Patent Application
20100130567
The present invention relates to a medicament for preventing or treating Alzheimer's disease, comprising an angiotensin II receptor blocker as an active ingredient.
No fundamental treatment protocol for Alzheimer's disease has been developed yet. Only cholinesterase inhibitor and the like are used palliatively. Besides, medicaments which seem to be effective in preventing Alzheimer's disease have not been found yet.
Recently, it has become clear that vascular risk factors are deeply involved in the background pathology of not only vascular dementia but also Alzheimer's disease; among all, hypertension is regarded as a crucial factor (Non-Patent Document 1). Some clinical tests have suggested that a part of calcium antagonist and angiotensin-converting enzyme inhibitor (both are antihypertensive drugs) may be capable of inhibiting the onset of Alzheimer's disease (Non-Patent Document 2). With respect to angiotensin II receptor blocker (ARB), no report of its efficacy for Alzheimer's disease has been made yet.
It is an object of the present invention to provide a medicament useful in preventing or treating Alzheimer's disease.
The present inventors examined the therapeutic effect of orally administered olmesartan using a mouse model called “Aβ injection model” which initiates cognitive impairment upon acute administration of amyloid β (a probable causative agent of Alzheimer's disease) to the lateral ventricle (
The present invention may be summarized as follows.
(1) A prophylactic or therapeutic agent for Alzheimer's disease or mild cognitive impairment which is an early state of cognitive impairment including Alzheimer's disease, comprising an angiotensin II receptor blocker as an active ingredient.
(2) An ameliorant for cerebral circulation or cerebral blood flow disorder, comprising an angiotensin II receptor blocker as an active ingredient.
(3) A prophylactic or therapeutic agent for amyloid β-induced brain dysfunction, comprising an angiotensin II receptor blocker as an active ingredient.
(4) The medicinal agent according to any one of (1) to (3), wherein the angiotensin II receptor blocker is losartan, candesartan cilexitil, valsartan, telmisartan, pratosartan, olmesartan medoxomil, irbesartan, azilsartan medoxomil, azilsartan kamedoxomil, 2-cyclopropyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or a salt thereof, or 2-cyclopropyl-1-{[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or a salt thereof.
(5) The medicinal agent according to any one of (1) to (3), comprising as an active ingredient a compound represented by the following general formula (I), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof:
wherein R1 represents a C1-C4 alkyl group;
R2 and R3, which may be the same or different, each represent a hydrogen atom or a C1-C4 alkyl group;
R4 represents a hydrogen atom or a C1-C4 alkyl group;
R5 represents a hydrogen atom, a C1-C4 alkyl group, a C2-C5 alkanoyloxymethyl or 1-(C2-C5 alkanoyloxy)ethyl group, a C1-C4 alkoxycarbonyloxymethyl or 1-(C1-C4 alkoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, a (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group; and
R6 represents a carboxy group or a tetrazol-5-yl group.
(6) The medicinal agent according to (5), which is a compound represented by general formula (I) wherein R1 is an ethyl group, a propyl group or a butyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(7) The medicinal agent according to (5), which is a compound represented by general formula (I) wherein R1 is a propyl group or a butyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(8) The medicinal agent according to (5), which is a compound represented by general formula (I) wherein R1 is a propyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(9) The medicinal agent according to any one of (5) to (8), which is a compound represented by general formula (I) wherein R2 and R3, which may be the same or different, each represent a hydrogen atom or a methyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(10) The medicinal agent according to any one of (5) to (8), which is a compound represented by general formula (I) wherein R2 and R3 are the same and each represents a methyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(11) The medicinal agent according to any one of (5) to (10), which is a compound represented by general formula (I) wherein R4 is a hydrogen atom or a methyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(12) The medicinal agent according to any one of (5) to (10), which is a compound represented by general formula (I) wherein R4 is a hydrogen atom, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(13) The medicinal agent according to any one of (5) to (12), which is a compound represented by general formula (I) wherein R5 is a hydrogen atom, a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(14) The medicinal agent according to any one of (5) to (12), which is a compound represented by general formula (I) wherein R5 is a hydrogen atom, a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(15) The medicinal agent according to any one of (5) to (12), which is a compound represented by general formula (I) wherein R5 is a hydrogen atom or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(16) The medicinal agent according to any one of (5) to (15), which is a compound represented by general formula (I) wherein R6 is a tetrazol-5-yl group, a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
(17) The medicinal agent according to (5), wherein the active ingredient is a compound selected from the group consisting of:
The present inventors have demonstrated a possibility that olmesartan, a type of angiotensin II receptor blocker, may improve the cognitive impairment of an Alzheimer's disease model mouse. To the best of the inventors' knowledge, there has been no report to date that angiotensin II receptor inhibitor has improved cognitive impairment in human Alzheimer's disease or model mice. In this point, the present invention has novelty. Besides, since this drug (olmesartan) has been used clinically as an antihypertensive drug, it is remarkably characteristic that Alzheimer's disease patients will have little problem in terms of safety in receiving oral administration of this drug.
