JP6866514B2 - Pparアゴニスト、化合物、医薬組成物、及びその使用方法 - Google Patents
Pparアゴニスト、化合物、医薬組成物、及びその使用方法 Download PDFInfo
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- JP6866514B2 JP6866514B2 JP2020016147A JP2020016147A JP6866514B2 JP 6866514 B2 JP6866514 B2 JP 6866514B2 JP 2020016147 A JP2020016147 A JP 2020016147A JP 2020016147 A JP2020016147 A JP 2020016147A JP 6866514 B2 JP6866514 B2 JP 6866514B2
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- imidazol
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- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
Description
本出願は、2015年10月7日に出願された米国仮特許出願第62/238,629号;2015年10月19日に出願された米国仮特許出願第62/243,263号;及び2016年6月20日に出願された米国仮特許出願第62/352,348号の利益を主張するものである。これらの出願の全内容は、参照により本明細書に援用される。
本出願は、ペルオキシソーム増殖因子活性化受容体(PPAR)の、特にPPARデルタ(PPARδ)のアゴニスト、及び1つ以上のPPARδ関連疾患の治療又は予防などのためのその使用方法に関する。
式中:
R1は、水素、ハロゲン、−C1−C4−アルキル、−C1−C4−ハロアルキル、−CN、C1−C4−アルコキシ、−C1−C4−ハロアルコキシ、又は−C3−C6−シクロアルキルであり;
Q1は、CH又はNであり;
R2は、水素、ハロゲン、−CN、−C1−C4−アルキル、−C1−C4−ハロアルキル、−C3−C6−シクロアルキル、−C1−C4−アルコキシ、−C1−C4−ハロアルコキシ、−S(C1−C4−アルキル)、−SO2(C1−C4−アルキル)、5又は6員環ヘテロ環、アリール、5員環ヘテロアリール、−≡−R2A、−O(CH2)mR2B、−NH(C1−C4−アルキル)、−N(C1−C4−アルキル)2、又は−C(O)(C1−C4−アルキル)であり、ここで、アリール及びヘテロアリールは、ハロゲ
ン、−OH、−CN、−C1−C4−アルキル、ホルミル、アセチル、アセトキシ、又はカルボキシで置換されていてもよく、並びにここで、mは、1、2、又は3の値を有する整数であり;
xは、1又は2の値を有する整数であり;
R2A及びR2Bは、各々独立して、−C1−C4−アルキル、−C1−C4−ハロアルキル、又は−C3−C6−シクロアルキルであり;
各R20は、独立して、水素、ハロゲン、−C1−C4−アルキル、−CN、又は−C1−C4−アルコキシであり;並びに
R3は、−CH3又は−CD3である。
単独で、又は「アルコキシ」、「ハロアルキル」、「ハロアルコキシ」、「シクロアルキル」などのより大きい部分の一部として用いられる「アルキル」の用語は、飽和脂肪族直鎖状又は分岐鎖状一価炭化水素ラジカルを意味する。特に断りのない限り、アルキル基は、典型的には、1から4個の炭素原子を有し、すなわち、C1−C4−アルキルである。本明細書で用いられる場合、「C1−C4−アルキル」基は、直鎖状又は分岐鎖状の配列で1から4個の炭素原子を有するラジカルを意味し、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、及びtert−ブチルを含む。
「アリール」の例は、フェニル、ナフチル、アントラセニル、1,2−ジヒドロナフチル、1,2,3,4−テトラヒドロナフチル、フルオレニル、インダニル、及びインデニルを含む。
マー的に濃縮、又はラセミ)を包含することは理解される。2つ以上のキラル中心を有する化合物が、キラル中心の立体化学を示すことなく命名され、又は示される場合、その名称又は構造は、その化合物の考え得るすべてのジアステレオマーの形態(例:ジアステレオマー的に純粋、ジアステレオマー的に濃縮、及び1つ以上のジアステレオマーの等モル混合物(例:ラセミ混合物)を包含することは理解される。
細書で開示される化合物の中性形態も、本発明に含まれる。
塩水、乳酸リンゲル液、通常スクロース、通常グルコース、結合剤、充填剤、崩壊剤、滑沢剤、コーティング剤、甘味剤、香味剤、塩溶液(リンゲル液など)、アルコール、油、ゼラチン、ラクトース、アミロース、又はデンプンなどの炭水化物、脂肪酸エステル、ヒドロキシメチルセルロース、ポリビニルピロリジン、及び着色剤などが挙げられる。そのような調製物は、滅菌されてよく、所望される場合は、本明細書で提供される化合物と有害に反応せず、又はその活性に干渉もしない滑沢剤、保存剤、安定剤、湿潤剤、乳化剤、浸透圧に影響を与えるための塩、緩衝剤、着色剤、及び/又は芳香剤などの補助剤と混合されてもよい。当業者であれば、他の医薬キャリア及び賦形剤が、開示される化合物との使用に適することは認識される。
本明細書において、一般式(I)、(II)、又は(III)を有する化合物:
式中:
R1は、水素、ハロゲン、−C1−C4−アルキル、−C1−C4−ハロアルキル、−CN、−C1−C4−アルコキシ、−C1−C4−ハロアルコキシ、又は−C3−C6−シ
クロアルキルであり;
Q1は、CH又はNであり;
R2は、水素、ハロゲン、−CN、−C1−C4−アルキル、−C1−C4−ハロアルキル、−C3−C6−シクロアルキル、−C1−C4−アルコキシ、−C1−C4−ハロアルコキシ、−S(C1−C4−アルキル)、−SO2(C1−C4−アルキル)、5又は6員環ヘテロ環、アリール、5員環ヘテロアリール、−≡−R2A、−O(CH2)mR2B、−NH(C1−C4−アルキル)、−N(C1−C4−アルキル)2、又は−C(O)(C1−C4−アルキル)であり、ここで、アリール及びヘテロアリールは、ハロゲン、−OH、−CN、−C1−C4−アルキル、ホルミル、アセチル、アセトキシ、又はカルボキシで置換されていてもよく、並びにここで、mは、1、2、又は3の値を有する整数であり;
xは、1又は2の値を有する整数であり;
R2A及びR2Bは、各々独立して、−C1−C4−アルキル、−C1−C4−ハロアルキル、又は−C3−C6−シクロアルキルであり;
各R20は、独立して、水素、ハロゲン、−C1−C4−アルキル、−CN、又は−C1−C4−アルコキシであり;並びに
R3は、CH3又はCD3である。
第二の実施形態では、化合物は、式(Ia)、(IIa)、又は(IIIa)の構造:
第三の実施形態では、化合物は、式(Iaa)の構造:
第四の実施形態では、化合物は、式(Ib)、(IIb)、又は(IIIb)の構造:
第五の実施形態では、化合物は、式(Ibb)の構造:
第六の実施形態では、化合物は、式(I)〜(III)、(Ia)〜(IIIa)、(Iaa)、(Ib)〜(IIIb)、又は(Ibb)のいずれか1つの構造を有し、式中、R2は、ハロゲン、−C1−C4−アルキル、−C1−C4−ハロアルキル、−C1−C4−ハロアルコキシ、−S(C1−C4−アルキル)、又はフラニルであり、ここで、フラニルは、所望に応じて、−C1−C4−アルキルで置換されていてよく;変数部分の残りは、第一の実施形態で定めた通りである。
(Iaa)、(Ib)〜(IIIb)、又は(Ibb)のいずれか1つの構造を有し、式中、R1は、水素又はハロゲンであり;変数部分の残りは、第一、第六、第七、第八、第九、第十、又は第十一の実施形態で定めた通りである。
式(I)、(II)、及び(III)の化合物を作製する方法が開示される。一般的に、R3が−CH3である式(I)の化合物は、式(IV)の化合物
続いて、式(V)の化合物を、2−メトキシベンジルアミンと反応させることで、式(VI)の化合物が得られ得る。
同様に、式(II)の化合物は、式(VII)の化合物を、(E)−エチル6−ブロモ−4−メチルヘキサ−4−エノエートと反応させて、式(IX)の化合物:
続いて、式(IX)の化合物の加水分解により、式(II)の化合物が得られる。
同様に、式(III)の化合物は、式(VII)の化合物を、(E)−エチル6−ブロモ−2,2−ジメチルヘキサ−4−エノエートと反応させて、式(X)の化合物:
続いて、式(X)の化合物の加水分解により、式(III)の化合物が得られる。
式(I)、(II)、及び(III)の例示的な化合物を作製するための詳細な合成プロトコルは、例2a〜2uに提示される。
対象におけるPPARδ関連疾患又は病状を治療する方法が開示される。これらの方法は、本明細書で提供される1つ以上の化合物又は組成物の治療有効量を対象に投与することを含み得る。
エメリ・ドレフュス型MD、顔面肩甲上腕型MD、ヒアリン体ミオパチー(hyaline body
myopathy)、肢帯型MD、筋肉ナトリウムチャネル障害、筋強直性軟骨ジストロフィー
、筋強直性ジストロフィー、筋細管ミオパチー、ネマリン小体疾患、眼咽頭型MD、及び腹圧性尿失禁が挙げられる。
常リポタンパク質血症、アポリポタンパク質A−I低タンパク血症、アテローム性動脈硬化、動脈硬化の疾患、心血管系の疾患、脳血管疾患、末梢循環疾患、メタボリックシンドローム、シンドロームX、肥満症、糖尿病(I型又はII型)、高血糖症、インスリン抵抗性、耐糖能障害、高インスリン症、糖尿病合併症、心不全、心筋梗塞、心筋症、高血圧
症、非アルコール性脂肪性肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、血栓、アルツハイマー病、神経変性疾患、脱髄性疾患、多発性硬化症、副腎性白質ジストロフィー、皮膚炎、乾癬、ざ瘡、皮膚老化、異所発毛症、炎症、関節炎、喘息、過敏性腸症候群(hypersensitive intestine syndrome)、潰瘍性大腸炎、クローン病、並びに膵炎が挙げられる。
さらなる治療剤
