JP2021024826A - Glycation product formation inhibitor and pharmaceutical composition - Google Patents
Glycation product formation inhibitor and pharmaceutical composition Download PDFInfo
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- JP2021024826A JP2021024826A JP2019144724A JP2019144724A JP2021024826A JP 2021024826 A JP2021024826 A JP 2021024826A JP 2019144724 A JP2019144724 A JP 2019144724A JP 2019144724 A JP2019144724 A JP 2019144724A JP 2021024826 A JP2021024826 A JP 2021024826A
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Abstract
Description
本発明は、糖化産物生成抑制剤及び医薬組成物に関する。 The present invention relates to an advanced glycation end product production inhibitor and a pharmaceutical composition.
アミノ酸と還元糖の混合物を加熱すると褐変する現象は、一般にメイラード反応と呼ばれる。グリコシルヘモグロビン（ＨｂＡ１ｃ）が生体内で同定され、糖尿病、老化等の進行に伴って蛋白質の糖化反応が、生体内で進行することが明らかにされた。このような蛋白質の糖化反応における終末糖化産物（Ａｄｖａｎｃｅｄ ｇｌｙｃａｔｉｏｎ ｅｎｄ ｐｒｏｄｕｃｔｓ、以下「ＡＧＥｓ」ともいう）について、糖尿病合併症、動脈硬化といった生活習慣病の発症、老化の進行等に関与することが報告されている。これらＡＧＥｓの体内蓄積は、腎糸球体組織硬化症、腎動脈硬化症などの糖尿病合併症だけでなく、アルツハイマー病などの神経変性疾患、皮膚の弾力性の低下や黄色化といった皮膚老化、骨の老化、眼球の老化、アルブミン蛋白の老化に深く関与することが報告されている。 The phenomenon of browning when a mixture of amino acids and reducing sugars is heated is generally called the Maillard reaction. Glycohemoglobin (HbA1c) was identified in vivo, and it was clarified that the protein glycation reaction proceeds in vivo with the progress of diabetes, aging and the like. It has been reported that advanced glycation end products (hereinafter also referred to as "AGEs") in the glycation reaction of such proteins are involved in the onset of lifestyle-related diseases such as diabetic complications and arteriosclerosis, and the progression of aging. ing. Accumulation of these AGEs in the body includes not only diabetic complications such as renal glomerular tissue sclerosis and renal arteriosclerosis, but also neurodegenerative diseases such as Alzheimer's disease, skin aging such as decreased skin elasticity and yellowing, and bone. It has been reported to be deeply involved in aging, eyeball aging, and albumin protein aging.
例えば、特許文献１には、アミノグアニジン等の化合物を含むメイラード反応阻害剤が記載されている。アミノグアニジンは、抗糖化作用を示す物質であるが、肝障害等の副作用のため、実用化には至っていない。また、特許文献２には、タウリンとビオチンを含む抗糖尿病用組成物が記載されている。 For example, Patent Document 1 describes a Maillard reaction inhibitor containing a compound such as aminoguanidine. Aminoguanidine is a substance that exhibits an anti-glycation effect, but has not been put into practical use due to side effects such as liver damage. Further, Patent Document 2 describes an antidiabetic composition containing taurine and biotin.
本発明は、糖化産物の生成を抑制可能な糖化産物生成抑制剤を提供することを目的とする。 An object of the present invention is to provide an advanced glycation end product production inhibitor capable of suppressing the production of advanced glycation end products.
第一態様は、式（１）で表される化合物又はその薬学的に許容される塩を有効成分として含む糖化産物生成抑制剤である。式中、Ａｒはアリール基を表し、Ｒ１は水素原子又は脂肪族基を表し、ｎは１から３の整数、ｍは１から４の整数を表す。 The first aspect is an advanced glycation end product production inhibitor containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. In the formula, Ar represents an aryl group, R 1 represents a hydrogen atom or an aliphatic group, n represents an integer of 1 to 3, and m represents an integer of 1 to 4.
第二態様は、式（１）で表される化合物又はその薬学的に許容される塩を有効成分として含む、糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種を処置するための医薬組成物である。式中、Ａｒはアリール基を表し、Ｒ１は水素原子又は脂肪族基を表し、ｎは１から３の整数、ｍは１から４の整数を表す。 The second aspect treats at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. It is a pharmaceutical composition for. In the formula, Ar represents an aryl group, R 1 represents a hydrogen atom or an aliphatic group, n represents an integer of 1 to 3, and m represents an integer of 1 to 4.
第三態様は、前記医薬組成物を、対象に投与することを含む、糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種の処置方法である。 A third aspect is at least one treatment method selected from a group of diseases derived from the production or accumulation of advanced glycation end products, which comprises administering the pharmaceutical composition to a subject.