According to the present invention, it becomes possible to provide a medicament useful in preventing or treating Alzheimer's disease.
The present specification encompasses the contents described in the specification and/or drawings of Japanese Patent Application No. 2007-165071 based on which the present patent application claims priority.
The present invention provides a prophylactic or therapeutic agent for Alzheimer's disease or mild cognitive impairment which is an early state of cognitive impairment including Alzheimer's disease, comprising an angiotensin II receptor blocker as an active ingredient. Further, the present invention provides an ameliorant for cerebral circulation or cerebral blood flow disorder, comprising an angiotensin II receptor blocker as an active ingredient. Still further, the present invention provides a prophylactic or therapeutic agent for amyloid β-induced brain dysfunction comprising an angiotensin II receptor blocker as an active ingredient. As for the angiotensin II receptor blocker, various medicaments have been proposed and clinically used in practice. Therefore, one of ordinary skill in the art could select appropriate medicaments that produce the effect of the present invention. Specific examples of such angiotensin II receptor blockers include, but are not limited to, losartan (preferably, losartan potassium), candesartan cilexitil, valsartan, telmisartan, pratosartan, olmesartan medoxomil, irbesartan, azilsartan medoxomil (i.e., 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxilic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof), azilsartan kamedoxomil (i.e., 2-ethoxy-1-{[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxilic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof), 2-cyclopropyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof, or 2-cyclopropyl-1-{[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof. Preferably, the angiotensin II receptor blocker is olmesartan medoxomil. In particular, olmesartan medoxomil may be prepared easily according to the method disclosed, for example, in Japanese Patent No. 2082519 (U.S. Pat. No. 5,616,599). With respect to azilsartan medoxomil, azilsartan kamedoxomil, 2-cyclopropyl-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof and 2-cyclopropyl-1-{[2′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl or salts thereof, their potentials as therapeutics for hypertension or the like are being examined. They may be prepared according to the methods disclosed, for example, in WO 2005/080384 or WO 2006/107062, with or without necessary modifications.
One example of the angiotensin II receptor blocker, which is the active ingredient of the present invention, is a compound represented by the following general formula (I), a pharmacologically acceptable salt thereof, or a pharmacologically acceptable ester thereof
In the above formula,
R1 represents a C1-C4 alkyl group;
R2 and R3, which may be the same or different, each represent a hydrogen atom or a C1-C4 alkyl group;
R4 represents a hydrogen atom or a C1-C4 alkyl group;
R5 represents a hydrogen atom, a C1-C4 alkyl group, a C2-C5 alkanoyloxymethyl or 1-(C2-C5 alkanoyloxy)ethyl group, a C1-C4 alkoxycarbonyloxymethyl or 1-(C1-C4 alkoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, a (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group; and
R6 represents a carboxy group or a tetrazol-5-yl group.
The C1-C4 alkyl group in R1, R2, R3 and R4 may be, for example, a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. The C1-C4 alkyl group in R1 is preferably an ethyl, propyl or butyl group, more preferably a propyl or butyl group, and especially preferably a propyl group. The C1-C4 alkyl group in R2 and R3 is preferably a methyl or ethyl group, and especially preferably a methyl group. The C1-C4 alkyl group in R4 is preferably a hydrogen atom or a methyl group, and especially preferably a hydrogen atom.
R5 may be, for example, a hydrogen atom; the above-described C1-C4 alkyl group; a C2-C5 alkanoyloxymethyl or 1-(C2-C5 alkanoyloxy)ethyl group (where the C2-C5 alkanoyl moiety may be, for example, acetyl, propionyl, butyrl, isobutyrl, valeryl, isovaleryl or pivaloyl, preferably acetyl or pivaloyl, and especially preferably pivaloyl); a C1-C4 alkoxycarbonyloxymethyl or 1-(C1-C4 alkoxycarbonyloxy)ethyl group (where the C1-C4 alkoxy moiety may be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy, preferably methoxy, ethoxy, propoxy or isopropoxy, and especially preferably ethoxy or isopropoxy); a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; a (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group. Preferably, R5 is a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group. Especially preferably, R5 is a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group. Most preferably, R5 is a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
The compound of the present invention which is represented by general formula (I) may be, if desired, converted to a corresponding pharmacologically acceptable salt by treating with an acid or base according to conventional methods. Such a “pharmacologically acceptable salt” may be, for example, an alkaline metal salt such as sodium salt, potassium salt or lithium salt; alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminium salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; or an amine salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt. The pharmacologically acceptable salt is preferably an alkali metal salt, and especially preferably a sodium salt.
