JP2019529459A - ドーパミン−b−ヒドロキシラーゼ阻害剤 - Google Patents
ドーパミン−b−ヒドロキシラーゼ阻害剤 Download PDFInfo
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- JP2019529459A JP2019529459A JP2019515915A JP2019515915A JP2019529459A JP 2019529459 A JP2019529459 A JP 2019529459A JP 2019515915 A JP2019515915 A JP 2019515915A JP 2019515915 A JP2019515915 A JP 2019515915A JP 2019529459 A JP2019529459 A JP 2019529459A
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- BRKSFFWVIHHFGJ-QMMMGPOBSA-N CC(N1)=C(C[C@@H](C2)c(c(F)ccc3)c3F)N2C1=S Chemical compound CC(N1)=C(C[C@@H](C2)c(c(F)ccc3)c3F)N2C1=S BRKSFFWVIHHFGJ-QMMMGPOBSA-N 0.000 description 1
- FCZUKDYWDKZOJM-QMMMGPOBSA-N CC(N1)=C(C[C@@H](C2)c3cc(Br)ccc3F)N2C1=S Chemical compound CC(N1)=C(C[C@@H](C2)c3cc(Br)ccc3F)N2C1=S FCZUKDYWDKZOJM-QMMMGPOBSA-N 0.000 description 1
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/4164—1,3-Diazoles
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- A61K31/4164—1,3-Diazoles
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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Abstract
Description
式中、
R1は水素、C1−C6アルキル、部分的にまたは完全に重水素化されたC1−C6アルキル、C3−C6シクロアルキル、C2−C6シアノアルキル、C1−C6メルカプトアルキルまたはアミノであり;
R4は水素またはC1−C3アルキルであり;
R5は水素またはC1−C2アルキルであり;
またはR4及びR5は、それらが連結される炭素原子と一緒になってCH2部分が任意で2つの重水素(D)原子によって置換されるシクロプロピル環を形成し;
R6はC1−C6アルキル、または部分的にまたは完全に重水素化されたC1−C6アルキルであり、
AはC5−C7シクロアルキル、フラニル、チオフェニル、メチルチオフェニルまたは
式中:
X1は水素、ハロまたはメチルであり;
X1’は水素またはハロであり;
X2は水素、ハロまたはメチルであり;
X2’は水素またはハロであり;
X3は水素またはフルオロであり;
nは0または1であり、nが0であるとき、単結合はnが1であるときCH2部分が連結される炭素原子を結合する。
「C1−C6アルキル」は1〜6の炭素原子を有する一価の非置換の飽和した直鎖または分岐鎖の炭化水素ラジカルを意味する。「C1−C2アルキル」、「C1−C3アルキル」、「C1−C4アルキル」及び「C1−C5アルキル」は類似の意味を有する。
本発明は上記で定義されているような式Iaの化合物、またはその薬学上許容できる塩または溶媒和物を提供する。
式Iaの一部の実施形態では、nは0であり、単結合はnが1であるとき、CH2部分が連結される炭素原子を結合して式Ib
R1は、水素、C1−C6アルキル、部分的にまたは完全に重水素化されたC1−C6アルキル、C3−C6シクロアルキル、C2−C6シアノアルキル、C1−C6メルカプトアルキル及びアミノから成る群から選択される。
一部の実施形態では、R1は水素である。
一部の実施形態では、R1はC1−C6アルキルである。
一部の実施形態では、R1は部分的に重水素化されたC1−C6アルキルである。
一部の実施形態では、R1は完全に重水素化されたC1−C6アルキルである。
一部の実施形態では、R1はC3−C6シクロアルキルである。
一部の実施形態では、R1はC2−C6シアノアルキルである。
一部の実施形態では、R1はC1−C6メルカプトアルキルである。
一部の実施形態では、R1はアミノである。
一部の実施形態では、R1は好ましくは水素である。
一部の実施形態では、R1は好ましくはメチルである。
一部の実施形態では、R1は好ましくはd3−メチルである。
一部の実施形態では、R1は好ましくはプロピルである。
一部の実施形態では、R1は好ましくはシクロプロピルである。
一部の実施形態では、R1は好ましくはシアノメチルである。
一部の実施形態では、R1は好ましくはメルカプトエチルである。
一部の実施形態では、R1は好ましくはアミノである。
R4は、水素及びC1−C3アルキルから成る群から選択される。
