WO2000043007A1 - Troglitazone-containing medicinal compositions for inhibiting apoptosis - Google Patents
Troglitazone-containing medicinal compositions for inhibiting apoptosis Download PDFInfo
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- WO2000043007A1 WO2000043007A1 PCT/JP2000/000226 JP0000226W WO0043007A1 WO 2000043007 A1 WO2000043007 A1 WO 2000043007A1 JP 0000226 W JP0000226 W JP 0000226W WO 0043007 A1 WO0043007 A1 WO 0043007A1
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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
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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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
- A61K31/425—Thiazoles
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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
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
Definitions
- the present invention relates to a medicament or composition for suppressing apoptosis containing troglitazone or a pharmacologically acceptable salt thereof as an active ingredient.
- necrosis There are two types of cell death: necrosis and apoptosis.
- Necrosis refers to death that occurs in a group of cells in a pathological condition, such as ischemia. That is, various external factors cause cell disruption and autolysis, but activation of intracellular enzymes is not essential.
- apoptosis is a mechanism by which cells spontaneously kill themselves for various reasons, such as when cells turn over in healthy tissues of animals or when unnecessary cells are removed during the developmental stages of various organs. Activated and dying, the activation of a series of enzymes called caspases plays a central role [Neuron, 20, 633-647 (1998); Ann. Neurol., 45, 421-429 (199 9)]. That is, it is said that caspase 8 and caspase 9 are activated by the cell death inducing factor, and apoptosis is caused by activation of caspase 3 by these.
- Apoptosis of neurons has been observed in Alzheimer's disease [J. Neurosci., 16, 1710-1719 (1996); Exp. Neurol, 133, 225-230 (19952. Amyotrophic lateral stiffness) Nerve cell death due to activation of force spase 1 and caspase 3 and apoptosis have also been reported in Gidori [J. Neuropathol. Exp. Neurol, 58, 459-471 (1999); Proc. Natl. Acad. Sci. USA, 95, 15763-15768 (1998)] In cerebral ischemic injury models, cell death due to apoptosis has been observed, and there have been many reports that cell death can be suppressed by a force-spase inhibitor [Exp. Opin.
- apoptosis is also involved in neuronal cell death caused by 1-methyl 4-phenylpyridinium ion (MPP +) known as a Parkinson's disease model [J. Neurochem., 69, 1382-1388]. (1997)].
- MPP + 1-methyl 4-phenylpyridinium ion
- L is Formula A "Y" (W,) -X- (W 2 ) -Y 2 - is a radical having a, A t is a Teroariru group to an optionally substituted, X is a single a bond, Y, and Y 2 is a single bond, one Omicron -!, X is a C -Cs alkylene group, and W 2 is a single bond, a gamma iota is Ariru radical, R represents C!
- the pharmaceutical composition containing troglitazone of the present invention has an action of suppressing apoptosis by suppressing caspase 3 activation.
- the above compound (A) contains phosphatase (PTPase).
- PTPase phosphatase
- RR 2 , R 4 and R 5 are C! —C 5 alkyl groups, R 3 is a hydrogen atom, W is CH 2 , Y and Z are oxygen atoms, and n is It is an integer of 1 to 3. ]
- the compound having the general formula (A) contains troglitazone.
- a neurodegenerative disease such as Alzheimer's disease
- a neurodegenerative disease is disclosed as a disease that is improved by the action of improving the endothelial cell activity.
- the pharmaceutical composition containing troglitazone of the present invention has an action of suppressing apoptosis by suppressing caspase 3 activation
- the publication discloses that the compound (B) improves endothelial cell activity. It only states that its action is useful for preventing or treating neurodegenerative diseases, and it does not disclose or suggest that it suppresses apoptosis by suppressing caspase 3 activation. Further, since endothelial cells are cells existing in blood vessels, they are completely different from nerve cells, and there is no known fact that endothelial cells have an effect of improving endothelial cell activity and a function of inhibiting caspase 3 activation.
- This publication discloses compounds having a blood insulin level lowering action
- Troglitazone is disclosed as a compound and a specific compound thereof, and "Alzheimer's disease” is disclosed as a disease ameliorated by the above action.
- the pharmaceutical composition containing toguchiglitazone of the present invention has an effect of suppressing apoptosis by suppressing caspase 3 activity.
- a thiazolidinedione compound containing troglitazone is disclosed.
- the above-mentioned blood insulin level lowering effect is useful for preventing or treating Alzheimer's disease, and the effect of suppressing caspase 3 activation to suppress apoptosis is disclosed or suggested.
- NTP Neuroreated Protein
- the disease improved by the troglitazone of the present invention includes Alzheimer's disease, including ischemic injury and inflammatory living brain disease. contains.
- R is an optionally substituted heterocyclic group
- Y is a group represented by one CO—, m and n are 0,
- R 1 is a hydrogen atom, and
- X is CH A is a bond, L and M are hydrogen atoms, and
- Q is a sulfur atom.
- troglitazone is disclosed as a compound having an apoptosis-suppressing action, but no data or the like showing that troglitazone suppresses apoptosis is specifically disclosed in the test examples of this publication. Has the best apoptosis-suppressing effect in the results of this test example The compound is disclosed to be rosiglitazone.
- troglitazone is so special that troglitazone cannot be inferred easily from the disclosure of this publication in terms of its apoptosis-suppressing effect (particularly, the rosiglitazone having the best apoptosis-suppressing effect in the results of the test examples in this publication). It was found for the first time to show excellent effects. In addition, this publication does not disclose or suggest the action of troglitazone to suppress apoptosis by suppressing caspase 3 activation. Disclosure of the invention
- troglitazone has an excellent apoptotic inhibitory action, and completed the present invention.
- An object of the present invention is to provide a pharmaceutical composition for suppressing apoptosis which contains troglitazone or a pharmacologically acceptable salt thereof as an active ingredient.
- Another object of the present invention is to use the above compound for producing a pharmaceutical composition for suppressing apoptosis.
- another object of the present invention is to administer a pharmacologically effective amount of the compound to a warm-blooded animal, to inhibit apoptosis, in particular, to inhibit apoptosis in nerve cells, and to activate caspase-3.
- nervous system diseases eg, ischemic injury; stroke; inflammatory brain diseases; neurodegenerative diseases such as Alheimer's disease and Parkinson's disease.
- a pharmaceutical composition for suppressing apoptosis comprising troglitazone or a pharmacologically acceptable salt thereof as an active ingredient
- the “troglitazone” in the above is a compound disclosed as a compound having a hypoglycemic action and a hypolipidemic action in Japanese Patent Application Laid-Open No. 60-51189 (EP 0 924 421 A). And the following equation (I)
- the "pharmacologically acceptable salt” in the present invention refers to the above-mentioned “troglitazone” since it can be converted into a salt, and such a salt is preferably a sodium salt, a potassium salt, or a sodium salt.
- Alkali metal salts such as lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; octylamine salts, dibenzylamine salts; Morpholine salt, darcosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyldalkamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine Salt, black mouth professional strength salt, professional strength salt, jetanolamine salt, N-B Amine salts such as organic salts such as benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt; and glycine salt, lysine salt, arginine salt, or Amino
- troglitazone may be left in the air or recrystallized to absorb water, adsorb water, or form hydrates. Included in the salts of the invention.
- the above “troglitazone” has various isomers. In the compounds of the present invention, these 'isomers and mixtures of these isomers are all represented by a single formula, ie, formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers.
- apoptosis refers to the spontaneous self-activation of cells due to various causes, such as when cells turn over in healthy animal tissues or when unnecessary cells are removed at the stage of developing various organs. It is a state where the mechanism for killing is activated and dies.
- Nerve cell death causes a variety of nervous system disorders.
- Causes include, for example, glutamate-induced neurotoxicity (glutamate cytotoxicity) and activation of caspases (eg, caspase 3 and caspase 9).
- glutamate cytotoxicity Is known as a risk factor for both apoptosis and necrosis, whereas caspases are known to be responsible for only apoptosis.
- Examples of the “nervous system disease” in the above include ischemic injury (eg, stroke, cerebral hemorrhage, cerebral infarction), inflammatory brain disease (eg, encephalitis sequelae, acute disseminated meningitis, bacterial meningitis, Tuberculous meningitis, fungal meningitis, viral meningitis, vaccine meningitis, neurodegenerative diseases (eg, Alheimer's disease, head trauma, cerebral palsy, Huntington's disease, Pick's disease, Down's syndrome, Parkinson's disease, AIDS encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, cerebellar ataxia).