本明細書で提供される1つ以上の化合物(そのような化合物の1、2、3、4、又は5つなど)、並びに典型的には、賦形剤、本開示の治療剤以外の公知の治療剤、及びこれらの組み合わせなどの少なくとも1つの追加の物質を含む医薬組成物が開示される。ある実施形態では、開示されるPPARアゴニストは、開示されるPPARアゴニストと共に有益な活性を有することが公知である他の剤と組み合わせて用いられてもよい。例えば、開示される化合物は、単独で、又はロシグリタゾン、ピオグリタゾン、トログリタゾン、及びこれらの組み合わせを含むチアゾリジンジオン、又はトルブタミド、トラザミド、グリピジド、カルブタミド、グリソキセピド、グリセンチド、グルボルヌリド、グリベンクラミド、グリキドン、グリメピリド、グリクラジド、及びこれらの化合物の医薬的に許容される塩などのスルホニル尿素剤若しくはその医薬的に許容される塩、又はムラグリタザル、ファルグリタザル、ナベグリタザル、ネトグリタゾン、リボグリタゾン、K−111、GW−677954、(−)−ハロフェナート、酸、アラキドン酸、クロフィブラート(clofbrate)、ゲムフィブロジル、フェノフィブラート、シプロフィブラート、ベザフィブラート、ロバスタチン、プラバスタチン、シンバスタチン、メバスタチン、フルバスタチン、インドメタシン、フェノプロフェン、イブプロフェン、及びこれらの化合物の医薬的に許容される塩などの1つ以上の他のPPARアゴニストと組み合わせて投与されてもよい。
代謝異常又は代謝障害に対して有利な効果を有する1つ以上の薬理活性物質との併用療法として投与されてもよい。例えば、開示される医薬組成物は、代謝性疾患及び心血管疾患を治療するための血中ブドウ糖を低下させる医薬であるRXRアゴニスト;Lantus、Apidra、及び他の速効型インスリンを含むインスリン及びインスリン誘導体、並びにGLP−1受容体修飾剤などの抗糖尿病剤;脂質異常症を治療するための活性成分;抗アテローム硬化性医薬;抗肥満剤;抗炎症性活性成分;悪性腫瘍を治療するための活性成分;抗血栓性活性成分;高血圧を治療するための活性成分;心不全を治療するための活性成分、並びにこれらの組み合わせと組み合わせて投与されてもよい。
対象に治療有効量を提供するための化合物の厳密な投与量は、投与のモード、疾患及び/又は病状の種類並びに重篤度に、並びに一般的健康状態、性別、年齢、体重、及び薬物に対する耐性などの対象の特性に依存する。当業者であれば、これらの、及び他の因子に応じて、適切な用量を決定することができる。他の治療剤と組み合わせて投与される場合、追加のいずれの治療剤の「治療有効量」も、用いられる薬物の種類に依存する。承認された治療剤についての適切な用量は知られており、当業者であれば、対象の病状、治療される病状の種類、及び用いられる本発明の化合物の量に応じて、例えば、文献に報告される用量、及びPhysician’s Desk Reference (57th ed., 2003)で推奨される用量に従って調節されてもよい。例えば、治療有効量は、単位剤形で与えられてよい(例:1日あたり0.1mgから約50g)。
例1a
PPARδ活性スクリーニング
細胞培養及びトランスフェクション:CV−1細胞を、DMEM+10%活性炭処理FCS中で増殖させた。トランスフェクションの前日に細胞を384ウェルプレートに播種して、トランスフェクション時に50〜80%のコンフルエントを得た。0.64マイクログラムのpCMX−PPAR Delta LBD、0.1マイクログラムのpCMX.beta.Gal、0.08マイクログラムのpGLMH2004レポーター、及び0.02マイクログラムのpCMX空ベクターを含有する合計で0.8gのDNAを、FuGeneトランスフェクション試薬を用い、製造元の説明書(Roche)に従って各ウェルにトランスフェクトした。細胞に48時間タンパク質を発現させ、続いて化合物を添加した。
れたPPARδアイソフォームのcDNAリガンド結合ドメイン(LBD)(PPARδ
アミノ酸128からC末端まで)を、酵母転写因子GAL4のDNA結合ドメイン(D
BD)に、断片をベクターpCMX GALにインフレームでサブクローニングすること
によって融合させ(Sadowski et al. (1992), Gene 118, 137)、プラスミドpCMX−
PPAR Delta LBDを作製した。得られた融合物を、シークエンシングによって確認した。pCMXMH2004ルシフェラーゼレポーターは、最小真核生物プロモーターの下でGAL4 DNA応答エレメントの複数のコピーを含んでいる(Hollenberg and Evans, 1988)。pCMXβGalを作製した。
Instruments)に従って行った。Perkin Elmer Envisionリーダー上でカウントすることによって発光を定量した。3−ガラクトシダーゼ活性を測定するために、各トランスフェクションライセートからの上清25μLを、新しい384マイクロプレートに移した。マイクロウェルプレート中において、Promega製のキットを用いてベータ−ガラクトシダーゼアッセイを行い、Perkin Elmer Envisionリーダーで読み取った。ベータ−ガラクトシダーゼのデータを用いて、ルシフェラーゼのデータを標準化した(トランスフェクション効率、細胞増殖など)。
薬物動態(PK)スクリーニング(I.V.)
この例では、オスのCD1マウスにおいて、本明細書で開示されるいくつかのPPARδアゴニストの静脈内PKプロファイルを特定した。本明細書で提供される他の化合物の分析にも、同様の方法を用いることができる。化合物はすべて、1mg/kg(i.v.)でCD1マウスに別々に投与したが、但し、以下に記載のように、2cに対する比較化合物は、3mg/kg(i.v.)で投与した。
ariation in liver weight, hepatic blood flow and antipyrine intrinsic clearance in extrapolation of Benzodiazepines and phenytoin. J. Pharmacokinet Biopharm 8: 165-176を参照されたい。
例2
化合物実施形態の合成による作製
略語
Me メチル
Et エチル
nPr n−プロピル
iPr イソプロピル
cPr シクロプロピル
nBu n−ブチル
iBu イソブチル
tBu tert−ブチル
Boc tert−ブチルオキシカルボニル
Ac アセチル
Ph フェニル
Tf トリフルオロメタンスルホニル
Ts 4−メチルフェニルスルホニル
DIAD ジイソプロピルアゾジカルボキシレート
EDCI 3−(3−ジメチルアミノプロピル)−1−エチルカルボジイミド
HOBt 1−ヒドロキシベンゾトリアゾール
HATU 1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート
HBTU N,N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェート
NBS N−ブロモスクシンイミド
DIPEA ジイソプロピルエチルアミン
mCPBA m−クロロ過安息香酸
Togni試薬 3,3−ジメチル−1−(トリフルオロメチル)−1,2−ベンズヨードキソール
DCM ジクロロメタン
DME ジメトキシエタン
DMF N,N−ジメチルホルムアミド
DMF.DMA N,N−ジメチルホルムアミドジメチルアセタール
DMSO ジメチルスルホキシド
TFA トリフルオロ酢酸
THF テトラヒドロフラン
MW マイクロ波照射
aq 水性
M mol/Lで表される濃度
RT 室温
TLC 薄層クロマトグラフィ
HPLC 高速液体クロマトグラフィ
MPLC 中圧液体クロマトグラフィ
LCMS 液体クロマトグラフィ−質量分析
ESI+ エレクトロスプレーイオン化 ポジティブモード
ESI− エレクトロスプレーイオン化 ネガティブモード
1H NMR(DMSO−d6) DMSO−d6中での1H NMRピークのδ(ppm)
s シングレット(スペクトル)
d ダブレット(スペクトル)
t トリプレット(スペクトル)
q カルテット(スペクトル)
dd ダブルダブレット(スペクトル)
br ブロードライン(スペクトル)
m マルチプレット(スペクトル)
例2a:
(R)−3−メチル−6−(2−((5−メチル−2−(4−(トリフルオロメトキシ)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2a)の合成
)をHClガスで3時間、−30℃でパージした。この反応混合物を、再シール可能反応管に移し、室温で12時間混合物を静置した。混合物を、NaOH溶液(4N、3L)で処理し、得られた混合物を、室温でさらに12時間撹拌した。反応の完了後(TLCでモニタリング)、反応混合物を、水(1000mL)で希釈し、ジエチルエーテル(3×1000mL)で洗浄した。水層を希HClで酸性化し(pH4)、その後、ジエチルエーテル(3×1000mL)で抽出した。1つにまとめた有機層を、無水Na2SO4上で乾燥し、減圧濃縮して、表題の化合物を得た(125g、74.8%)。
1H NMR(300MHz,DMSO−d6):δ12.01(s,1H),5.07(t,J=6.9Hz,1H),2.22(dd,J=15.0,6.0Hz,1H),2.03−1.78(m,4H),1.64(s,3H),1.56(s,3H),1.36−1.17(m,2H),0.88(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ5.08(t,J=6.9Hz,1H),4.12(q,J=7.2Hz,2H),2.29(dd,J=14.7,6.0Hz,1H),2.12−2.05(m,1H),1.99−1.94(m,3H),1.66(s,3H),1.58(s,3H),1.39−1.16(m,2H),1.24(t,J=6.9Hz,3H),0.93(d,J=6.6Hz,3H)。
L)で、続いて水(1L)で洗浄した。有機層を、塩水で洗浄し、無水Na2SO4上で乾燥し、減圧濃縮して、表題の化合物を得た(99.5g、92.0%)。
1H NMR(300MHz,CDCl3):δ4.12(q,J=7.2Hz,2H),2.69(t,J=5.4Hz,1H),2.30(dd,J=8.7,1.5Hz1H),2.17−2.09(m,1H),2.04−1.97(m,1H),1.55−1.42(m,4H),1.30(s,3H),1.27(s,3H),1.25(t,J=7.2Hz,3H),0.95(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ9.79(s,1H),4.11(q,J=7.2Hz,2H),2.48−2.43(m,2H),2.27(dd,J=15