一部の実施形態では、R4は水素である。
一部の実施形態では、R4はC1−C3アルキルである。
一部の実施形態では、R4は好ましくは水素である。
一部の実施形態では、R4は好ましくはメチルである。
R5は、水素及びC1−C2アルキルから成る群から選択される。
一部の実施形態では、R5は水素である。
一部の実施形態では、R5はC1−C2アルキルである。
一部の実施形態では、R5は好ましくは水素である。
一部の実施形態では、R5は好ましくはメチルである。
R6はC1−C6アルキル、及び部分的にまたは完全に重水素化されたC1−C6アルキルから選択される。
一部の実施形態では、R6は部分的に重水素化されたC1−C6アルキルである。
一部の実施形態では、R6は完全に重水素化されたC1−C6アルキルである。
一部の実施形態では、R6は好ましくはメチルである。
一部の実施形態では、R6は好ましくはn−ブチルである。
一部の実施形態では、R6は好ましくはd3−メチルである。
Aは、C5−C7シクロアルキル、フラニル、チオフェニル、メチルチオフェニル及び
式中、
X1は水素,ハロまたはメチルであり;
X1’は水素またはハロであり;
X2は水素、ハロまたはメチルであり;
X2’は水素またはハロであり;
X3は水素またはフルオロである。
式中、X1、X1’、X2、X2’及びX3は上記で定義されたとおりである。
式中、
X1は水素、フルオロ、クロロまたはメチルであり;
X1’は水素、フルオロまたはクロロであり;
X2は水素、フルオロ、クロロ、ブロモまたはメチルであり;
X2’は水素、フルオロ、クロロまたはブロモであり;
X3は水素またはフルオロである。
好まれる一実施形態では、X1、X1’、X2、X2’及びX3のすべてが水素であるわけではない。
置換基R1、R4、R5、R6、A、X、X1、X1’、X2、X2’及びX3の種々の実施形態は上記B1〜B5で議論されている。これらの「置換基」の実施形態は、上記B0で議論された「コア構造」の実施形態のいずれかと組み合わせて式Iaの化合物のさらなる実施形態を形成することができる。上記で議論されている「置換」の実施形態と「コア構造」の実施形態を組み合わせることによって形成される式Iaの化合物の実施形態すべてが出願者の発明の範囲内であり、式Iの化合物の一部の好まれるさらなる実施形態が以下で提供されている。
式中、
R1は、水素及びメチルから成る群から選択され;
R4は(存在するならば)水素及びメチルから成る群から選択され;
R5は(存在するならば)水素及びメチルから成る群から選択され;
R6はメチルであり;
Aは、
式中、
Aは、
(5aS,6aR)−5a−(2,5−ジフルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(5aS,6aR)−5a−(3,5−ジフルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(S)−1−ブチル−6−(3,5−ジフルオロフェニル)−6,7−ジヒドロ−2H−ピロロ[1,2−c]イミダゾール−3(5H)−チオン;
(S)−6−(3,5−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(R)−1−メチル−6−(2,3,5,6−テトラフルオロフェニル)−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(S)−1−メチル−6−(2,3,5,6−テトラフルオロフェニル)−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(S)−6−(2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(5aS,6aR)−5a−(5−クロロ−2−フルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(5aS,6aR)−5a−(5−クロロ−2−フルオロフェニル)−1−(メチル−d3)−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(R)−6−(3−クロロ−2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(S)−6−(3−クロロ−2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(5aS,6aR)−5a−(3−ブロモ−2,6−ジフルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(5aS,6aR)−5a−(5−ブロモ−2−フルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(5aS,6aR)−5a−(3−クロロ−2,6−ジフルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(R)−6−(3−ブロモ−2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(S)−6−(3−ブロモ−2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(5aS,6aR)−5a−(3−クロロ−5−フルオロフェニル)−1−メチル−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(5aS,6aR)−5a−(5−ブロモ−2−フルオロフェニル)−1−(メチル−d3)−5,5a,6,6a−テトラヒドロシクロプロパ[3,4]ピロロ[1,2−c]イミダゾール−3(2H)−チオン;