さらに本発明は、式（１）で表される化合物又はその薬学的に許容される塩の前記糖化産物生成抑制剤又は前記医薬組成物の製造における使用を包含する。 Furthermore, the present invention includes the use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the production of the advanced glycation end product production inhibitor or the pharmaceutical composition.
本発明によれば、糖化産物の生成を抑制可能な糖化産物生成抑制剤を提供することができる。 According to the present invention, it is possible to provide an advanced glycation end product production inhibitor capable of suppressing the production of advanced glycation end products.
本明細書において組成物中の各成分の含有量は、組成物中に各成分に該当する物質が複数存在する場合、特に断らない限り、組成物中に存在する当該複数の物質の合計量を意味する。以下、本発明の実施形態を詳細に説明する。ただし、以下に示す実施形態は、本発明の技術思想を具体化するための、糖化産物生成抑制剤等を例示するものであって、本発明は、以下に示す糖化産物生成抑制剤等に限定されない。 In the present specification, the content of each component in the composition is the total amount of the plurality of substances present in the composition unless otherwise specified, when a plurality of substances corresponding to each component are present in the composition. means. Hereinafter, embodiments of the present invention will be described in detail. However, the embodiments shown below exemplify an advanced glycation end product production inhibitor or the like for embodying the technical idea of the present invention, and the present invention is limited to the advanced glycation end product production inhibitor or the like shown below. Not done.
糖化産物生成抑制剤及び医薬組成物は、下記式（１）で表される化合物又はその薬学的に許容される塩の少なくとも１種を有効成分として含む。医薬組成物は、糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種を処置するために用いられる。 The advanced glycation end product production inhibitor and the pharmaceutical composition contain at least one of the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition is used to treat at least one selected from a group of diseases resulting from the production or accumulation of advanced glycation end products.
式中、Ａｒはアリール基を表し、Ｒ１は水素原子又は脂肪族基を表し、ｎは１から３の整数、ｍは１から４の整数を表す。 In the formula, Ar represents an aryl group, R 1 represents a hydrogen atom or an aliphatic group, n represents an integer of 1 to 3, and m represents an integer of 1 to 4.
式（１）で表される化合物は、生体内における糖化産物の生成を抑制することができる。したがって、式（１）で表される化合物を含む医薬組成物を、対象者に投与することで、対象者における糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種を処置することができる。また、健常者に投与することで、糖尿病、糖尿病合併症等の糖化産物の生成又は蓄積に由来する疾患を予防することができる。なお、式（１）で表される化合物が、生体内における糖化産物の生成を抑制する作用機序の詳細については未だ不明である。 The compound represented by the formula (1) can suppress the production of advanced glycation end products in vivo. Therefore, by administering the pharmaceutical composition containing the compound represented by the formula (1) to the subject, at least one selected from the disease group derived from the production or accumulation of advanced glycation end products in the subject is treated. be able to. In addition, by administering to a healthy person, it is possible to prevent diseases caused by the production or accumulation of advanced glycation end products such as diabetes and diabetic complications. The details of the mechanism of action of the compound represented by the formula (1) in suppressing the production of advanced glycation end products in vivo are still unknown.
式（１）において、Ａｒは、例えば、置換基を有していてもよい炭素数６から１０のアリール基である。アリール基の具体例としては、フェニル基、ナフチル基等を挙げることができ、これらからなる群から選択される少なくとも１種であることが好ましい。 In formula (1), Ar is, for example, an aryl group having 6 to 10 carbon atoms which may have a substituent. Specific examples of the aryl group include a phenyl group, a naphthyl group and the like, and at least one selected from the group consisting of these groups is preferable.
Ａｒにおけるアリール基は少なくとも１つの置換基を有していてもよい。置換基としては、例えば、ハロゲン原子、ヒドロキシ基、ニトロ基、シアノ基、ホルミル基、炭素数１から６のアルキルカルボニル基、カルバモイル基、炭素数１から６のモノ又はジアルキルカルバモイル基、炭素数１から６のアシルアミノ基、炭素数１から６のアルキル基、炭素数１から６のアルケニル基、炭素数１から６のアルキニル基、炭素数６から１０のアリール基、炭素数１から６のアルキルオキシ基、炭素数１から６のアルケニルオキシ基、炭素数１から６のアルキニルオキシ基、アミノ基、炭素数１から６のモノ又はジアルキルアミノ基、カルボキシ基、スルホ基等を挙げることができ、これらからなる群から選択される少なくとも１種であることが好ましい。Ａｒにおける置換基は、可能な場合には、ハロゲン原子、ヒドロキシ基等の置換基を更に有していてもよい。また、Ａｒにおける置換基は、複数の置換基が連結して、脂肪族の縮合環構造を形成してもよい。更に置換基としてのアルキル基、アルケニル基及びアルキニル基は、直鎖状、分岐鎖状又は環状のいずれであってもよい。 The aryl group in Ar may have at least one substituent. Examples of the substituent include a halogen atom, a hydroxy group, a nitro group, a cyano group, a formyl group, an alkylcarbonyl group having 1 to 6 carbon atoms, a carbamoyl group, a mono or dialkylcarbamoyl group having 1 to 6 carbon atoms, and 1 carbon group. To 6 acylamino groups, 1 to 6 carbon alkyl groups, 1 to 6 carbon alkenyl groups, 1 to 6 carbon alkynyl groups, 6 to 10 carbon aryl groups, 1 to 6 carbon alkyloxy Examples thereof include a group, an alkenyloxy group having 1 to 6 carbon atoms, an alkynyloxy group having 1 to 6 carbon atoms, an amino group, a mono or dialkylamino group having 1 to 6 carbon atoms, a carboxy group, a sulfo group and the like. It is preferably at least one selected from the group consisting of. If possible, the substituent in Ar may further have a substituent such as a halogen atom or a hydroxy group. Further, as the substituent in Ar, a plurality of substituents may be linked to form an aliphatic condensed ring structure. Further, the alkyl group, alkenyl group and alkynyl group as the substituent may be linear, branched chain or cyclic.