,6.6Hz,1H),2.17−2.10(m,1H),2.02−1.96(m,1H),1.72−1.66(m,1H),1.54−1.50(m,1H),1.25(t,J=7.2Hz,3H),0.96(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ4.12(q,J=7.2Hz,2H),3.64(t,J=6.3Hz,2H),2.30(dd,J=14.7,6.6Hz,1H),2.17−2.09(m,1H),2.02−1.96(m,1H),1.67−1.56(m,5H),1.26(t,J=7.2Hz,3H),0.95(d,J=6.6Hz,3H)
工程6:エチル(R)−6−ブロモ−3−メチルヘキサノエートの合成:
mol)のDMF(200mL)中の撹拌溶液を、順にEDCI.HCl(22.24g、116.49mmol)、HOBt(16.01g、116.49mmol)、及びEt3N(20.4mL、145.62mmol)により、窒素雰囲気下、室温で処理した。この反応混合物を、窒素雰囲気下、室温で12時間撹拌した。反応の完了後(TLCでモニタリング)、反応混合物を、氷冷水で希釈し、固体を析出させた。この固体をろ過し、減圧乾燥して、表題の化合物を得た(22.0g、95.4%)。
1H NMR(400MHz,DMSO−d6):δ9.08(brs,1H),7.99(d,J=8.7Hz,2H),7.48(d,J=8.1Hz,2H),4.05−4.03(m,2H),3.14(t,J=2.4Hz,1H)
LCMS(ESI+,m/z):244.2(M+H)+。
1H NMR(300MHz,DMSO−d6):δ7.55(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.28(m,1H),7.05(d,J=8.4Hz,1H),6.91−6.86(m,2H),6.37(d,J=7.5Hz,1H),5.14(s,2H),3.80(s,3H),2.08(s,3H)
19F NMR(300MHz,DMSO−d6):δ−52.03
LCMS(ESI+,m/z):363.6(M+H)+。
19F NMR(300MHz,DMSO−d6):δ−56.76
LCMS(ESI+,m/z):349.3(M+H)+。
LCMS(ESI+,m/z):505.4(M+H)+。
1H NMR(400MHz,DMSO−d6,80℃):δ11.70(brs,1H),7.57(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),7.24(t,J=7.2Hz,1H),7.01(d,J=8.4Hz,1H),6.89(s,1H),6.85(t,J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),5.16(s,2H),4.02(t,J=6.4Hz,2H),2.20(dd,J=14.8,6.0Hz,1H),2.11(s,3H),2.06−2.00(m,1H),1.90−1.88(m,1H),1.75−1.71(m,2H),1.48−1.45(m,1H),1.33−1.29(m,1H),0.91(d,J=6.8Hz,3H)
19F NMR(400MHz,DMSO−d6):δ−56.80
LCMS(ESI+,m/z):477.8(M+H)+
HPLC:98.19%(210nm)。
(R)−6−(2−((2−(4−クロロフェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2b)の合成
収率:4.52g(73.0%)
1H NMR(400MHz,DMSO−d6):δ9.21(brs,1H),7.85(d,J=8.8Hz,2H),7.53(d,J=8.8Hz,2H),4.04−4.02(m,2H),3.12(t,J=2.8Hz,1H)
LCMS(ESI+,m/z):194.0,196.0(M+H)+。
1H−イミダゾールの合成:
収率:0.81g(51.1%)
1H NMR(400MHz,CDCl3):δ7.41(d,J=8.8Hz,2H),7.30−725(m,3H),6.98(s,1H),6.93−6.88(m,2H),6.58(d,J=7.2Hz,1H),5.09(s,2H),3.86(s,3H),2.11(s,3H),
LCMS(ESI+,m/z):313.1,315.1(M+H)+。
収率:0.62g(81.15%)
LCMS(ESI+,m/z):299.3,301.3(M+H)+。
収率:0.321g(35.1%)
LCMS(ESI+,m/z):454.5,456.5(M+H)+。
収率:0.05g(18%)
1H NMR(400MHz,DMSO−d6,80℃):δ7.48(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),7.24(t,J=7.6Hz,1H),7.00(d,J=8.4Hz,1H),6.88(s,1H),6.84(t,J=7.6Hz,1H),6.51(d,J=7.2Hz,1H),5.14(s,2H),3.99(t,J=5.6Hz,2H),2.19−2.16(m,1H),2.09(s,3H),2.06−2.00(m,1H),1.93−1.86(m,1H),1.72−1.67(m,2H),1.45−1.42(m,1H),1.32−1.26(m,1H),0.91(d,J=6.4Hz,3H)
LCMS(ESI+,m/z):427.2,429.2(M+H)+
HPLC:95.84%(210nm)。
(R)−6−(2−((2−(4−(フラン−2−イル)フェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2c)の合成:
LCMS(ESI+,m/z):487.3(M+H)+。
収率:0.04g(23.6%)
1H NMR(400MHz,DMSO−d6,80℃):δ7.68(d,J=8.8Hz,2H),7.65(s,1H),7.50(d,J=8.8Hz,2H),7.24(t,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),6.90−6.84(m,3H),6.57−6.56(m,1H),6.48(d,J=8.4Hz,1H),5.18(s,2H),4.02(d,J=6.0Hz,2H),2.19−2.15(m,1H),2.10(s,3H),2.04−1.98(m,1H),1.91−1.86(m,1H),1.72−1.70(m,2H),1.47−1.42(m,1H),1.31−1.29(m,1H),0.89(d,J=6.8Hz,3H)
LCMS(ESI+,m/z):459.2(M+H)+
HPLC:97.50%(210nm)。
(R)−3−メチル−6−(2−((5−メチル−2−(4−(トリフルオロメチル)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2d)の合成
1H NMR(300MHz,CDCl3):δ7.90(d,J=8.1Hz,2H),7.71(d,J=8.8Hz,2H),6.47(brs,1H),4.28−4.62(m,2H),3.12(t,J=2.4Hz,1H)
LCMS(ESI+,m/z):228.2(M+H)+。
1H NMR(400MHz,CDCl3):δ7.59−7.54(m,4H),7.30−7.23(m,1H),7.00(s,1H),6.91−6.86(m,2H),6.57(d,J=7.2Hz,1H),5.11(s,2H),3.84(s,3H),2.11(s,3H)
LCMS(ESI+,m/z):347.3(M+H)+。
1H NMR(400MHz,DMSO−d6):δ9.99(s,1H),7.88(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.33(s,1H),7.14−7.10(m,1H),6.83(d,J=8.0Hz,1H),6.74−6.70(m,1H),6.55(d,J=6.8Hz,1H),5.21(s,2H),2.16(s,3H)
LCMS(ESI+,m/z):333.3(M+H)+。
LCMS(ESI+,m/z):489.3(M+H)+。
1H NMR(400MHz,DMSO−d6):δ12.00(brs,1H),7.71(d,J=8.4Hz,2H),7.62(d,J=8.4Hz,2H),7.26−7.21(m,1H),7.01(d,J=8.4Hz,1H),6.93(s,1H),6.86−6.83(m,1H),6.38(d,J=6.8Hz,1H),5.16(s,2H),3.98(t,J=6.0Hz,2H),2.19−2.14(m,1H),2.08(s,3H),1.99−1.93(m,1H),1.84−1.76(m,1H),1.67−1.65(m,2H),1.45−1.42(m,1H),1.28−1.18(m,1H),0.83(d,J=6.4Hz,3H)19F NMR(400MHz,DMSO−d6):δ−56.4
LCMS(ESI+,m/z):460.8(M+H)+
HPLC:98.89%(210nm)。
以下で詳細に述べるように、異なる結晶化実験から、様々な形態の化合物2dを形成することができる。
化合物2dを、50℃の酢酸エチル、50℃の2−プロパノール、25℃のアセトン、25℃の水、25℃の水/メタノール、又は25℃のエタノール中でスラリー化することによって、化合物2dの新規な形態Bを得た。
化合物2dを、50℃のアセトニトリル、4℃の水/アセトニトリル、及び4℃の2−メチルテトラヒドロフラン中でスラリー化することによって、化合物2dの新規な形態Cを得た。
化合物2dを、50℃のシクロペンチルメチルエーテル、25℃のトルエン中でスラリー化することによって、及びジクロロメタンからの蒸発結晶化によって、化合物2dの新規な形態Dを得た。
化合物2dを、25℃のメタノール中でスラリー化することによって、化合物2dの新規な形態Eを得た。
50mLのバイアル中、883.2mgの化合物2dを、35mLのメタノールに溶解した。次に、H2SO4(1920μL、H2O中の1M、1当量)をピペットで添加した。溶媒をN2下で蒸発させた。蒸発後、2−プロパノール(18mL)をピペットで添加し、続いてスターラーバーを入れた。バイアルの蓋を閉め、50℃のスターラープレート上に1時間置き、次に温度を25℃に低下させ、その間、撹拌を1日行った。1日後、固体を真空ろ過し、風乾させた。