(S)−6−(5−ブロモ−2−フルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(R)−1−メチル−6−(2,3,6−トリフルオロフェニル)−6,7−ジヒドロ−2H−ピロロ[1,2−c]イミダゾール−3(5H)−チオン;
(R)−6−(5−ブロモ−2−フルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(R)−6−(2,6−ジフルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;
(R)−6−(5−クロロ−2−フルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン;及び
(S)−6−(5−クロロ−2−フルオロフェニル)−1−メチル−2,5,6,7−テトラヒドロ−3H−ピロロ[1,2−c]イミダゾール−3−チオン
医薬用途を対象とした本発明の化合物は、単独で投与されてもよいし、または本発明の他の1以上の化合物との併用で、もしくは1以上の他の薬剤との併用で(もしくはその任意の組み合わせとして)投与されてもよい。一般に、それらは1以上の薬学上許容できる賦形剤と関連した製剤として投与されるであろう。従って、本発明は、(i)治療上有効な量の、上記で定義されたような式Iaの化合物またはその薬学上許容できる塩または溶媒和物と、(ii)薬学上許容できる賦形剤とを含む医薬組成物にも関する。
本発明はまた、治療法での使用のための、特にDβHの阻害によって改善される状態の治療での使用のための、上記で定義されているような式Iaの化合物、またはその薬学上許容できる塩または溶媒和物にも関する。
本発明の化合物の合成に使用される方法を以下のスキームによって説明する。これらの化合物を調製するのに使用される出発物質及び試薬は供給業者から入手可能であり、または当業者に明白な方法によって調製することができる。スキームを読み易くするために、特定の位置で重水素を取り込む選択肢は示さない。具体的には、重水素化した生成物は以下の実施例で使用したものを含むが、これらに限定されない具体的に重水素化された出発物質を用いて作製することができる。
スキーム1
スキーム2
スキーム3
スキーム4
スキーム5
スキーム6
化合物及び中間体はすべてNMRによって特徴付けた。スペクトルは内部標準として使用した溶媒を用いてBruker Avance III 600MHz分光計で記録した。13Cのスペクトルは150MHzで記録し、1Hのスペクトルは600MHzで記録した。データは以下の順:近似の化学シフト(ppm)、プロトンの数、多重度(br:幅広線、d:二重線、m:多重線、s:一重線、t:三重線)及びカップリング定数(Hz)で報告する。
工程1:(E)−1,3−ジフルオロ−5−(2−ニトロビニル)ベンゼン
1H NMR(DMSO−d6):11.66(1H,brs),7.28(2H,m),7.20(1H,m),4.06(1H,d,J=12.0Hz),3.78(1H,d,J=12.0Hz),2.86(1H,dd,J=8.2,4.3Hz),2.09(1H,m),2.04(3H,s),1.63(1H,dd,J=8.1,5.4Hz),1.13(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):158.8,158.7,157.2,157.1,155.7,130.3,128.8,128.8,128.8,128.7,128.6,117.2,117.1,117.0,116.9,116.8,115.9,115.8,115.7,115.7,114.8,51.5,32.5,22.4,20.3,9.4.
1H NMR(DMSO−d6):1.63(1H,br s),7.10(3H,m),4.17(1H,d,J=12.0Hz),4.00(1H,d,J=12.2Hz),2.97(1H,dd,J=8.3,4.3Hz),2.03(3H,s),1.65(1H,dd,J=8.2,5.1Hz),1.15(1H,m).
13C NMR(DMSO−d6):163.4,163.3,161.8,161.7,156,145,130.2,114.5,110,110,109.9,109.9,102.1,50.7,36.1,25.4,22.4,9.4.
工程1:4−(3,5−ジフルオロフェニル)−2−(メトキシ(メチル)カルバモイル)ピロリジン−1−カルボン酸(4S)−tert−ブチル
1H NMR(DMSO−d6):11.71(1H,s),7.13(3H,m),4.14(1H,dd,J=11.2,7.9Hz),4.07(1H,五重項,J=8.1Hz),3.67(1H,dd,J=11.1,8.3Hz),3.20(1H,dd,J=15.0,7.8Hz),2.84(1H,dd,J=15.1,8.8Hz),2.35(2H,t,J=7.5Hz),1.50(2H,m),1.26(2H,m),0.86(3H,t,J=7.4Hz).