Further, the compound of the invention which is represented by general formula (I) may be converted to a pharmacologically acceptable ester according to conventional methods. The types of the “pharmacologically acceptable ester” are not particularly limited. Any type of ester may be used as long as it has the same pharmaceutical applicability as the compound represented by general formula (I) and is pharmacologically acceptable. Examples include: a C1-C4 alkoxy alkyl group such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a C1-C4 alkoxylated C1-C4 alkoxy C1-C4 alkyl group such as 2-methoxyethoxymethyl; a C6-C10 aryloxy C1-C4 alkyl group such as phenoxymethyl; a halogenated C1-C4 alkoxy C1-C4 alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a C1-C4 alkoxycarbonyl C1-C4 alkyl group such as methoxycarbonylmethyl; a cyano C1-C4 alkyl group such as cyanomethyl or 2-cyanoethyl; a C1-C4 alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a C6-C10 arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C1-C4 alkylsulfonyl C1-C4 lower alkyl group which may be substituted with a halogen atom(s), such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C6-C10 arylsulfonyl C1-C4 alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; a C1-C7 aliphatic acyloxy C1-C4 alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxyhexyl; a C5-C6 cycloalkylcarbonyloxy C1-C4 alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; a C6-C10 arylcarbonyloxy C1-C4 alkyl group such as benzoyloxymethyl; a C1-C6 alkoxycarbonyloxy C1-C4 alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; a C5-C6 cycloalkyloxycarbonyloxy C1-C4 alkyl group such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; a [5-(C1-C4 alkyl)-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl or (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; a [5-(phenyl which may be substituted with a C1-C4 alkyl, C1-C4 alkoxy or halogen atom(s))-2-oxo-1,3-dioxolen-4-yl]methyl group such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl; or a phthalidyl group which may be substituted with a C1-C4 alkyl or C1-C4 alkoxy group(s), such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl. It should be noted that esters of the compound represented by general formula (I) are not limited to those enumerated above.
A “pharmacologically acceptable salt of a pharmacologically acceptable ester” of the compound (I) of the present invention is a pharmacologically acceptable salt of the above-described “pharmacologically acceptable ester”. Examples include: a hydrohalogenic acid salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate; a C1-C4 alkanesulfonic acid salt which may be substituted with a halogen atom(s), such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C6-C10 arylsulfonic acid salt which may be substituted with a C1-C4 alkyl group(s), such as a benzenesulfonate or p-toluenesulfonate; a C1-C6 aliphatic acid salt such as an acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt; a hydrochloride, nitrate, sulfate or phosphate is preferred and a hydrochloride is especially preferred.
When the compound of the present invention which is represented by general formula (I) (hereinafter, referred to as the “compound (I)”) has asymmetric carbon(s) within its molecule, racemate or optically active substances thereof are also included in the present invention.
The compound (I) and salts thereof, which are the active ingredient of the present invention, may become hydrates as a result of absorption of moisture or attachment of adsorbed water when they have been left in the air. Such salts are also included in the present invention.
Further, the compound (I) and salts thereof, which are the active ingredient of the present invention, may become solvates as a result of absorption of certain other solvents. Such salts are also included in the present invention.
The compound (I) is preferably:
(1) a compound wherein R1 is an ethyl group, a propyl group or a butyl group,
(2) a compound wherein R1 is a propyl group or a butyl group,
(3) a compound wherein R1 is a propyl group,
(4) a compound wherein R2 and R3, which may be the same or different, each represent a hydrogen atom or a methyl group,
(5) a compound wherein R2 and R3 are the same and each represents a methyl group,
(6) a compound wherein R4 is a hydrogen atom or a methyl group,
(7) a compound wherein R4 is a hydrogen atom,
(8) a compound wherein R5 is a hydrogen atom, a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group,
(9) a compound wherein R5 is a hydrogen atom, a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group,
(10) a compound wherein R5 is a hydrogen atom or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or
(11) a compound wherein R6 is a tetrazol-5-yl group. It should be noted here that among classes referring to the same group such as R1 or R2, the greater the class number, the greater the degree of preference (e.g., among R1 classes, (1) is preferable; (2) is more preferable; and (3) is especially preferable).
Alternatively, a preferable compound may be obtained by selecting R1 from among classes (1) to (3), selecting R2 and R3 from between classes (4) and (5), selecting R4 from between classes (6) and (7), selecting R5 from among classes (8) to (10), and combining the selected groups or combining them with R6 in class (11). For example, the following compounds may be enumerated.