1H NMR(400MHz,DMSO−d6):δ7.85(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.36(s,1H),7.27(t,J=8.4Hz,1H),7.02(d,J=8.4Hz,1H),6.85(t,J=7.6Hz,1H),6.62(d,J=7.2Hz,1H),5.26(s,2H),3.96(t,J=6.0Hz,2H),2.21−2.16(m,4H),1.96(dd,J=8.0,15.2Hz,1H),1.83−1.80(m,1H),1.67−1.59(m,2H),1.35−1.31(m,1H),1.28−1.18(m,1H),0.85(d,J=6.4Hz,3H)
質量スペクトル(ESI)m/e 461.2
元素分析:計算値:C 58.93%;H 5.54%;N 5.50%;S 3.15。測定値:C 58.30%;H 5.36%;N 5.42%;S 3.47。
化合物2dのヘミ硫酸塩の形態1のおよそ90から110mgを秤量し、4mLの琥珀ガラスバイアルへ移し、続いて、0.8mLのメタノール及びマグネティックスターラーバーを入れた。バイアルをシールし、25℃に設定した温度制御スターラープレート上に置き、500rpmで15日間撹拌した。この実験から、化合物2dのヘミ硫酸塩の形態2として識別された固体単離物が得られ、詳細には、XRPDによって同定された。
(E)−4−メチル−6−(2−((5−メチル−2−(4−(トリフルオロメトキシ)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサ−4−エン酸(化合物2e)の合成
収率:0.180g
LCMS(ESI+,m/z):489.4(M+H)+。
1H NMR(400MHz,DMSO−d6):δ7.69(d,J=8.8Hz,2H),7.49(d,J=8.4Hz,2H),7.44(s,1H),7.26(t,J=7.6Hz,1H),7.01(d,J=8.0Hz,1H),6.83(t,J=7.2Hz,1H),6.72(d,J=6.8Hz,1H),5.33−5.28(m,3H),4.52(d,J=6.4Hz,2H),2.34−2.27(m,4H),2.22(s,3H),1.66(s,3H)
19F NMR(400MHz,DMSO−d6):δ−56.77
LCMS(ESI+,m/z):475.3(M+H)+
HPLC:95.75%(210nm)。
(R)−3−メチル−6−(2−((5−メチル−2−(p−トリル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2f)の合成:
1H NMR(400MHz,CDCl3):δ7.37(d,J=8.4Hz,2H),7.29(d,J=7.8Hz,1H),7.14(d,J=8.4Hz,2H),6.97(s,1H),6.91(d,J=8.1Hz,2H),6.62(d,J=7.2Hz,1H),5.12(s,2H),3.84(s,3H),2.34(s,3H),2.10(s,3H)。
メチル)フェノールの合成:
収率:0.23g
LCMS(ESI+,m/z):279.3(M+H)+。
収率:0.21g(58.4%)
LCMS(ESI+,m/z):436.5(M+H)+。
/分;移動相:A/B=0.1%TFA水溶液/MeCN;T/%B=0/30、2/40、8/80]によって精製した。
収率:0.029g(15.5%)
1H NMR(400MHz,DMSO−d6,80℃):δ7.34(d,J=8.0Hz,2H),7.25−7.22(m,1H),7.16(d,J=8.0Hz,2H),7.00(d,J=8.0Hz,1H),6.87−6.84(m,2H),6.48(brs,1H),5.13(s,2H),4.04(t,J=6.4Hz,2H),2.30(s,3H),2.14−2.13(m,1H),2.07(s,3H),2.05−1.99(m,1H),1.91−1.86(m,1H),1.71−1.69(m,2H),1.48−1.40(m,1H),1.35−1.23(m,1H),0.91(d,J=8.0Hz,3H)
LCMS(ESI+,m/z):407.1(M+H)+
HPLC:99.28%(210nm)。
(R)−6−(2−((2−(4−フルオロフェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2g)の合成
収率:4.25g(67.22%)
1H NMR(300MHz,CDCl3):δ7.82−7.77(m,2H),7.12(t,J=8.4Hz,2H),6.21(bs,1H),4.26−4.23(m,2H),2.29(t,J=2.8Hz,1H)。
収率:3.51g(69.9%)
1H NMR(300MHz,CDCl3):δ7.46−7.41(m,2H),7.30(d,J=8.1Hz,1H),7.04−6.87(m,5H),6.58(d,J=7.2Hz,1H),5.08(s,2H),3.85(s,3H),2.11(s,3H)
19F NMR(300MHz,CDCl3):δ−113.0
LCMS(ESI+,m/z):297.3(M+H)+。
収率:2.7g(81.1%)
LCMS(ESI+,m/z):283.3(M+H)+。
収率:0.62g
LCMS(ESI+,m/z):439.4(M+H)+。
収率:0.111g(18.9%)
1H NMR(400MHz,DMSO−d6,80℃):δ7.50−7.47(m,2H),7.28−7.16(m,3H),7.03(d,J=8.0Hz,1H),6.89−6.85(m,2H),6.46(d,J=7.2Hz,1H),5.14(s,2H),4.03(t,J=5.6Hz,2H),2.24−2.20(m,1H),2.11(s,3H),2.08−2.03(m,1H),1.95−1.90(m,1H),1.80−1.67(m,2H),1.50−1.42(m,1H),1.38−1.28(m,1H),0.93(d,J=6.8Hz,3H).
19F NMR(400MHz,DMSO−d6):δ−113.00
LCMS(ESI+,m/z):411.4(M+H)+
HPLC:99.3%(210nm)。
6−(2−((2−(3−フルオロ−4−(トリフルオロメチル)フェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−2,2−ジメチルヘキサン酸(化合物2h)の合成:
収率:4.71g(79.7%)
1H NMR(400MHz,DMSO−d6):δ9.25(t,J=5.2Hz,1H),7.93−7.83(m,3H),4.07−4.05(m,2H),3.16(t,J=2.4Hz,1H)
19F NMR(400MHz,DMSO−d6):δ:−115.11,−60.32LCMS(ESI+,m/z):246.1(M+H)+。
収率:2.3g(61.8%)
1H NMR(400MHz,DMSO−d6):δ7.78(t,J=7.8Hz,1H),7.52(d,J=12.3Hz,1H),7.45(d,J=8.4Hz,1H),7.30−7.24(m,1H),7.04(d,J=7.8Hz,1H),6.96(s,1H),6.88−6.83(m,1H),6.38(d,J=7.5Hz,1H),5.21(s,2H),3.78(s,3H),2.10(s,3H)
19F NMR(400MHz,DMSO−d6):δ:−115.36,−59.90LCMS(ESI+,m/z):365.0(M+H)+。
収率:1.1g(未精製)
LCMS(ESI+,m/z):351.2(M+H)+。
収率:0.31g(41.81%)
LCMS(ESI+,m/z):520.7(M+H)+。
収率:0.120g(46.4%)
1H NMR(400MHz,DMSO−d6,80℃):δ7.73(t,J=8.4Hz,1H),7.49−7.45(m,2H),7.26(m,J=7.6Hz,1H),7.04(d,J=8.4Hz,1H),6.96(s,1H),6.86(t,J=7.6Hz,1H),6.46(d,J=7.2Hz,1H),5.23(s,2H),4.03(t,J=6.4Hz,2H),2.14(s,3H),1.71−1.67(m,2H),1.53−1.49(m,2H),1.41−1.36(m,2H),1.06(s,6H)
19F NMR(400MHz,DMSO−d6):δ−115.25,−59.87
LCMS(ESI+,m/z):493.3(M+H)+
HPLC:97.62%(210nm)。
6−(2−((2−(4−クロロ−3−フルオロフェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−2,2−ジメチルヘキサン酸(化合物2i)の合成
収率:5.2g(85.5%)
1H NMR(400MHz,DMSO−d6):δ9.09(t,J=5.2Hz,1H),7.82(dd,J=10.0,0.8Hz,1H),7.72−7.69(m,
2H),4.04−4.02(m,2H),3.13(t,J=2.4Hz,1H)
19F NMR(400MHz,DMSO−d6):δ:−115.48
LCMS(ESI+,m/z):212.0,214.0(M+H)+。
収率:1.3g(23.7%)
1H NMR(300MHz,CDCl3):δ7.36−7.28(m,3H),7.21−7.17(m,1H),6.99(brs,1H),6.95−6.88(m,2H),6.56(d,J=8.1Hz,1H),5.11(s,2H),3.87(s,3H),2.13(s,3H)
19F NMR(400MHz,DMSO−d6):δ−114.79
LCMS(ESI+,m/z):330.7,332.7(M+H)+。
収率:1.1g(88.7g)
LCMS(ESI+,m/z):317.0,319.0(M+H)+。
ル−1H−イミダゾール−1−イル)メチル)フェノキシ)−2,2−ジメチルヘキサノエートの合成:
収率:0.25g(46.3%)
LCMS(ESI+,m/z):486.9,488.9(M+H)+。
収率:0.070g(29.8%)
1H NMR(400MHz,DMSO−d6,80℃):δ12.02(brs,1H),7.59(t,J=8.0Hz,1H),7.38(d,J=10.8Hz,1H),7.28−7.24(m,2H),7.05(d,J=8.4Hz,1H),6.93(s,1H),6.87(t,J=7.6Hz,1H),6.38(d,J=7.6Hz,1H),5.15(s,2H),4.02(t,J=6.0Hz,2H),2.10(s,3H),1.69−1.65(m,2H),1.50−1.46(m,2H),1.41−1.33(m,2H),1.08(s,6H)