13C NMR(DMSO−d6):163.3,163.2,161.7,161.6,155.1,145.8,145.7,145.6,127.6,120,110.8,110.7,110.6,110.6,102.6,102.5,102.3,49.9,46.5,30.4,29.8,23.6,21.5,13.6.
工程1:2−(シアノ(ヒドロキシ)メチル)−4−(3,5−ジフルオロフェニル)ピロリジン−1−カルボン酸(4S)−tert−ブチル
1H NMR(DMSO−d6):11.69(1H,brs),7.13(3H,m),5.76(1H,s),4.15(1H,dd,J=11.2,7.9Hz),4.07(1H,五重項,J=7.8Hz),3.66(1H,dd,J=11.2,8.4Hz),3.18(1H,m),2.82(1H,ddd,J=15.0,8.9,1.3Hz),1.98(3H,s).
13C NMR(DMSO−d6):163.3,163.2,161.7,161.6,155.1,145.7,145.7,145.6,127.8,115.4,110.8,110.7,110.6,110.6,102.6,102.5,102.3,50.0,46.5,30.0,9.4.
1H NMR(DMSO−d6):11.74(1H,br s),7.85(1H,m),4.49(1H,五重項,J=8.5Hz),4.42(1H,m),4.15(1H,dd,J=11.6,9.2Hz),3.76(1H,dd,J=11.7,7.8Hz),3.27(1H,dd,J=15.6,9.2Hz),2.89(1H,dd,J=15.4,7.9Hz),1.97(3H,s).
13C NMR(DMSO−d6):155.0,146.4,146.3,146.3,145.3,145.2,144.8,144.7,144.6,143.7,143.6,127.5,120.5,120.4,120.3,115.3,105.9,105.7,105.6,48.4,35.9,28.6,9.3.
1H NMR(DMSO−d6):11.74(1H,br s),7.85(1H,m),4.49(1H,五重項,J=8.5Hz),4.15(1H,dd,J=11.6,9.2Hz),3.76(1H,dd,J=11.7,7.8Hz),3.27(1H,dd,J=15.6,9.2Hz),2.89(1H,dd,J=15.4,7.9Hz),1.97(3H,s).
13C NMR(DMSO−d6):155,146.4,146.3,146.3,145.3,145.2,144.8,144.7,144.6,143.7,143.6,127.5,120.5,120.4,120.3,115.3,105.9,105.7,105.6,48.7,48.4,35.9,28.6,9.3.
1H NMR(DMSO−d6):11.72(1H,br s),7.40(1H,m),7.13(2H,m),4.41(1H,五重項,J=8.7Hz),4.12(1H,br t,J=10.1Hz),3.70(1H,dd,J=8.8,10.8Hz),3.21(1H,br dd,J=15.3,9.2Hz),2.84(1H,br dd,J=15.2,8.6Hz),1.97(3H,s).
13C NMR(DMSO−d6):161.6,161.6,160.0,159.9,155.0,129.8,129.7,129.7,127.8,116.6,116.5,116.4,115.2,112.3,112.2,112.1,112.1,48.6,35.4,28.8,9.3.
1H NMR(DMSO−d6):11.65(1H,br s),7.47(1H,dd,J=6.5,2.6Hz),7.42(1H,ddd,J=8.8,4.4,2.7Hz),7.29(1H,dd,J=10.0,8.9Hz),4.06(1H,d,J=11.7Hz),3.77(1H,d,J=12.0Hz),2.87(1H,dd,J=8.2,4.3Hz),2.04(3H,m),1.64(1H,dd,J=8.1,5.4Hz),1.12(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):161.3,159.7,155.7,130.3,130.1,130.1,129.3,129.3,129.0,128.9,128.3,128.3,117.6,117.4,114.8,51.5,51.5,32.3,22.3,20.2,9.4.