Ｒ１は、水素原子又は炭素数１から６の脂肪族基を表す。脂肪族基としては、アルキル基、アルケニル基、アルキニル基等を挙げることができ、これらからなる群から選択される少なくとも１種であることが好ましい。Ｒ１における脂肪族基は、ハロゲン原子等の置換基を更に有していてもよい。 R 1 represents a hydrogen atom or an aliphatic group having 1 to 6 carbon atoms. Examples of the aliphatic group include an alkyl group, an alkenyl group, an alkynyl group and the like, and at least one selected from the group consisting of these groups is preferable. The aliphatic group in R 1 may further have a substituent such as a halogen atom.
式（１）において、ｎは１から３の整数を表し、例えば、１であってよい。また、ｍは１から４の整数を表し、例えば、２であってよい。 In equation (1), n represents an integer from 1 to 3, and may be 1, for example. Further, m represents an integer from 1 to 4, and may be 2, for example.
式（１）で表される化合物又はその薬学的に許容される塩は、公知の方法によって製造することができる。例えば、アリールアルキルカルボン酸と、アミノアルキルスルホン酸とを公知の縮合剤を用いて縮合することで製造することができる。また、アリールアルキルカルボン酸のハロゲン化物とアミノアルキルスルホン酸とを反応させて製造することができる。 The compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be produced by a known method. For example, it can be produced by condensing an arylalkylcarboxylic acid and an aminoalkylsulfonic acid using a known condensing agent. Further, it can be produced by reacting a halide of an arylalkylcarboxylic acid with an aminoalkylsulfonic acid.
糖化産物生成抑制剤又は医薬組成物は、式（１）で表される化合物を薬学的に許容される塩として含んでいてもよい。式（１）で表される化合物の塩としては、アルカリ金属塩、アルカリ土類金属塩、アンモニウム塩、置換アンモニウム塩等を挙げることができ、これらからなる群から選択される少なくとも１種であることが好ましく、アルカリ金属塩から選択される少なくとも１種であることがより好ましい。アルカリ金属塩としては、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩等が挙げられる。アルカリ土類金属塩としては、マグネシウム塩、カルシウム塩等が挙げられる。また、置換アンモニウム塩としては、テトラメチルアンモニウム、テトラエチルアンモニウム、メチルアミン、ジメチルアミン、トリメチルアミン、トリエチルアミン、ジエチルアミン、エチルアミン、エチレンジアミン、エタノールアミン、ジエタノールアミン、ピペリジン、ピペラジン、トリスヒドロキシメチルアミノメタン（トリス）等が挙げられる。 The advanced glycation end product production inhibitor or pharmaceutical composition may contain the compound represented by the formula (1) as a pharmaceutically acceptable salt. Examples of the salt of the compound represented by the formula (1) include alkali metal salts, alkaline earth metal salts, ammonium salts, substituted ammonium salts and the like, and at least one selected from the group consisting of these. It is preferable, and it is more preferable that it is at least one selected from alkali metal salts. Examples of the alkali metal salt include lithium salt, sodium salt, potassium salt, cesium salt and the like. Examples of the alkaline earth metal salt include magnesium salt and calcium salt. Examples of the substituted ammonium salt include tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, trishydroxymethylaminomethane (tris) and the like. Can be mentioned.