(12) a compound wherein
R1 is an ethyl group, a propyl group or a butyl group;
R2 and R3, which may be the same or different, each represent a hydrogen atom or a methyl group;
R4 is a hydrogen atom or a methyl group; and
R5 is a hydrogen atom, a methyl group, an ethyl group, an acetoxymethyl group, a 1-(acetoxy)ethyl group, a pivaloyloxymethyl group, a 1-(pivaloyloxy)ethyl group, a methoxycarbonyloxymethyl group, a 1-(methoxycarbonyloxy)ethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a propoxycarbonyloxymethyl group, a 1-(propoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group;
(13) a compound wherein
R1 is a propyl group or a butyl group;
R2 and R3 are the same and each represents a methyl group;
R4 is a hydrogen atom;
R5 is a hydrogen atom, a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(ethoxycarbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group or a phthalidyl group; and
R6 is a tetrazol-5-yl group;
(14) a compound wherein
R1 is a propyl group;
R2 and R3 are the same and each represents a methyl group;
R4 is a hydrogen atom;
R5 is a hydrogen atom or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; and
R6 is a tetrazol-5-yl group.
Preferable compounds of general formula (I) may be specifically exemplied by the compounds shown in Table 1 below.
In the above Table, preferable compounds are illustrated compound Nos. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 79 and 80.
More preferable compounds are illustrated compound Nos. 5, 6, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 and 74. Still more preferable compounds are illustrated compound Nos. 5, 6, 8, 9, 10, 11, 12, 14, 15, 17, 18, 22, 23, 24, 25, 26, 27, 29, 32, 33, 34, 35, 36, 37, 38, 49, 50, 55, 56, 58, 63, 65, 68, 69, 70, 71, 72, 73 and 74.
Especially preferable compounds are:
Illustrated compound No. 11: pivaloyloxymethyl 4-hydroxymethyl-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 12: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-hydroxymethyl-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 17: pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 18: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxyethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 29: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylic acid,
Illustrated compound No. 32: pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 33: ethoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,
Illustrated compound No. 34: 1-(ethoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,
Illustrated compound No. 35: isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,
Illustrated compound No. 36: 1-(isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate,
Illustrated compound No. 37: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-c arboxylate,
Illustrated compound No. 68: pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 69: ethoxycarbonyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 70:1-(ethoxycarbonyloxy)ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 71: isopropoxycarbonyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate,
Illustrated compound No. 72: 1-(isopropoxycarbonyloxy)ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate, and
Illustrated compound No. 73: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]-methylimidazole-5-carboxylate.
Most preferable compounds are:
Illustrated compound No. 29: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylic acid (Japanese designation: olmesartan), and
Illustrated compound No. 37: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methyl-imidazole-5-c arboxylate (Japanese designation: olmesartan medoxomil).
Olmesartan medoxomil (illustrated compound No. 37) is a prodrug of olmesartan (illustrated compound No. 29), in which the carboxylic acid at position 5 of the imidazole ring is medoxomil ester. Upon oral administration, this prodrug is hydrolyzed by esterase, mainly in the small intestinal epithelium, and thus converted to the active form olmesartan.
The compound (I) which is the active ingredient of the present invention, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof are known (see, for example, Japanese Unexamined Patent Publication No. Hei 5-78328) or they may be prepared by known methods (see, for example, Japanese Unexamined Patent Publication No. Hei 5-78328).
The medicament of the present invention may be used in the prevention or treatment of Alzheimer's disease. The medicament of the present invention may also be used to improve cerebral circulation or cerebral blood flow disorder. Further, the medicament of the present invention may be used in the prevention or treatment of amyloid β-induced brain dysfunction. The term “prevention or treatment” used herein encompasses not only improvement or curing of the disease but also inhibition of the progress of the disease, prevention of onset of the disease, and prevention of recurrence of the disease. In no sense should the term “prevention or treatment” be interpreted in any limitative manner. This term must be in interpreted most broadly.
Alzheimer's disease is a neurodegenerative disease. A characteristic pathological finding called senile plaques is observed in autopsy brain specimen from patients with Alzheimer's disease. It is known that the major component of these senile plaques is a protein called amyloid β (Aβ), and it is presumed that Aβ is a causative agent for Alzheimer's disease. Recently, epidemiologic studies have shown that the presence of hypertension in middle-aged people is an independent risk factor for Alzheimer's disease, and large-scale clinical tests revealed that antihypertensive therapy reduces the risk of developing Alzheimer's disease. Thus, a possibility has been suggested that hypertension is deeply involved in the background pathology of Alzheimer's disease.
As shown in Examples described later, the medicament of the present invention is capable of improving the dysfunction/impairment which amyloid β induces, e.g., impairment of spatial memory and cerebrovascular disorders such as cerebral circulation/cerebral blood flow disorders. Further, the dysfunction/impairment-improving effect of the medicament of the present invention is not limited to its action on amyloid β-induced dysfunction/impairment.