1H NMR(DMSO−d6):11.65(1H,s),7.47(1H,dd,J=6.6,2.8Hz),7.42(1H,ddd,J=8.8,4.4,2.7Hz),7.29(1H,m),4.06(1H,d,J=11.9Hz),3.77(1H,d,J=12.0Hz),2.87(1H,dd,J=8.3,4.3Hz),1.64(1H,dd,J=8.3,5.4Hz),1.12(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):161.3,159.7,155.7,155.6,130.3,130.1,130.1,129.3,129.3,129.0,128.9,128.3,128.3,117.6,117.4,114.7,114.6,51.5,51.5,32.3,22.3,20.2.
1H−NMR(DMSO−d6):11.73(1H,br s),7.61(1H,td,J=8.8,5.6Hz),7.21(1H,t,J=9.5Hz),4.44(1H,quin,J=8.6Hz),4.13(1H,dd,J=11.4,9.2Hz),3.72(1H,dd,J=11.6,7.9Hz),3.23(1H,m),2.84(1H,dd,J=15.5,8.1Hz),1.97(3H,s).
13C−NMR(DMSO−d6):160.2,160.1,158.5,158.5,156.6,156.5,155,154.9,154.9,129.7,129.7,127.7,118.9,118.7,118.6,116.1,116.1,116.0,116.0,115.2,113.3,113.3,113.1,113.1,48.5,35.8,28.7,9.4.
1H−NMR(DMSO−d6):11.73(1H,br s),7.61(1H,td,J=8.8,5.6Hz),7.21(1H,t,J=9.5Hz),4.44(1H,quin,J=8.6Hz),4.13(1H,dd,J=11.4,9.2Hz),3.72(1H,dd,J=11.6,7.9Hz),3.23(1H,m),2.84(1H,dd,J=15.5,8.1Hz),1.97(3H,s).
13C−NMR(DMSO−d6):160.2,160.1,158.5,158.5,156.6,156.5,154.9,154.9,129.7,129.6,127.7,118.9,118.7,118.6,116.1,116.1,116.0,115.9,115.2,113.3,113.3,113.1,113.1,48.5,35.7,28.7,9.4.
1H NMR(DMSO−d6):11.68(1H,br s),7.74(1H,td,J=8.4,5.9Hz),7.15(1H,td,J=9.2,1.2Hz),4.01(1H,d,J=12.3Hz),3.71(1H,d,J=12.0Hz),2.72(1H,dd,J=8.3,4.5Hz),2.05(3H,s),1.65(1H,dd,J=8.2,5.6Hz),1.25(1H,t,J=5.0Hz).
13C NMR(DMSO−d6):161.9,161.9,160.3,160.2,158.8,158.8,157.2,157.1,155.7,133.0,133.0,130.0,117.2,117.1,115.1,113.5,113.3,103.7,103.7,103.6,51.4,26.5,21.8,20.9,9.4.
1H NMR(DMSO−d6):11.65(1H,s),7.59(1H,dd,J=6.7,2.5Hz),7.55(1H,ddd,J=8.7,4.5,2.6Hz),7.24(1H,dd,J=10.1,8.7Hz),4.05(1H,d,J=12.0Hz),3.76(1H,d,J=12.0Hz),2.87(1H,dd,J=8.3,4.3Hz),2.04(3H,s),1.64(1H,dd,J=8.2,5.3Hz),1.12(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):161.8,160.2,155.7,132.9,132.9,132.3,132.2,130.2,129.4,129.3,118,117.8,116.2,116.2,114.8,51.5,51.5,32.2,22.2,20.2,9.3.
1H NMR(DMSO−d6):11.68(1H,s),7.63(1H,td,J=8.6,5.8Hz),7.21(1H,t,J=8.6Hz),4.01(1H,d,J=12.2Hz),3.72(1H,d,J=12.2Hz),2.73(1H,dd,J=8.2,4.4Hz),2.05(3H,s),1.65(1H,dd,J=8.2,5.6Hz),1.25(1H,t,J=5.0Hz).
13C NMR(DMSO−d6):161.2,161.2,159.6,159.6,157.8,157.8,156.2,156.1,155.7,130.3,130.2,129.9,117.2,117.1,117,115.7,115.7,115.6,115.6,115.1,112.9,112.9,112.8,112.8,51.4,26.4,21.7,20.8,9.4.
