JP2018534355A - 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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Abstract
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。
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。
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。
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。
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。
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。
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
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)。
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:
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)+。
1H NMR(300MHz,DMSO−d6):δ9.93(s,1H),7.55(d,J=9.0Hz,2H),7.39(d,J=8.1Hz,2H),7.11−7.06(m,1H),6.91−6.82(m,2H),6.70(t,J=6.9Hz,1H),6.27(d,J=7.8Hz,1H),5.09(s,2H),2.06(s,3H)
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)+。
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)。
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)+。
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,−60.32
LCMS(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,−59.90
LCMS(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)+。
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:
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)+。
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−(トリフルオロメトキシ)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)+。
LCMS(ESI+,m/z):350.1(M+H)+。
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
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)。
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)+。
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。
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。
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。
グラフ作成及び統計的検定には、GraphPad Prismソフトウェア,Version6.05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 (21)
- 式(I)、(II)、又は(III)の化合物:
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]
またはその医薬的に許容される塩。 - R3が、−CH3である、請求項1に記載の化合物。
- R2が、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、前記フラニルは、−C1−C4−アルキルで置換されていてもよい、請求項1〜6のいずれか一項に記載の化合物。
- R2が、ハロゲン、−CH3、−C1−ハロアルキル、−C1−ハロアルコキシ、−SCH3、又はフラニルであり、前記フラニルは、CH3で置換されていてもよい、請求項1〜7のいずれか一項に記載の化合物。
- R1が、水素又はハロゲンである、請求項1〜8のいずれか一項に記載の化合物。
- 各R20が、独立して、水素又はハロゲンである、請求項1〜9のいずれか一項に記載の化合物。
- R2が、クロロ、無置換フラニル、−CH3、−CF3、−OCF3、−OCHF2、又は−SCH3である、請求項7〜10のいずれか一項に記載の化合物。
- R2が、−CF3又は−OCF3である、請求項1〜11のいずれか一項に記載の化合物。
- R2が、−CF3である、請求項1〜12のいずれか一項に記載の化合物。
- R1が、水素又はフルオロである、請求項9〜13のいずれか一項に記載の化合物。
- R20が、水素又はフルオロである、請求項10〜14のいずれか一項に記載の化合物。
- R1が、水素であり、R2が、−CF3であり、R20が、水素である、請求項4に記載の化合物又はその医薬的に許容される塩。
- R1が、水素であり、R2が、−CF3であり、R20が、水素である、請求項6に記載の化合物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1〜17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。
- 対象におけるPPARδ関連疾患又は病状の治療方法であって、それを必要とする前記対象に、1つ以上の請求項1〜17のいずれか一項に記載の化合物若しくはその医薬的に許容される塩の治療有効量、又は請求項18に記載の医薬組成物の治療有効量を投与することを含む、方法。
- 前記PPARδ関連疾患が、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19に記載の方法。
- 前記筋肉構造障害が、ベスレムミオパチー、セントラルコア病、先天性筋線維タイプ不均等症、遠位型筋ジストロフィー(MD)、デュシェンヌ型及びベッカー型MD、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、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、又は腹圧性尿失禁から選択され、
前記ニューロン活性化障害が、筋萎縮性側索硬化症、シャルコー・マリー・トゥース病、ギラン・バレー症候群、ランバート・イートン症候群、多発性硬化症、重症筋無力症、神経病変、末梢神経障害、脊髄性筋萎縮症、遅発性尺骨神経麻痺、又は中毒性神経筋障害から選択され、
前記筋肉疲労障害が、慢性疲労症候群、糖尿病(I型又はII型)、糖原病、線維筋痛症、フリートライヒ運動失調症、間欠性跛行、脂質貯蔵ミオパチー、MELAS、ムコ多糖症、ポンペ病、又は甲状腺中毒性ミオパチーから選択され、
前記筋肉量障害が、悪液質、軟骨変性、脳性麻痺、コンパートメント症候群、重症疾患ミオパチー、封入体筋炎、筋萎縮症(廃用性)、筋肉減少症、ステロイドミオパチー、又は全身性エリテマトーデスであり;
前記ミトコンドリア疾患が、アルパース病、CPEO−慢性進行性外眼筋麻痺、カーンズ・セイヤー症候群(KSS)、レーベル遺伝性視神経症(LHON)、MELAS−高乳酸血症と脳卒中様症状をもつミトコンドリア脳筋症、MERRF−赤色ぼろ線維を伴うミオクローヌスてんかん、NARP−神経原性筋力低下・運動失調・網膜色素変性症、又はピアソン症候群から選択され、
前記ベータ酸化疾患が、全身性カルニチン輸送体、カルニチンパルミトイルトランスフェラーゼ(CPT)II欠損症、極長鎖アシルCoAデヒドロゲナーゼ(LCHAD又はVLCAD)欠損症、三機能酵素欠損症、中鎖アシルCoAデヒドロゲナーゼ(MCAD)欠損症、短鎖アシルCoAデヒドロゲナーゼ(SCAD)欠損症、又はβ−酸化のリボフラビン応答性障害(RR−MADD)から選択され、
前記代謝性疾患が、高脂血症、脂質代謝異常、高コレステロール血症、高トリグリセリド血症、低HDLコレステロール血症、高LDLコレステロール血症、及び/若しくは非HLDコレステロール血症、VLDL高タンパク血症、異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、潰瘍性大腸炎、クローン病、又は膵炎から選択され、
前記癌が、結腸癌、大腸癌、皮膚癌、乳癌、前立腺癌、卵巣癌、又は肺癌であり;
前記血管疾患が、末梢血管不全、末梢血管疾患、間欠性跛行、末梢血管疾患(PVD)、末梢動脈疾患(PAD)、末梢動脈閉塞性疾患(PAOD)、又は末梢閉塞性動脈症から選択され、
前記眼血管疾患が、加齢黄斑変性(AMD)、シュタルガルト病、高血圧性網膜症、糖尿病性網膜症、網膜症、黄斑変性症、網膜出血、又は緑内障から選択され、
前記眼筋疾患が、斜視、進行性外眼筋麻痺、内斜視、外斜視、屈折及び調節障害、遠視、近視、乱視、不同視、老視、調節障害、又は内眼筋麻痺から選択され、並びに
前記腎疾患が、糸球体腎炎、糸球体硬化症、ネフローゼ症候群、高血圧性腎硬化症、急性腎炎、反復性血尿、持続性血尿、慢性腎炎、急速進行性腎炎、急性腎不全、慢性腎不全、糖尿病性腎症、又はバーター症候群から選択される、
請求項20に記載の方法。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |