JP2014105196A - Pharmaceutical composition for treating and preventing dementia - Google Patents
Pharmaceutical composition for treating and preventing dementia Download PDFInfo
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- JP2014105196A JP2014105196A JP2012260046A JP2012260046A JP2014105196A JP 2014105196 A JP2014105196 A JP 2014105196A JP 2012260046 A JP2012260046 A JP 2012260046A JP 2012260046 A JP2012260046 A JP 2012260046A JP 2014105196 A JP2014105196 A JP 2014105196A
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- amyloid
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- pharmaceutical composition
- alzheimer
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Abstract
Description
本発明は、認知症、特にアルツハイマー病の治療及び予防に有用な医薬組成物及び食品組成物に関する。 The present invention relates to a pharmaceutical composition and a food composition useful for the treatment and prevention of dementia, particularly Alzheimer's disease.
認知症は、大脳の障害によって一度正常に発達した知的機能が低下し、社会生活や日常生活に障害をきたす状態で意識障害がない疾患を言う。初老期から老年期に起こることが多く、進行性の認知症を特徴とする。現在、我が国には、300万人以上の認知症患者が存在するが、今後人口の高齢化に伴いその数は確実に増加すると予想される。認知症患者の約半数がアルツハイマー病を原因疾患としており、現在、国内の患者数は150万人以上と言われている。 Dementia refers to a disease in which intellectual functions once normally developed due to a cerebral disorder are reduced, and there is no disturbance of consciousness in a state in which social life and daily life are impaired. It often occurs from early age to old age and is characterized by progressive dementia. Currently, there are more than 3 million people with dementia in Japan, but the number is expected to increase steadily as the population ages. About half of the patients with dementia are caused by Alzheimer's disease. Currently, the number of patients in Japan is said to be over 1.5 million.
アルツハイマー病の臨床症状は、記憶障害、高次脳機能障害(失語、失行、失認、構成失行)等である。一方、アルツハイマー病の特徴的な病理組織所見としては、老人斑と神経原線維変化がある。前者の主構成成分はβシート構造をとったアミロイドβタンパク質(以下、Aβと略記することもある)であり、後者のそれは過剰リン酸化されたタウ蛋白である。分子遺伝学的研究や神経病理学的研究によって、最初にアミロイドβが凝集してオリゴマーを形成し、さらにβシート構造をとったアミロイドβタンパク質となって沈着して老人斑を形成する。ついで過剰リン酸化されたタウ蛋白が凝集した神経原線維変化ができて、神経細胞死がおこり、認知症を発症するというアミロイド仮説(アミロイドカスケード仮説とも言う)が有力である(非特許文献１)。アルツハイマー病においては臨床症状が発症するかなり前から、脳内では凝集したアミロイドβタンパク質の蓄積等の上記病理的組織変化が始まっていることが知られている。 Clinical symptoms of Alzheimer's disease include memory impairment, higher brain dysfunction (aphasia, aphasia, agnosia, constitutive apraxia) and the like. On the other hand, characteristic pathological findings of Alzheimer's disease include senile plaques and neurofibrillary tangles. The former main component is an amyloid β protein having a β sheet structure (hereinafter sometimes abbreviated as Aβ), and the latter is an overphosphorylated tau protein. Through molecular genetic studies and neuropathological studies, amyloid β first aggregates to form oligomers, and then forms amyloid β protein with a β-sheet structure to form senile plaques. Next, the amyloid hypothesis (also referred to as the amyloid cascade hypothesis) that neurofibrillary tangles caused by aggregation of hyperphosphorylated tau protein, neuronal cell death, and dementia develops is prominent (Non-patent Document 1). . In Alzheimer's disease, it is known that the pathological tissue changes such as accumulation of aggregated amyloid β protein have started in the brain long before clinical symptoms develop.
アルツハイマー病の治療法としては、2012年4月1日現在で、我が国で認可及び販売されている薬剤は、アセチルコリンエステラーゼ阻害薬であるドネペジル、ガランタミン、リバスチグミン、及びグルタミン酸のNMDA受容体拮抗薬であるメマンチンの4種類である(非特許文献２)。これらはいずれも、神経伝達物質やその受容体を標的にした治療薬で、アミロイドβタンパク質凝集体やタウ蛋白凝集体等の病理変化を治療する治療薬ではないので、認知症状の改善効果や進行を遅らせる効果はあるものの、根本的な治療薬ではない(非特許文献２)。したがって、アミロイド仮説に基づく新たな認知症治療薬の開発が臨まれている。 As for the treatment of Alzheimer's disease, as of April 1, 2012, the drugs approved and sold in Japan are the acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine, and glutamate NMDA receptor antagonists There are four types of memantine (Non-patent Document 2). These are therapeutic agents targeting neurotransmitters and their receptors, and are not therapeutic agents for treating pathological changes such as amyloid β protein aggregates and tau protein aggregates. Although it has the effect of delaying the drug, it is not a fundamental therapeutic drug (Non-patent Document 2). Therefore, development of a new therapeutic agent for dementia based on the amyloid hypothesis is underway.
現在、研究が進められているアルツハイマー病の治療薬としては、アミロイドワクチン療法、ガンマセクレターゼ阻害薬、ガンマセクレターゼ修飾薬、ベータセクレターゼ阻害薬、アミロイドβタンパク質などの異常蛋白の凝集抑制剤などがある(非特許文献３、４、５)。このうち、アミロイドβタンパク質などの異常蛋白の凝集抑制剤としてIn vitro実験系で効果が報告されているものとして、ワイン関連ポリフェノール、エピガロカテキンガレート(EGCG)、クルクミン、ロスマリン酸、ニコチン、リファンピシン、メラトニン、ポリ硫酸化合物、クリオキノールなどが挙げられる(非特許文献５)。こうした化合物の中で、これまでに臨床試験が行われている化合物としては、EGCG、ポリ硫酸化合物、クリオキノール、そしてクルクミンが挙げられる(非特許文献５)。 Currently being studied, Alzheimer's disease treatments include amyloid vaccine therapy, gamma secretase inhibitors, gamma secretase modifiers, beta secretase inhibitors, and aggregation inhibitors of abnormal proteins such as amyloid β protein. Non-patent documents 3, 4, 5). Among these, as an inhibitor of aggregation of abnormal proteins such as amyloid β protein, those that have been reported to be effective in in vitro experimental systems include wine-related polyphenols, epigallocatechin gallate (EGCG), curcumin, rosmarinic acid, nicotine, rifampicin, Examples include melatonin, polysulfate compound, and clioquinol (Non-patent Document 5). Among these compounds, EGCG, polysulfate compound, clioquinol, and curcumin are compounds that have been clinically tested so far (Non-patent Document 5).
クルクミンは、アルツハイマー病の遺伝子改変モデルマウスで治療効果が報告されており(非特許文献６、７)、アルツハイマー患者を対象にした臨床試験も行われている(非特許文献８)。しかしながら、臨床試験の結果は、認知機能の有意な改善効果は認められず(非特許文献８)、クルクミンよりもより効果のある化合物の開発が望まれている。 Curcumin has been reported to have therapeutic effects in genetically modified model mice of Alzheimer's disease (Non-Patent Documents 6 and 7), and clinical trials targeting Alzheimer patients have also been conducted (Non-Patent Document 8). However, the results of clinical trials show no significant improvement in cognitive function (Non-Patent Document 8), and the development of compounds that are more effective than curcumin is desired.
また、特許文献１には、クルクミン誘導体及びケト・エノール互変異性を有するある種の化合物をアルツハイマー病の画像診断薬として使用することが開示されている。しかしながら、画像診断薬、対外診断薬及び染色薬以外の用途については記載されていない。 Patent Document 1 discloses the use of a curcumin derivative and a certain compound having keto-enol tautomerism as an image diagnostic agent for Alzheimer's disease. However, there is no description about uses other than diagnostic imaging agents, external diagnostic agents, and staining agents.
アルツハイマー病をはじめとする認知症の治療薬としては、前記のようにいくつかの化合物が実用化あるいは提案されている。しかしながら、いずれも根本的な治療薬ではなく、治療効果のある化合物の開発が求められている。 As described above, several compounds have been put to practical use or proposed as therapeutic agents for dementia including Alzheimer's disease. However, there is a need for the development of compounds that are not fundamental therapeutic agents but therapeutic effects.
そこで、本発明は、認知症の根本的な治療を可能とする医薬組成物を提供することを目的とする。また、本発明は、認知症を効果的に予防できる食品組成物を提供することを目的とする。 Then, an object of this invention is to provide the pharmaceutical composition which enables fundamental treatment of dementia. Another object of the present invention is to provide a food composition that can effectively prevent dementia.