Briefly, the medicament of the present invention comprising a specific angiotensin II receptor blocker (such as olmesartan medoxomil) as an active ingredient may be used in preventing or treating Alzheimer's disease in warm-blooded animals including human, as well as to improve cerebral circulation or cerebral blood flow disorder, and to treat or prevent amyloid β-induced brain dysfunction.
Since the above-described angiotensin II receptor blocker is generally administered orally, it is desirable to administer the medicament of the present invention orally. However, the administration route of the medicament of the present invention is not limited to oral administration. It may also be administered parenterally, such as intravenously, intrarectally, percutaneously, transmucosally or subcutaneously. Examples of dosage forms suitable for oral administration include, but are not limited to, powder, granules, tablets and capsules. In the preparation of unit dosage form, pharmacologically acceptable additives for formulation such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, correctives or diluents may be used appropriately.
Examples of “excipients” that may be used include: organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as microcrystalline cellulose; gum arabic; dextran; and pullulan; and inorganic excipients including silicate derivatives such as light silicic acid anhydride, synthetic aluminium silicate, calcium silicate or magnesium aluminometasilicate; phosphates such as calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate.
Examples of “lubricants” that may be used include: stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride and silicic hydrate; and the starch derivatives described above.
Examples of “binders” that may be used include: hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-described excipients.
Examples of “disintegrants” that may be used include: cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; and chemically modified starch/cellulose derivatives such as carboxymethylstarch or carboxymethylstarch sodium.
Examples of “emulsifiers” that may be used include: colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminium hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylenealkylether, polyoxyethylene sorbitan fatty acid ester or sucrose esters of fatty acids.
Examples of “stabilizers” that may be used include: p-hydroxybenzoate esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Examples of “correctives” that may be used include: sweeteners such as saccharin sodium or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; and flavors such as menthol, lemon or orange.
Examples of “diluents” that may be used include conventionally used diluents, such as, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, and mixtures of these compounds.
Doses of the medicament of the present invention may be appropriately selected depending on various factors such as the administration route, the type of the active ingredient, the age, body weight or symptoms of the patient, the purpose of administration (prevention or treatment), etc. Generally, the medicament of the present invention is administered at a level within a range from the lower limit of 0.08 mg/kg (preferably 0.33 mg/kg, more preferably 0.50 mg/kg) per day to the upper limit of 1.13 mg/kg (preferably 1.0 mg/kg) per day. This dose may be administered once or 2 to 6 times a day depending on the symptoms.
The medicament of the present invention may be used in combination with other preparations that are effective against the target disease (e.g., Alzheimer's disease). For example, donepezil hydrochloride effective for Alzheimer's disease may be used jointly.
Hereinbelow, the present invention will be described in more detail with reference to Test Examples and Preparation Examples. However, the scope of the present invention is not limited to these Examples.
Amyloid β (Aβ) 1-40 and Aβ 40-1 (Peptide Institute, Inc.)
*Aβ 40-1 has a sequence reverse to that of Aβ 1-40. This was used as a control peptide.
ddY mouse (CLEA Japan, Inc.)
Olmesartan medoxomil (Daiichi Sankyo Company, Limited)
Hydralazine (Sigma)
The therapeutic effect of olmesartan medoxomil in Aβ injection model and the dose dependency thereof were examined according to the following experimental schedule.
[Experimental Schedule]: Prior to the experiment, 8-week old male ddY mice were administered olmesartan medoxomil (0.5 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day or 6 mg/kg/day) or distilled water orally for four weeks (day −28 to −1). Then, Aβ 1-40 was administered to the mice intracerebroventricularly (day 0). (Although Aβ 1-40 was administered into one of the lateral ventricles in WO 2006/059777, Aβ 1-40 was administered in Test Example 1 to both lateral ventricles with an interval of one day between two administrations. Except for this point, Aβ 1-40 administration was performed in the same manner as in WO 2006/059777.) From one week thereafter, a behavioral test to evaluate cognitive function (Morris water maze test; Morris R et al., J Neuroscience Methods 1984, 11, 47-60) was performed (day 7 to 12). As a negative control, mice which had received oral administration of distilled water for four weeks were administered Aβ 40-1 intracerebroventricularly. The administration of olmesartan medoxomil or distilled water was continued until the end of the behavioral test. Measurements were performed as described below.
Hidden platform test: A platform is placed below the water surface of a water pool 150 cm in diameter filled with white water-colored. Mice are released into the water, and the time it takes them to reach the platform is measured. This trial is performed three times a day and for five consecutive days. As they learn, mice become able to reach the platform more quickly day by day.
Visible platform test: Mice are released into the water under such conditions that they can see the platform. The time it takes them to reach the platform is measured.