医薬組成物は、例えば、糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種（以下、「特定疾患」ともいう）を処置するために用いられる。特定疾患には、例えば、糖尿病、糖尿病合併症、動脈硬化症、高血圧症、腎障害、認知症、アルツハイマー病、パーキンソン病等が含まれ、これらからなる群から選択される少なくとも１種が挙げられる。また、糖尿病合併症としては、糖尿病網膜症、糖尿病腎症、糖尿病神経症、糖尿病血管合併症等が挙げられ、これらからなる群から選択される少なくとも１種が好ましい。ここで、本明細書において用いられる「処置」とは、疾患について施される何らかの処置であればよく、例えば、疾患の治療、改善、進行の抑制（悪化の防止）等が挙げられる。 The pharmaceutical composition is used, for example, to treat at least one selected from a group of diseases derived from the production or accumulation of advanced glycation end products (hereinafter, also referred to as "specific disease"). Specific diseases include, for example, diabetes, diabetic complications, arteriosclerosis, hypertension, renal disorders, dementia, Alzheimer's disease, Parkinson's disease and the like, and at least one selected from the group consisting of these can be mentioned. .. In addition, examples of diabetic complications include diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic vascular complications, and the like, and at least one selected from the group consisting of these is preferable. Here, the "treatment" used in the present specification may be any treatment given to the disease, and examples thereof include treatment, improvement, and suppression of progression (prevention of deterioration) of the disease.
医薬組成物は、式（１）で表される化合物に加えて、薬学的に許容される担体を含んでいてもよい。薬学的に許容される担体としては、乳糖、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤；デンプン、ゼラチン、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤；乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤；白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤；第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤；グリセリン、デンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤；緩衝剤；矯味剤；懸濁化剤；乳化剤；着色剤；粘稠剤等が挙げられる。 The pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to the compound represented by the formula (1). Pharmaceutically acceptable carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; starch, gelatin, carboxymethyl cellulose, cellac, methyl cellulose, etc. Binders such as potassium phosphate and polyvinylpyrrolidone; dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc. Disintegrant; Disintegration inhibitor such as sucrose, stear, cacao butter, hydrogenated oil; Absorption promoter such as quaternary ammonium base, sodium lauryl sulfate; Moisturizer such as glycerin, starch; Starch, lactose, kaolin, bentonite , Excipients such as colloidal silicic acid; starches such as purified starch, stearate, powder borate, polyethylene glycol; buffers; flavoring agents; suspending agents; emulsifiers; colorants; thickeners, etc. Can be mentioned.
また、医薬組成物が液状製剤の場合、医薬組成物は有効成分に加えて溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、ｐＨ調整剤、無痛化剤等を含んでいてもよい。液状製剤における溶剤としては、例えば、精製水、エタノール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油などが挙げられる。溶解補助剤としては、例えば、プロピレングリコール、Ｄ−マンニトール、安息香酸ベンジル、エタノール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。懸濁化剤としては、例えば、塩化ベンザルコニウム、カルメロース、ヒドロキシプロピルセルロース、プロピレングリコール、ポビドン、メチルセルロース、モノステアリン酸グリセリンなどが挙げられる。等張化剤としては、例えば、ブドウ糖、Ｄ−ソルビトール、塩化ナトリウム、Ｄ−マンニトールなどが挙げられる。緩衝剤またはｐＨ調整剤としては、例えば、リン酸水素ナトリウム、酢酸ナトリウム、炭酸ナトリウム、クエン酸ナトリウムなどが挙げられる。無痛化剤としては、例えば、ベンジルアルコールなどが挙げられる。 When the pharmaceutical composition is a liquid preparation, the pharmaceutical composition contains a solvent, a solubilizing agent, a suspending agent, an tonicity agent, a buffering agent, a pH adjusting agent, a soothing agent, etc. in addition to the active ingredient. You may. Examples of the solvent in the liquid preparation include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizing agent include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, D-mannitol and the like. Examples of the buffer or pH adjuster include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. Examples of the soothing agent include benzyl alcohol and the like.
医薬組成物は、公知の糖尿病薬剤、ＡＧＥｓ生成抑制効果を有する他の薬剤等をさらに含んでいてもよい。他の薬剤としては、例えば、インスリン抵抗性改善薬、脂質異常症治療薬、アンジオテンシンII１型受容体拮抗薬、アンジオテンシン変換酵素阻害剤、メトホルミン等が例示される。 The pharmaceutical composition may further contain a known diabetic drug, another drug having an AGEs production inhibitory effect, and the like. Examples of other agents include insulin sensitizers, dyslipidemia therapeutic agents, angiotensin type II receptor antagonists, angiotensin converting enzyme inhibitors, metformin and the like.