本発明者らは、上記課題を解決すべく、鋭意研究を重ねた結果、アルツハイマー病診断のための磁気共鳴造影剤として開発した化合物(特許文献１)をアルツハイマー病の遺伝子改変モデルマウスに投与して、その効果を調べたところ、驚くべきことに、従来から知られていたクルクミンに比し、より治療効果が高いことを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors administered a compound (patent document 1) developed as a magnetic resonance contrast agent for diagnosis of Alzheimer's disease to a genetically modified model mouse of Alzheimer's disease. As a result, the inventors have surprisingly found that the therapeutic effect is higher than that of conventionally known curcumin, and completed the present invention.
本発明は、これら知見に基づき、完成されたものであり、次の医薬組成物及び食品組成物を提供するものである。 The present invention has been completed based on these findings, and provides the following pharmaceutical composition and food composition.
項１．ケト型とエノール型が存在する1,3-ジカルボニル構造を有する化合物を含有する認知症の治療及び／又は予防用の医薬組成物であって、該化合物は脳内に移行可能であり且つケト型とエノール型でアミロイドβタンパク質の凝集体に対する親和性が異なり、1,3-ジカルボニル構造の2位が置換基を有する１つのアルキル基で置換されている、医薬組成物。 Item 1. A pharmaceutical composition for the treatment and / or prevention of dementia comprising a compound having a 1,3-dicarbonyl structure in which a keto type and an enol type are present, wherein the compound can be transferred into the brain and is keto A pharmaceutical composition in which the affinity for an amyloid β protein aggregate is different between the type 1 and the enol type, and the 2-position of the 1,3-dicarbonyl structure is substituted with one alkyl group having a substituent.
項２．前記化合物はケト型に比べてエノール型の方がアミロイドβペプチドの凝集体に対する親和性が高い、項１に記載の医薬組成物。 Item 2. Item 2. The pharmaceutical composition according to Item 1, wherein the compound has a higher affinity for the amyloid β peptide aggregate in the enol type than in the keto type.
項３．前記化合物が式(I)： Item 3. Said compound is of formula (I):
(式中、R1a及びR1bはそれぞれ独立に置換されていてもよいアリール基又はヘテロアリール基であり、Aはアルコキシ置換アルキル、アルコキシカルボニル置換アルキル又はジメチルアミノカルボニル置換アルキルである)で表される化合物又はその塩である、項１又は２に記載の医薬組成物。 (Wherein R 1a and R 1b are each independently an optionally substituted aryl group or heteroaryl group, and A is an alkoxy-substituted alkyl, alkoxycarbonyl-substituted alkyl, or dimethylaminocarbonyl-substituted alkyl). Item 3. The pharmaceutical composition according to Item 1 or 2, which is a compound or a salt thereof.
項４．前記化合物が式(II)： Item 4. Said compound is of formula (II):
(式中、R2a及びR2bはそれぞれ独立に水素原子、アルキル、アセチル又はメトキシカルボニルであり、R3a及びR3bはそれぞれ独立にフッ素原子、CHF2-、CF3-、CHF2O-又はCF3O-であり、R4a及びR4bはそれぞれ独立に水素原子又はフッ素原子であり、A1はR5-(CH2)m-であり、R5はアルコキシ、アルコキシカルボニル又はジメチルアミノカルボニルであり、mは1〜5の整数である)で表されるクルクミン誘導体又はその塩である、項１〜３のいずれかに記載の医薬組成物。 (Wherein R 2a and R 2b are each independently a hydrogen atom, alkyl, acetyl or methoxycarbonyl, and R 3a and R 3b are each independently a fluorine atom, CHF 2- , CF 3- , CHF 2 O- or CF 3 O-, R 4a and R 4b are each independently a hydrogen atom or a fluorine atom, A 1 is R 5- (CH 2 ) m- , and R 5 is alkoxy, alkoxycarbonyl or dimethylaminocarbonyl. And m is an integer of 1 to 5.) The pharmaceutical composition according to any one of Items 1 to 3, which is a curcumin derivative represented by the formula:
項５．前記認知症がアルツハイマー病である、項１〜４のいずれかに記載の医薬組成物。 Item 5. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein the dementia is Alzheimer's disease.
項６．ケト型とエノール型が存在する1,3-ジカルボニル構造を有する化合物を含有する食品組成物であって、該化合物は脳内に移行可能であり且つケト型とエノール型でアミロイドβタンパク質の凝集体に対する親和性が異なり、1,3-ジカルボニル構造の2位が置換基を有する１つのアルキル基で置換されている、食品組成物。 Item 6. A food composition comprising a compound having a 1,3-dicarbonyl structure in which a keto type and an enol type are present, the compound being capable of transferring into the brain, and coagulating amyloid β protein in the keto type and the enol type A food composition wherein the affinity for the aggregate is different and the 2-position of the 1,3-dicarbonyl structure is substituted with one alkyl group having a substituent.
項７．前記化合物はケト型に比べてエノール型の方がアミロイドβペプチドの凝集体に対する親和性が高い、項６に記載の食品組成物。 Item 7. Item 7. The food composition according to Item 6, wherein the enol type compound has a higher affinity for amyloid β peptide aggregates than the keto type compound.
項８．前記化合物が式(I)： Item 8. Said compound is of formula (I):
(式中、R1a及びR1bはそれぞれ独立に置換されていてもよいアリール基又はヘテロアリール基であり、Aはアルコキシ置換アルキル、アルコキシカルボニル置換アルキル又はジメチルアミノカルボニル置換アルキルである)で表される化合物又はその塩である、項６又は７に記載の食品組成物。 (Wherein R 1a and R 1b are each independently an optionally substituted aryl group or heteroaryl group, and A is an alkoxy-substituted alkyl, alkoxycarbonyl-substituted alkyl, or dimethylaminocarbonyl-substituted alkyl). Item 8. The food composition according to Item 6 or 7, which is a compound or a salt thereof.
項９．前記化合物が式(II)： Item 9. Said compound is of formula (II):
(式中、R2a及びR2bはそれぞれ独立に水素原子、アルキル、アセチル又はメトキシカルボニルであり、R3a及びR3bはそれぞれ独立にフッ素原子、CHF2-、CF3-、CHF2O-又はCF3O-であり、R4a及びR4bはそれぞれ独立に水素原子又はフッ素原子であり、A1はR5-(CH2)m-であり、R5はアルコキシ、アルコキシカルボニル又はジメチルアミノカルボニルであり、mは1〜5の整数である)で表されるクルクミン誘導体又はその塩である、項６〜８のいずれかに記載の食品組成物。 (Wherein R 2a and R 2b are each independently a hydrogen atom, alkyl, acetyl or methoxycarbonyl, and R 3a and R 3b are each independently a fluorine atom, CHF 2- , CF 3- , CHF 2 O- or CF 3 O-, R 4a and R 4b are each independently a hydrogen atom or a fluorine atom, A 1 is R 5- (CH 2 ) m- , and R 5 is alkoxy, alkoxycarbonyl or dimethylaminocarbonyl. The food composition according to any one of Items 6 to 8, which is a curcumin derivative represented by the formula:
項１０．前記認知症がアルツハイマー病である、項６〜９のいずれかに記載の食品組成物。 Item 10. Item 10. The food composition according to any one of Items 6 to 9, wherein the dementia is Alzheimer's disease.
本発明の医薬組成物は、アミロイドβタンパク質に対する高い親和性と高い血液脳関門透過性を有している上に、アミロイドβタンパク質凝集体の脳内濃度を減少させることが可能であり、認知症の進行を予防及び治療することができる。また、本発明の食品組成物を接種することにより、認知症の進行の予防の効果が期待される。 The pharmaceutical composition of the present invention has high affinity for amyloid β protein and high blood-brain barrier permeability, and can reduce the concentration of amyloid β protein aggregates in the brain. Can be prevented and treated. Moreover, the effect of preventing the progression of dementia is expected by inoculating the food composition of the present invention.
以下、本発明の医薬組成物、食品組成物等について詳細に説明する。 Hereinafter, the pharmaceutical composition and food composition of the present invention will be described in detail.
本発明の認知症の治療及び／又は予防用の医薬組成物、並びに本発明の食品組成物は、ケト型とエノール型が存在する1,3-ジカルボニル構造を有する化合物を含有し、該化合物は脳内に移行可能であり且つケト型とエノール型でアミロイドβタンパク質の凝集体に対する親和性が異なり、1,3-ジカルボニル構造の2位が置換基を有する１つのアルキル基で置換されていることを特徴とする。 The pharmaceutical composition for the treatment and / or prevention of dementia of the present invention and the food composition of the present invention comprise a compound having a 1,3-dicarbonyl structure in which a keto type and an enol type exist, and the compound Can be transferred into the brain, and the keto type and enol type have different affinity for amyloid β protein aggregates, and the 2-position of the 1,3-dicarbonyl structure is substituted with one alkyl group having a substituent. It is characterized by being.