19F NMR(400MHz,DMSO−d6):δ−110.89
LCMS(ESI+,m/z):459.2,461.2(M+H)+
HPLC:98.95%(210nm)。
(R)−6−(2−((2−(4−クロロ−3−フルオロフェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2j)の合成:
ロ−3−フルオロフェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノール(0.350g、1.11mmol)及びエチル(R)−6−ブロモ−3−メチルヘキサノエート(0.784g、3.32mmol)から合成した。
収率:0.15g(28.6%)
LCMS(ESI+,m/z):472.9,474.9(M+H)+。
収率:0.115g(81.5%)
1H NMR(400MHz,DMSO−d6,80℃):δ12.02(brs,1H),7.61(t,J=8.0Hz,1H),7.43(d,J=10.8Hz,1H),7.29−7.24(m,2H),7.04(d,J=8.4Hz,1H),6.99(s,1H),6.86(t,J=7.6Hz,1H),6.43(d,J=7.6Hz,1H),5.18(s,2H),4.00(t,J=6.4Hz,2H),2.23−2.18(m,1H),2.11(s,3H),2.02−1.99(m,1H),1.89−1.80(m,1H),1.75−1.64(m,2H),1.45−1.35(m,1H),1.31−1.25(m,1H),0.87(d,J=6.8Hz,3H)19F NMR(400MHz,DMSO−d6):δ−115.50
LCMS(ESI+,m/z):445.2,447.2(M+H)+
HPLC:97.30%(210nm)。
(R)−6−(4−フルオロ−2−((5−メチル−2−(4−(トリフルオロメチル)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2k)の合成
収率:0.901g(56.3%)
LCMS(ESI+,m/z):365.6(M+H)+。
収率:0.3g(未精製)
LCMS(ESI+,m/z):350.9(M+H)+。
収率:0.2g(46.2%)
LCMS(ESI+,m/z):507.5(M+H)+。
収率:0.06g(63.4%)
1H NMR(400MHz,DMSO−d6):δ12.08(brs,1H),7.76(d,J=8.0Hz,2H),7.67(d,J=7.6Hz,2H),7.08(d,J=8.4Hz,2H),6.97(s,1H),6.14(brs,1H),5.18(s,2H),3.97(brs,2H),2.25−2.13(m,1H),2.13(s,3H),2.02−1.97(m,1H),1.86−1.82(m,1H),1.75−1.62(m,2H),1.45−1.35(m,1H),1.29−1.19(m,1H),0.86(d,J=6.4Hz,3H)
19F NMR(400MHz,DMSO−d6):δ−123.14,−61.17
LCMS(ESI+,m/z):478.8(M+H)+
HPLC:94.6%(210nm)。
(R)−6−(2−((2−(4−(ジフルオロメトキシ)フェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2l)の合成
収率:1.61g(66.9%)
1H NMR(300MHz,DMSO−d6):δ8.97(t,J=5.1Hz,1H),7.92(d,J=8.7Hz,2H),7.36(t,J=73.8Hz,1H),7.26(d,J=8.7Hz,2H),4.07−4.04(m,2H),3.14(t,J=2.4Hz,1H)
LCMS(ESI+,m/z):226.0(M+H)+。
収率:2.5g(未精製)
LCMS(ESI+,m/z):349.3,351.3(M+H)+。
LCMS(ESI+,m/z):441.2(M+H)+。
0%EtOAc)を用いて精製して、表題の化合物を得た(0.33g、97.9%)。LCMS(ESI+,m/z):331.4(M+H)+。
収率:0.25g(51.4%)
LCMS(ESI+,m/z):487.6(M+H)+。
収率:0.05g(53.2%)
1H NMR(400MHz,DMSO−d6):δ7.50(d,J=8.8Hz,2H),7.24(t,J=7.6Hz,1H),7.16(d,J=8.8Hz,2H),7.14(d,J=74.0Hz,1H),7.01(d,J=8.8Hz,1H),6.87−6.83(m,2H),6.46(d,J=7.6Hz,1H),5.15(s,2H),4.01(t,J=6.4Hz,2H),2.23−2.18(m,1H),2.09(s,3H),2.08−2.02(m,1H),1.93−1.88(m,1H),1.75−1.69(m,2H),1.49−1.43(m,1H),1.33−1.27(m,1H),0.93(d,J=6.4Hz,3H)
19F NMR(400MHz,DMSO−d6):δ−82.36
LCMS(ESI+,m/z):458.9(M+H)+
HPLC:95.49%(210nm)。
(R)−3−メチル−6−(4−メチル−2−((5−メチル−2−(4−(トリフルオロメトキシ)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2m)の合成
収率:0.35g(32.3%)
1H NMR(300MHz,CDCl3):δ7.51(d,J=6.9Hz,2H),7.17(d,J=8.0Hz,2H),7.09(d,J=8.1Hz,1H),6.98(s,1H),6.81(d,J=8.1Hz,1H),6.38(s,1H),5.08(s,2H),3.83(s,3H),2.19(s,3H),2.12(s,3H)
LCMS(ESI+,m/z):377.3(M+H)+。
収率:0.22g(65.4%)
LCMS(ESI+,m/z):363.3(M+H)+。
収率:0.14g(98.5%)
LCMS(ESI+,m/z):519.0(M+H)+。
収率:0.01g(10.6%)
1H NMR(400MHz,DMSO−d6,90℃):δ7.57(d,J=8.4Hz,2H),7.27(d,J=8.0Hz,2H),6.99(d,J=8.0Hz,1H),6.85−6.82(m,2H),6.36(s,1H),5.09(s,2H),3.89(d,J=4.8Hz,2H),2.09(s,6H),2.08−2.03(m,2H),1.86−1.82(m,1H),1.60−1.59(m,2H),1.38−1.18(m,2H),0.87(d,J=6.4Hz,3H)
LCMS(ESI+,m/z):490.8(M+H)+
HPLC:95.7%(210nm)。
(R)−3−メチル−6−(2−((5−メチル−2−(6−(トリフルオロメチル)ピリジン−3−イル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2n)の合成
1H NMR(300MHz,CDCl3):δ9.08(d,J=2.1Hz,1H),8.32(dd,J=8.4,2.4Hz,1H),7.78(d,J=7.8Hz,1H),6.62(brs,1H),4.30−4.28(m,2H),2.33(t,J=2.4Hz,1H)
LCMS(ESI+,m/z):229.2(M+H)+。
収率:0.8g(52.6%)
1H NMR(400MHz,CDCl3):δ8.79(s,1H),8.07(d,J=8.1Hz,1H),7.68(d,J=8.1Hz,1H),7.31(t,J=8.4Hz,1H),7.09(s,1H),6.94−6.87(m,2H),6.56(d,J=7.5Hz,1H),5.16(s,2H),3.87(s,3H)
LCMS(ESI+,m/z):348.3(M+H)+。
収率:0.5g(65.1%)
1H NMR(400MHz,DMSO−d6):δ9.92(s,1H),8.83(s,1H),8.12(d,J=8.1Hz,1H),7.94(d,J=8.1Hz,1H),7.12(d,J=6.9Hz,1H),7.02(s,1H),6.87(d,J=7.8Hz1H),6.73(t,J=7.2Hz,1H),6.37(d,J=7.2Hz,1H),5.20(s,2H),2.15(s,3H)
LCMS(ESI+,m/z):334.3(M+H)+。
収率:0.45g(61.3%)
LCMS(ESI+,m/z):491.0(M+H)+。
収率:0.166g(39.2%)
1H NMR(400MHz,DMSO−d6):δ11.96(brs,1H),8.79(s,1H),8.05(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.24(t,J=7.6Hz,1H),7.02(d,J=8.4Hz,1H),7.00(s,1H),6.84(t,J=7.6Hz,1H),6.43(d,J=7.2Hz,1H),5.21(s,2H),3.98(t,J=6.0Hz,2H),2.19−2.14(m,1H),2.13(s,3H),2.03−1.94(m,1H),1.85−1.80(m,1H),1.68−1.66(m,2H),1.38−1.36(m,1H),1.28−1.18(m,1H),0.85(d,J=6.4Hz,3H)
19F NMR(400MHz,DMSO−d6):δ−66.46
LCMS(ESI+,m/z):462.3(M+H)+
HPLC:95.11%(210nm)。
2つの別々の方法を用いて、化合物2nのメグルミン塩を作製した。
方法1
化合物2n(102.7mg)を、メグルミン(43.7mg)及び2mLの2−プロパノールと、4mLのガラスバイアル中で混合した。バイアルを蓋でシールし、内容物を、25℃で20分間の超音波処理に掛け、続いて、50℃で60分間撹拌した。次に、バイアルを新たな撹拌プレートに移し、バイアル中のスラリーを25℃で撹拌した。
化合物2n(102.2mg)を、メグルミン(43.2mg)及び2mLのアセトニトリルと、4mLのガラスバイアル中で混合した。バイアルを蓋でシールし、内容物を、25℃で20分間の超音波処理に掛け、続いて、50℃で60分間撹拌した。次に、バイアルを新たな撹拌プレートに移し、バイアル中のスラリーを25℃で撹拌した。
化合物2nのメグルミン塩の水和物の作製