- the troglitazone of the present invention can be produced by the method described in Japanese Patent Application Laid-Open No. Sho 60-51189 (EP0124924A).
- Troglitazone or a pharmacologically acceptable salt thereof is useful as an apoptosis inhibitor.
- troglitazone or a pharmacologically acceptable salt thereof is used as the above-mentioned therapeutic or prophylactic agent, it is mixed with a pharmaceutically acceptable excipient, diluent or the like per se or appropriately.
- Tablets It can be administered orally by capsules, granules, powders or syrups or parenterally by injections or suppositories.
- These preparations may contain excipients (eg, lactose, sucrose, dextrose, sugar derivatives such as mannitol, sorbitol; corn starch, starch, starch derivatives such as ⁇ -starch, dextrin; cellulose derivatives such as crystalline cellulose).
- excipients eg, lactose, sucrose, dextrose, sugar derivatives such as mannitol, sorbitol; corn starch, starch, starch derivatives such as ⁇ -starch, dextrin; cellulose derivatives such as crystalline cellulose).
- Lubricants eg, stearic acid such as stearic acid, calcium stearate, magnesium stearate
- Acid metal salt talc
- colloidal silica Waxes such as veegum and gay
- boric acid adipic acid
- sulfates such as sodium sulphate; glycophosphate; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium lauryl sulphate, magnesium lauryl sulphate
- silicic acid such as silicic anhydride and silicic acid
- Disintegrants eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internal Bridge carboxymethylcellulose nato Cellulose derivatives such as lime; carboxymethyl starch, sodium carboxymethyl starch, chemically modified starches such as cross-linked polyvinyl pyrrolidone, and celluloses; and stabilizers (methyl paraben, propyl paraben).
- Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as fuynol and cresol; thimerosal; dehydroacetic acid; and sorbin Acids can be mentioned.
- Flavoring agents for example, commonly used sweeteners, acidulants, flavors, etc.).
- Manufactured by a well-known method using additives such as a diluent.
- the amount of troglitazone or a pharmacologically acceptable salt thereof varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg per day (preferably lmg) and the upper limit is 10 mg per day. 0 O mg (good 500 mg), and in the case of intravenous administration, a lower limit of 0.1 mg (preferably 0.1 mg) per day and an upper limit of 500 mg (preferably 200 mg) for adults. It is desirable to administer once or several times a day according to the symptoms.
- Example 1 Inhibition of apoptosis (1)
- the cerebellum was removed from an 8-day-old newborn SD rat, cut into small pieces with a scalpel, and then treated with trypsin (Sigma) at 37 C for 20 minutes.
- the dispersed cells are washed with BME medium (Gibco) supplemented with 10% fetal calf serum (Gibco) and 2 OmM potassium bicarbonate, and suspended again in the above culture solution.
- BME medium Gibco
- a 48-well plate (Costar) coated with polylysine was seeded at a concentration of 3-4 ⁇ 10 5 cells / cm 2 and cultured at 37 ° C. in a 5% CO 2 incubator.
- a culture solution containing Ara-C manufactured by Sigma
- the cells After 5 to 6 days of culture, the cells are washed once with a serum-free MEM medium (manufactured by Nissui Pharmaceutical Co., Ltd., containing 5.6 mM potassium chloride), and then a serum-free MEM medium containing the compound of the present invention. And treated with low potassium.
- a serum-free MEM medium manufactured by Nissui Pharmaceutical Co., Ltd., containing 5.6 mM potassium chloride
- a serum-free MEM medium containing the compound of the present invention. And treated with low potassium.
- some cells were cultured in a serum-free MEM medium supplemented with 2 OmM chlorinated ridium and treated with high-strength ridium.
- the cerebellum was removed from an 8-day-old newborn Wister rat, cut into small pieces with a scalpel, and treated with papain (Sigma) at 37 ° C for 15 minutes.
- the dispersed cells are washed with MEM medium (manufactured by Gibco) supplemented with 10 ° / o ⁇ fetal serum (manufactured by Asahi Techno Glass) and 2 OmM potassium bicarbonate, and then suspended again in the above culture medium.
- MEM medium manufactured by Gibco
- 10 ° / o ⁇ fetal serum manufactured by Asahi Techno Glass
- 2 OmM potassium bicarbonate 2 OmM potassium bicarbonate
- a culture solution containing Ara-C (manufactured by Sigma) was added.
- the cells are washed once with a serum-free MEM medium (manufactured by Asahi Techno Glass Co., Ltd., containing 5.6 mM potassium chloride). And subjected to a low-strength realm treatment.
- a serum-free MEM medium manufactured by Asahi Techno Glass Co., Ltd., containing 5.6 mM potassium chloride.
- As a control some cells were cultured in a serum-free MEM medium supplemented with 2 OmM chlorinated reames, and treated with high-strength lime.
- troglitazone exhibited a superior apoptosis-suppressing effect as compared to rosiglitazone.
- Example 3 Caspase 3 activation inhibitory action
- the caspase-3 activity of the cells was determined by washing the cells cultured in a low potassium or high potassium medium for 8 hours with phosphate-buffered saline (PBS) and then using the caspase-3 substrate Ac-DEVD-MCA (peptide study).
- PBS phosphate-buffered saline
- the product (7-amino- 4 ) was incubated at 37 ° C for 60 minutes in a reaction solution (20 mM Hepes-NaOH, 2 mM dithiothreitol, pH 7.5) containing 20 ⁇ . -methylcoumarin) (excitation wavelength 360 nm, emission wavelength 460 nm).
- the non-specific activity was defined as the activity in the presence of Ac-DEVD-CH0 (1 ⁇ ), which is a caspase 3 inhibitor, and the value obtained by subtracting the non-specific activity from the total activity was defined as caspase 3 activity.
- troglitazone After mixing 5 g of troglitazone, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, knead with 300 g of a 10% aqueous solution of hydroxypropylcellulose. This is granulated using an extruder and dried to obtain granules.
- capsules are obtained by filling 18 mg each in No. 3 capsules.
- tablets After mixing 5 g of troglitazone, 90 g of lactose and 34 g of corn starch, 20 g of crystal cell mouth and 1 g of magnesium stearate with a blender, tablets are obtained using a tablet machine.
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Abstract
Description
明細書 トログリタゾンを含有するアポトーシスを抑制するための医薬組成物 技術分野 Description Pharmaceutical composition containing troglitazone for inhibiting apoptosis
本発明は、 トログリタゾン又はその薬理上許容される塩を有効成分として含有するアポトー シスを抑制するための医薬,組成物に関する。 技術背景' The present invention relates to a medicament or composition for suppressing apoptosis containing troglitazone or a pharmacologically acceptable salt thereof as an active ingredient. Technology Background '
細胞死には、 ネクローシスとアポトーシスの二つのタイプがある。 There are two types of cell death: necrosis and apoptosis.
ネクローシスとは、 虚血などのように病的状態で一団の細胞に生じる死を示す。 すなわち、 様々な外的要因により細胞の崩壊及び自己融解が起こるが， 細胞内酵素の活性化は必須ではな いとされている。 Necrosis refers to death that occurs in a group of cells in a pathological condition, such as ischemia. That is, various external factors cause cell disruption and autolysis, but activation of intracellular enzymes is not essential.
一方、 アポトーシスとは、 動物の健常組織における細胞のターンオーバ一や種々の臓器の発 生段階において不要な細胞を除去する際など、様々な原因により細胞が自発的に自分自身を殺 す機構を活性ィヒして死んでいく状態であり、 カスパーゼと呼ばれる一連の酵素の活性化がその 中心的な役割を担っている [Neuron, 20, 633-647 (1998); Ann. Neurol., 45, 421-429 (199 9)]。 すなわち、 細胞死誘発因子によりカスパーゼ 8やカスパーゼ 9が活十生化され、 これらが カスパーゼ 3を活性化することによりアポトーシスが引き起こされるとされている。 On the other hand, apoptosis is a mechanism by which cells spontaneously kill themselves for various reasons, such as when cells turn over in healthy tissues of animals or when unnecessary cells are removed during the developmental stages of various organs. Activated and dying, the activation of a series of enzymes called caspases plays a central role [Neuron, 20, 633-647 (1998); Ann. Neurol., 45, 421-429 (199 9)]. That is, it is said that caspase 8 and caspase 9 are activated by the cell death inducing factor, and apoptosis is caused by activation of caspase 3 by these.