本発明において、アミロイドβタンパク質とは38〜43個のアミノ酸からなるタンパク質で、アミロイド前駆体タンパク質からプロテアーゼの作用により産生されるタンパク質を意味し、アミロイドβタンパク質凝集体とは4量体以上を意味する。 In the present invention, amyloid β protein is a protein consisting of 38 to 43 amino acids, which means a protein produced from the amyloid precursor protein by the action of protease, and amyloid β protein aggregate means a tetramer or more. To do.
本発明で使用する化合物は、ケト型とエノール型が存在する1,3-ジカルボニル構造を有する化合物であり、ここで、1,3-ジカルボニル構造を有する化合物とは以下の構造を有する化合物である。 The compound used in the present invention is a compound having a 1,3-dicarbonyl structure in which a keto type and an enol type exist, and the compound having a 1,3-dicarbonyl structure is a compound having the following structure: It is.
本発明の化合物において、ケト型とは１位と3位において両方ケトンとなっているものを示し、エノール型とは1位と3位のどちらか一方がエノール化しているものを示す。本発明の化合物は、エノール型の化合物であっても、1,3-ジカルボニル構造を取り得る化合物を包含する。 In the compounds of the present invention, the keto type refers to those that are both ketones at the 1-position and the 3-position, and the enol-type refers to those in which either the 1-position or the 3-position is enolized. The compound of the present invention includes a compound capable of taking a 1,3-dicarbonyl structure even if it is an enol-type compound.
本発明の化合物は、ケト・エノール互変異性を有し、水溶液中でエノール型が0.01〜50%、好ましくは0.01〜10%、より好ましくは0.01〜5%含まれる。このエノール型の比率の測定には、リン酸緩衝液に本発明の1,3-ジカルボニル構造を有する化合物を0.01〜5 mMの濃度で溶解した水溶液(pH：7.5、温度：20℃)を使用する。エノール型の比率は、NMRにより、当該水溶液中でのケト型及びエノール型それぞれの1H、19F又は13C、好ましくは19Fのピークの面積強度を測定することにより求めることができる。 The compounds of the present invention have keto-enol tautomerism and contain 0.01 to 50%, preferably 0.01 to 10%, more preferably 0.01 to 5% enol form in aqueous solution. To measure the enol-type ratio, an aqueous solution (pH: 7.5, temperature: 20 ° C.) in which a compound having a 1,3-dicarbonyl structure of the present invention is dissolved in a phosphate buffer at a concentration of 0.01 to 5 mM. use. The ratio of the enol type can be determined by measuring the area intensity of the 1 H, 19 F, or 13 C, preferably 19 F peak of each of the keto type and the enol type in the aqueous solution by NMR.
本発明の化合物は、アルツハイマー病の原因物質であるアミロイドβタンパク質凝集体に対してケト型とエノール型で親和性が異なるという性質を有し、好ましくはケト型に比べてエノール型の方がアミロイドβタンパク質の凝集体に対する親和性が高いという性質を有する。本発明の化合物のエノール型とケト型のアミロイドβタンパク質凝集体に対する親和性の差は、蛍光阻害試験のIC50値で10倍以上であることが望ましい(特許文献１参照)。 The compound of the present invention has the property that the affinity of keto type and enol type is different for the amyloid β protein aggregate which is the causative agent of Alzheimer's disease, and preferably the enol type is more amyloid than the keto type It has the property of high affinity for β-protein aggregates. The difference in the affinity of the compound of the present invention for the enol-type and keto-type amyloid β protein aggregates is preferably 10 times or more in the IC 50 value of the fluorescence inhibition test (see Patent Document 1).
本発明の化合物は、1,3-ジカルボニル構造の2位が置換基を有する１つのアルキル基で置換されている。このような置換基を有することにより、本発明の化合物は、極性の高い水中では主としてケト型で存在し、極性の低い有機溶媒中ではエノール型で存在するようになる。本発明の化合物が不斉炭素を含む場合は、常法に従い分離した光学異性体、及びラセミ体の両方が本発明の化合物に含まれる。 In the compound of the present invention, the 2-position of the 1,3-dicarbonyl structure is substituted with one alkyl group having a substituent. By having such a substituent, the compound of the present invention exists mainly in a keto form in highly polar water, and exists in an enol form in a low polarity organic solvent. When the compound of the present invention contains an asymmetric carbon, both optical isomers and racemates separated according to a conventional method are included in the compound of the present invention.
本発明の化合物は脳内に移行可能であり、このような特性を有するためには1,3-ジカルボニル構造の2位が、アルコキシ置換アルキル、アルコキシカルボニル置換アルキル、ジメチルアミノカルボニル置換アルキルなどにより置換されていることが好ましい。中でもアルコキシカルボニル置換アルキルにより置換されていることが特に好ましい。 The compound of the present invention can be transferred into the brain, and in order to have such properties, the 2-position of the 1,3-dicarbonyl structure is substituted with alkoxy-substituted alkyl, alkoxycarbonyl-substituted alkyl, dimethylaminocarbonyl-substituted alkyl, etc. It is preferably substituted. Especially, it is especially preferable that it is substituted by alkoxycarbonyl-substituted alkyl.
本発明の化合物は塩であってもよく、そのような塩としては、医薬上許容される塩であればよく、例えば、カリウム塩、ナトリウム塩のようなアルカリ金属塩；カルシウム塩のようなアルカリ土類金属塩；トリエタノールアミン塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機アミン塩などが挙げられる。また、これらの塩の中で結晶水を持つものもある。 The compound of the present invention may be a salt. Such a salt may be a pharmaceutically acceptable salt, for example, an alkali metal salt such as a potassium salt or a sodium salt; an alkali such as a calcium salt; Earth metal salts; organic ethanol salts such as triethanolamine salts and tris (hydroxymethyl) aminomethane salts. Some of these salts have water of crystallization.
本発明の好ましい化合物としては、以下の化合物を挙げることができる。
式(I)：
Preferred compounds of the present invention include the following compounds.
Formula (I):
式中、R1a及びR1bはそれぞれ独立に置換されていてもよいアリール基又はヘテロアリール基であり、Aはアルコキシ置換アルキル、アルコキシカルボニル置換アルキル又はジメチルアミノカルボニル置換アルキル、好ましくはアルコキシカルボニル置換アルキルである。 In the formula, R 1a and R 1b are each independently an optionally substituted aryl group or heteroaryl group, and A is an alkoxy-substituted alkyl, alkoxycarbonyl-substituted alkyl or dimethylaminocarbonyl-substituted alkyl, preferably an alkoxycarbonyl-substituted alkyl. It is.
式(I)の化合物における用語について以下説明する。 The terms in the compound of formula (I) are explained below.
「アリール基」とは、5又は6員の芳香族炭化水素環からなる単環又は多環系の基を意味し、具体例としては、フェニル、ナフチル、フルオレニル、アントリル、ビフェニリル、テトラヒドロナフチル、クロマニル、２，３−ジヒドロ−１，４−ジオキサナフタレニル、インダニル及びフェナントリルが挙げられる。 “Aryl group” means a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic hydrocarbon ring. Specific examples include phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, chromanyl. 2,3-dihydro-1,4-dioxanaphthalenyl, indanyl and phenanthryl.
「ヘテロアリール基」とは、N、O及びSから選択される1〜3個のヘテロ原子を含む、5又は6員の芳香環からなる単環又は多環系の基を意味し、多環系の場合には少なくとも1つの環が芳香環であればよく、具体例としては、フリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、チアゾリル、イソオキサゾリル、イソチアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、インドリル、キノリル、イソキノリル、ベンゾ［ｂ］チエニル及びベンズイミダゾリルが挙げられる。 “Heteroaryl group” means a monocyclic or polycyclic group consisting of 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from N, O and S. In the case of the system, at least one ring may be an aromatic ring, and specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, Quinolyl, isoquinolyl, benzo [b] thienyl and benzimidazolyl.
Aの置換基を有している「アルキル基」は、直鎖状のC1-5アルキル基が好ましく、その具体例としては、メチル、エチル、ｎ−プロピル、ｎ−ブチル及びｎ−ペンチルが挙げられ、直鎖状のC1-3アルキル基が特に好ましい。 The “alkyl group” having a substituent of A is preferably a linear C 1-5 alkyl group, and specific examples thereof include methyl, ethyl, n-propyl, n-butyl and n-pentyl. And a straight-chain C 1-3 alkyl group is particularly preferable.