500mLの丸底フラスコ中、((R)−3−メチル−6−(2−((5−メチル−2−(6−(トリフルオロメチル)ピリジン−3−イル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(20g、43.33mmol)のTHF(100mL)及び水(100mL)中の撹拌溶液を、メグルミン(8.45g、43.33mmol)により0℃で処理した。得られた反応混合物を、室温で6時間撹拌した。反応混合物を減圧濃縮し、得られた固体を減圧乾燥して(3時間)、表題の化合物を白色固体として得た(28.5g、98.95%)。
1H NMR(400MHz,CD3OD):δ8.75(s,1H),8.02(d,J=8.4Hz,1H),7.82(d,J=8.0Hz1H),7.26(t,J=8.4Hz,1H),7.03(s,1H),6.99(d,J=8Hz,1H),6.85(t,J=7.6Hz,1H),6.50(d,J=7.6Hz,1H),5.25(s,2H),4.09−3.99(m,3H),3.97−3.77(m,2H),3.74−3.61(m,3H),3.29−3.06(m,2H),2.64(s,3H),2.22(s,3H),2.18−2.14(m,1H),1.99−1.94(m,2H),1.83−1.75(m,2H),1.51−1.38(m,1H),1.32−1.22(m,1H),0.86(d,J=6.0Hz,3H)
19F NMR(400MHz,CD3OD):δ−69.39
元素分析:C31H43F3N4O8.H2Oに対する計算値:C,55.18;H,6.72;N,8.30.測定値:C,54.95;H,6.89;N,8.07
水分含有量(カールフィッシャー):2.33%。
(R)−6−(2−((2−(4−(ジフルオロメチル)フェニル)−5−メチル−1H−イミダゾール−1−イル)メチル)フェノキシ)−3−メチルヘキサン酸(化合物2o)の合成
収率:1.5g(62.5%)
1HNMR(400MHz,CDCl3):δ7.88(d,J=8.0Hz,2H),7.60(d,J=8.0Hz,2H),6.70(t,J=56.0Hz,1H),6
.47(brs,1H),4.29−4.27(m,2H),2.31(t,J=2.4Hz,1H)。
収率:2.3g(43.3%)
1H NMR(300MHz,CDCl3):δ7.65(dd,J=7.8,1.2Hz,1H),7.55−7.48(m,4H),7.32−7.19(m,2H),7.04(m,1H),6.64(t,J=56.0Hz,1H),6.63−6.62(m,1H),5.16(s,2H),2.13(s,3H)
LCMS(ESI+,m/z):376.8,378.8(M+H)+。
収率:0.18g(32.2%)
1H NMR(300MHz,CDCl3):δ7.92(dd,J=7.2,1.5Hz,1H),7.59(d,J=8.4Hz,2H),7.46(d,J=8.1Hz,2H),7.42−7.36(m,1H),7.32−7.26(m,1H),7.02(bs,1H),6.75(d,J=7.8Hz,1H),6.62(t,J=56.1Hz,1H),5.48(s,2H),2.11(s,3H),1.31−1.23(s,12)19F NMR(300MHz,CDCl3):δ−111.02
LCMS(ESI+,m/z):424.0(M+H)+。
収率:0.12g(44.4%)
LCMS(ESI+,m/z):314.7(M+H)+。
収率:0.13g(未精製)
LCMS(ESI+,m/z):471.1(M+H)+。
収率:0.091g(32.3%)
1H NMR(400MHz,DMSO−d6):δ12.03(s,1H),7.57(bs,4H),7.26−7.23(m,1H),7.04−7.01(m,1H),7.02(t,J=56.0Hz,1H),6.93(s,1H),6.90−6.84(m,1H),6.39−6.37(m,1H),5.16(s,2H),3.99(t,J=6.4Hz,2H),2.19−2.17(m,1H),2.09(s,3H),2.02−1.97(m,1H),1.86−1.84(m,1H),1.70−1.62(m,2H),1.45−1.42(m,1H),1.28−1.18(m,1H),0.87(d,J=6.4Hz,2H)
19F NMR(400MHz,DMSO−d6):δ−110.00
LCMS(ESI+,m/z):443.0(M+H)+
HPLC:95.65%(210nm)。
(R)−3−メチル−6−(2−((5−メチル−2−(4−(メチルチオ)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2p)の合成
収率:13.81g(94.5%)
1H NMR(300MHz,CDCl3):δ7.70(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),6.32(brs,1H),4.26−4.24(m,2H),2.51(s,3H),2.29(t,J=2.7Hz,1H)
LCMS(ESI+,m/z):206.3(M+H)+。
収率:4.38g(80.3%)
LCMS(ESI+,m/z):372.9,374.9(M+H)+。
収率:2.1g
LCMS(ESI+,m/z):421.2(M+H)+。
収率:0.530g
LCMS(ESI+,m/z):311.4(M+H)+。
収率:0.43g
LCMS(ESI+,m/z):467.3(M+H)+。
収率:0.075g(25.7%)
1H NMR(400MHz,DMSO−d6,90℃):δ7.38(d,J=8.4Hz,2H),7.26−7.22(m,3H),7.02(d,J=8.4Hz,1H
),6.88−6.84(m,2H),6.42(d,J=7.6Hz,1H),5.14(s,2H),4.03(t,J=6.4Hz,2H),2.47(s,3H),2.24−2.18(m,1H),2.06(s,3H),2.04−1.99(m,1H),1.92−1.89(m,1H),1.76−1.70(m,2H),1.49−1.43(m,1H),1.35−1.26(m,1H),0.92(d,J=6.8Hz,3H)
LCMS(ESI+,m/z):439.0(M+H)+
HPLC:98.5%(210nm)。
2,2−ジメチル−6−(2−((5−メチル−2−(4−(トリフルオロメチル)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2q)の合成
収率:0.121g
LCMS(ESI+,m/z):502.7(M+H)+。
収率:0.04g(35.0%)
1H NMR(400MHz,DMSO−d6):δ7.71−7.66(m,4H),7.26−7.22(m,1H),7.02(d,J=8.0Hz,1H),6.94(s,1H),6.86(t,J=7.6Hz,1H),6.45(d,J=7.6Hz,1H),5.20(s,2H),4.03(t,J=6.4Hz,2H),2.12(s,3H),1.71−1.54(m,2H),1.52−1.49(m,2H),1.41−1.34(m,2H),1.07(s,6H)
19F NMR(400MHz,DMSO−d6):δ−61.16
LCMS(ESI+,m/z):474.8(M+H)+
HPLC:98.49%(210nm)。
(R)−3−メチル−6−(2−((5−(メチル−d3)−2−(4−(トリフルオロメチル)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2r)の合成
1H NMR(300MHz,DMSO−d6):δ8.02(d,J=8.1Hz,2H),7.81(d,J=8.1Hz,2H),3.64(s,4H)
19F NMR(300MHz,DMSO−d6):δ−66.22
LCMS(ESI+,m/z):215.2(M+H)+
HPLC(210nm):90.59%。
1H NMR(400MHz,DMSO−d6):δ12.81(brs,1H),8.14(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),7.23(s,2H)
19F NMR(400MHz,DMSO−d6):δ−60.98
LCMS(ESI+,m/z):213.0(M+H)+。
1H NMR(300MHz,DMSO−d6):δ7.80(brs,4H),7.30−7.26(m,2H),7.10(s,1H),7.01(d,J=8.1Hz,1H),6.89(t,J=6.9Hz,1H)6.75(dd,J=7.5,1.8Hz,1H),5.29(s,2H),3.68(s,3H)
19F NMR(300MHz,DMSO−d6):δ−61.10
LCMS(ESI+,m/z):333.2(M+H)+。
1H NMR(400MHz,CDCl3):δ7.59(s,4H),7.33−7.29(m,1H),7.27(s,1H),6.93−6.90(m,2H),6.62(d,J=8.0Hz,1H),5.24(s,2H),3.85(s,3H)
LCMS(ESI+,m/z):410.5(M+H)+。
滴下することによって処理した。この反応混合物を、室温で3時間撹拌した。反応の完了後(TLCでモニタリング)、反応混合物を、NaHCO3水溶液で塩基性化し(約pH9)、得られた固体をろ過し、n−ヘキサン(3×5mL)で洗浄した。この固体生成物を、減圧乾燥して、表題の化合物を得た(12mg)。この粗物質を、さらなる精製を行わずに次の工程で用いた。
LCMS(ESI+,m/z):336.3(M+H)+。
LCMS(ESI+,m/z):492.4(M+H)+。
1H NMR(300MHz,DMSO−d6):δ12.00(brs,1H),7.74(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.28−7.23(m,1H),7.04(d,J=8.1Hz,1H),6.95(s,1H),6.89−6.84(m,1H),6.40(d,J=7.5Hz,1H),5.18(s,2H),4.01(t,J=6.6Hz,2H),2.27−2.16(m,1H),2.03−1.95(m,1H),1.84−1.76(m,1H),1.67−1.65(m,2H),1.45−1.38(m,1H),1.28−1.23(m,1H),0.85(d,J=6.6Hz,3H)
19F NMR(300MHz,DMSO−d6):δ−61.11
2D NMR(600MHz,CD3OD):δ2.04
LCMS(ESI+,m/z):464.4(M+H)+
HPLC:98.21%(210nm)。
(S)−3−メチル−6−(2−((5−メチル−2−(4−(トリフルオロメチル)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2s)の合成