医薬組成物の剤形としては、口腔内崩壊錠、チュアブル錠、発泡錠、分散錠、溶解錠等の錠剤；カプセル剤；発泡顆粒剤等の顆粒剤；散剤；エリキシル剤、懸濁剤、乳剤、リモナーデ剤等の経口液剤；シロップ剤（シロップ用剤）；経口ゼリー剤；トローチ剤、舌下錠、バッカル錠、付着錠、ガム剤等の口腔用錠剤；口腔用スプレー剤；口腔用半固形剤；含嗽剤；輸液剤、埋め込み注射剤、持続性注射剤等の注射剤；腹膜透析用剤、血液透析用剤等の透析用剤；吸入粉末剤、吸入液剤、吸入エアゾール剤等の吸入剤；坐剤；直腸用半固形剤；注腸剤；点眼剤；眼軟膏剤；点耳剤；点鼻粉末剤、点鼻液剤等の点鼻剤；膣錠；膣用坐剤；外用固形剤（外用散剤）；リニメント剤、ローション剤等の外用液剤；外用エアゾール剤、ポンプスプレー剤等のスプレー剤；軟膏剤；クリーム剤；ゲル剤；テープ剤、パップ剤等の貼付剤などが挙げられる。これらの中でも経口投与のし易さの点で、錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤、口腔用錠剤、口腔用スプレー剤、口腔用半固形剤および含嗽剤が好ましく、生体内に吸収され易い点で、錠剤、カプセル剤、顆粒剤、散剤がより好ましい。 Dosage forms of the pharmaceutical composition include tablets such as orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, and dissolving tablets; capsules; granules such as effervescent granules; powders; elixirs, suspensions, emulsions. , Oral solutions such as limonade; syrups (syrups); oral jelly; troche, sublingual tablets, buccal tablets, adhesive tablets, oral tablets such as gums; oral sprays; semi-solid oral Agents; gargles; infusions, implantable injections, long-acting injections and other injections; peritoneal dialysis agents, blood dialysis agents and other dialysis agents; inhalation powders, inhalation solutions, inhalation aerosols and other inhalants Suppositories; Semi-solids for rectal organs; Enemas; Eye drops; Eye ointments; Ear drops; Nasal drops such as nasal drops and nasal drops; Vaginal tablets; Vaginal suppositories; Topical solids (External powder); External liquids such as liniments and lotions; Sprays such as external aerosols and pump sprays; Ointments; Creams; Gels; Tapes, patches such as poultices and the like. Among these, in terms of ease of oral administration, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, oral tablets, oral sprays, oral semi-solids and gargling agents Is preferable, and tablets, capsules, granules, and powders are more preferable because they are easily absorbed in a living body.
また、医薬組成物は、エキス剤、丸剤、酒精剤、浸剤、煎剤、茶剤、チンキ剤、芳香水剤、流エキス剤等の生薬関連製剤に、式（１）で表される化合物を添加した剤形で使用することもできる。これら剤形は、糖尿病、糖尿病合併症等の特定疾患の程度、その他の疾病の程度、年齢、性別等の条件に応じて適宜選択される。 In addition, the pharmaceutical composition is a crude drug-related preparation such as an extract, a pill, a liquor, a dipping agent, a decoction, a tea agent, a tincture agent, an aromatic water agent, and a flow extract agent, and a compound represented by the formula (1) is used. It can also be used in the added dosage form. These dosage forms are appropriately selected according to conditions such as the degree of specific diseases such as diabetes and diabetic complications, the degree of other diseases, age, and gender.
医薬組成物の投与量は、糖尿病、糖尿病合併症等の特定疾患の程度、その他の疾病の程度、年齢、性別等の条件に応じて適宜選択される。例えば、糖化産物の生成を抑制することができる量（以下、「糖化産物生成抑制有効量」とも称する）の式（１）で表される化合物を投与すればよい。糖化産物生成抑制有効量は、各種の非臨床および臨床試験の少なくとも一方を含む、当業者に周知の方法を用いて適宜決定することができる。 The dose of the pharmaceutical composition is appropriately selected according to conditions such as the degree of specific diseases such as diabetes and diabetic complications, the degree of other diseases, age, and gender. For example, a compound represented by the formula (1) in an amount capable of suppressing the production of advanced glycation end products (hereinafter, also referred to as “effective amount for suppressing advanced glycation end products”) may be administered. The effective amount for suppressing advanced glycation end production can be appropriately determined using a method well known to those skilled in the art, including at least one of various non-clinical and clinical trials.
医薬組成物は、糖化産物生成抑制有効量の式（１）で表される化合物を一度に投与するものであってもよく、間隔を置いて複数回に分けて投与するものであってもよい。複数回に分けて投与する場合は、一日に投与される式（１）で表される化合物の合計量が糖化産物生成抑制有効量となればよく、例えば、食事の回数に合わせて投与してもよい。 The pharmaceutical composition may be one in which the compound represented by the formula (1) in an effective amount for suppressing the production of advanced glycation end is administered at one time, or may be administered in a plurality of divided doses at intervals. .. When the dose is divided into a plurality of doses, the total amount of the compounds represented by the formula (1) administered daily may be the effective amount for suppressing the production of advanced glycation end products. You may.