「置換されていてもよいアリール基及びヘテロアリール基」は、好ましくは、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、アセトキシ、メトキシカルボニルオキシ、フッ素、CHF2-、CF3-、CHF2O-、CF3O-、メチルアミノ、CH3OOCCH2O-、及びHOOCCH2O-から選択される1〜4個の原子又は基で置換されていてもよいアリール基及びヘテロアリール基である。 The “optionally substituted aryl group and heteroaryl group” is preferably hydroxy, C 1-6 alkyl, C 1-6 alkoxy, acetoxy, methoxycarbonyloxy, fluorine, CHF 2- , CF 3- , CHF An aryl group and a heteroaryl group optionally substituted with 1 to 4 atoms or groups selected from 2 O-, CF 3 O-, methylamino, CH 3 OOCCH 2 O-, and HOOCCH 2 O- is there.
「アルコキシ」及び「アルコキシカルボニル」中のアルキル基は、直鎖又は分枝状のいずれでもよく、好ましくはC1-6アルキルである。 The alkyl group in “alkoxy” and “alkoxycarbonyl” may be linear or branched, and is preferably C 1-6 alkyl.
本発明のより好ましい化合物としては、以下の化合物を挙げることができる。
式(II)：
More preferable compounds of the present invention include the following compounds.
Formula (II):
式中、R2a及びR2bはそれぞれ独立に水素原子、アルキル、アセチル又はメトキシカルボニルであり、R3a及びR3bはそれぞれ独立にフッ素原子、CHF2-、CF3-、CHF2O-又はCF3O-であり、R4a及びR4bはそれぞれ独立に水素原子又はフッ素原子であり、A1はR5-(CH2)m-であり、R5はアルコキシ、アルコキシカルボニル又はジメチルアミノカルボニル、好ましくはアルコキシカルボニルであり、mは1〜5、好ましくは1〜3の整数である。 In the formula, R 2a and R 2b are each independently a hydrogen atom, alkyl, acetyl or methoxycarbonyl, and R 3a and R 3b are each independently a fluorine atom, CHF 2- , CF 3- , CHF 2 O- or CF 3 O-, R 4a and R 4b are each independently a hydrogen atom or a fluorine atom, A 1 is R 5- (CH 2 ) m- , R 5 is alkoxy, alkoxycarbonyl or dimethylaminocarbonyl, Preferred is alkoxycarbonyl, and m is an integer of 1 to 5, preferably 1 to 3.
R2a及びR2bのアルキル基、並びにR5のアルコキシ及びアルコキシカルボニル中のアルキル基は、直鎖又は分枝状のいずれでもよく、好ましくはC1-6アルキルである。 The alkyl group of R 2a and R 2b and the alkyl group in alkoxy and alkoxycarbonyl of R 5 may be either linear or branched, and is preferably C 1-6 alkyl.
C1-6アルキルの具体例としてはメチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、ｔｅｒｔ-ブチル、ｎ−ペンチル、イソペンチル、及びヘキシルが挙げられる。 Specific examples of C 1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.
本発明の化合物は、公知の方法(例えば、国際公開公報2010/098502号など)に従い製造することができる。 The compound of the present invention can be produced according to a known method (for example, International Publication No. 2010/098502).
本発明の化合物の具体例を以下の第１表に示す。 Specific examples of the compounds of the present invention are shown in Table 1 below.
本発明の化合物は、アミロイドβタンパク質に対する高い親和性と高い血液脳関門透過性を有している。現状のアルツハイマー治療薬は、Aβ凝集体を減少させるものではなく、根本的な治療効果は期待できない。それに対して、本発明の化合物は、現状の治療薬とはメカニズムが異なるものであり、Aβ凝集体の脳内濃度を減少させることが可能である。そのため、本発明の化合物により、認知症の根本治療が可能となることが期待される。また、本発明の化合物は、進行が進んだタイプの認知症に対しても効果が期待される。 The compounds of the present invention have high affinity for amyloid β protein and high blood brain barrier permeability. The current Alzheimer's therapeutics do not reduce Aβ aggregates, and a fundamental therapeutic effect cannot be expected. In contrast, the compound of the present invention is different in mechanism from current therapeutic agents, and can reduce the concentration of Aβ aggregates in the brain. Therefore, it is expected that the compound of the present invention can fundamentally treat dementia. The compounds of the present invention are also expected to be effective against advanced types of dementia.
本発明の化合物は、試験例で示されているように経口接種でも効果があるため、サプリメントとしても有用である。 Since the compound of the present invention is effective even by oral inoculation as shown in Test Examples, it is also useful as a supplement.
認知症としては、アルツハイマー病に加え、異常蛋白が脳に蓄積する前頭側頭葉型認知症、ピック病、レビー小体病、プリオン病等が挙げられる。 As dementia, in addition to Alzheimer's disease, frontotemporal lobar dementia in which abnormal proteins accumulate in the brain, Pick's disease, Lewy body disease, prion disease and the like can be mentioned.
本発明の医薬組成物は、ヒトを含む哺乳動物に対して投与される。本発明の医薬組成物の投与は、局所的であってもよく、全身的であってもよい。投与方法には特に制限はなく、経口的又は非経口的に投与される。非経口的投与経路としては、皮下、腹腔内、静脈、動脈又は脊髄液への注射又は点滴、経皮的投与等が挙げられる。 The pharmaceutical composition of the present invention is administered to mammals including humans. Administration of the pharmaceutical composition of the present invention may be local or systemic. There is no restriction | limiting in particular in an administration method, It administers orally or parenterally. Examples of parenteral administration routes include subcutaneous, intraperitoneal, intravenous, arterial or spinal fluid injection or infusion, and transdermal administration.
本発明の医薬組成物は、ヒトへの投与に適した医薬上許容される形態であって、生理学的に許容し得る添加剤を含む。かかる組成物は、適宜、医薬として許容し得る希釈剤、緩衝剤、可溶化剤(例えば、シクロデキストリン、ポリエチレングリコール、あるいはTween、プルロニック、クレモフォール、リン脂質などの界面活性剤)、無痛化剤等を添加してもよく、更に必要に応じて、医薬として許容し得る溶剤、安定化剤又は酸化防止剤(例えばアスコルビン酸等)のような成分を含んでもよい。本発明の医薬組成物の投与量は、用法、患者の年齢、性別その他の条件、及び疾患の程度により適宜選択される。 The pharmaceutical composition of the present invention is a pharmaceutically acceptable form suitable for administration to humans, and contains physiologically acceptable additives. Such a composition may contain a pharmaceutically acceptable diluent, buffer, solubilizer (e.g., cyclodextrin, polyethylene glycol, or surfactant such as Tween, pluronic, cremophor, phospholipid), a soothing agent. And a component such as a pharmaceutically acceptable solvent, a stabilizer, or an antioxidant (for example, ascorbic acid) may be further contained as necessary. The dosage of the pharmaceutical composition of the present invention is appropriately selected depending on the usage, patient age, sex and other conditions, and the degree of disease.
本発明の医薬組成物における上記化合物の含量は、0.01〜100重量%、好ましくは0.1〜100重量%の範囲から適宜選択することが可能である。 The content of the compound in the pharmaceutical composition of the present invention can be appropriately selected from the range of 0.01 to 100% by weight, preferably 0.1 to 100% by weight.
本発明の医薬組成物は認知症の進行の予防及び治療に有用である。 The pharmaceutical composition of the present invention is useful for preventing and treating the progression of dementia.
本発明の食品組成物には、動物(ヒトを含む)が摂取できるあらゆる食品組成物が含まれる。本発明の食品組成物には、必要に応じて、アミノ酸、核酸、ミネラル類、ビタミン類、フラボノイド類、キノン類、ポリフェノール類、結合剤、清涼剤、甘味料、必須脂肪酸、崩壊剤、滑沢剤、香料、安定化剤、着色料、防腐剤、界面活性剤、徐放調整剤、溶解剤、湿潤剤等を配合することができる。 The food composition of the present invention includes any food composition that can be ingested by animals (including humans). The food composition of the present invention includes, as necessary, amino acids, nucleic acids, minerals, vitamins, flavonoids, quinones, polyphenols, binders, refreshing agents, sweeteners, essential fatty acids, disintegrants, lubricants. Agents, fragrances, stabilizers, colorants, preservatives, surfactants, sustained release regulators, solubilizers, wetting agents and the like can be blended.