1H NMR(DMSO−d6):11.73(1H,br s),7.72(1H,ddd,J=8.9,8.1,5.8Hz),7.16(1H,m),4.44(1H,五重項,J=8.6Hz),4.13(1H,dd,J=11.5,9.2Hz),3.71(1H,dd,J=11.6,7.9Hz),3.23(1H,dd,J=15.5,9.3Hz),2.84(1H,dd,J=15.4,8.1Hz),1.97(3H,s).
13C NMR(DMSO−d6):160.8,160.8,159.2,159.1,157.5,157.5,155.9,155.8,155,132.4,132.4,127.7,118.8,118.7,118.6,115.1,113.8,113.8,113.6,113.6,104.1,104,103.9,103.9,48.5,35.8,28.7,9.3.
1H NMR(DMSO−d6):11.72(1H,br s),7.72(1H,ddd,J=8.9,8.1,5.8Hz),7.16(1H,m),4.44(1H,t,J=8.7Hz),4.13(1H,dd,J=11.5,9.2Hz),3.71(1H,dd,J=11.6,7.9Hz),3.23(1H,dd,J=15.5,9.3Hz),2.84(1H,dd,J=15.5,8.1Hz),1.97(3H,s).
13C NMR(DMSO−d6):160.8,160.8,159.2,159.1,157.5,157.5,155.9,155.8,155,132.4,132.4,127.7,118.8,118.7,118.6,115.1,113.8,113.8,113.6,113.6,104.1,104,103.9,103.9,48.5,35.8,28.7,9.3.
1H NMR(DMSO−d6):11.64(1H,s),7.30(1H,dt,J=8.7,2.1Hz),7.28(1H,t,J=1.6Hz),7.23(1H,dt,J=10.0,1.8Hz),4.19(1H,d,J=12.2Hz),3.99(1H,d,J=12.0Hz),3.00(1H,dd,J=8.3,4.3Hz),2.03(3H,s),1.64(1H,dd,J=8.3,5.2Hz),1.14(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):163.1,161.4,156,145,144.9,134.1,134.1,130.2,123,123,114.5,114.3,114.1,112.9,112.8,50.8,36,36,25.2,22.2,9.3.
1H NMR(DMSO−d6):11.65(1H,s),7.59(1H,dd,J=6.7,2.6Hz),7.55(1H,ddd,J=8.7,4.5,2.6Hz),7.23(1H,dd,J=10.1,8.7Hz),4.05(1H,d,J=12.0Hz),3.76(1H,d,J=12.0Hz),2.87(1H,dd,J=8.2,4.3Hz),1.64(1H,dd,J=8.3,5.4Hz),1.12(1H,t,J=4.8Hz).
13C NMR(DMSO−d6):161.8,160.2,155.7,132.9,132.9,132.3,132.2,130.3,129.4,129.3,118,117.8,116.2,116.2,114.7,51.5,51.5,32.3,22.2,20.2.
1H NMR(DMSO−d6):11.70(1H,br s),7.58(1H,dd,J=6.7,2.5Hz),7.53(1H,ddd,J=8.7,4.5,2.5Hz),7.23(1H,dd,J=10.3,8.8Hz),4.20(1H,五重項,J=8.1Hz),4.11(1H,dd,J=10.9,8.1Hz),3.71(1H,dd,J=11.3,7.9Hz),3.18(1H,dd,J=15.2,8.1Hz),2.85(1H,ddd,J=15.2,8.3,1.2Hz),1.98(3H,s).
13C NMR(DMSO−d6):160.3,158.7,155.1,131.8,131.8,131.4,131.4,130.6,130.5,127.5,118,117.9,116.5,116.4,115.4,49,40.5,29,9.3.
1H NMR(DMSO−d6):11.72(1H,br s),7.47(1H,qd,J=9.4,5.0Hz),7.17(1H,tdd,J=9.6,9.6,3.7,1.9Hz),4.43(1H,五重項,J=8.7Hz),4.14(1H,dd,J=11.3,9.2Hz),3.73(1H,dd,J=11.5,8.1Hz),3.24(1H,dd,J=15.6,9.2Hz),2.86(1H,dd,J=15.4,8.4Hz),1.97(3H,s).