Probe test: The platform is removed, and mice are released and allowed to swim freely. Those mice with good learning/memory swim in the quadrant where the platform was located searching for the platform. The time they spent in that quadrant is measured.
Annulus crossing: The number of times mice crossed the platform in the probe test is counted.
Further, assessment of blood pressure was performed by the tail-cuff method (using a sphygmomanometer wound around the mouse tail) (Bunag R D, J Lab Clin Med. 1971, 78, 957-62) immediately before the start of administration of olmesartan medoxomil or distilled water (day −30), immediately before (day −1) and immediately after (day 2) the Aβ intracerebroventricular administration, and after completion of the behavioral test (day 14) (see
Blood pressure: No difference between groups was observed in the blood pressure before the start of administration of olmesartan medoxomil or distilled water (day −30). After 4-week administration (day −1), the blood pressures in olmesartan medoxomil administration groups were significantly lowered compared to the distilled water administration group. Even the group with the lowest dose of olmesartan medoxomil (0.5 mg/kg/day) showed a significant lowering in the blood pressure. A similar tendency was observed in the measurements performed immediately after Aβ administration (day 2) and after completion of the behavioral test (day 14) (see
Cognitive function: It was confirmed in the hidden platform test that the escape latency was significantly longer in Aβ 1-40 administration group () than in Aβ 40-1 administration group (▪) on day 4 and 5 after the start of learning (session 4 and 5) and that the former group had impairment in spatial memory and learning ability. However, this dysfunction was improved significantly in olmesartan medoxomil 0.5 mg/kg/day administration group (Δ), 1.0 mg/kg/day administration group (▴) and 3.0 mg/kg/day administration group (◯) (see
In order to examine whether the improvement effect on cognitive function achieved by oral administration of olmesartan medoxomil (Test Example 1) was caused by lowered blood pressure per se or not, a similar experiment was performed using hydralazine administration group as a hypotensive control (see
Open field test: A cubic box (30×30×30 cm) is used. On each X and Y bank of the open-field area, two infrared beams are attached 2 cm above the floor at a 10 cm interval. The number of successive interceptions by the subject of the two adjoining beams on each bank is counted as locomotion score.
Long-term retention: On day 12 after the completion of the hidden platform test as a water maze test, mice are released into the water and the time it takes them to reach the platform is measured.
Working memory task: The platform is transferred and fixed at a new place. Mice are given four consecutive trials at intervals of as short as 20 seconds, and the time it takes them to reach the platform is measured. The average of the escape latency values for the 2nd to 4th trial was taken as an indicator of working memory task.
Swimming speed: The time it takes the mice to reach the platform is affected by the swimming speed of each mouse. In order to eliminate this influence, swimming speed is measured.
Blood pressure: No significant difference was observed in blood pressure between groups before the start of oral administration, but after 4-week administration (day −1), it was confirmed that the blood pressures in olmesartan medoxomil 1 mg/kg/day group and hydralazine 30 mg/kg/day group were lowered significantly and by almost equal levels compared to distilled water administration group (see
Cognitive function: In the hidden platform test, the time it took the mice to reach the platform was shortened through successive sessions in Aβ 40-1 administration group. However, the time was not shortened in Aβ 1-40 administration group. In Aβ 1-40+ olmesartan medoxomil administration group, the time it took the mice to reach the platform was shortened through successive sessions, as compared to Aβ 40-1 administration group. In Aβ 1-40+ hydralazine administration group, the time was not shortened (
Visible platform test: No significant difference was observed between groups (
Probe test: The time it took the mice to reach the platform was shortened through successive sessions in Aβ 40-1 administration group. However, the time was not shortened in Aβ 1-40 administration group. In Aβ 1-40+ olmesartan medoxomil administration group, the time it took the mice to reach the platform was shortened through successive sessions, as compared to Aβ 40-1 administration group. In Aβ 1-40+ hydralazine administration group, the time was not shortened (
Annulus crossings means the number of times that mice crossed the platform in the probe test. In Aβ 40-1 administration group, the time it took the mice to reach the plat form was shortened. However, the number of platform crossings was smaller in Aβ 1-40 administration group than in Aβ 40-1 administration group. While the number of platform crossings increased in Aβ 1-40+ olmesartan medoxomil administration group compared to Aβ 1-40 administration group, there was increase in Aβ 1-40+ hydralazine administration group (
Swimming speed: No significant difference was observed between groups (
Long-term retention: On day 17, the time it took the mice to reach the platform was longer in Aβ 1-40 administration group than in Aβ 40-1 administration group. The time it took the mice to reach the platform was shortened in Aβ 1-40+ olmesartan medoxomil administration group compared to Aβ 1-40 administration group. However, the time it took the mice to reach the platform was not shortened in Aβ 1-40+ hydralazine administration group (
Working memory task: The time it took the mice to reach the platform was longer in Aβ 1-40 administration group than in Aβ 40-1 administration group. The time it took the mice to reach the platform was shortened in Aβ 1-40+ olmesartan medoxomil administration group compared to Aβ 1-40 administration group. However, the time it took the mice to reach the platform was not shortened in Aβ 1-40+ hydralazine administration group (
Open field test: No significant difference was observed between groups (
What has been stated so far may be summarized as follows. It was confirmed in the Morris water test that the spatial memory impairment and learning disability evoked by intracerebroventricular administration of Aβ 1-40 were significantly improved in olmesartan medoxomil 1 mg/kg/day group as in Test Example 1, but this effect was not observed in hydralazine 30 mg/kg/day group. It was confirmed in the open field test and the like that there was no considerable difference in confounding factors such as the activity or swimming ability of mice.