本発明の食品組成物の種類は、特に限定されず、例えば、飲料類(コーヒー、ジュース、茶飲料のような清涼飲料、乳飲料、炭酸飲料、日本酒、洋酒、果実酒のような酒等)；スプレッド類(カスタードクリーム等)；ペースト類(フルーツペースト等)；洋菓子類(チョコレート、ドーナツ、パイ、シュークリーム、ガム、ゼリー、キャンデー、クッキー、ケーキ、プリン等)；和菓子類(大福、餅、饅頭、カステラ、あんみつ、羊羹等)；氷菓類(アイスクリーム、アイスキャンデー、シャーベット等)；食品類(カレー、牛丼、雑炊、味噌汁、スープ、ミートソース、パスタ、漬物、ジャム、ローヤルゼリー等)；乳製品；発酵食品(ヨーグルト、ローヤルゼリー等)；調味料類(ドレッシング、ふりかけ、旨味調味料、スープの素等)などが挙げられる。 The type of the food composition of the present invention is not particularly limited, for example, beverages (soft drinks such as coffee, juice, tea drinks, milk drinks, carbonated drinks, sake, liquor such as sake, fruit liquor, etc.) Spreads (such as custard cream); pastes (such as fruit paste); pastries (chocolate, donuts, pies, cream puffs, gums, jelly, candy, cookies, cakes, puddings, etc.); Ice cakes (ice cream, popsicle, sherbet, etc.); Foods (curry, beef bowl, miso soup, miso soup, soup, meat sauce, pasta, pickles, jam, royal jelly, etc.); Dairy products Fermented foods (yogurt, royal jelly, etc.); seasonings (dressing, sprinkle, umami seasoning, soup base, etc.) and the like.
また、本発明の食品組成物は、健康食品、機能性食品、栄養補助食品、サプリメント、又は特定保健用食品としても使用できる。サプリメントとして使用する際の投与単位形態については特に限定されず適宜選択できるが、例えば錠剤、顆粒剤、液剤、カプセル剤、散剤等が挙げられる。 The food composition of the present invention can also be used as a health food, functional food, nutritional supplement, supplement, or food for specified health use. The dosage unit form for use as a supplement is not particularly limited and can be appropriately selected. Examples thereof include tablets, granules, liquids, capsules, and powders.
本発明の食品組成物における上記化合物の含量は、食品組成物全量中0.01〜100重量%、好ましくは0.1〜100重量%の範囲から適宜選択することが可能である。 The content of the compound in the food composition of the present invention can be appropriately selected from the range of 0.01 to 100% by weight, preferably 0.1 to 100% by weight, based on the total amount of the food composition.
本発明の食品組成物の摂取量は、摂取者の体重、年齢、性別、症状などの種々の条件に応じて適宜設定することができる。 The intake of the food composition of the present invention can be appropriately set according to various conditions such as the body weight, age, sex, and symptoms of the user.
本発明の食品組成物の接種により、認知症の進行の予防の効果が期待される。 By inoculating the food composition of the present invention, an effect of preventing the progression of dementia is expected.
次に本発明に係わる合成例及び試験例を記載するが、本発明はこれらに限定されるわけではない。 Next, although the synthesis example and test example concerning this invention are described, this invention is not necessarily limited to these.
合成例１：１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−メトキカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン(化合物１)の合成
４−アセチル−５−オキソヘキサン酸メチル0.93 g (5 mmol)と三酸化二ホウ素0.28 g (4 mmol)の酢酸エチル(10 mL)溶液を40℃に30分間加熱した後、４−ヒドロキシ−３−（トリフルオロメトキシ）ベンズアルデヒド2.06 g (10 mmol)とホウ酸トリ−ｎ−ブチル2.7 mL (10 mmol)を加え、同じ温度でさらに30分間加熱を続けた。ついで、ｎ−ブチルアミン0.5 mL (5 mmol)の酢酸エチル(1 mL)溶液を加えて、40℃で3時間加熱した。反応液を室温に冷却した後、1M−塩酸(15 mL)を加え、10分間激しく攪拌した。反応液に酢酸エチル(100 mL)を加え、有機層を0.5M−塩酸で洗い、ついで飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥し、ロータリーエバポレーターにて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶離液：酢酸エチル：ｎ−ヘキサン＝1：2)により精製して得られた物質に少量のジクロロメタンを加えて室温に放置すると、融点142−143℃の１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−メトキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン1.51 gが得られた。
1HNMR (d6DMSO) : δ2.0〜3.2 (4H), δ3.60 (s, 1.4H), δ3.64 (s, 1.6H), δ4.65 (t, J=7.0Hz, 0.55H), δ7.03 (d, J=16.2Hz, 1.1H), δ7.10 (d, J=8.6Hz, 1.1H), δ7.12 (d, J=8.6Hz, 0.9H), δ7.25 (d, J=16.2Hz, 0.9H), δ7.6〜7.75 (arom.H, 4H), δ7.81 (d, J=16.2Hz, 2H), δ10.90 (br.s, 2H), δ17.90 (s, 0.45H)
19FNMR (d6DMSO) : δ−58.09 (s), δ−57.96 (s)
Synthesis Example 1: Synthesis of 1,7-bis (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-methoxycarbonylethyl-1,6-heptadiene-3,5-dione (Compound 1) 4-acetyl A solution of 0.93 g (5 mmol) of methyl 5-oxohexanoate and 0.28 g (4 mmol) of diboron trioxide in ethyl acetate (10 mL) was heated to 40 ° C. for 30 minutes, and then 4-hydroxy-3- (tri Fluoromethoxy) benzaldehyde (2.06 g, 10 mmol) and tri-n-butyl borate (2.7 mL, 10 mmol) were added, and heating was continued at the same temperature for another 30 minutes. Then, a solution of n-butylamine 0.5 mL (5 mmol) in ethyl acetate (1 mL) was added and heated at 40 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (15 mL) was added, and the mixture was vigorously stirred for 10 min. Ethyl acetate (100 mL) was added to the reaction solution, and the organic layer was washed with 0.5 M hydrochloric acid, then washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed with a rotary evaporator. Left. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 2), and a small amount of dichloromethane was added to the material obtained and left at room temperature. -Bis (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-methoxycarbonylethyl-1,6-heptadiene-3,5-dione 1.51 g was obtained.
1 HNMR (d 6 DMSO): δ2.0-3.2 (4H), δ3.60 (s, 1.4H), δ3.64 (s, 1.6H), δ4.65 (t, J = 7.0Hz, 0.55H ), δ7.03 (d, J = 16.2Hz, 1.1H), δ7.10 (d, J = 8.6Hz, 1.1H), δ7.12 (d, J = 8.6Hz, 0.9H), δ7.25 (d, J = 16.2Hz, 0.9H), δ7.6-7.75 (arom.H, 4H), δ7.81 (d, J = 16.2Hz, 2H), δ10.90 (br.s, 2H), δ17.90 (s, 0.45H)
19 FNMR (d 6 DMSO): δ-58.09 (s), δ-57.96 (s)
合成例２：１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−エトキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン(化合物３)の合成
４−アセチル−５−オキソヘキサン酸エチル200 mg (1 mmol)と三酸化二ホウ素56 mg (0.8 mmol)の酢酸エチル(2 mL)溶液を40℃に30分間加熱した後、４−ヒドロキシ−３−（トリフルオロメトキシ）ベンズアルデヒド412 mg (2 mmol)とホウ酸トリ−ｎ−ブチル0.54 mL (2 mmol)を加え、同じ温度でさらに30分間加熱を続けた。ついで、ｎ−ブチルアミン0.1 mL (1 mmol)の酢酸エチル(0.2 mL)溶液を加えて、40℃で3時間加熱した。反応液を室温に冷却した後、1M−塩酸(3 mL)を加え、10分間激しく攪拌した。反応液に酢酸エチル(20 mL)を加え、有機層を0.5M−塩酸で洗い、ついで飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥し、ロータリーエバポレーターにて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶離液：酢酸エチル：ｎ−ヘキサン＝1：2)により精製して得られた物質に少量のジクロロメタンを加えて室温に放置すると、融点155−156℃の１，７−（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−エトキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン246 mgが得られた。
1HNMR (d6DMSO) : δ1.13 (t, J=7Hz), δ1.15 (t, J=7Hz) 両者合わせて３Ｈ
δ2.03 (m), δ2.30 (m), δ2.46 (m), δ2.98 (m) 合わせて４Ｈ
δ4.00 (q, J=7Hz), δ4.05 (q, 7Hz) 両者合わせて２Ｈ, δ4.60 (t, J=7Hz, 0.6H)
δ6.98 (d, J=16Hz), δ7.05 (d, J=8Hz), δ7.07 (d, J=8Hz), δ7.21 (d, J=16Hz) 合わせて４Ｈ
δ7.55〜7.70 (4H), δ7.76 (d, J=16Hz, 2H), δ10.87 (br.s, 2H), δ17.84 (s, 0.4H)
19FNMR (d6DMSO):δ−57.84 (s), δ−57.71 (s)
Synthesis Example 2: Synthesis of 1,7-bis (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-ethoxycarbonylethyl-1,6-heptadiene-3,5-dione (Compound 3) 4-acetyl After heating a solution of ethyl 5-oxohexanoate 200 mg (1 mmol) and diboron trioxide 56 mg (0.8 mmol) in ethyl acetate (2 mL) to 40 ° C. for 30 minutes, 4-hydroxy-3- (tri 412 mg (2 mmol) of fluoromethoxy) benzaldehyde and 0.54 mL (2 mmol) of tri-n-butyl borate were added, and heating was continued at the same temperature for another 30 minutes. Then, a solution of n-butylamine 0.1 mL (1 mmol) in ethyl acetate (0.2 mL) was added and heated at 40 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 1M-hydrochloric acid (3 mL) was added, and the mixture was vigorously stirred for 10 min. Ethyl acetate (20 mL) was added to the reaction mixture, and the organic layer was washed with 0.5 M hydrochloric acid, then with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed with a rotary evaporator. Left. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 2), and a small amount of dichloromethane was added to the material obtained and left at room temperature. 246 mg of-(4'-hydroxy-3'-trifluoromethoxyphenyl) -4-ethoxycarbonylethyl-1,6-heptadiene-3,5-dione was obtained.