アルツハイマー病では神経細胞がアポトーシスを起こしていることが認められている [J. Neurosci., 16, 1710-1719 (1996); Exp. Neurol, 133, 225-230 (19952。 筋萎縮性側索硬ィ匕 症でも力スパーゼ 1及びカスパーゼ 3の活性化とアポトーシスによる神経細胞死が報告され てレヽる [J. Neuropathol. Exp. Neurol, 58, 459-471 (1999); Proc. Natl. Acad. Sci. USA, 95, 15763-15768 (1998)]。脳虚血障害モデルではアポトーシスによる細胞死が認められ、 力 スパーゼ阻害剤により細胞死を抑制し得る事が数多く報告されている [Exp. Opin. Invest. Drugs, 8, 1599-1610 (1999); Nature, 399, Supp, A7-A14, ひ 999)]。 また、 アルツハイマー 病やハンチントン舞踏病のそれぞれの原因遺伝子産物はカスパーゼによって限定分解され、 そ れに伴って細胞毒性を持つ分解産物が産生され得る事が報告されている [Cell, 97, 395-406 (1999); Neuron, 22, 623-633 (1999)]。 更にパーキンソン病モデルとして知られる 1—メチ ルー 4—フエニルピリジニゥムイオン (MPP+)による神経細胞死にもアポトーシスが関与して いることが示唆されている [J. Neurochem., 69, 1382-1388 (1997)]。以上のようにアポトー シスは神経細胞死に広く関与していると考えられており、 アポトーシスを抑制する化合物は多 くの神経変性疾患等の予防又は治療に有効であると考えられる。 本願発明の先行技術としては、 以下のものがある。 Apoptosis of neurons has been observed in Alzheimer's disease [J. Neurosci., 16, 1710-1719 (1996); Exp. Neurol, 133, 225-230 (19952. Amyotrophic lateral stiffness) Nerve cell death due to activation of force spase 1 and caspase 3 and apoptosis have also been reported in Gidori [J. Neuropathol. Exp. Neurol, 58, 459-471 (1999); Proc. Natl. Acad. Sci. USA, 95, 15763-15768 (1998)] In cerebral ischemic injury models, cell death due to apoptosis has been observed, and there have been many reports that cell death can be suppressed by a force-spase inhibitor [Exp. Opin. Invest. Drugs, 8, 1599-1610 (1999); Nature, 399, Supp, A7-A14, hi999)]. Alzheimer's It has been reported that the respective gene products of the disease and Huntington's disease can be limitedly degraded by caspases, and concomitantly produce cytotoxic degradation products [Cell, 97, 395-406 (1999)] Neuron, 22, 623-633 (1999)]. Furthermore, it has been suggested that apoptosis is also involved in neuronal cell death caused by 1-methyl 4-phenylpyridinium ion (MPP +) known as a Parkinson's disease model [J. Neurochem., 69, 1382-1388]. (1997)]. As described above, apoptosis is considered to be widely involved in nerve cell death, and compounds that suppress apoptosis are considered to be effective for prevention or treatment of many neurodegenerative diseases and the like. The prior art of the present invention includes the following.
(1) WO 97/40017号公報 (1) WO 97/40017
本公報には、ホスファターゼ（PTP a s e)阻害作用を有する化合物として以下一般式（A) In this publication, a compound having a phosphatase (PTPase) inhibitory action is represented by the following general formula (A):
(L)n— Ar，一 R「 A (A) (L) n—Ar, one R “A ( A )
[上記式中、 Lは式 A「 Y「 (W,) —X— (W2) —Y2—を有する基であり、 Atは置換され てもよいへテロァリール基であり、 Xは単結合であり、 Y,及び Y2は単結合、 一 Ο -であり、 Xは C!—Csアルキレン基であり、 及び W2は単結合であり、 A Γ ιはァリール基であり、 R は C!— C6アルキレン基であり、 Aは 2， 4ージォキソチアゾリジニル基である。] を有する化合物が開示されており、 上記一般式 （A) を有する化合物はトログリタゾンを含有 する。 また、 上記ホスファターゼ （PTP a s e) 阻害作用により改善される疾病として 「ァ ルツハイマー病等の脳における疾患」 が開示されている。 [In the formula, L is Formula A "Y" (W,) -X- (W 2 ) -Y 2 - is a radical having a, A t is a Teroariru group to an optionally substituted, X is a single a bond, Y, and Y 2 is a single bond, one Omicron -!, X is a C -Cs alkylene group, and W 2 is a single bond, a gamma iota is Ariru radical, R represents C! —C 6 alkylene group, A is a 2,4-dioxothiazolidinyl group.], And the compound having the above general formula (A) contains troglitazone Further, "diseases in the brain such as Alzheimer's disease" are disclosed as diseases improved by the phosphatase (PTPase) inhibitory action.
本願発明のトログリタゾンを含有する医薬組成物は、 カスパーゼ 3活性化を抑制することに よりアポトーシスを抑制する作用を有しているが、 本公報には、 上記化合物 （A) がホスファ ターゼ （PTP a s e) 阻害作用を有することによって脳疾患を予防または治療に有用である 旨の記載があるのみであり、 カスパーゼ 3活性化を抑制することによりアポトーシスを抑制す るという作用は開示も示唆もされておらず、 ホスファターゼ （PTP a s e) 阻害作用から力 スパ一ゼ 3活性化の抑制作用を関連させるような事実も知られていない。 The pharmaceutical composition containing troglitazone of the present invention has an action of suppressing apoptosis by suppressing caspase 3 activation. However, in this publication, the above compound (A) contains phosphatase (PTPase). There is only description that it has an inhibitory effect, which is useful for preventing or treating brain diseases, and there is no disclosure or suggestion of an effect of suppressing apoptosis by suppressing caspase 3 activation. But not from phosphatase (PTPase) inhibition There is no known fact relating to the inhibitory effect of the activation of Spanze3.
( 2 ) WO 9 7 / 4 6 2 3 8号公報 (2) WO97 / 4663238
本公報には、 内皮細胞活性を改善する作用を有する化合物として以下一般式 （B ) In this publication, compounds having the action of improving endothelial cell activity are represented by the following general formula (B):
[上記式中、 R R2、 R4及び R5は C!— C5アルキル基であり、 R3は水素原子であり、 Wは C H2であり、 Y及び Zは酸素原子であり、 nは 1乃至 3の整数である。] [Wherein RR 2 , R 4 and R 5 are C! —C 5 alkyl groups, R 3 is a hydrogen atom, W is CH 2 , Y and Z are oxygen atoms, and n is It is an integer of 1 to 3. ]
を有する化合物が開示されており、 上記一般式 （A) を有する化合物はトログリタゾンを含有 する。 また、 上記内皮細胞活性を改善する作用により改善される疾病として 「アルツハイマー 病のような神経変性疾患」 が開示されている。 The compound having the general formula (A) contains troglitazone. In addition, "a neurodegenerative disease such as Alzheimer's disease" is disclosed as a disease that is improved by the action of improving the endothelial cell activity.
本願発明のトログリタゾンを含有する医薬組成物は、カスパーゼ 3活性化を抑制することに よりアポトーシスを抑制する作用を有しているが、 本公報には、 上記化合物 （B ) が内皮細胞 活性の改善作用によつて神経変性疾患を予防または治療に有用である旨の記載があるのみで あり、 カスパーゼ 3活性化を抑制することによりアポト一シスを抑制するという作用は開示も 示唆もされておらず、更に内皮細胞は血管内に存在する細胞であるので神経細胞とは全く異な り、 内皮細胞活性の改善作用からカスパーゼ 3活性化の抑制作用を関連させるような事実も知 られていない。 Although the pharmaceutical composition containing troglitazone of the present invention has an action of suppressing apoptosis by suppressing caspase 3 activation, the publication discloses that the compound (B) improves endothelial cell activity. It only states that its action is useful for preventing or treating neurodegenerative diseases, and it does not disclose or suggest that it suppresses apoptosis by suppressing caspase 3 activation. Further, since endothelial cells are cells existing in blood vessels, they are completely different from nerve cells, and there is no known fact that endothelial cells have an effect of improving endothelial cell activity and a function of inhibiting caspase 3 activation.
