JP7196202B2 - 新規置換n9-アデニン誘導体、これを含有する医薬組成物、およびその使用 - Google Patents
新規置換n9-アデニン誘導体、これを含有する医薬組成物、およびその使用 Download PDFInfo
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- JP7196202B2 JP7196202B2 JP2020569123A JP2020569123A JP7196202B2 JP 7196202 B2 JP7196202 B2 JP 7196202B2 JP 2020569123 A JP2020569123 A JP 2020569123A JP 2020569123 A JP2020569123 A JP 2020569123A JP 7196202 B2 JP7196202 B2 JP 7196202B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
・Rが、5もしくは6員環アリール基または5もしくは6員環ヘテロアリール基であり、アリールまたはヘテロアリールが、その自由位置で、ジュウテリウム、ハロゲン原子、-OH、-CH3、-CN、-OCH3、OCH2CH3、-CH2COOH、-CH2COOCH3、-COOH、-COCH3、-COHから選択される、1つまたは複数の、同一または異なる置換基で置換されている可能性があり、
・R1およびR2が、H、直鎖もしくは分岐の(C1-22)アルキル基、(C2-22)アルケニル基、(C2-22)アルキニル基、(C3-7)シクロアルキル基、(C3-22)-COOHアルキル基、(C5-6)-COOHアリール基、アミノ酸、好ましくはアラニン基、セリン基もしくはアルギニン基、グリセロール基、コリン基、もしくはスフィンゴミエリン基から互いに独立して選択される;またはこれらが、アルカリ金属もしくはアルカリ土類金属カチオン、特にナトリウムもしくはマグネシウムから互いに独立して選択され、かつ遷移金属カチオンもしくは任意の許容可能なカチオンであることもでき、
かつこのとき:
- 「アリール基」が5または6員環芳香族炭化水素基であり、アリールが、ハロゲン原子、メチル、エチル、プロピル、イソプロピルおよびシクロプロピル、ジュウテリウムおよびヒドロキシルからなる群から独立して選択される、同一または異なる置換基で、非置換または一置換または多置換されている可能性があり、
- 「ヘテロアリール基」が、少なくとも1つの環炭素がN、O、S、P、またはSeで置き換えられている5または6員環芳香族炭化水素基であり、
- ホスホニル基
- 希釈剤として:乳糖、ブドウ糖、ショ糖、マンニトール、ソルビトール、微結晶性セルロース、グリセリン;
- 潤滑剤として:シリカ、タルク、ステアリン酸ならびにそのマグネシウム塩およびカルシウム塩、ポリエチレングリコール;
- 結合剤として:ケイ酸アルミニウムマグネシウム、デンプン、ゼラチン、トラガカントガム、メチルセルロース、カルボキシメチルセルロースナトリウム、およびポリビニルピロリドン;
- 崩壊剤として:寒天、アルギン酸およびそのナトリウム塩、発泡性混合物;
- 可溶化剤として:シクロデキストリン、ポリビニルカプロラクタム、ポリ酢酸ビニル、ポリエチレングリコール。
以下の実施例において、式(I)の化合物、特にN9-(3-ジエチルホスホニル)フェニル-アデニンの好ましい実施形態の一例の合成手順について記述し、本発明をさらに説明していくが、これは本発明を限定するものと解釈してはならない。この式(I)の化合物の特定の例において、Rがフェニル基であり、R1およびR2がともにエチル基である。