1 HNMR (d 6 DMSO): δ1.13 (t, J = 7Hz), δ1.15 (t, J = 7Hz)
δ2.03 (m), δ2.30 (m), δ2.46 (m), δ2.98 (m) 4H in total
δ4.00 (q, J = 7Hz), δ4.05 (q, 7Hz) Both 2H, δ4.60 (t, J = 7Hz, 0.6H)
δ6.98 (d, J = 16Hz), δ7.05 (d, J = 8Hz), δ7.07 (d, J = 8Hz), δ7.21 (d, J = 16Hz)
δ7.55 ~ 7.70 (4H), δ7.76 (d, J = 16Hz, 2H), δ10.87 (br.s, 2H), δ17.84 (s, 0.4H)
19 FNMR (d 6 DMSO): δ-57.84 (s), δ-57.71 (s)
合成例３：１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−イソプロポキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン(化合物４)の合成
４−アセチル−５−オキソヘキサン酸イソプロピル214 mg (1 mmol)と三酸化二ホウ素56 mg (0.8 mmol)の酢酸エチル(2 mL)溶液を40℃に30分間加熱した後、４−ヒドロキシ−３−（トリフルオロメトキシ）ベンズアルデヒド412 mg (2 mmol)とホウ酸トリ−ｎ−ブチル0.54 mL (2 mmol)を加え、同じ温度でさらに30分間加熱を続けた。ついで、ｎ−ブチルアミン0.1 mL (1 mmol)の酢酸エチル(0.2 mL)溶液を加えて、40℃に3.5時間加熱した。反応液を室温に冷却した後、1M−塩酸(3 mL)を加え、5分間激しく攪拌した。反応液に酢酸エチル(20 mL)を加え、有機層を0.5M−塩酸で洗い、ついで飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥し、ロータリーエバポレーターにて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶離液：酢酸エチル：ｎ−ヘキサン＝1：3)により精製して得られた物質に少量のジクロロメタンを加えて室温に放置すると、融点191℃の１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−イソプロポキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン310 mgが得られた。
1HNMR (d6DMSO): δ1.13 (d, J=6.2Hz, 0.45H), δ1.19 (d, J=6.2Hz, 0.55H), δ2.07 (m, 1.2H), δ2.26 (m, 1.2H), δ2.43 (m, 0.8H), δ2.98 (m, 0.8H), δ4.59 (t, J=6.7Hz, 0.6H), δ4.86 (septet, J=6.2Hz, 1H), δ6.98 (d, J=15.9Hz, 1.2H), δ7.0〜7.1 (2H), δ7.21 (d, J=15.9Hz, 0.8H), δ7.55〜7.7 ( 4H), δ7.76 (d, J=15.9Hz, 2H), δ17.83 (s, 0.4H)
19FNMR (d6DMSO): δ−58.34 (s), δ−58.21 (s)
Synthesis Example 3 Synthesis of 1,7-bis (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-isopropoxycarbonylethyl-1,6-heptadiene-3,5-dione (Compound 4) 4- A solution of isopropyl acetyl-5-oxohexanoate 214 mg (1 mmol) and diboron trioxide 56 mg (0.8 mmol) in ethyl acetate (2 mL) was heated at 40 ° C. for 30 minutes, and then 4-hydroxy-3- ( Trifluoromethoxy) benzaldehyde 412 mg (2 mmol) and tri-n-butyl borate 0.54 mL (2 mmol) were added, and heating was continued at the same temperature for another 30 minutes. Then, a solution of n-butylamine 0.1 mL (1 mmol) in ethyl acetate (0.2 mL) was added and heated to 40 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (3 mL) was added, and the mixture was vigorously stirred for 5 min. Ethyl acetate (20 mL) was added to the reaction mixture, and the organic layer was washed with 0.5 M hydrochloric acid, then with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed with a rotary evaporator. Left. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 3), and a small amount of dichloromethane was added to the obtained substance and left at room temperature to leave 1,7-bis having a melting point of 191 ° C. 310 mg of (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-isopropoxycarbonylethyl-1,6-heptadiene-3,5-dione was obtained.
1 HNMR (d 6 DMSO): δ1.13 (d, J = 6.2Hz, 0.45H), δ1.19 (d, J = 6.2Hz, 0.55H), δ2.07 (m, 1.2H), δ2. 26 (m, 1.2H), δ2.43 (m, 0.8H), δ2.98 (m, 0.8H), δ4.59 (t, J = 6.7Hz, 0.6H), δ4.86 (septet, J = 6.2Hz, 1H), δ6.98 (d, J = 15.9Hz, 1.2H), δ7.0 ~ 7.1 (2H), δ7.21 (d, J = 15.9Hz, 0.8H), δ7.55 ~ 7.7 (4H), δ7.76 (d, J = 15.9Hz, 2H), δ17.83 (s, 0.4H)
19 FNMR (d 6 DMSO): δ-58.34 (s), δ-58.21 (s)
合成例４：１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−ｔｅｒｔ−ブトキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン(化合物５)の合成
４−アセチル−５−オキソヘキサン酸ブチル（ｔｅｒｔ）228 mg (1 mmol)と三酸化二ホウ素56 mg (0.8 mmol)の酢酸エチル(2 mL)溶液を40℃に30分間加熱した後、４−ヒドロキシ−３−（トリフルオロメトキシ）ベンズアルデヒド412 mg (2 mmol)とホウ酸トリ−ｎ−ブチル0.54 mL (2 mmol)を加え、同じ温度でさらに30分間加熱を続けた。ついで、ｎ−ブチルアミン0.1 mL (1 mmol)の酢酸エチル(0.2 mL)溶液を加えて、40℃に3.5時間加熱した。反応液を室温に冷却した後、1M−塩酸(3 mL)を加え、5分間激しく攪拌した。反応液に酢酸エチル(20 mL)を加え、有機層を0.5M−塩酸で洗い、ついで飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥し、ロータリーエバポレーターにて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶離液：酢酸エチル：n−ヘキサン＝1：3)により精製して得られた物質に少量のジクロロメタンを加えて室温に放置すると、融点175℃の１，７−ビス（４’−ヒドロキシ−３’−トリフルオロメトキシフェニル）−４−ｔｅｒｔ−ブトキシカルボニルエチル−１，６−ヘプタジエン−３，５−ジオン264 mgが得られた。
1HNMR (d6DMSO):δ1.35 (s), δ1.38 (s) 両者合わせて９Ｈ
δ2.03 (m), δ2.19 (m), δ2.39 (m), δ2.95 (m) 合わせて４Ｈ, δ4.57 (t, J=7Hz,0.5H), δ6.98 (d, J=16Hz), δ7.05 (d, J=8Hz), δ7.07 (d, J=8Hz), δ7.21 (d, J=16Hz) 合わせて４Ｈ，
δ7.55〜7.70 (4H), δ7.76 (d, J=16Hz, 2H), δ10.87 (br.s, 2H), δ17.79 (s, 0.5H)
19FNMR (d6DMSO): δ−58.31 (s), δ−58.18 (s)
Synthesis Example 4: Synthesis 4 of 1,7-bis (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-tert-butoxycarbonylethyl-1,6-heptadiene-3,5-dione (Compound 5) -A solution of butyl acetyl-5-oxohexanoate (tert) 228 mg (1 mmol) and diboron trioxide 56 mg (0.8 mmol) in ethyl acetate (2 mL) was heated to 40 ° C for 30 minutes, and then 4-hydroxy -3- (Trifluoromethoxy) benzaldehyde 412 mg (2 mmol) and tri-n-butyl borate 0.54 mL (2 mmol) were added, and heating was continued at the same temperature for another 30 minutes. Then, a solution of n-butylamine 0.1 mL (1 mmol) in ethyl acetate (0.2 mL) was added and heated to 40 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, 1M hydrochloric acid (3 mL) was added, and the mixture was vigorously stirred for 5 min. Ethyl acetate (20 mL) was added to the reaction mixture, and the organic layer was washed with 0.5 M hydrochloric acid, then with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed with a rotary evaporator. Left. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 3), and a small amount of dichloromethane was added to the material, which was allowed to stand at room temperature. 1,7-bis having a melting point of 175 ° C. 264 mg of (4′-hydroxy-3′-trifluoromethoxyphenyl) -4-tert-butoxycarbonylethyl-1,6-heptadiene-3,5-dione was obtained.