13C NMR(DMSO−d6):156.9,156.9,156.9,156.9,155.3,155.3,155.3,155.3,155,149.1,149,149,148.9,147.5,147.5,147.4,147.4,147.3,147.3,145.9,145.9,145.8,145.8,127.6,118.9,118.8,118.8,118.7,116.5,116.4,116.3,116.3,115.2,112,112,111.9,111.9,111.8,111.8,111.8,111.7,48.4,35.7,28.6,9.3.
1H NMR(DMSO−d6):11.70(1H,br s),7.58(1H,dd,J=6.6,2.5Hz),7.53(1H,ddd,J=8.7,4.5,2.5Hz),7.23(1H,dd,J=10.3,8.7Hz),4.20(1H,五重項,J=8.1Hz),4.11(1H,dd,J=10.9,8.2Hz),3.71(1H,dd,J=11.3,7.9Hz),3.18(1H,dd,J=15.2,8.1Hz),2.85(1H,ddd,J=15.2,8.4,1.1Hz),1.98(3H,s).
13C NMR(DMSO−d6):160.3,158.7,155.1,131.8,131.8,131.4,131.4,130.6,130.5,127.6,118,117.9,116.5,116.4,115.4,49,40.5,29,9.3.
1H NMR(DMSO−d6):11.72(1H,br s),7.40(1H,tt,J=8.4,6.6Hz),7.13(2H,m),4.41(1H,五重項,J=8.8Hz),4.12(1H,m),3.70(1H,dd,J=11.4,8.4Hz),3.21(1H,dd,J=15.2,9.2Hz),2.84(1H,dd,J=15.4,8.7Hz),1.97(3H,s).
13C NMR(DMSO−d6):161.6,161.6,160,159.9,155,129.8,129.7,129.7,127.8,116.6,116.5,116.4,115.2,112.3,112.2,112.1,112.1,48.6,35.4,28.8,9.3.
1H NMR(DMSO−d6):11.70(1H,br s),7.46(1H,dd,J=6.5,2.7Hz),7.40(1H,ddd,J=8.8,4.4,2.6Hz),7.29(1H,dd,J=10.1,8.8Hz),4.20(1H,五重項,J=8.1Hz),4.11(1H,dd,J=10.8,8.1Hz),3.72(1H,dd,J=11.3,7.9Hz),3.18(1H,dd,J=15.1,8.1Hz),2.85(1H,ddd,J=15.2,8.3,1.2Hz),1.98(3H,s).
13C NMR(DMSO−d6):159.8,158.2,155.1,130.2,130.1,128.9,128.8,128.5,128.5,127.6,117.6,117.4,115.5,49.1,49.1,40.5,29,9.3.
以下の細胞アッセイを用いて、化合物のDβH活性を阻害する能力を評価してもよい。本発明の目的では、この細胞アッセイにて化合物が10μmで≦20%の「対照の%」での活性を示せば、化合物は「DβHの阻害剤」であると見なされる。本発明の好まれる化合物(上記の具体的な実施例のほとんどを含む)はこの細胞アッセイにて1.0μmで≦50%の「対照の%」での活性を示す。本発明のさらに好まれる化合物はこの細胞アッセイにて1.0μmで≦20%の「対照の%」での活性を示す。本発明の特に好まれる化合物はこの細胞アッセイにて100nmで≦50%の「対照の%」での活性を示す。
Claims (16)
- 式Ia
式中
R1は水素、C1−C6アルキル、部分的にまたは完全に重水素化されたC1−C6アルキル、C3−C6シクロアルキル、C2−C6シアノアルキル、C1−C6メルカプトアルキルまたはアミノであり;
R4は水素またはC1−C3アルキルであり;
R5は水素またはC1−C2アルキルであり;
またはR4及びR5はそれらが連結される炭素原子と一緒に結合して、CH2部分が任意で2つの重水素原子によって置換されるシクロプロピル環を形成し;
R6はC1−C6アルキル、または部分的にまたは完全に重水素化されたC1−C6アルキルであり、
AはC5−C7シクロアルキル、フラニル、チオフェニル、メチルチオフェニルまたは
X1は水素、ハロまたはメチルであり;
