silica gel, talcum, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose compositions, typically acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourants or pigments may be added to the tablets or dragee coatings, for example to identify or indicate different doses of active ingredient.
Other pharmaceutical compositions for oral administration are dry-filled gelatin capsules as well as soft closed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, typically in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talcum or magnesium stearate. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilisers can also be added.
Suitable pharmaceutical compositions for rectal administration are typically suppositories consisting of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons and higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a base substance may also be used. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
Suitable compositions for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, typically a water-soluble salt, and also suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
For preventive treatments, unit dosage forms for oral administration are preferred, typically tablets or capsules and, in acute treatments, i.v. application forms. The dose of the active ingredient can depend of various factors, e.g. mode of application, species of warm-blooded animal, age and/or individual state. The estimated normal dose for oral administration to a patient weighing about 75 kg is an approximate dose of about 10 mg to about 250 mg of AT receptor antagonist.
In a preferred embodiment of this invention, pharmaceutically acceptable compositions comprising valsartan are used. The daily dose for oral administration of AT •] -antagonist valsartan in a unit dose form is preferably about 20 mg to about 160 mg, more preferably about 40 mg or about 80 mg.
The following Example illustrates the above invention without, however, limiting it in its scope in any way.
Formulation Example 1 : A hard gelatin capsule, comprising as active ingredient e.g. (S)-N-(1-carboxy-2-methylprop- 1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine, can be formulated, for example, as follows: Composition: (1) valsartan 80.0 mg (2) microcrystalline cellulose 110.0 mg (3) polyvidone K30 45.2 mg (4) sodium lauryl sulfate 1.2 mg (5) crospovidone 26.0 mg (6) magnesium stearate 2.6 mg
Components (1 ) and (2) are granulated with a solution of components (3) and (4) in water. The components (5) and (6) are added to the dry granulate and the mixture is filled into size 1 hard gelatin capsules.
Formulation Example 2: Diovan tablet
Figure imgf000024_0001
Figure imgf000025_0001
LEGENDS FOR FIGURES
Figure 1. Changes in average mBP and subtraction between before and after 1 year in mBP (ZlmBP) of control group and treated group. In treated group, average mBP was decreased and ZlmBP was decreased significantly in comparison with control group. Values are mean ± SD. §: p<0.001 versus control group. Figure 2. Changes in % power of frequency bands (delta, theta, alphal , alpha2, betal and beta2) of control group and treated group. Control group showed a significant increase of delta. Treated group showed a decreasing tendency of delta and an increasing tendency of betal . Figure 3. The change in % power of all frequency bands (Zldelta, Ztheta, Zlslow, Zalphal , Zalpha2, Zlalpha, Zlbetal , Zbeta2 and Zlfast) of control group and treated group. Treated group showed a significant decrease of Zldelta and Zlslow, and an increasing tendency of Zialphal in comparison with control group. Values are mean (SD). f: p<0.10, *: p<0.05, **: p<0.01 versus control group. These results show that antihypertensive agents do not deteriorate baseline EEG, and rather improve it in comparison with untreated patients. Figure 4. Changes in average mBP of σ1 -blocker, β\ -blocker, ACE-I, ARB and Ca-antagonist. Average mBP of β\ -blocker, ACE-I, ARB and Ca-antagonist were decreased significantly. Values are mean ± SD. f: p<0.10, §: pθ.001 versus before. These results show that βl -blocker, ACE-I, ARB and Ca-antagonist lower mBP. Figure 5.
The change in mBP (ZlmBP) of control group and each treated group with σ1 -blocker, βl- blocker, ACE-I, ARB and Ca-antagonist. ZimBP of ^1-blocker, ACE-I, ARB and Ca antagonist were decreased significantly in comparison with control group, f: p<0.10, *: p<0.05, **: p<0.01 versus control group.
These results show that ?1 -blocker, ACE-I, ARB and Ca-antagonist have each different degree of lowering mBP. Ca-antagonist has the strongest reduction of mBP.
Figure 6.
Changes in % power of frequency bands (delta, theta, alphal, alpha2, betal and beta2) of σ1 -blocker, £1 -blocker, ACE-I, ARB and Ca-antagonist. ARB showed a decreasing tendency of delta and an increasing tendency of alphal . Only in ARB, the basic rhythm became to be alpha Values are mean ± SD. p<0.10 versus before.
These results show that only ARB has a improving tendency of baseline EEG.
ARB shifting a baseline EEG to a more normal EEG may restore cerebral circulation and function.
Figure 7.
The change in % power of all frequency bands (Zldelta, Zltheta, Zlslow, Zlalphal ,
Zalpha2, Zalpha, Zlbetal, Zlbeta2 and Zlfast) of σ1-blocker, β1-blocker, ACE-I, ARB and
Ca-antagonist. In comparison with control group, σ1 -blocker showed a decreasing tendency of Zldelta. βλ -blocker showed a decrease of Zldelta and Z)alpha2 and an increase of
Zlbetal . ACE-I showed a decrease of Zldelta. ARB showed a decrease of Zldelta, a decreasing tendency of Zlslow, an increase of Zalphal and an increasing tendency of
Zalpha. Values are mean (SD). f: p<0.10, *: p<0.05, **: p<0.01 versus control group.
These results show that σ1 -blocker and Ca-antagonist have no significant EEG change as well as control group. The desirable EEG change, decreasing slow waves and increasing alpha waves, is observed only for ARB-treated elderly hypertensive patients.

Claims

What is claimed is
1. Use of an antihypertensive agent selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha-adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof for the preparation of a pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy.
2. Use of an AT-i-receptor antagonist selected from the group consisting of:
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
or, in each case, of a pharmaceutically acceptable salt thereof according to claim 1.
3. Use of valsartan of formula
Figure imgf000030_0002
or of a salt thereof according to claim 1.
4. A pharmaceutical composition for the prevention and treatment of insufficient blood flow and cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , comprising a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha- adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
5. A method for the prevention and treatment of insufficient blood flow and or cerebrovascular disorders including asymptomatic cerebral infarction, atherothrombotic cerebral infarction, lacuna infarction, cardiogenic cerebral infarction, transient ischemic attack (TIA), cerebral apoplexy, cerebrovascular dementia, hypertensive encephalopathy , which comprises administering a therapeutically effective amount of an antihypertensive selected from the group of Angiotensin II receptor antagonists (especially valsartan), Alpha- adrenergic antagonists, Beta-blockers, calcium channel blockers (CCBs) and ACE inhibitors, or of a pharmaceutical salt thereof.
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JP2019052115A (en) * 2017-09-15 2019-04-04 国立研究開発法人理化学研究所 Pharmaceutical composition

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