1 HNMR (d 6 DMSO): δ1.35 (s), δ1.38 (s) Both 9H
δ2.03 (m), δ2.19 (m), δ2.39 (m), δ2.95 (m) 4H, δ4.57 (t, J = 7Hz, 0.5H), δ6.98 (d , J = 16Hz), δ7.05 (d, J = 8Hz), δ7.07 (d, J = 8Hz), δ7.21 (d, J = 16Hz)
δ7.55 ~ 7.70 (4H), δ7.76 (d, J = 16Hz, 2H), δ10.87 (br.s, 2H), δ17.79 (s, 0.5H)
19 FNMR (d 6 DMSO): δ-58.31 (s), δ-58.18 (s)
試験例１．化合物のヒト老人斑(アミロイドβタンパク質凝集体)への結合能の検証
化合物１−４の各2 mg/mlのDMSO溶液を調製した後、各々200μlを量りとり、0.3%-Triton X100含有0.1 Mリン酸緩衝液(pH7.4)(以下、PBS-T)を加えて4 mlの試験溶液とした(薬液濃度：200μg/ml)。
Test Example 1 Verification of the ability of the compound to bind to human senile plaques (amyloid β protein aggregates) After preparing 2 mg / ml DMSO solutions of each compound 1-4, weighed 200 μl each and added 0.1 M containing 0.3% -Triton X100 Phosphate buffer (pH 7.4) (hereinafter PBS-T) was added to make a 4 ml test solution (chemical solution concentration: 200 μg / ml).
アルツハイマー症例のヒト脳組織固定標本(20μm厚)を2%スキムミルク入りPBS-T液中に室温で1時間浸漬した後、マウス抗ヒトアミロイドβモノクローナル抗体(4G8, Signet社、3,000倍希釈)と4℃で一晩反応させた。ついで本検体をPBS-Tで10分間3回洗浄した後、遮光のうえAlexa647抗マウスIgG抗体(Molecular Probes社)と室温で4時間反応させた。4時間後、切片を取り出し上記試験試薬中に移し、遮光下に室温で1時間浸漬した後、PBS-Tで5分間3回洗浄した。更に50 mMトリス塩酸バッファー(pH7.5)で5分間洗浄後、グリセロール封入を行なったものを検体とし倒立型蛍光顕微鏡(IX70、オリンパス)にて老人斑への化合物の結合能を観察した。なお、化合物像はWBフィルターで、アミロイドβタンパク質像はCy5フィルターで測定した。また、陰性対照試験として0.1%-DMSO含有PBS-T溶液を用いて同染色処理をおこなった。 A human brain tissue fixed specimen (20 μm thick) of Alzheimer's case was immersed in PBS-T solution containing 2% skim milk for 1 hour at room temperature, then mouse anti-human amyloid β monoclonal antibody (4G8, Signet, diluted 3,000 times) and 4 The reaction was allowed to proceed overnight at 0 ° C. Next, this specimen was washed with PBS-T three times for 10 minutes, and then allowed to react with Alexa647 anti-mouse IgG antibody (Molecular Probes) for 4 hours at room temperature in the dark. After 4 hours, the sections were taken out and transferred into the above-described test reagents, immersed for 1 hour at room temperature in the dark, and then washed 3 times for 5 minutes with PBS-T. Furthermore, after washing with 50 mM Tris-HCl buffer (pH 7.5) for 5 minutes and using glycerol-encapsulated specimens, the ability of the compound to bind to senile plaques was observed with an inverted fluorescence microscope (IX70, Olympus). The compound image was measured with a WB filter, and the amyloid β protein image was measured with a Cy5 filter. In addition, the same staining treatment was performed using a PBS-T solution containing 0.1% -DMSO as a negative control test.
図１にアルツハイマー病患者の死後脳側頭葉皮質切片における化合物１−４の蛍光染色像を、図２に化合物１−２の蛍光染色像と抗アミロイドβ抗体による老人斑の二重染色像を示す。左列は化合物(WB)の染色像、右列はアミロイドβ抗体の染色像を示す。化合物１−２は老人斑を形成するアミロイドβタンパク質と親和性を有し、同一位置に染色を認めた。なお、陰性対照では老人斑特異的な蛍光染色像は認められなかった。 Fig. 1 shows a fluorescent staining image of compound 1-4 in a postmortem brain temporal cortex section of a patient with Alzheimer's disease, and Fig. 2 shows a fluorescent staining image of compound 1-2 and a double staining image of senile plaques by anti-amyloid β antibody. Show. The left column shows a stained image of compound (WB), and the right column shows a stained image of amyloid β antibody. Compound 1-2 had affinity with amyloid β protein forming senile plaques, and staining was observed at the same position. In the negative control, no senile plaque-specific fluorescent staining image was observed.
試験例２．化合物が血液脳関門を通過することの検証
無麻酔下のマウスに尾静脈から化合物１−５について25 mg/kg又は50 mg/kgをワンショットで投与し、5分後、30分後に血液及び脳を採取した。高速液体クロマトグラフィーにて、各化合物及びその代謝産物である化合物２の濃度を測定した。血清及び脳内の濃度変化をグラフ化し、それぞれ折れ線内の面積値(Area Under the Curve; 以下AUC)を求めた(図３)。化合物の脳内移行率は、脳内AUC/血清AUC x 100 (%)として計算した。各化合物の投与5分後と30分後の血清及び脳内濃度(主な代謝産物を含めた総量で表示)の測定結果を図３に示す。各化合物の構造式と脳内移行率を第２表に示す。
Test Example 2 Verification of compound crossing the blood-brain barrier One-shot administration of 25 mg / kg or 50 mg / kg of compound 1-5 from the tail vein to unanesthetized mice, 5 minutes, 30 minutes later The brain was collected. The concentration of each compound and its metabolite Compound 2 was measured by high performance liquid chromatography. The changes in serum and brain concentrations were graphed, and the area values (Area Under the Curve; hereinafter referred to as AUC) in the polygonal line were obtained (FIG. 3). The intracerebral transfer rate of the compound was calculated as brain AUC / serum AUC × 100 (%). FIG. 3 shows the measurement results of serum and brain concentrations (expressed in total amount including main metabolites) 5 minutes and 30 minutes after administration of each compound. Table 2 shows the structural formula of each compound and the brain migration rate.
第２表の結果は、中央の側鎖をカルボン酸にした化合物２以外の化合物は脳内に移行することを示している。逆に言えば、中央の側鎖をカルボン酸にすると脳に移行しなくなることが分かる。 The results in Table 2 indicate that compounds other than Compound 2 having a central side chain as a carboxylic acid migrate into the brain. Conversely, it can be seen that when the central side chain is made carboxylic acid, it does not migrate to the brain.