一般的な合成機構は、非特許文献10に記載されるように、中性アデニンとハロアリールボロン酸、例えば3-ブロモフェニルボロン酸または4-ブロモフェニルボロン酸の間で化学量論量の銅(II)塩によって媒介されるChan-Lamカップリングによって制御される。カラムクロマトグラフィー精製によりカップリング生成物、例えば9-(3-ブロモフェニル)アデニンおよび9-(4-ブロモフェニル)アデニンを得るために、ジアルキルホスフィンを、根岸カップリングに類似した条件下で、触媒としてテトラキス(トリフェニルホスフィン(trifefilphosphine))-パラジウム(0)、塩基としてトリエチルアミン、および溶媒として無水ジメチルホルムアミドを用いてカップリングさせる。その後で、ホスホン酸塩の2つのエステル結合を、塩酸水溶液を用いて酸性媒体中で加水分解させて、対応するホスホン酸誘導体を得た後、続いて、塩、例えば二ナトリウムに変換し、水性媒体中で水酸化ナトリウムと反応させることができる。
ステップ1:3-ブロモフェニル-N9-アデニン
このステップは非特許文献10を適用する。
2mmolの3-ブロモフェニル-N9-アデニン、3mmolのトリエチルアミン、0.1mmolのテトラキス(トリフェニルホスフィン)-パラジウム(0)、および3mmolの亜リン酸ジエチルを50mL丸底フラスコに入れた。次いで、10mLの無水ジメチルホルムアミドを添加し、混合液を100℃で1時間攪拌した。ジメチルホルムアミドを蒸発させ、得られた固形物を、シリカゲルと溶離液としてCH2Cl2:MeOH(10:1)を用いてクロマトグラフィーで精製した。r=0.20の所望の生成物N9-(3-ジエチルホスホニル)フェニル-アデニンを白色/ベージュ結晶性固体として得た。収率90%。純度>98%。融点104℃。
IR(KBr)、cm-1:3297ms、3102ms、1676s、1599s、1487ms、1307s、1050ms、1022s、656m、562m(ms=中強、s=強、m=中)。
1H-NMR(300MHz、dmso-d6):δ(ppm)=8.67s(1H、H8アデニン)、8.30dd(1H、H1、JPH=16.6Hz、Jm=1.2Hz)、8.23s(1H2ade CH)、8.17-8.14m(1H、H2)、7.79-7.75m(2H、H3+H4)、7.43bs(2H、NH2)、4.08dq(4H、CH2、JP-H=15.3Hz、JH-H=7.2Hz)、1.29-1.25t(6H CH3、JH-H=7.2Hz)ppm.
HRMS(ESI)[M+H]+[C15H18N5PO3+H]+:計算m/z=348.1218;測定m/z=348.1220。
マウス筋芽細胞腫細胞株(Sigma-Aldrich社)のC2C12細胞を96ウェルプレートの200μLの増殖培地(高グルコースDMEM、10%ウシ胎児血清(PBS)、ペニシリン、およびストレプトアビジン)に10,000細胞/ウェルの細胞密度で播種した。細胞はコンフルエンスまで増殖させ、アッセイの日に、100μLの増殖培地で関心の化合物とともにインキュベーターで37℃、5%CO2で1~24時間インキュベートした。全条件を4回くり返して試験した。化合物は、さまざまな濃度の滅菌無水ジメチルスルホキシドに加えて溶解した。AMPK活性化の陽性対照として、終濃度が100μLのアデノシン一リン酸(AMP)溶液を用いた。対応する回数の後、培地を除去し、室温でPBSを用いて細胞を慎重に3回洗浄し、ELISAキット(Abcam社)を用いてリン酸化α-AMPK:総α-AMPKの比を定量化した。メーカーの指示に従い、Licor Odissey(登録商標)スキャナーを用いて信号を定量化した。4時間インキュベートした後、化合物N9-(3-ジエチルホスホニル)フェニル-アデニンは、30ナノモルという低濃度でAMP陽性対照よりも高いAMPK活性を示した。