( 3 ) WO 9 8 / 3 9 9 6 7号公報 (3) WO98 / 399767
本公報には、血中インスリンレベルの低下作用を有する化合物と This publication discloses compounds having a blood insulin level lowering action and
合物及びその具体的な化合物としてトログリタゾンが開示されており、 上記作用により改善さ れる疾病として 「アルツハイマー病」 が開示されている。 本願発明のト口グリタゾンを含有する医薬組成物は、 カスパーゼ 3活性ィ匕を抑制することに よりアポトーシスを抑制する作用を有しているが、 本公報には、 トログリタゾンを含有するチ ァゾリジンジオン化合物が上記血中インスリンレベルの低下作用によってアルツハイマー病 を予防または治療に有用である旨の記載があるのみであり、 カスパーゼ 3活性化を抑制するこ とによりアポトーシスを抑制するという作用は開示も示唆もされておらず、 更に血中インスリ ンレベルの低下作用が N T P (Neural Treated Protein) 活性を阻害する作用は開示されてい るが、血中インスリンレベルの低下作用からカスパーゼ 3活性化の抑制作用を関連させるよう な記載は全くなく、 事実も知られていない。 Troglitazone is disclosed as a compound and a specific compound thereof, and "Alzheimer's disease" is disclosed as a disease ameliorated by the above action. The pharmaceutical composition containing toguchiglitazone of the present invention has an effect of suppressing apoptosis by suppressing caspase 3 activity.In this publication, a thiazolidinedione compound containing troglitazone is disclosed. There is only description that the above-mentioned blood insulin level lowering effect is useful for preventing or treating Alzheimer's disease, and the effect of suppressing caspase 3 activation to suppress apoptosis is disclosed or suggested. Although the effect of lowering blood insulin levels inhibits NTP (Neural Treated Protein) activity, it has been disclosed that the effect of lowering blood insulin levels may be related to the inhibitory effect of caspase 3 activation. There is no description and no facts are known.
また、 本公報には、 改善される疾病としてはアルツハイマー病のみが開示されているが、 本 願発明のトログリタゾンによって改善される疾病としてはアルツハイマー病を含め、虚血障害 や炎症生脳疾患をも含有する。 Although this publication discloses only Alzheimer's disease as the disease to be improved, the disease improved by the troglitazone of the present invention includes Alzheimer's disease, including ischemic injury and inflammatory living brain disease. contains.
( 4 ) WO 9 9 / 2 5 3 4 6号公報 (4) WO 9 9/25 3 4 6
本公報には、 アポトーシス抑制作用を有する化合物として、 以下一般式 （C) In this gazette, compounds having an apoptosis-suppressing action are represented by the following general formula (C)
[上記式中、 Rは置換されてもよい複素環基であり、 Yは一 C O—で示される基であり、 m及 び nは 0であり、 R 1は水素原子であり、 Xは C Hであり、 Aは結合手であり、 L及び Mは水 素原子であり、 Qは硫黄原子である。] [In the above formula, R is an optionally substituted heterocyclic group, Y is a group represented by one CO—, m and n are 0, R 1 is a hydrogen atom, and X is CH A is a bond, L and M are hydrogen atoms, and Q is a sulfur atom. ]
を有する化合物及びインスリン感受性増強作用を有する化合物が開示されている。 And a compound having an insulin sensitivity enhancing action.
本公報では、 アポトーシス抑制作用を有する化合物としてトログリタゾンが開示されている が、本公報の試験例にトログリタゾンがアポトーシスを抑制する旨を示すようなデータ等は具 体的に全く開示されておらず、該試験例の結果において最も優れたアポトーシス抑制作用を有 する化合物はロジグリタゾンであることが開示されている。 In this publication, troglitazone is disclosed as a compound having an apoptosis-suppressing action, but no data or the like showing that troglitazone suppresses apoptosis is specifically disclosed in the test examples of this publication. Has the best apoptosis-suppressing effect in the results of this test example The compound is disclosed to be rosiglitazone.
しかしながら、 本願発明では、 トログリタゾンが、 アポトーシス抑制作用において本公報の 開示 （特に、 本公報の試験例の結果において最も優れたアポト一シス抑制作用を有するロジグ リタゾン） カ ら容易に推考できない程格別に優れた効果を示すことが初めて見出されたのであ る。 また、 本公報には、 トログリタゾンがカスパーゼ 3活性化を抑制することによりアポトー シスを抑制するという作用は開示も示唆もされていない。 発明の開示 However, according to the present invention, troglitazone is so special that troglitazone cannot be inferred easily from the disclosure of this publication in terms of its apoptosis-suppressing effect (particularly, the rosiglitazone having the best apoptosis-suppressing effect in the results of the test examples in this publication). It was found for the first time to show excellent effects. In addition, this publication does not disclose or suggest the action of troglitazone to suppress apoptosis by suppressing caspase 3 activation. Disclosure of the invention
本発明者らは、 トログリタゾンの医薬としての用途について鋭意研究を行った結果、 トログ リタゾンが優れたアポト一シス抑制作用を有することを見出し、 本発明を完成した。 The present inventors have conducted intensive studies on the use of troglitazone as a medicament, and as a result, have found that troglitazone has an excellent apoptotic inhibitory action, and completed the present invention.
本発明の目的は、 トログリタゾン又はその薬理上許容される塩を有効成分として含有するァ ポト一シスを抑制するための医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition for suppressing apoptosis which contains troglitazone or a pharmacologically acceptable salt thereof as an active ingredient.
また、 本発明の他の目的は、 アポト一シスを抑制するための医薬組成物を製造するために、 上記化合物を使用することである。 Another object of the present invention is to use the above compound for producing a pharmaceutical composition for suppressing apoptosis.
更に、 本発明の他の目的は、 上記化合物の薬理的に有効な量を温血動物に投与する、 アポト 一シスを抑制する方法、 特に、 神経細胞におけるアポトーシスを抑制する方法、 カスパーゼ 3 活性化を抑制する方法、 神経系の疾患 （例えば， 虚血障害；脳卒中；炎症性脳疾患；アルッハ イマ一病、 パーキンソン病のような神経変性疾患等） の予防方法又は治療方法を提供すること である。 Furthermore, another object of the present invention is to administer a pharmacologically effective amount of the compound to a warm-blooded animal, to inhibit apoptosis, in particular, to inhibit apoptosis in nerve cells, and to activate caspase-3. And methods for preventing or treating nervous system diseases (eg, ischemic injury; stroke; inflammatory brain diseases; neurodegenerative diseases such as Alheimer's disease and Parkinson's disease). .
すなわち、 本発明は、 That is, the present invention
( 1 ) トログリタゾン又はその薬理上許容される塩を有効成分として含有するアポトーシス を抑制するための医薬組成物 (1) A pharmaceutical composition for suppressing apoptosis, comprising troglitazone or a pharmacologically acceptable salt thereof as an active ingredient
に関し、 好適には、 Preferably,
( 2 ) 神経細胞におけるアポトーシスを抑制するための （1 ) に記載の医薬組成物、 (2) The pharmaceutical composition according to (1) for suppressing apoptosis in nerve cells,
( 3 ) カスパーゼ 3活性化を抑制するための （1 ) 又は （2 ) に記載の医薬組成物、(3) The pharmaceutical composition according to (1) or (2) for suppressing caspase-3 activation,
( 4 ) 神経系の疾患の予防又は治療のための （1 ) 乃至 （3 ) から選択されるいずれか 1項 に記載の医薬組成物、 (4) Any one selected from (1) to (3) for prevention or treatment of a nervous system disease The pharmaceutical composition according to,
(5) 神経系の疾患が虚血障害である、 （4) に記載の医薬組成物、 (5) the pharmaceutical composition according to (4), wherein the nervous system disease is ischemic injury;
(6) 神経系の疾患が脳卒中である、 （4) に記載の医薬組成物、 (6) The pharmaceutical composition according to (4), wherein the nervous system disease is stroke.