試験例３．アルツハイマー病遺伝子改変モデルマウスの学習及び記憶能力に対する化合物の治療効果の検証
脳血液関門を通過する化合物１と通過しない化合物２をアルツハイマー病遺伝子改変モデルマウスに投与し治療効果を検証した。アルツハイマー病遺伝子改変モデルマウスは、ジャクソン研究所で開発されたヒト変異型アミロイド前駆タンパク(APP)遺伝子とヒト変異型プレセニリン1 (PS1)遺伝子のダブルトランスジェニックマウス(APP/PS1マウス)を用いた。9月齢のAPP/PS1マウスに、クルクミン、化合物１又は化合物２を0.05%混合したAIM-93M飼料を6月間与え、投与終了前の7日間にモーリス水迷路試験を実施した。
Test Example 3 Verification of therapeutic effect of compound on learning and memory ability of Alzheimer's disease genetically modified model mice Compound 1 that passes the brain-blood barrier and compound 2 that does not pass are administered to Alzheimer's disease genetically modified model mice to verify the therapeutic effect. As the Alzheimer's disease gene-modified model mice, double transgenic mice (APP / PS1 mice) of human mutant amyloid precursor protein (APP) gene and human mutant presenilin 1 (PS1) gene developed at Jackson Laboratory were used. 9 month old APP / PS1 mice were fed AIM-93M diet containing 0.05% curcumin, compound 1 or compound 2 for 6 months, and Morris water maze test was conducted for 7 days before the end of administration.
まずプール内に放したマウスが水面下1 cmに設置したプラットフォームへ到達するまでの時間を測定した。測定は最大90秒間記録し、その間に到達しなかった場合は90秒と記録した。この試行を1日5回繰り返し6日間実施した。7日目にプローブ試行を実施した。プラットフォームを取り除いたプールにマウスを放ち100秒間泳がせた。そして100秒間の遊泳時間の内、それまでプラットフォームが設置されていた区画における滞留時間を測定した。図４にモーリス水迷路試験の結果を示す。 First, the time required for a mouse released in the pool to reach a platform placed 1 cm below the water surface was measured. The measurement was recorded for a maximum of 90 seconds, and if not reached during that time, it was recorded as 90 seconds. This trial was repeated 5 times a day for 6 days. A probe trial was performed on day 7. The mouse was released into the pool from which the platform was removed and allowed to swim for 100 seconds. And within 100 seconds of swimming time, the residence time in the section where the platform was installed was measured. FIG. 4 shows the results of the Morris water maze test.
図４Ａ：正常な野生型マウス(○+破線)では、学習と共に水中のプラットフォームを発見する時間が短くなり、3日目以降では1日目と比べて統計的に有意に短い時間で発見できている(**p < 0.01, ***p < 0.001)。一方、アルツハイマー病モデルマウスは、何日たっても発見するまでの時間に変化はない(○+実線)。クルクミン(▲+実線)、血液脳関門を通らない化合物２(◆+実線)を食べたアルツハイマー病モデルマウスでも、発見するまでの時間に変化はなかった。しかし、化合物１を食べさせたアルツハイマー病モデルマウス(■+実線)は学習効果が認められ、5日目、6日目では1日目と比べて統計的に有意に短い時間で発見できている(##p < 0.01)。 Fig. 4A: In normal wild-type mice (circles + dashed lines), the time to discover the underwater platform is shortened with learning, and it can be found in a significantly shorter time than the first day after the third day. (** p <0.01, *** p <0.001). On the other hand, Alzheimer's disease model mice have no change in the time to discovery, regardless of the number of days (○ + solid line). Alzheimer's disease model mice that ate curcumin (▲ + solid line) and compound 2 (♦ + solid line) that does not cross the blood-brain barrier did not change the time to discovery. However, Alzheimer's disease model mice fed with Compound 1 (■ + solid line) showed a learning effect, and were found in a significantly shorter time on the 5th and 6th days than on the 1st day. (## p <0.01).
図４Ｂ：7日目に水中のプラットフォームを外してマウスを100秒間泳がせたところ、正常な野生型マウスでは、アルツハイマー病モデルマウスに比べて、プラットフォームのあった場所にマウスが長い時間留まって泳いでいた(*p < 0.05)。クルクミンや化合物２を食べたアルツハイマー病モデルマウスでは、時間の変化は認められなかった。しかし、化合物１を食べさせたアルツハイマー病モデルマウスでは、正常マウスのようにプラットフォームのあった場所に長い時間留まっていた(#p < 0.05)。 Figure 4B: On the 7th day, the underwater platform was removed and the mouse was allowed to swim for 100 seconds. With normal wild-type mice, the mouse stayed in the place where the platform was located for a longer time than the Alzheimer's disease model mouse. (* P <0.05). In Alzheimer's disease model mice that ate curcumin or compound 2, no change in time was observed. However, Alzheimer's disease model mice fed with Compound 1 remained for a long time at the place where the platform was located like normal mice (#p <0.05).
さらに、本発明者は、化合物１については毒性が低く、変異原性がないことを確認している。 Furthermore, the present inventor has confirmed that Compound 1 has low toxicity and is not mutagenic.
試験例４．アルツハイマー病遺伝子改変モデルマウスの脳内に蓄積するアミロイドβタンパク質凝集体に対する化合物の効果の検証
アルツハイマー病の遺伝子改変モデルマウスとしてヒト変異型アミロイド前駆タンパク質(APP)遺伝子とヒト変異型プレセニリン1 (PS1)遺伝子のダブルトランスジェニックマウス(APP/PS1マウス)を用いた。9月齢のAPP/PS1マウスに、クルクミン、化合物１又は化合物２を0.05%混合したAIM-93M飼料を6月間与えた。その後、マウスを安楽死させた後、脳を摘出した。
Test Example 4 Verification of the effects of compounds on amyloid β protein aggregates accumulated in the brain of Alzheimer's disease genetically modified mouse models Human mutant amyloid precursor protein (APP) gene and human mutant presenilin 1 (PS1) Gene double transgenic mice (APP / PS1 mice) were used. 9 month old APP / PS1 mice were fed AIM-93M diet containing 0.05% curcumin, compound 1 or compound 2 for 6 months. The mouse was then euthanized and the brain was removed.
摘出した脳組織湿重量150 mgあたり1 mLのトリス緩衝生理食塩水(TBS)を加え、ホモジナイズした後、遠心した。上清をTBS可溶性画分として分離し、沈渣には上記と同量の70%ギ酸(Formic acid, FA)を加え、ホモジナイズした後、遠心した。上清を1 Mトリス溶液にて20倍希釈したものをギ酸(FA)抽出画分とした。 1 mL of Tris-buffered physiological saline (TBS) was added per 150 mg of wet brain tissue wet weight, homogenized, and centrifuged. The supernatant was separated as a TBS soluble fraction, and the same amount of 70% formic acid (Formic acid, FA) was added to the precipitate, homogenized, and centrifuged. The supernatant diluted 20-fold with 1 M Tris solution was used as the formic acid (FA) extract fraction.
それぞれの画分に含まれるAβ量はヒト／ラットβアミロイド(1-40) ELISAキットワコーII (294-64701, 和光純薬)及びヒト／ラットβアミロイド(1-42) ELISAキットワコー (290-62601, 和光純薬)を用いて測定した。なお、TBS可溶性画分は可溶性Aβを、ギ酸(FA)抽出画分は不溶性のAβ凝集体を含むと考えられている。結果を図５に示す。 The amount of Aβ contained in each fraction was determined by human / rat β amyloid (1-40) ELISA kit Wako II (294-64701, Wako Pure Chemical Industries) and human / rat β amyloid (1-42) ELISA kit Wako (290- 62601, Wako Pure Chemicals). The TBS soluble fraction is considered to contain soluble Aβ, and the formic acid (FA) extracted fraction is considered to contain insoluble Aβ aggregates. The results are shown in FIG.
トリス緩衝生理食塩水(TBS)で回収した分画では、可溶性Aβ40、可溶性Aβ42ともにいずれの群においても統計的な差は見られなかった(図４上)。一方、ギ酸で抽出した分画では、Aβ40凝集体の脳内濃度は、化合物１含有食を食べたマウスで低い傾向にあったが、統計的に有意な差ではなかった。一方、Aβ42凝集体の脳内濃度は、化合物１含有食を食べたマウスで統計的に有意に減少した(図４下)。 In the fraction collected with Tris-buffered saline (TBS), there was no statistical difference in either group for both soluble Aβ40 and soluble Aβ42 (upper figure 4). On the other hand, in the fraction extracted with formic acid, the brain concentration of Aβ40 aggregates tended to be low in mice that ate a compound 1-containing diet, but this was not a statistically significant difference. On the other hand, the concentration of Aβ42 aggregates in the brain was statistically significantly decreased in the mice that ate the compound 1-containing diet (bottom of FIG. 4).
本発明は、アルツハイマー病をはじめとする認知症の治療に利用される。 The present invention is used for the treatment of dementia including Alzheimer's disease.
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