医薬組成物は、糖尿病、糖尿病合併症等の特定疾患に罹患した対象者又は健常者のいずれに対しても投与することができる。糖化産物との関連性が高い糖尿病等の特定疾患に罹患した対象者に対して投与することが好ましい。例えば、糖尿病に罹患した対象者とは、ヘモグロビンＡ１ｃが６．１％（ＪＤＳ値）以上で、且つ、以下の（１）から（３）のいずれかに該当する者を指す：（１）空腹時血糖値が１２６ｍｇ／ｄＬ以上、（２）随時血糖値（空腹か食後かにかかわらず）が２００ｍｇ／ｄＬ以上、および（３）ブドウ糖負荷後２時間値が２００ｍｇ／ｄＬ以上。糖尿病診断基準の詳細は、日本糖尿病学会による「糖尿病の分類と診断基準に関する委員会報告」（同学会のホームページ等から入手可能）に記載されている。 The pharmaceutical composition can be administered to either a subject or a healthy person suffering from a specific disease such as diabetes and diabetic complications. It is preferably administered to a subject suffering from a specific disease such as diabetes, which is highly related to advanced glycation end products. For example, a subject suffering from diabetes refers to a person who has hemoglobin A1c of 6.1% (JDS value) or more and falls under any of the following (1) to (3): (1) Hunger. The hourly blood glucose level is 126 mg / dL or higher, (2) the occasional blood glucose level (whether hungry or postprandial) is 200 mg / dL or higher, and (3) the 2-hour value after glucose loading is 200 mg / dL or higher. Details of diabetes diagnostic criteria can be found in the "Committee Report on Diabetes Classification and Diagnostic Criteria" by the Japan Diabetes Foundation (available from the Japan Diabetes Foundation's website, etc.).
処置方法
処置方法は、有効量の前記医薬組成物を、対象に投与することを含み、糖化産物の生成又は蓄積に由来する疾患群から選択される少なくとも１種の疾患を処置する方法である。前記疾患群は、例えば、糖尿病、糖尿病合併症、動脈硬化症、高血圧症、腎障害、認知症、アルツハイマー病及びパーキンソン病からなる群から選択される少なくとも１種の特定疾患であってもよい。医薬組成物の詳細および投与方法は既述の通りである。処置の対象は、例えば、哺乳動物であり、哺乳動物はヒトを含む。また、処置の対象は非ヒト動物であってもよい。
Treatment method The treatment method is a method for treating at least one disease selected from a group of diseases derived from the production or accumulation of advanced glycation end products, which comprises administering an effective amount of the pharmaceutical composition to a subject. The disease group may be, for example, at least one specific disease selected from the group consisting of diabetes, diabetic complications, arteriosclerosis, hypertension, nephropathy, dementia, Alzheimer's disease and Parkinson's disease. The details of the pharmaceutical composition and the administration method are as described above. The subject of treatment is, for example, a mammal, which includes a human. In addition, the target of treatment may be a non-human animal.
本発明は、別の態様として、糖化産物の生成又は蓄積に由来する疾患の処置に用いられる医薬組成物の製造における式（１）で表される化合物の使用、糖化産物の生成又は蓄積に由来する疾患の処置における式（１）で表される化合物の使用、糖化産物の生成又は蓄積に由来する疾患の処置に使用される式（１）で表される化合物を包含する。 As another aspect, the present invention is derived from the use of a compound represented by the formula (1) in the production of a pharmaceutical composition used for treating a disease derived from the production or accumulation of advanced glycation end products, and the production or accumulation of advanced glycation end products. It includes the compound represented by the formula (1) used in the treatment of the disease, and the compound represented by the formula (1) used in the treatment of the disease derived from the production or accumulation of advanced glycation end products.
以下、本発明を実施例により具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、特に断りのない限り、「部」及び「％」は質量基準である。 Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples. Unless otherwise specified, "parts" and "%" are based on mass.
参考例１
フェニルアセチルタウリンの合成
１ｍｏｌ／Ｌの水酸化ナトリウム水溶液１０ｍＬにタウリン１０．５ｍｍｏｌを溶解した溶液へ、撹拌、３０℃以下に冷却しながら、溶液が弱アルカリ性を示すような速度で、フェニルアセチルクロリド１０ｍｍｏｌと３ｍｏｌ／Ｌの水酸化ナトリウム水溶液とを別々に添加した。添加終了後、混合物を２時間撹拌した。次いで混合物を３ｍＬの濃塩酸を含む１００ｍＬのビーカーへ注いだ。生じた沈殿を吸引濾過で集め、冷水で洗浄し、乾燥させた。エタノール−水から再結晶して目的物としてフェニルアセチルタウリンを得た。
Reference example 1
Synthesis of phenylacetyl taurine 10 mmol of phenylacetyl chloride at a rate at which the solution shows weak alkalinity while stirring and cooling to 30 ° C. or lower in a solution prepared by dissolving 10.5 mmol of taurine in 10 mL of a 1 mol / L sodium hydroxide aqueous solution. And a 3 mol / L aqueous sodium hydroxide solution were added separately. After completion of the addition, the mixture was stirred for 2 hours. The mixture was then poured into a 100 mL beaker containing 3 mL of concentrated hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with cold water and dried. Phenylacetyl taurine was obtained as a target product by recrystallization from ethanol-water.