(7) 神経系の疾患が炎症性脳疾患である、 （4) に記載の医薬組成物、 (7) the pharmaceutical composition according to (4), wherein the nervous system disease is an inflammatory brain disease;
(8) 神経系の疾患が神経変性疾患である、 （4) に記載の医薬組成物、 (8) The pharmaceutical composition according to (4), wherein the nervous system disease is a neurodegenerative disease.
(9) 神経変性疾患がアルツハイマー病である、 （8) に記載の医薬組成物、 (9) The pharmaceutical composition according to (8), wherein the neurodegenerative disease is Alzheimer's disease.
(10) 神経変性疾患がパーキンソン病である、 （8) に記載の医薬組成物 (10) The pharmaceutical composition according to (8), wherein the neurodegenerative disease is Parkinson's disease.
を挙げることができる。 Can be mentioned.
更に本発明は、 Furthermore, the present invention
(1 1) アポトーシスを抑制するための医薬組成物を製造するための、 卜ログリタゾン又は その薬理上許容される塩の使用 (11) Use of troglitazone or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for suppressing apoptosis
に関し、 好適には、 Preferably,
(12) (1 1) に記載の神経細胞におけるアポト一シスを抑制するための医薬組成物を製 造するための使用、 (12) Use for producing a pharmaceutical composition for suppressing apoptosis in nerve cells according to (11),
(1 3) (1 1) 又は （12) に記載のカスパーゼ 3活性化を抑制するための医薬組成物を 製造するための使用、 (13) Use for producing a pharmaceutical composition for suppressing caspase-3 activation according to (11) or (12),
(14) (1 1) 乃至 （13) から選択されるいずれか 1項に記載の神経系の疾患の予防又 は治療のための医薬組成物を製造するための使用、 (14) Use for producing a pharmaceutical composition for preventing or treating a nervous system disease according to any one of (11) to (13),
(1 5) 神経系の疾患が虚血障害である、 （14) に記載の医薬組成物を製造するための使 用、 (15) use for producing the pharmaceutical composition according to (14), wherein the nervous system disease is ischemic injury;
(1 6) 神経系の疾患が脳卒中である、 （ 14) に記載の医薬組成物を製造するための使用、 (16) the use for producing the pharmaceutical composition according to (14), wherein the nervous system disease is stroke;
(1 7) 神経系の疾患が炎症性脳疾患である、 （14) に記載の医薬組成物を製造するため の使用、 (17) use for producing the pharmaceutical composition according to (14), wherein the nervous system disease is an inflammatory brain disease;
(18) 神経系の疾患が神経変性疾患である、 （1 4) に記載の医薬組成物を製造するため の使用、 (18) The use for producing the pharmaceutical composition according to (14), wherein the nervous system disease is a neurodegenerative disease,
(1 9) 神経変性疾患がアルツハイマー病である、 （1 8) に記載の医薬組成物を製造する ための使用、 (19) The pharmaceutical composition according to (18), wherein the neurodegenerative disease is Alzheimer's disease. Use for the
( 2 0 ) 神経変性疾患がパーキンソン病である、 （1 8 ) に記載の医薬組成物を製造するた めの使用 (20) The use for producing the pharmaceutical composition according to (18), wherein the neurodegenerative disease is Parkinson's disease.
を挙げることができる。 Can be mentioned.
上記における 「トログリタゾン」 は、 特開昭 6 0 - 5 1 1 8 9号公報 （E P 0 1 2 9 4 2 1 A) に血糖低下作用、 血中脂質低下作用を有する化合物として開示されている化合物であり、 下記式 （ I ) The “troglitazone” in the above is a compound disclosed as a compound having a hypoglycemic action and a hypolipidemic action in Japanese Patent Application Laid-Open No. 60-51189 (EP 0 924 421 A). And the following equation (I)
を有する。 Having.
本発明における 「薬理上許容される塩」 とは、 上記 「トログリタゾン」 は、 塩にすることが できるのでその塩をいい、 そのような塩としては、 好適には、 ナトリウム塩、 カリウム塩、 リ チウム塩のようなアルカリ金属塩、 カルシウム塩、 マグネシウム塩のようなアルカリ土類金属 塩、 アルミニウム塩、 鉄塩等の金属塩；アンモニゥム塩のような無機塩、 t一才クチルァミン 塩、 ジベンジルァミン塩、 モルホリン塩、 ダルコサミン塩、 フエニルグリシンアルキルエステ ル塩、 エチレンジァミン塩、 N—メチルダルカミン塩、 グァニジン塩、 ジェチルァミン塩、 ト リエチルァミン塩、 ジシクロへキシルァミン塩、 N， N ' —ジベンジルエチレンジァミン塩、 クロ口プロ力イン塩、 プロ力イン塩、 ジェタノ一ルァミン塩、 N—ベンジルフエネチルァミン 塩、 ピぺラジン塩、 テトラメチルアンモニゥム塩、 トリス （ヒ ドロキシメチル） ァミノメタン 塩のような有機塩等のァミン塩；及び、 グリシン塩、 リジン塩、 アルギニン塩、 オル二チン塩、 グルタミン酸塩、 ァスパラギン酸塩のようなアミノ酸塩を挙げることができる。 The "pharmacologically acceptable salt" in the present invention refers to the above-mentioned "troglitazone" since it can be converted into a salt, and such a salt is preferably a sodium salt, a potassium salt, or a sodium salt. Alkali metal salts such as lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; octylamine salts, dibenzylamine salts; Morpholine salt, darcosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyldalkamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine Salt, black mouth professional strength salt, professional strength salt, jetanolamine salt, N-B Amine salts such as organic salts such as benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt; and glycine salt, lysine salt, arginine salt, or Amino acid salts such as tin salt, glutamate and aspartate can be mentioned.
上記 「トログリタゾン」 は、 大気中に放置したり、 又は、 再結晶をすることにより、 水分を 吸収し、 吸着水が付いたり、 水和物となる場合があり、 そのような水和物も本発明の塩に包含 される。 上記 「トログリタゾン」 は、 種々の異性体を有する。 本発明の化合物においては、 これらの '異性体およびこれらの異性体の混合物がすべて単一の式、 即ち式 （I ) で示されている。 従つ て、 本発明はこれらの異性体及びこれらの異性体の混合物をもすベて含むものである。 The above-mentioned “troglitazone” may be left in the air or recrystallized to absorb water, adsorb water, or form hydrates. Included in the salts of the invention. The above “troglitazone” has various isomers. In the compounds of the present invention, these 'isomers and mixtures of these isomers are all represented by a single formula, ie, formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers.
上記における 「アポトーシス」 とは、 前述した通り、 動物の健常組織における細胞のターン オーバーや種々の臓器の発生段階において不要な細胞を除去する際など、様々な原因により細 胞が自発的に自分自身を殺す機構を活性化して死んでいく状態である。 As described above, “apoptosis” refers to the spontaneous self-activation of cells due to various causes, such as when cells turn over in healthy animal tissues or when unnecessary cells are removed at the stage of developing various organs. It is a state where the mechanism for killing is activated and dies.
アポトーシスを含む神経細胞死は、 様々な神経系の疾患を引き起こす。 その原因としては、 例えば、 グルタミン酸により誘発される神経毒性 （グルタミン酸細胞毒性） やカスパーゼ （例 えば、 カスパーゼ 3、 カスパーゼ 9を挙げることができる。） 活性化が挙げられ、 特に、 グル タミン酸細胞毒性はアポトーシス及びネクロ一シス両方の危険因子として知られており、一方 カスパーゼは、 アポトーシスのみを起こす原因であることが知られている。 Nerve cell death, including apoptosis, causes a variety of nervous system disorders. Causes include, for example, glutamate-induced neurotoxicity (glutamate cytotoxicity) and activation of caspases (eg, caspase 3 and caspase 9). In particular, glutamate cytotoxicity Is known as a risk factor for both apoptosis and necrosis, whereas caspases are known to be responsible for only apoptosis.