X1’は水素またはハロであり;
X2は水素、ハロまたはメチルであり;
X2’は水素またはハロであり;
X3は水素またはフルオロであり;
nは0または1であり、nが0のとき、単結合はnが1であるときCH2部分が連結される炭素原子を結合する、
前記化合物、またはその薬学上許容できる塩または溶媒和物。 - nが0である請求項1に記載の化合物。
- R4及びR5はそれらが連結される炭素原子と一緒に結合してCH2が任意で2つの重水素原子によって置換されるシクロプロピル環を形成する請求項1または2に記載の化合物。
- 50%を超える置換基R5及びAが式Id
- 50%を超える置換基R5及びAが式Ie
- Aが
- R1が水素、メチル、d3−メチル、プロピル、シクロプロピル、シアノメチル、メルカプトエチルまたはアミノである請求項1〜6に記載の化合物。
- R4が水素またはメチルである請求項1〜2または4〜7に記載の化合物。
- R5が水素またはメチルである請求項1〜2または4〜8に記載の化合物。
- R6がメチル、n−ブチルまたはd3−メチルである請求項1〜9に記載の化合物。
- Aが
X1が水素、フルオロ、クロロまたはメチルであり;
X1’が水素、フルオロまたはクロロであり;
X2が水素、フルオロ、クロロ、ブロモまたはメチルであり;
X2’が水素、フルオロ、クロロまたはブロモであり;
X3が水素またはフルオロである、請求項1〜10に記載の化合物。 - 治療法で使用するための請求項1に記載の式Iaの化合物、またはその薬学上許容できる塩または溶媒和物。
- ドーパミン−ベータ−ヒドロキシラーゼの阻害によって改善される状態の治療で使用するための請求項1に記載の式Iaの化合物、またはその薬学上許容できる塩または溶媒和物。
- ドーパミン−ベータ−ヒドロキシラーゼの阻害によって改善される状態の治療のための薬物の製造における請求項1に記載の式Iaの化合物、またはその薬学上許容できる塩または溶媒和物の使用。
- ドーパミン−ベータ−ヒドロキシラーゼの阻害によって改善される状態を治療するまたは予防する方法であって、それを必要とする患者に治療上有効な量の請求項1に記載の式Iaの化合物、またはその薬学上許容できる塩または溶媒和物を投与することを含む、前記方法。
- (i)治療上有効な量の請求項1に記載の式Iaの化合物、またはその薬学上許容できる塩または溶媒和物と、(ii)薬学上許容できる賦形剤とを含む医薬組成物。
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JPS61161267A (ja) * | 1985-01-08 | 1986-07-21 | スミスクライン・ベツクマン・コーポレイシヨン | ドーパミン‐β‐ヒドロキシラーゼ阻害剤 |
JPH04506967A (ja) * | 1989-07-27 | 1992-12-03 | ジー.ディー.サール アンド カンパニー | 高血圧症治療用腎選択性生成物 |
JPH07173143A (ja) * | 1993-12-17 | 1995-07-11 | Wakamoto Pharmaceut Co Ltd | 新規2−チオキソ−4−チアゾリジノン誘導体及び医薬 |
JPH09512269A (ja) * | 1994-04-26 | 1997-12-09 | シンテックス(ユー・エス・エイ) インコーポレイテッド | ベンゾシクロアルキルアゾールチオン誘導体 |
JP2019529460A (ja) * | 2016-09-23 | 2019-10-17 | ビアル−ポルテラ エ コンパニア,ソシエダッド アノニマ | 血管脳関門透過剤ドーパミン−b−ヒドロキシラーゼ阻害剤 |
Cited By (2)
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JP2021505568A (ja) * | 2017-12-04 | 2021-02-18 | ビアル−ポルテラ エ コンパニア,ソシエダッド アノニマ | ドーパミン−β−ヒドロキシラーゼ阻害剤 |
JP7167155B2 (ja) | 2017-12-04 | 2022-11-08 | ビアル-ポルテラ エ コンパニア,ソシエダッド アノニマ | ドーパミン-β-ヒドロキシラーゼ阻害剤 |
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