Using an Aβ injection model, the present inventors found a possibility that the spatial memory impairment and learning disability evoked by intracerebroventricular administration of Aβ 1-40 may be improved by oral administration of a low dose of olmesartan medoxomil (Test Example 1). Further, by performing a similar experiment using hydralazine as a control drug, the inventors confirmed that this effect was not produced by lowered blood pressure per se (Test Example 2). The effect was not observed in olmesartan medoxomil high dose groups (3-6 mg/kg/day), probably because the cerebral blood flow was reduced by excessive lowering of blood pressure (i.e. somatic blood pressure dropped below the lower limit of cerebrovascular autoregulation).
Electrophysiology: Long term potentiation was measured as previously reported (Niisato K, Fujikawa A, Komai S, Shintani T, Watanabe E, Sakaguchi G; Katsuura Manabe T, Noda M: Age-dependent enhancement of hippocampal long-term potentiation and impairment of spatial learning through the Rho-associated kinase pathway in protein tyrosine phosphatase receptor type Z-deficient mice. J Neurosci 2005; 25:1081-1088). Transverse hippocampal slices (400 μm thick) were prepared from 5- to 10-week-old mice or from 13- to 31-week-old mice and placed in an interface-type holding chamber for at least 1 hr. A single slice was then transferred to a recording chamber and submerged beneath a continuously perfusing medium saturated with 95% O2 and 5% CO2. The medium was composed of 119 mM NaCl, 2.5 mM KCl, 1.3 mM MgSO4, 2.5 mM CaCl2, 1.0 mM NaH2PO4, 26.2 mM NaHCO3 and 11 mM glucose. All of the perfusing solutions contained 100 μM picrotoxin in order to block GABAA receptor-mediated inhibitory synaptic responses. The field potential recordings were made with a glass electrode (3 M NaCl) placed in the stratum radiatum. The whole-cell pipette solution contained 122.5 mM Cs gluconate, 17.5 mM CsCl, 10 mM HEPES, 0.2 mM EGTA, 8 mM NaCl, 2 mM Mg-ATP and 0.3 mM Na3-GTP, pH 7.2; 290-300 mM mOsm. For evoking synaptic responses, a bipolar tungsten stimulating electrode was placed in the stratum radiatum, and Schaffer collateral/commissural fibers were stimulated at 0.1 Hz. The stimulus strength was adjusted so that it gave rise to AMPA receptor-mediated EPSPs of the slope values between 0.10 and 0.15 mV/ms. For the analysis of EPSPs, the inventors measured their early rising phase in order to avoid contamination by voltage-dependent components as much as possible. Each data point represents the averaged slope value for 1 min that was normalized to the baseline slope value. All experiments were performed at 25° C. The data are expressed as mean±SEM. Student's t test or ANOVA was used to determine whether there was a significant difference (p<0.05) in the mean. The majority of electrophysiological experiments were blind tests, and the results were essentially identical to those of the non-blind experiments; thus, all of the data were pooled. Picrotoxin was purchased from Wako (Osaka, Japan).
Monitoring of cerebral blood flow: A small craniotomy (2×2 mm) was performed to expose the somatosensory cortex; the dura was removed; and the site was perfused with a modified Ringer's solution (37° C.; pH 7.3-7.4) (Iadecola C, Zhang F, Niwa K, Eckman C, Turner S K, Fischer E, Younkin S, Borchelt D R, Hsiao K K, Carlson G A: SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 1999; 2:157-161). Cerebral blood flow (CBF) was continuously monitored at the site of perfusion with a laser-Doppler probe positioned stereotaxically on the cortical surface and connected to a computerized data acquisition system. CBF values were expressed as percent increase relative to the resting level. Zero values for CBF were obtained after the heart was stopped by an overdose of isoflurane at the end of the experiment.