上記における 「神経系の疾患」 としては、 例えば、 虚血障害 （例えば、 脳卒中、 脳出血、 脳 梗塞）、 炎症性脳疾患 （例えば、 脳炎後遺症、 急性散在性脳髄膜炎、 細菌性髄膜炎、 結核性髄 膜炎、 真菌性髄膜炎、 ウィルス性髄膜炎、 ワクチン性髄膜炎）、 神経変性疾患 （例えば、 アル ッハイマー病、 頭部外傷、 脳性麻痺、 ハンチントン病、 ピック病、 ダウン症、 パーキンソン病、 エイズ脳症、 多発性硬化症、 筋萎縮性側索硬化症、 小脳失調症） を挙げることができる。 本願発明のトログリタゾンは、 特開昭 6 0— 5 1 1 8 9号公報 （E P 0 1 2 9 4 2 1 A) に 記載の方法によって製造することができる。 Examples of the “nervous system disease” in the above include ischemic injury (eg, stroke, cerebral hemorrhage, cerebral infarction), inflammatory brain disease (eg, encephalitis sequelae, acute disseminated meningitis, bacterial meningitis, Tuberculous meningitis, fungal meningitis, viral meningitis, vaccine meningitis, neurodegenerative diseases (eg, Alheimer's disease, head trauma, cerebral palsy, Huntington's disease, Pick's disease, Down's syndrome, Parkinson's disease, AIDS encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, cerebellar ataxia). The troglitazone of the present invention can be produced by the method described in Japanese Patent Application Laid-Open No. Sho 60-51189 (EP0124924A).
発明の効果 The invention's effect
トログリタゾン又はその薬理上許容される塩は、 アポトーシス抑制剤として有用である。 産業上の利用可能性 Troglitazone or a pharmacologically acceptable salt thereof is useful as an apoptosis inhibitor. Industrial applicability
トログリタゾン又はその薬理上許容される塩を、上記治療剤又は予防剤として使用する場合 には、 それ自体或は適宜の薬理学的に許容される、 賦形剤、 希釈剤等と混合し、 例えば、 錠剤、 力プセル剤、 顆粒剤、 散剤若しくはシロップ剤等による経口的又は注射剤若しくは坐剤等によ る非経口的に投与することができる。 When troglitazone or a pharmacologically acceptable salt thereof is used as the above-mentioned therapeutic or prophylactic agent, it is mixed with a pharmaceutically acceptable excipient, diluent or the like per se or appropriately. , Tablets, It can be administered orally by capsules, granules, powders or syrups or parenterally by injections or suppositories.
これらの製剤は、 賦形剤 （例えば、 乳糖、 白糖、 葡萄糖、 マンニトール、 ソルビトールのよ うな糖誘導体； トウモロコシデンプン、 ノ レイショデンプン、 α澱粉、 デキストリンのような 澱粉誘導体；結晶セルロースのようなセルロース誘導体；アラビアゴム デキストラン；プル ランのような有機系賦形剤：及び、 軽質無水珪酸、 合成珪酸アルミニウム、 珪酸カルシウム、 メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体；燐酸水素カルシウムのような燐酸 塩；炭酸カルシウムのような炭酸塩；硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げ ることができる。）、 滑沢剤 （例えば、 ステアリン酸、 ステアリン酸カルシウム、 ステアリン酸 マグネシウムのようなステアリン酸金属塩；タルク ；コロイ ドシリカ ；ビーガム、 ゲイ蠟のよ うなワックス類；硼酸；ァジピン酸；硫酸ナトリウムのような硫酸塩；グリコ一ノレ；フマル酸； 安息香酸ナトリウム； D Lロイシン；脂肪酸ナトリウム塩；ラウリル硫酸ナトリウム、 ラウリ ル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸、 珪酸水和物のような珪酸類；及び、 上記澱粉誘導体を挙げることができる。）、 結合剤 （例えば、 ヒ ドロキシプロピルセルロース、 ヒ ドロキシプロピルメチルセル口一ス、 ポリビニルピロリ ドン、 マクロゴール、 及び、 前記賦 形剤と同様の化合物を挙げることができる。）、 崩壊剤 （例えば、 低置換度ヒ ドロキシプロピル セルロース、 カルボキシメチルセルロース、 カルボキシメチルセルロースカルシウム、 内部架 橋カルボキシメチルセルロースナトリゥムのようなセルロース誘導体；カルボキシメチルスタ ーチ、 カルボキシメチルスターチナトリウム、 架橋ポリビニルピロリ ドンのような化学修飾さ れたデンプン 'セルロース類を挙げることができる。）、 安定剤 （メチルパラベン、 プロピルパ ラベンのようなパラォキシ安息香酸エステル類；クロロブタノール、 ベンジルアルコール、 フ ェニルエチルアルコールのようなアルコール類；塩化ベンザルコニゥム ；フユノール、 クレゾ ールのようなフエノール類；チメ口サール；デヒ ドロ酢酸；及び、 ソルビン酸を挙げることが できる。）、 矯味矯臭剤 （例えば、 通常使用される、 甘味料、 酸味料、 香料等を挙げることがで きる。）、 希釈剤等の添加剤を用いて周知の方法で製造される。 These preparations may contain excipients (eg, lactose, sucrose, dextrose, sugar derivatives such as mannitol, sorbitol; corn starch, starch, starch derivatives such as α-starch, dextrin; cellulose derivatives such as crystalline cellulose). Gum arabic dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; Inorganic excipients such as carbonates such as calcium carbonate; sulfates such as calcium sulfate can be mentioned.) Lubricants (eg, stearic acid such as stearic acid, calcium stearate, magnesium stearate) Acid metal salt; talc; colloidal silica Waxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulphate; glycophosphate; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium lauryl sulphate, magnesium lauryl sulphate Such as lauryl sulfate; silicic acid such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.) Binders (eg, hydroxypropyl cellulose, hydroxypropyl methylcellulose) Examples thereof include polyvinylpyrrolidone, macrogol, and the same compounds as the excipients described above. Disintegrants (eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internal Bridge carboxymethylcellulose nato Cellulose derivatives such as lime; carboxymethyl starch, sodium carboxymethyl starch, chemically modified starches such as cross-linked polyvinyl pyrrolidone, and celluloses; and stabilizers (methyl paraben, propyl paraben). Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as fuynol and cresol; thimerosal; dehydroacetic acid; and sorbin Acids can be mentioned.), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.). ), Manufactured by a well-known method using additives such as a diluent.
トログリタゾン又はその薬理上許容される塩の使用量は、 症状、 年齢等により異なるが、 経 口投与の場合には、 1回当り 1 日下限 0 . l m g (好適には、 l m g )、 上限 1 0 0 O m g (好 適には、 500mg) を、 静脈内投与の場合には、 1回当り 1 日下限 0. O lmg (好適には、 0. lmg)、 上限 500mg (好適には、 200mg) を成人に対して、 1 日当り 1または 数回に分けて、 症状に応じて投与することが望ましい。 発明を実施するための最良の形態 The amount of troglitazone or a pharmacologically acceptable salt thereof varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg per day (preferably lmg) and the upper limit is 10 mg per day. 0 O mg (good 500 mg), and in the case of intravenous administration, a lower limit of 0.1 mg (preferably 0.1 mg) per day and an upper limit of 500 mg (preferably 200 mg) for adults. It is desirable to administer once or several times a day according to the symptoms. BEST MODE FOR CARRYING OUT THE INVENTION
以下に、 実施例及び製剤例を示し、 本発明を更に詳細に説明するが、 本発明の範囲はこれら に限定するものではない。 実施例 1. アポトーシス抑制作用 （1) Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the scope of the present invention is not limited thereto. Example 1. Inhibition of apoptosis (1)
培養小脳顆粒細胞は高力リゥム培地で培養するとよく生存するが、培地中の力リゥム濃度を 低下させることによってアポト一シスを起こすことから、神経細胞のアポトーシスのモデルと して用いられている [D'Melloet. al.， Proc. Natl. Acad. Sci. USA, 90, 10989-10993 (1993)]。 アポトーシスに対する抑制作用は、 以下の方法を用いて評価した。 Cultured cerebellar granule cells survive well when cultured in a high-strength readium medium, but are used as a model of neuronal apoptosis because apoptosis occurs by reducing the concentration of spheroids in the medium [ D'Melloet. Al., Proc. Natl. Acad. Sci. USA, 90, 10989-10993 (1993)]. The inhibitory effect on apoptosis was evaluated using the following method.