5.0mmol)の溶液を、水(100mL)中のAgNO3(25.2g、149.0mmol)により、0℃で処理した。この反応混合物を、暗所で30分間撹拌し、(3S)−3,7−ジメチルオクタ−6−エナール(10.0g、65.0mmol)により、0℃で処理した。反応混合物を、室温で18時間撹拌した。反応の完了後(TLCでモニタリング)、反応混合物を、セライト(登録商標)パッドでろ過し、熱水で洗浄した。1つにまとめたろ液を、濃HClで酸性化し(pH2)、ジエチルエーテルで抽出した。有機抽出物を、無水Na2SO4上で乾燥し、減圧濃縮した。得られた残渣を、さらなる精製を行わずに次の工程で用いた。
収率:10.0g(90.9%)
1H NMR(400MHz,CDCl3):δ8.8(brs,1H),5.09(t,J=7.2Hz,1H),2.39−2.34(dd,J=15.0,6.0Hz,1H),2.17−2.12(dd,J=15.0,6.0Hz,1H),2.03−1.94(m,3H),1.67(s,3H),1.59(s,3H),1.36−1.17(m,2H),0.97(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ5.08(t,J=6.9Hz,1H),4.12(q,J=7.2Hz,2H),2.29(dd,J=14.7,6.0Hz,1H),2.12−2.05(m,1H),1.99−1.94(m,3H),1.67(s,3H),1.59(s,3H),1.39−1.16(m,2H),1.24(t,J=6.9Hz,3H),0.93(d,J=6.6Hz,3H)。
1H NMR(400MHz,CDCl3):δ4.11(q,J=7.2Hz,2H),2.69(t,J=5.4Hz,1H),2.30(dd,J=8.7,1.5Hz,1H),2.17−2.09(m,1H),2.04−1.98(m,1H),1.55−1.42(m,4H),1.30(s,3H),1.27(s,3H),1.25(t,J=7.2Hz,3H),0.96(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ9.79(s,1H),4.16−4.07(m,2H),2.48−2.43(m,2H),2.27(dd,J=15,6.6Hz,1H),2.17−2.10(m,1H),2.02−1.96(m,1H),1.72−1.66(m,1H),1.54−1.50(m,1H),1.25(t,J=7.2Hz,3H),0.95(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ4.15−4.07(m,2H),3.65(t,J=6.3Hz,2H),2.30(dd,J=14.7,6.6Hz,1H),2.17−2.09(m,1H),2.02−1.96(m,1H),1.67−1.56(m,5H),1.26(t,J=7.2Hz,3H),0.93(d,J=6.6Hz,3H)。
ートの合成:
1H NMR(300MHz,CDCl3):δ4.23−4.09(m,4H),3.00(s,3H),2.32−2.11(m,2H),2.02−1.96(m,1H),1.78−1.72(m,2H),1.46−1.41(m,2H),1.26(t,J=7.2Hz,3H),0.96(d,J=6.6Hz,3H)。
1H NMR(300MHz,CDCl3):δ7.90(d,J=8.1Hz,2H),7.71(d,J=8.8Hz,2H),6.47(brs,1H),4.28−4.62(m,2H),3.12(t,J=2.4Hz,1H)
LCMS(ESI+,m/z):228.2(M+H)+。
1H NMR(400MHz,CDCl3):δ7.59−7.54(m,4H),7.30−7.23(m,1H),7.00(s,1H),6.91−6.86(m,2H),6.57(d,J=7.2Hz,1H),5.11(s,2H),3.84(s,3H),2.11(s,3H)
LCMS(ESI+,m/z):347.3(M+H)+。
1H NMR(400MHz,DMSO−d6):δ9.99(s,1H),7.88(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.33(s,1H),7.14−7.10(m,1H),6.83(d,J=8.0Hz,1H),6.74−6.70(m,1H),6.55(d,J=6.8Hz,1H),5.21(s,2H),2.16(s,3H)
LCMS(ESI+,m/z):333.3(M+H)+。
1H NMR(300MHz,CDCl3):δ7.59(d,J=1.5Hz,4H),7.33(s,1H),7.02(d,J=0.9Hz,1H),6.91(s,1H),6.89(s,1H),6.60(d,J=6.8Hz,1H),5.12(s,2H),4.15−4.01(m,4H),2.19−2.14(m,1H),2.10−1.95(m,1H),2.04(s,3H),1.85−1.76(m,2H),1.55−1.45(m,1H),1.40−1.30(m,1H),1.28−1.18(m,4H),0.83(d,J=6.4Hz,3H)
LCMS(ESI+,m/z):488.5(M+H)+。
1H NMR(400MHz,DMSO−d6):δ12.00(brs,1H),7.74(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.26(t,J=8.4Hz,1H),7.04(d,J=8.0Hz,1H),6.95(s,1H),6.87(t,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),5.18(s,2H),3.99(t,J=6.0Hz,2H),2.19−2.14(m,1H),2.10(s,3H),1.99−1.93(m,1H),1.84−1.76(m,1H),1.67−1.65(m,2H),1.45−1.38(m,1H),1.28−1.23(m,1H),0.84(d,J=6.4Hz,3H)19F NMR(400MHz,DMSO−d6):δ−61.61
LCMS(ESI+,m/z):460.7(M+H)+
HPLC:98.65%(210nm)。
(S)−3−メチル−6−(2−((5−メチル−2−(6−(トリフルオロメチル)ピリジン−3−イル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2t)の合成
1H NMR(400MHz,DMSO−d6):δ9.39(t,J=5.6Hz,1H),9.14(s,1H),8.46(d,J=8.4Hz,1H),8.05(d,J=7.6Hz,1H),4.12−4.10(m,2H),3.20(t,J=0.4Hz,1H)
19F NMR(400MHz,DMSO−d6):δ−66.70
LCMS(ESI+,m/z):229.2(M+H)+。
1H NMR(400MHz,DMSO−d6):δ8.83(s,1H),8.08(d,J=8.4Hz,1H),7.94(d,J=7.6Hz,1H),7.29(t,J=9.2Hz,1H),7.05(d,J=7.6Hz,1H),7.01(s,1H),6.88(t,J=8.4Hz,1H),6.42(d,J=7.2Hz,1H),5.23(s,2H),3.78(s,3H),2.13(s,3H).
19F NMR(400MHz,DMSO−d6):δ−66.43。
1H NMR(400MHz,DMSO−d6):δ9.94(s,1H),8.83(s,1H),8.12(d,J=8.0Hz,1H),7.93(d,J=8.4Hz,1H),7.11(t,J=8.0Hz,1H),7.01(s,1H),6.86(d,J=8.0Hz1H),6.72(d,J=8.8Hz,1H),6.36(d,J=7.6Hz,1H),5.20(s,2H),2.14(s,3H)
19F NMR(400MHz,DMSO−d6):δ−66.44
LCMS(ESI+,m/z):334.3(M+H)+
HPLC:99.23%(210nm)。
LCMS(ESI+,m/z):490.2(M+H)+。
1H NMR(400MHz,DMSO−d6):δ12.01(brs,1H),8.81(s,1H),8.06(d,J=8.4Hz,1H),7.91(d,J=8.4Hz,1H),7.26(t,J=7.6Hz,1H),7.05−7.02(m,2H),6.86(t,J=7.6Hz,1H),6.43(d,J=6.8Hz,1H),5.22(s,2H),3.99(t,J=6.4Hz,2H),2.22−2.14(m,1H),2.14(s,3H),2.01−1.86(m,1H),1.86−1.81(m,1H),1.72−1.66(m,2H),1.43−1.37(m,1H),1.28−1.22(m,1H),0.86(d,J=6.8Hz,3H)19F NMR(400MHz,DMSO−d6):δ−66.77
LCMS(ESI+,m/z):463.1(M+H)+
HPLC:97.23%(210nm)。
(R)−3−メチル−6−(2−((5−(メチル−d3)−2−(6−(トリフルオロメチル)ピリジン−3−イル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2u)の合成
1H NMR(300MHz,CDCl3):δ9.05(s,1H),8.28(d,J=8.1Hz,1H),7.74(d,J=8.1Hz,1H),4.10−3.50(bs,4H)(注:NHプロトンはNMRで観察されない)
19F NMR(300MHz,CDCl3):δ−68.07
LCMS(ESI+,m/z):216.2(M+H)+。
ンの合成:
1H NMR(400MHz,CDCl3):δ13.0(s,1H),9.30(s,1H),8.51(d,J=8.4Hz,1H),7.99(d,J=8.1Hz,1H),7.43(s,1H),7.16(s,1H)
LCMS(ESI+,m/z):214.2(M+H)+。
1H NMR(300MHz,DMSO−d6):δ8.96(s,1H),8.25(d,J=8.4Hz,1H),7.98(d,J=8.1Hz1H),7.39(s,1H),7.28(t,J=8.1Hz,1H),7.14(s,1H),6.98(d,J=8.1Hz,1H),6.88(t,J=7.2Hz,1H),6.81(d,J=7.5Hz,1H),5.32(s,2H),3.67(s,3H)
19F NMR(300MHz,CDCl3):δ−66.43
LCMS(ESI+,m/z):334.2(M+H)+。