実施例１
アルブミン糖化実験
ダルベッコりん酸緩衝生理食塩水（Ｃａ，Ｍｇ不含）（ＤＰＢＳ：ナカライテスク社製）中のα−グルコース（ナカライテスク社製）の最終濃度が０．２ｍｏｌ／Ｌで、ヒトアルブミン（ＳＩＧＭＡ社製）の最終濃度が８ｍｇ／ｍｌとなるように、エッペンドルフチューブ（７５０μｌ／ｔｕｂｅ）に調製した。各チューブにフェニルアセチルタウリンを所定の最終濃度になるように適量添加して、６０℃で４０時間インキュベーションした。インキュベーション後の糖化アルブミン（糖化産物；ＡＧＥｓ）の生成レベルを、マイクロプレートリーダー（ＴＥＣＡＮ）を用いて蛍光強度（励起波長３７０ｎｍ、検出波長４４０ｎｍ）を測定することで評価した。また、フェニルアセチルタウリンの代わりに、陽性対照としてアミノグアニジン（ＡＧ；和光純薬社製）を、比較としてタウリンを用い、同様にして糖化アルブミンの生成レベルを評価した。結果を図１に示す。図１にはコントロールを１００％としたときの抑制率を併せて示す。なお、「＋」を付した数値は生成レベルを上昇させたことを意味する。また、水を用いたコントロールを１００としたときの相対蛍光強度を表１に示す。
Example 1
Albumin saccharification experiment The final concentration of α-glucose (manufactured by Nacalai Tesque) in Dalbecco phosphate buffered saline (Ca, Mg-free) (DPBS: manufactured by Nacalai Tesque) is 0.2 mol / L, and human albumin (DPBS: manufactured by Nacalai Tesque). It was prepared in an Eppendorf tube (750 μl / tube) so that the final concentration of (SIGMA) was 8 mg / ml. An appropriate amount of phenylacetyl taurine was added to each tube to a predetermined final concentration, and the tube was incubated at 60 ° C. for 40 hours. The production level of glycated albumin (advanced glycation end products; AGEs) after incubation was evaluated by measuring the fluorescence intensity (excitation wavelength 370 nm, detection wavelength 440 nm) using a microplate reader (TECAN). Further, instead of phenylacetyl taurine, aminoguanidine (AG; manufactured by Wako Pure Chemical Industries, Ltd.) was used as a positive control, and taurine was used as a comparison, and the production level of glycated albumin was evaluated in the same manner. The results are shown in FIG. FIG. 1 also shows the suppression rate when the control is set to 100%. The numerical value with "+" means that the generation level has been increased. Table 1 shows the relative fluorescence intensities when the control using water is set to 100.
図１から、フェニルアセチルタウリンはアルブミンの糖化抑制作用を有することが認められた。一方、タウリンはアルブミンの糖化抑制作用を示さなかった。 From FIG. 1, it was confirmed that phenylacetyl taurine has an albumin glycation inhibitory effect. On the other hand, taurine did not show an inhibitory effect on albumin glycation.
実施例２
コラーゲン糖化実験
コラーゲン抗糖化アッセイキット（グリセルアルデヒド）（コスモバイオ社製）を用いて、フェニルアセチルタウリンのコラーゲン糖化抑制能を評価した。陽性対照にはキットに付属のアミノグアニジンを用い、比較としてタウリンを用いた。アッセイはキットに付属の説明書に準じて行い、３７℃で２４時間のインキュベーションで行った。結果を図２に示す。図２には、コントロールを１００％としたときの抑制率を併せて示す。なお、「＋」を付した数値は生成レベルを上昇させたことを意味する。また、水を用いたコントロールを１００としたときの相対蛍光強度を表２に示す。
Example 2
Collagen glycation experiment Using a collagen anti-glycation assay kit (glyceraldehyde) (manufactured by Cosmobio), the ability of phenylacetyl taurine to suppress collagen glycation was evaluated. Aminoguanidine included in the kit was used as a positive control, and taurine was used as a comparison. The assay was performed according to the instructions included with the kit and was incubated at 37 ° C. for 24 hours. The results are shown in FIG. FIG. 2 also shows the suppression rate when the control is set to 100%. The numerical value with "+" means that the generation level has been increased. Table 2 shows the relative fluorescence intensities when the control using water is set to 100.