すなわち、 8日齢の新生 SD系ラットより小脳を取りだし、 メスで細かく細断した後、 トリ プシン （シグマ社製） にて 37 C、 20分処理した。分散した細胞を、 10%ゥシ胎児血清（ギ ブコ社製） および 2 OmMの炭酸水素カリウムを添加した BME培地 （ギブコ社製） で洗浄し た後、 再び上記の培養液に懸濁し、 あらかじめポリリジンでコーティングしておいた 48孔プ レート （コースター社製） に 3— 4 X 105 細胞 /cm2 の濃度でまき、 37°C、 5% C02ィ ンキュベータ一で培養した。 培養翌日に A r a— C (シグマ社製） を含む培養液を追加した。 培養 5— 6日目に、 無血清の MEM培地 （日水製薬社製、 5. 6 mMの塩化カリウムを含む） で細胞を一回洗浄した後、 本願発明の化合物を含む無血清の MEM培地で培養し、 低カリウム 処置を行った。 対照として、 一部の細胞を 2 OmMの塩化力リゥムを添加した無血清の MEM 培地で培養し、 高力リゥム処置を行った。 That is, the cerebellum was removed from an 8-day-old newborn SD rat, cut into small pieces with a scalpel, and then treated with trypsin (Sigma) at 37 C for 20 minutes. The dispersed cells are washed with BME medium (Gibco) supplemented with 10% fetal calf serum (Gibco) and 2 OmM potassium bicarbonate, and suspended again in the above culture solution. A 48-well plate (Costar) coated with polylysine was seeded at a concentration of 3-4 × 10 5 cells / cm 2 and cultured at 37 ° C. in a 5% CO 2 incubator. The next day after the culture, a culture solution containing Ara-C (manufactured by Sigma) was added. After 5 to 6 days of culture, the cells are washed once with a serum-free MEM medium (manufactured by Nissui Pharmaceutical Co., Ltd., containing 5.6 mM potassium chloride), and then a serum-free MEM medium containing the compound of the present invention. And treated with low potassium. As a control, some cells were cultured in a serum-free MEM medium supplemented with 2 OmM chlorinated ridium and treated with high-strength ridium.
アポトーシスを起こした細胞から漏出した LDH量は、 LDH測定キッ ト （Boehringer Mannheim社製） を用いて測定した。本願発明の化合物のアポトーシス抑制率を以下の計算式に より求めた。 アポトーシス抑制率 （％) = The amount of LDH leaked from apoptotic cells was measured using an LDH measurement kit (Boehringer Mannheim). The apoptosis inhibition rate of the compound of the present invention was determined by the following formula. Apoptosis inhibition rate (%) =
(低カリウム群の LDH遊離量一低カリウム及び本願発明の化合物群の LDH遊離量） X 100/ (LDH release amount of low potassium group-LDH release amount of low potassium and compound group of the present invention) X 100 /
(低カリウム群の LDH遊離量一高力' jクム群の LDH遊離量） (LDH release in the low potassium group vs. LDH release in the jukum group)
本願発明の化合物 アポトーシス抑制率 （％) トログリタゾン (2 g/ml) 70. 6 上記の結果、 卜ログリタゾンは、 優れたアポトーシス抑制作用を示した。 実施例 2. アポトーシス抑制作用 （2) Compound Apoptosis inhibition rate the present invention (%) troglitazone (2 g / m l) 70. 6 above results, Bok Roguritazon exhibited effects superior apoptosis inhibitory. Example 2. Apoptosis inhibitory action (2)
8日齢の新生 Wister系ラットより小脳を取りだし、 メスで細かく細断した後、パパイン（シ グマ社製） にて 37°C、 1 5分処理した。 分散した細胞を、 10°/oゥシ胎児血清 （旭テクノガ ラス社製） および 2 OmMの炭酸水素カリウムを添加した MEM培地 （ギブコ社製） で洗浄し た後、 再び上記の培養液に懸濁し、 あらかじめポリリジンでコーティングしておいた 96孔プ レート （Becton Dickinson社製） に 4一 8 X 105細胞/ cm2の濃度でまき、 37 C、 5% C 02インキュベーターで培養した。 培養翌日に A r a— C (シグマ社製） を含む培養液を追加 した。 培養 7— 8日目に、 無血清の MEM培地 （旭テクノガラス社製、 5. 6 mMの塩化カリ ゥムを含む） で細胞を一回洗浄した後、 試験化合物を含む無血清の MEM培地で培養し、 低力 リゥム処置を行った。 対照として、 一部の細胞を 2 OmMの塩化力リゥムを添加した無血清の MEM培地で培養し、 高力リゥム処置を行った。 The cerebellum was removed from an 8-day-old newborn Wister rat, cut into small pieces with a scalpel, and treated with papain (Sigma) at 37 ° C for 15 minutes. The dispersed cells are washed with MEM medium (manufactured by Gibco) supplemented with 10 ° / o ゥ fetal serum (manufactured by Asahi Techno Glass) and 2 OmM potassium bicarbonate, and then suspended again in the above culture medium. Nigoshi, plated at a concentration of 4 one 8 X 10 5 cells / cm 2 in 96 Anapu rate which had been previously coated with polylysine (Becton Dickinson) and cultured at 37 C, 5% C 0 2 incubator. The next day after the culture, a culture solution containing Ara-C (manufactured by Sigma) was added. On days 7 and 8 of culture, the cells are washed once with a serum-free MEM medium (manufactured by Asahi Techno Glass Co., Ltd., containing 5.6 mM potassium chloride). And subjected to a low-strength realm treatment. As a control, some cells were cultured in a serum-free MEM medium supplemented with 2 OmM chlorinated reames, and treated with high-strength lime.
アポトーシスを起こした細胞から漏出した LDH量は、 LDH測定キット （Promega社製） を用いて測定し、 アポトーシス抑制活¾を求めた。 表 2 試験化合物 I C50 g/ml) トログリタゾン 0 . 2 4 The amount of LDH leaked from apoptotic cells was measured using an LDH measurement kit (Promega) to determine the apoptosis-inhibiting activity. (Table 2 Test compound IC 50 g / ml) Troglitazone 0.2 4
> 6 上記の結果、 トログリタゾンは、 ロジグリタゾンに比べて優れたアポトーシス抑制作用を示 した。 実施例 3 . カスパーゼ 3活性化抑制作用 > 6 As a result, troglitazone exhibited a superior apoptosis-suppressing effect as compared to rosiglitazone. Example 3 Caspase 3 activation inhibitory action
細胞のカスパ一ゼ 3活性は、 低カリウムあるいは高カリウム培地で 8 時間培養した細胞を phosphate-buffered sal ine ( P B S ) で洗浄した後、 カスバ一ゼ 3基質である Ac- DEVD- MCA (ペプチド研究所製； 2 0 μ Μ) を含む反応液 （ 2 0 mM Hepes- NaOH, 2 mM dithiothreitol, pH 7. 5) で 3 7 °C、 6 0分インキュベートして生成した産物 （7- amino- 4- methylcoumarin) の蛍 光強度を測定した （励起波長 360 nm, 蛍光波長 460 nm)。 非特異的活性はカスパーゼ 3の阻害 剤である Ac-DEVD- CH0 (1 μΜ) 存在下での活性とし、 全活性より非特異的活性を差し引いた値 をカスパーゼ 3活性とした。 カスパーゼ 3の活性化抑制率は以下の計算式により求めた。 カスパーゼ 3活性化抑制率 （％) = The caspase-3 activity of the cells was determined by washing the cells cultured in a low potassium or high potassium medium for 8 hours with phosphate-buffered saline (PBS) and then using the caspase-3 substrate Ac-DEVD-MCA (peptide study). The product (7-amino- 4 ) was incubated at 37 ° C for 60 minutes in a reaction solution (20 mM Hepes-NaOH, 2 mM dithiothreitol, pH 7.5) containing 20 μΜ. -methylcoumarin) (excitation wavelength 360 nm, emission wavelength 460 nm). The non-specific activity was defined as the activity in the presence of Ac-DEVD-CH0 (1 μΜ), which is a caspase 3 inhibitor, and the value obtained by subtracting the non-specific activity from the total activity was defined as caspase 3 activity. The activation inhibition rate of caspase 3 was determined by the following formula. Caspase 3 activation suppression rate (%) =
(低カリウム群のカス/、' -セ" 3活性-低カリウム及び試験化合物群のカス '、° - ' 3活性） X 100/ (Low potassium group scum /, '-se' 3 activity-low potassium and test compound group scum ', °-' 3 activity) X 100 /
(低カリゥム群のカス'、' -セ" 3活性-高カリゥム群のカス'、' -セ" 3活性） . 表 3 試験化合物 カスパーゼ 3活性化抑制率 （％) トログリタゾン (6 g/ml) 85. 0 ロジグリタゾン (6 U g/ml) 0 上記の結果、 トログリタゾンは、 ロジグリタゾンに比べて優れたカスパーゼ 3活性化抑制作 用を示した。 · 製剤例 1. 散剤 (Low-Casmic group's, '-Se'3 activity-High-Calm group's,'-Se'3 activity). Table 3 Test compound Caspase-3 activation inhibition rate (%) Troglitazone (6 g / ml) 85.0 Rosiglitazone (6 U g / ml) 0 As a result of the above, troglitazone has superior caspase-3 activity as compared to rogiglitazone The effect was shown. · Formulation Example 1. Powder
トログリタゾン 5 g、乳糖 895 g及びトウモロコシデンプン 1 00 gをブレンダー で混合すると、 散剤が得られる。 Mixing 5 g of troglitazone, 895 g of lactose and 100 g of corn starch with a blender gives a powder.