1H NMR(400MHz,DMSO−d6):δ8.87(s,1H),8.15(d,J=8.4Hz,1H),7.98(d,J=8.4Hz1H),7.39(s,1H),7.28(t,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H),6.87(t,J=7.2Hz,1H),6.47(d,J=6.0Hz,1H),5.30(s,2H),3.74(s,3H)
19F NMR(300MHz,CDCl3):δ−66.55
LCMS(ESI+,m/z):412.2,414.2(M+H)+。
LCMS(ESI+,m/z):351.1(M+H)+。
LCMS(ESI+,m/z):337.1(M+H)+。
LCMS(ESI+,m/z):493.6(M+H)+
工程8:(R)−3−メチル−6−(2−((5−(メチル−d3)−2−(6−(トリフルオロメチル)ピリジン−3−イル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸(化合物2u)の合成:
1H NMR(400MHz,DMSO−d6):δ12.00(brs,1H),8.81(s,1H),8.07(d,J=7.2Hz,1H),7.92(d,J=8.4Hz1H),7.26(t,J=7.2Hz,1H),7.04(d,J=7.2Hz,1H),7.03(s,1H),6.86(t,J=7.6Hz,1H),6.46(d,J=7.2Hz,1H),5.23(s,2H),3.99(t,J=6.0Hz,2H),2.28−2.17(m,1H),2.02−1.96(m,1H),1.84−1.76(m,1H),1.70−1.65(m,2H),1.45−1.38(m,1H),1.28−1.22(m,1H),0.86(d,J=6.8Hz,3H)19F NMR(400MHz,DMSO−d6):δ−66.45
2D NMR(600MHz,CH3OH):δ2.10(s,3D)
LCMS(ESI+,m/z):465.2(M+H)+
HPLC:95.27%(210nm)。
デュシェンヌ型筋ジストロフィー(DMD)の筋肉細胞におけるミトコンドリア新生及びミトコンドリア機能の改善
原理:脂肪酸代謝及び新生を含むがこれらに限定されないミトコンドリア障害が、デュシェンヌ型筋ジストロフィーのモデルシステムにおいて観察される。Rybalka, E., et al., Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency. PLoS One, 2014. 9(12): p. e115763を参照されたい。本例では、市販されているデュシェンヌ型筋ジストロフィー患者からの筋芽細胞を、化合物2dで処理し、脂肪酸酸化及びミトコンドリア新生の改善について試験した。
ilent Technologies)に播種し、7日間にわたって分化させた。分化
した細胞を、媒体又は化合物2dで24時間処理し、その後、ピルビン酸、グルコース、グルタミンを含まず、ガラクトース及び500μMのカルニチンを添加したDMEM培地でアッセイした。
ついてのウェルの平均で除した。この比を、パルミチン酸酸化の結果である呼吸の量として用いた。次に、これらの値を媒体の平均FCCP OCR値に対して標準化して、報告
したパルミチン酸酸化の倍数変化を得た。
体、化合物2dで処理するか、又は200の感染様式でPGC−1αアデノウィルス若しくはLacZアデノウィルスに感染させた。3日後、細胞を、培地中、2時間にわたってブロモデオキシウリジン(BrdU)で標識した。インキュベーション後、細胞を洗浄し、次に抗BrdU抗体と共に4℃で一晩インキュベートした。翌日、サンプルを洗浄し、抗マウスIgG HRPと共に37℃で45分間インキュベートし、その後洗浄した。SpectraMax M5(Molecular Devices)により、光学密度を450nMの波長で測定した。
ミトコンドリア新生は、化合物2dの処理により、用量依存的に増加した(図2)。転写因子PGC1aの過剰発現を、アッセイのポジティブコントロールとして用いた。
デュシェンヌ型筋ジストロフィーのマウスモデルにおける持久運動能力の増加
原理:PPARδは、脂肪酸利用の増加を誘発する運動に応答して活性化される。デュシェンヌ型筋ジストロフィーは、タンパク質ジストロフィンの喪失に起因する筋肉機能の障害を伴う進行性の早期発症型筋肉変性疾患である。脂肪酸代謝及び変化したミトコンドリア機能が、この疾患の態様であると報告されている。この実証では、デュシェンヌ型筋ジストロフィーのmdxマウスモデルに、化合物2dの経口投与による処理を5週間にわたって毎日行い、トレッドミルによる持久運動能力について試験した。
デュシェンヌ型筋ジストロフィーのマウスモデルにおけるジストロフィー筋肉フェノタイプの減少
原理:デュシェンヌ型筋ジストロフィーにおける筋肉病態に類似して、mdxマウスは、生まれた直後に明らかである骨格筋のジストロフィー病態を有している。病態によって明らかであるこのフェノタイプの重要な態様は、アポトーシス/壊死による筋線維の喪失、筋線維再生の形跡、免疫細胞の浸潤、及び筋線維症の増加である。この実証では、mdxマウスに化合物2dを経口投与し、筋肉の病態について評価した。
組織学的病態評価:四頭筋、腓腹筋、及び前脛骨筋を剖検時に採取し、10%中性緩衝ホルマリンに浸漬することによって固定し、パラフィン中に包埋した。各ブロックから5μmでの組織切片を作り、スライドを、委員会が認定した獣医学の病理学者が評価した。病理組織学的評価には、それぞれ、表1、2、及び3に概略的に示されるように、筋線維壊死、炎症、筋線維再生、及び間質性線維症に対する定性的及び半定量的評価を含めた。
Elementsソフトウェア,V4.4(ニコン、東京、日本)を用いて一緒に繋ぎ合わせた。Image J 1.50b,Java(登録商標) 1.8.0_60(64ビ
ット)を用いて分析を完了した。
ロリンシグナルが、コラーゲンリッチな腱ではなく、筋肉に由来することを確実にした。ヒドロキシプロリンアッセイを、製造元の説明書に従って行った(Sigma−Aldrich ヒドロキシプロリンアッセイキット)。最終値は、以下の様にして算出した:
東京、日本)を用いて一緒に繋ぎ合わせた。Image J 1.50b,Java 1.
8.0_60(64ビット)を用いて分析を完了した。壊死領域の平均サイズは、大きく減少した(図5)。
筋肉損傷の量は、化合物2dで処理したmdxマウスで減少する一方で、有益な筋肉再生は、化合物2dによって増加している(図7)。
例6
虚血再灌流後のPPARδ調節が腎傷害を低減する
動物、手術、及び用量:標準的な餌及び水に自由にアクセスさせたおよそ280〜300gの雄スプラーグドーリーラットをこれらの実験で用いた。ラットを、イソフルランで麻酔し、温度制御された加熱した手術用プラットホーム上に腹位に置いた。背側面を皮膚切開し、両腎臓を側複切開を通して露出した。血管クリップを両腎茎に取り付け、遮断を45分間継続した。45分後、クリップを取り外し、腎臓を良好な再灌流についてモニタリングし、手術部位を縫合した。シャムグループに、遮断クランプを取り付けなかったこと以外は同様の手術手順を施した。各化合物を試験する4つの独立した実験を行った。化合物は、純水中の0.25%カルボキシメチルセルロースナトリウム、0.25%Tween−80による新しい懸濁液として毎日製剤した。化合物は、動物が手術から目覚めた4時間後に30mg/kgで経口投与し、シャム手術及びIRIコントロール動物には、同様にして媒体を投与した。
。3000rpmの遠心分離を4℃で10分間行って、血漿を分離した。血漿クレアチニンを、完全自動臨床生化学分析装置(Siemens Dimension(登録商標) Xpand(登録商標) Plus Integrated Chemistry System)を用いて分析した。
グラフ作成及び統計的検定には、GraphPad Prismソフトウェア,Ver
sion6.05を用いた。D’Agostino−Pearsonオムニバス正規性検定及びShapiro−Wilk正規性検定により、すべてのグループにおけるクレアチニンの正規分布について検定した。正規分布データは、対応のない両側t検定に掛けた。非正規分布データは、Mann−Whitney検定(非パラメトリック)に掛けた。統計的有意差は、化合物処理グループと比較したIRI−媒体のp<0.05によって判定する。
Claims (14)
- R3が、−CH3である、請求項1に記載の化合物、またはその医薬的に許容される塩。
- R1が、水素又はハロゲンである、請求項1〜4のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- 各R20が、独立して、水素又はハロゲンである、請求項1〜5のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- R 2 が、−OCF 3 又は−OCHF 2 である、請求項1〜6のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- R 2 が、−OCF 3 である、請求項1〜7のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- R1が、水素又はフルオロである、請求項5〜8のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- R20が、水素又はフルオロである、請求項6〜9のいずれか一項に記載の化合物、又はその医薬的に許容される塩。
- (R)−3−メチル−6−(2−((5−メチル−2−(4−(トリフルオロメトキシ)フェニル)−1H−イミダゾール−1−イル)メチル)フェノキシ)ヘキサン酸、又はその医薬的に許容される塩。
- 医薬的に許容されるキャリア又は賦形剤、及び請求項1〜11のいずれか一項に記載の化合物、又はその医薬的に許容される塩を含む、医薬組成物。
- PPARδ関連疾患又は病状の治療に使用するための、医薬的に許容されるキャリア又は賦形剤、及び請求項1〜11のいずれか一項に記載の化合物、又はその医薬的に許容される塩を含む、医薬組成物。
- 前記PPARδ関連疾患又は病状が、筋肉構造障害、ニューロン活性化障害、筋肉疲労障害、筋肉量障害、ミトコンドリア疾患、ベータ酸化疾患、代謝性疾患、癌、血管疾患、眼血管疾患、眼筋疾患、又は腎疾患である、請求項13に記載の医薬組成物。
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