Effect of topical application of Aβ40 on functional hyperemia: The cranial window was first perfused with Ringer's solution, and CBF responses to whisker stimulation were recorded. The whiskers were gently stroked for 60 sec with a cotton-tipped applicator. After testing CBF responses during Ringer's solution perfusion, the perfusion solution was changed to Ringer's solution containing Aβ40 (5 μM; Peptide Institute, Osaka, Japan). This concentration of Aβ40 was previously found to produce maximal cerebrovascular effects (Niwa K, Younkin L, Ebeling C, Turner S K, Westaway D, Younkin S, Ashe K H, Carlson G A, Iadecola C: Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA 2000; 97:9735-9740).
Cerebrovascular autoregulation: Techniques used for studying cerebrovascular autoregulation in rodents were similar to those previously described (Ishitsuka T, Iadecola C, Underwood M D, Reis D J: Lesions of nucleus tractus solitarii globally impair cerebrovascular autoregulation. Am J Physiol 1986; 251:H269-281). Mice were anesthetized in preparation for CBF measurement by LDF. After stabilization of MAP and blood gases, MAP was elevated or decreased in 10-mmHg steps, either by intravenous infusion of phenylephrine (1-2 μg·kg−1·min−1) or via controlled exsanguination (100-400 μl of arterial blood), (Ishitsuka T, Iadecola C, Underwood M D, Reis D J: Lesions of nucleus tractus solitarii globally impair cerebrovascular autoregulation. Am J Physiol 1986; 251:H269-281). The range of MAP studied was 20-160 mmHg. CBF values were recorded 5 min after MAP was changed. In view of potential pathological effects of changes in MAP above or below the autoregulated range, the lower and upper limits of autoregulation were tested in separate animals (Ishitsuka T, Iadecola C, Underwood M D, Reis D J: Lesions of nucleus tractus solitarii globally impair cerebrovascular autoregulation. Am J Physiol 1986; 251:H269-281).
Measurement of long-term potentiation in hippocampus (CA1/Schaffer collaterals) of Aβ40-injected mice (with or without ARB olmesartan treatment)
Long-term potentiation (LTP) in the hippocampus is believed to be a cellular basis for learning and memory. The inventors measured long-term potentiation (
Measurement of cerebral blood flow induced by neuronal activity of Aβ-injected mice (with or without ARB olmesartan treatment)
The inventors measured the cerebral blood flow induced by neuronal activity of Aβ-injected mice (with or without ARB olmesartan treatment). Neuronal activity was evoked in somatosensory-cortex by whisker stimulation (
Measurement of cerebral blood flow of Aβ-injected mice (with or without ARB olmesartan treatment) (
Cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP) is known to be impaired by Aβ. The inventors found cerebrovascular autoregulation impaired by Aβ is recovered by ARB olmesartan (
In summary, it is possible to say that ARB olmesartan recovered Aβ-induced impairment of spatial memory associated with recovery of neurovascular coupling (
The above-listed powders are mixed and passed through a 60 mesh screen. The resultant mixed powder is filled in 250 mg No. 3 gelatin capsules.
The above-listed powders are mixed and pressed on a tabletting machine into tablets each weighing 200 mg. The thus obtained tablets may be coated with sugar, if necessary.
All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.
The medicament of the present invention comprising a specific angiotensin II receptor blocker (such as olmesartan medoxomil) as an active ingredient is useful in preventing or treating Alzheimer's disease, in improving cerebral circulation or cerebral blood flow disorder, and in preventing or treating amyloid β-induced brain dysfunction. This medicament is preferably for use in warm-blooded animals, more preferably for use in human.
Representative causative diseases for dementia are Alzheimer's disease and vascular dementia, but actually a great number of patients with Alzheimer's disease also suffer from cerebrovascular disorder (AD with CVD) (
The improvement of cognitive function in Alzheimer's disease model mouse that was achieved by the present invention has suggested that olmesartan is effective in directly improving the pathology of Alzheimer's disease. In actual clinical applications, management of hypertension is further added as an important value. By administering olmesartan to patients with Alzheimer's disease or mild cognitive impairment (MCT) which is an early state of cognitive impairment including Alzheimer's disease and who also suffer from hypertension, it might be possible to inhibit progress of the cognitive impairment. Moreover, by performing hypotensive treatment with olmesartan on hypertensive patients, it might be possible to reduce the risk of the onset of Alzheimer's disease in future. Since management of hypertension is also effective in the prevention of vascular dementia, it is believed that such management may contribute greatly to the overall medical care for dementia.
Specifically, it is contemplated that a currently approved, conventional amount of olmesartan may be administered to hypertension-complicated Alzheimer's disease patients or hypertension-complicated MCI patients to thereby inhibit the progress of cognitive impairment.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2007-165071 | Jun 2007 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2008/060513 | 6/9/2008 | WO | 00 | 12/21/2009 |