製剤例 2. 顆粒剤 Formulation example 2. Granules
トログリタゾン 5 g、乳糖 865 g及び低置換度ヒ ドロキシプロピルセルロース 10 0 gを混合した後、 1 0%ヒ ドロキシプロピルセルロース水溶液 300 gを加えて練合する。 これを押し出し造粒機を用いて造粒し、 乾燥すると顆粒剤が得られる。 After mixing 5 g of troglitazone, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, knead with 300 g of a 10% aqueous solution of hydroxypropylcellulose. This is granulated using an extruder and dried to obtain granules.
製剤例 3. カプセル剤 Formulation example 3. Capsule
トログリタゾン 5 g、乳糖 1 15 gおよびトウモロコシデンプン 58 g及びステアリ ン酸マグネシウム 2 gを V型混合機を用いて混合した後、 3号カプセルに 18 Omgずつ充 填すると、 カプセル剤が得られる。 After 5 g of troglitazone, 115 g of lactose, 58 g of corn starch and 2 g of magnesium stearate are mixed using a V-type mixer, capsules are obtained by filling 18 mg each in No. 3 capsules.
製剤例 4. 錠剤 Formulation Example 4. Tablet
トログリタゾン 5 g、 乳糖 90 gおよびトウモロコシデンプン 34 g、 結晶セル口一 ス 20 g及びステアリン酸マグネシウム 1 gをプレンダ一で混合した後、 錠剤機で打錠す ると錠剤が得られる。 After mixing 5 g of troglitazone, 90 g of lactose and 34 g of corn starch, 20 g of crystal cell mouth and 1 g of magnesium stearate with a blender, tablets are obtained using a tablet machine.
Claims
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|---|---|
| AU (2) | AU3073600A (en) |
| WO (2) | WO2000043007A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1518556A1 (en) * | 2002-06-28 | 2005-03-30 | Yamanouchi Pharmaceutical Co. Ltd. | Therapeutic agent for brain hemorrhage |
| CN112521382A (en) * | 2020-12-14 | 2021-03-19 | 西南大学 | Aloe-emodin thiazolidinedione compound and preparation method and application thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62234085A (en) * | 1985-12-18 | 1987-10-14 | Sankyo Co Ltd | Remedy for diabetic complication comprising thiazolidine derivative as active ingredient |
| JPH05202042A (en) * | 1992-01-24 | 1993-08-10 | Sankyo Co Ltd | Therapeutic agent for diabetic complication |
| WO1998010760A1 (en) * | 1996-09-12 | 1998-03-19 | Sankyo Company, Limited | Glutathione reductase activity potentiator containing troglitazone |
| WO1998039967A1 (en) * | 1997-03-12 | 1998-09-17 | The General Hospital Corporation | A method for treating or preventing alzheimer's disease |
| WO1999025346A1 (en) * | 1997-11-19 | 1999-05-27 | Takeda Chemical Industries, Ltd. | Novel apoptosis inhibitors |
| WO1999059586A1 (en) * | 1998-05-19 | 1999-11-25 | Regents Of The University Of California | Thiazolidine and oxazolidine derivatives for the treatment of acute myocardial infarction and inhibition of cardiomyocyte apoptosis |
| WO2000000194A1 (en) * | 1998-06-27 | 2000-01-06 | Photogenesis, Inc. | Ophthalmic uses of ppargamma agonists and ppargamma antagonists |
| WO2000004890A1 (en) * | 1998-07-21 | 2000-02-03 | Smithkline Beecham P.L.C. | Use of glucose uptake enhancer for reducing apoptosis |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5522636A (en) * | 1978-08-04 | 1980-02-18 | Takeda Chem Ind Ltd | Thiazoliding derivative |
| US4873255A (en) * | 1987-02-04 | 1989-10-10 | Sankyo Company Limited | Thiazolidinone derivatives, their preparation and their use |
| ATE186724T1 (en) * | 1987-09-04 | 1999-12-15 | Beecham Group Plc | SUBSTITUTED THIAZOLIDINEDIONE DERIVATIVES |
| CA2083891A1 (en) * | 1991-12-03 | 1993-06-04 | Angus Murray Macleod | Heterocyclic compounds, compositions containing them and their use in therapy |
| US5326770A (en) * | 1992-07-17 | 1994-07-05 | The Du Pont Merck Pharmaceutical Company | Monoamine oxidase-B (MAO-B) inhibitory 5-substituted 2,4-thiazolidinediones useful in treating memory disorders of mammals |
| CZ293016B6 (en) * | 1995-06-01 | 2004-01-14 | Sankyo Company Limited | Benzimidazole derivatives and pharmaceutical compositions in which the derivatives are comprised |
| KR19990087076A (en) * | 1996-04-05 | 1999-12-15 | 다께다 구니오 | A pharmaceutical combination containing angiotensin II and a compound having antagonistic activity |
| WO1997040017A2 (en) * | 1996-04-19 | 1997-10-30 | Novo Nordisk A/S | Modulators of molecules with phosphotyrosine recognition units |
| GB9611947D0 (en) * | 1996-06-07 | 1996-08-07 | Glaxo Group Ltd | Medicaments |
-
2000
- 2000-01-19 AU AU30736/00A patent/AU3073600A/en not_active Abandoned
- 2000-01-19 WO PCT/JP2000/000226 patent/WO2000043007A1/en not_active Ceased
- 2000-01-19 WO PCT/JP2000/000225 patent/WO2000043006A1/en not_active Ceased
- 2000-01-19 AU AU30737/00A patent/AU3073700A/en not_active Abandoned
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62234085A (en) * | 1985-12-18 | 1987-10-14 | Sankyo Co Ltd | Remedy for diabetic complication comprising thiazolidine derivative as active ingredient |
| JPH05202042A (en) * | 1992-01-24 | 1993-08-10 | Sankyo Co Ltd | Therapeutic agent for diabetic complication |
| WO1998010760A1 (en) * | 1996-09-12 | 1998-03-19 | Sankyo Company, Limited | Glutathione reductase activity potentiator containing troglitazone |
| WO1998039967A1 (en) * | 1997-03-12 | 1998-09-17 | The General Hospital Corporation | A method for treating or preventing alzheimer's disease |
| WO1999025346A1 (en) * | 1997-11-19 | 1999-05-27 | Takeda Chemical Industries, Ltd. | Novel apoptosis inhibitors |
| WO1999059586A1 (en) * | 1998-05-19 | 1999-11-25 | Regents Of The University Of California | Thiazolidine and oxazolidine derivatives for the treatment of acute myocardial infarction and inhibition of cardiomyocyte apoptosis |
| WO2000000194A1 (en) * | 1998-06-27 | 2000-01-06 | Photogenesis, Inc. | Ophthalmic uses of ppargamma agonists and ppargamma antagonists |
| WO2000004890A1 (en) * | 1998-07-21 | 2000-02-03 | Smithkline Beecham P.L.C. | Use of glucose uptake enhancer for reducing apoptosis |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000043006A1 (en) | 2000-07-27 |
| AU3073600A (en) | 2000-08-07 |
| AU3073700A (en) | 2000-08-07 |
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