図２及び表２から、フェニルアセチルタウリンは、用量依存的にコラーゲンの糖化抑制作用を有することが認められた。一方、タウリンは、コラーゲンの糖化抑制作用を示さず、むしろ、コラーゲンの糖化を促進した。 From FIG. 2 and Table 2, it was confirmed that phenylacetyl taurine has a dose-dependent inhibitory effect on collagen glycation. On the other hand, taurine did not show an inhibitory effect on collagen glycation, but rather promoted collagen glycation.
実施例３
２型糖尿病モデルマウスであるＫＫ／Ｔａ Ｊｃｌマウス（１０週齢、オス、コントロール群ｎ＝５、被験群ｎ＝３）を通常飼料（ＣＥ−２）で飼育し、８週間に渡って被験物質としてフェニルアセチルタウリン（Ｐｈ−Ｔ）を腹腔内へ投与（ｉｐ）して、体重、尿糖、及びＨｂＡ１ｃの変化を調べた。具体的には、フェニルアセチルタウリン２ｍｇを蒸留水１ｍＬに溶解したもの５ｍＬ／ｋｇ（１０ｍｇ／ｋｇ）を、１日１回連日腹腔内投与した。コントロールには水のみを投与した。１週毎に、絶食時に代謝ケージにて蓄尿し、尿糖試験紙（新ウリエースＧａ）を用いて尿糖を測定した。また、２週毎に、ＤＣＡ Ｖａｎｔａｇｅ ＨｂＡ１ｃカートリッジ（シーメンスヘルスケア社製）を用いてＨｂＡ１ｃを測定した。体重及び尿糖の変化を図３に、ＨｂＡ１ｃの測定結果を図４及び表３に示す。
Example 3
KK / Ta Jcl mice (10-week-old male, control group n = 5, test group n = 3), which are type 2 diabetes model mice, were bred on a normal diet (CE-2) and tested substances for 8 weeks. As a result, phenylacetyl taurine (Ph-T) was intraperitoneally administered (ip), and changes in body weight, urinary sugar, and HbA1c were examined. Specifically, 5 mL / kg (10 mg / kg) of phenylacetyl taurine dissolved in 1 mL of distilled water was intraperitoneally administered once daily every day. Only water was administered to the control. Urine was collected in a metabolic cage at the time of fasting every week, and urine sugar was measured using a urine sugar test paper (New Uriace Ga). In addition, HbA1c was measured every two weeks using a DCA Vantage HbA1c cartridge (manufactured by Siemens Healthcare). Changes in body weight and urinary sugar are shown in FIG. 3, and the measurement results of HbA1c are shown in FIGS. 4 and 3.
図３に示すように、コントロールに比べて被験物質の腹腔内投与群は、体重の増加が有意に緩やかであり、尿糖の陽性化が遅延した。また、図４及び表３に示すように、コントロールに比べて被験物質の投与群は、ＨｂＡ１ｃ値が低値であった。 As shown in FIG. 3, the intraperitoneal administration group of the test substance had a significantly slower weight gain and delayed urinary sugar positivity as compared with the control. Further, as shown in FIG. 4 and Table 3, the HbA1c value was lower in the test substance-administered group than in the control.
実施例４
２型糖尿病モデルマウスであるＫＫ／Ｔａ Ｊｃｌマウス（１０週齢、オス、コントロール群ｎ＝３、各被験群ｎ＝３）を通常飼料（ＣＥ−２）で飼育し、８週間に渡って被験物質としてフェニルアセチルタウリン（Ｐｈ−Ｔ）を経口投与（ｐｏ）して、ＨｂＡ１ｃの変化を調べた。具体的には、フェニルアセチルタウリン５ｍｇを蒸留水１ｍＬに溶解したものを、１日１回経口で投与した。コントロールには水のみを投与した。２週毎に、ＤＣＡ Ｖａｎｔａｇｅ ＨｂＡ１ｃカートリッジ（シーメンスヘルスケア社製）を用いてＨｂＡ１ｃを測定した。測定結果を図５及び表４に示す。
Example 4
Type 2 diabetes model mice, KK / Ta Jcl mice (10 weeks old, male, control group n = 3, each test group n = 3) were bred on normal diet (CE-2) and tested for 8 weeks. Phenylacetyl taurine (Ph-T) was orally administered (po) as a substance, and changes in HbA1c were examined. Specifically, 5 mg of phenylacetyl taurine dissolved in 1 mL of distilled water was orally administered once a day. Only water was administered to the control. HbA1c was measured every two weeks using a DCA Vantage HbA1c cartridge (manufactured by Siemens Healthcare). The measurement results are shown in FIGS. 5 and 4.
図５及び表４に示すように、コントロールに比べて被験物質の経口投与群は、ＨｂＡ１ｃ値が低値であった。 As shown in FIGS. 5 and 4, the HbA1c value was lower in the oral administration group of the test substance than in the control.
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| JP2017505823A (en) * | 2014-02-13 | 2017-02-23 | 武田薬品工業株式会社 | Heterocyclic compounds |
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