マウス筋芽細胞腫細胞株(Sigma-Aldrich社)のC2C12細胞を、照度計の使用に対応したホワイト96ウェルプレートに10,000細胞/ウェルの細胞密度で播種した。細胞は200μL/ウェルの増殖培地(高グルコースDMEM、10%ウシ胎児血清(PBS)、ペニシリン、およびストレプトアビジン)で37℃、5%CO2のインキュベーターで5日間増殖させた。培地は2日ごとに交換した。その後、培地を分化培地(低グルコースDMEM、2%N-ヒドロキシスクシンイミド、ペニシリン、およびストレプトアビジン)に交換し、3日間にわたって細胞を筋管に分化させた。培地は毎日交換した。試験の前日に細胞を血清飢餓状態にした(低グルコースDMEM、ペニシリン、およびストレプトアビジン)。次いで、培地を、グルコースを含まないDMEM培地に交換し、化合物N9-(3-ジエチルホスホニル)フェニル-アデニンをさまざまな濃度で1時間インキュベートし、各条件を4回くり返した。陽性対照は100ナノモルのヒトインスリン溶液(Sigma)であった。Promegaのグルコース消費キットをメーカーの指示に従って使用した。キットは、グルコースの化学的類似体である2-デオキシグルコースの細胞内取り込みに基づき、ルシフェリン・ルシフェラーゼ(発光酵素)アッセイと組み合わせたもので、得られた結果が該グルコース類似体の細胞内濃度に比例するという事実に関連する。
MTTレドックスアッセイは、ミトコンドリア酵素コハク酸デヒドロゲナーゼによって生成される3-(4,5-ジメチルチアゾール-2-イル)-2,5-ジフェニルテトラゾール(MTT)の臭化物の代謝還元に基づき、ホルマザン色素(青色)の呈色により、処理した細胞のミトコンドリア機能を決定できる。
ヒト成人を対象として1日経口用量で薬剤を処方するための医薬組成物の一例に、本発明による化合物20mgを賦形剤(微結晶性セルロース、カルボキシメチルスターチナトリウムのタイプA(ジャガイモ由来)、無水コロイドシリカ、およびステアリン酸マグネシウム)とともに圧縮粒子形態にしたものがある。
Claims (9)
- N9-フェニル-3-ホスホニル-アデニンである、請求項1に記載の置換N9-アデニン誘導体。
- N9-(3-ジエチルホスホニル)フェニル-アデニンである、請求項1に記載の置換N9-アデニン誘導体。
- N9-(2-フラニル)-5-ホスホニル-アデニンである、請求項1に記載の置換N9-アデニン誘導体。
- 請求項1~4のうちいずれか一項に記載の少なくとも1つの化合物を、1つまたは複数の薬学的に許容される賦形剤と組み合わせて含有する医薬組成物。
- 請求項1~6のうちいずれか一項に記載の化合物が、治療対象の体重1kg当たり1μg~1,000mgの有効投与量で存在する、請求項5に記載の医薬組成物。
- 請求項1~6のうちいずれか一項に記載の化合物が、体重1kg当たり1~300mgの有効投与量で存在する、請求項6に記載の医薬組成物。
- AMPK活性化薬の製造に使用するための、請求項5~7のうちいずれか一項に記載の医薬組成物。
- 高コレステロール血症、肥満、2型糖尿病、もしくはメタボリックシンドロームなどの代謝疾患から選択される障害および疾患の治療ならびに/または予防のため、筋骨格機能、内分泌機能、細胞恒常性、環境ストレスに対する適応のため、ならびにAMPKホロ酵素活性化によって管理および/または逆行させることができる皮膚科病態の治療または予防のための薬剤の製造に使用する、請求項8に記載の医薬組成物。
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WO1996023801A2 (en) | 1995-02-01 | 1996-08-08 | Gilead Sciences, Inc. | Novel compounds and methods for making and using same |
WO2010108051A2 (en) | 2009-03-20 | 2010-09-23 | Ligand Pharmaceuticals | Inhibitors of diacylglycerol o-acyltransferase 1(dgat-1) and uses thereof |
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CN112272668B (zh) | 2023-05-09 |
US11992498B2 (en) | 2024-05-28 |
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