JP6253668B2 - 認識障害の処置のためのヒスタミンh3受容体調節因子としてのビフェニル−エチル−ピロリジン誘導体 - Google Patents
認識障害の処置のためのヒスタミンh3受容体調節因子としてのビフェニル−エチル−ピロリジン誘導体 Download PDFInfo
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- JP6253668B2 JP6253668B2 JP2015551856A JP2015551856A JP6253668B2 JP 6253668 B2 JP6253668 B2 JP 6253668B2 JP 2015551856 A JP2015551856 A JP 2015551856A JP 2015551856 A JP2015551856 A JP 2015551856A JP 6253668 B2 JP6253668 B2 JP 6253668B2
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- diyl
- biphenyl
- methylpyrrolidin
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- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- 229940020965 zoloft Drugs 0.000 description 1
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Description
本発明は、ヒスタミンH3受容体(H3R)の活性を調節し、H3受容体関連障害、例えば、認知障害、てんかん、脳損傷、うつ病、肥満、睡眠および覚醒状態の障害、例えば、日中の過剰な眠気、ナルコレプシー、交代勤務睡眠障害、投薬からの副作用としての嗜眠状態、職務などの完遂に役立てるための覚醒状態の維持、脱力発作、過眠症、傾眠症候群、時差ぼけ、睡眠時無呼吸など、注意欠陥多動性障害(ADHD)、統合失調症、アレルギー、上気道におけるアレルギー反応、アレルギー性鼻炎、鼻閉、認知症、アルツハイマー病、疼痛、掻痒などの処置方法において有用である式(Ia)の化合物およびその医薬組成物に関する。
R1はC1〜C4アルキルであり、
R2は、C1〜C4アルコキシカルボニル、カルボキシルおよびテトラゾリルから選択され、
Wは、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびカルボニルから選択され、または
Wは存在せず、
Xは、−O−、−NHC=O−およびカルボニルから選択され、または
Xは存在せず、
Yは、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレン(heterocycylene)から選択され、または
Yは存在しない)
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体を包含する。
明確さおよび一貫性のため、本特許文書を通して、以下の定義を使用する。
(1)疾患を防止すること;例えば、疾患、状態または障害に罹りやすくなっている可能性があるが、その疾患の病変または兆候をまだ体験していないまたは示していない個体におけるこの疾患、状態または障害を防止すること、
(2)疾患を阻止すること;例えば、疾患、状態または障害の病変または兆候を体験しているまたは示している個体におけるこの疾患、状態または障害を阻止すること(すなわち、その病変および/または兆候のさらなる進行を停止させること)、および
(3)疾患を改善すること;例えば、疾患、状態または障害の病変または兆候を体験しているまたは示している個体におけるこの疾患、状態または障害を改善すること(すなわち、その病変および/または兆候を逆転させること)
の1つまたは複数を含む、研究者、獣医、医師または他の臨床医もしくは介護者;あるいは個人によって求められる、組織、系、動物、個体またはヒトにおいて生物学的または医薬的応答を誘発する活性な化合物または薬剤の量を指す。
化学基、部分またはラジカル
本発明の化合物:
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
いくつかの実施形態では、R1はC1〜C4アルキルである。
いくつかの実施形態では、R1はメチルである。
いくつかの実施形態では、R2は、C1〜C4アルコキシカルボニル、カルボキシルおよびテトラゾリルから選択される。
いくつかの実施形態では、R2は、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択される。
いくつかの実施形態では、R2はC1〜C4アルコキシカルボニルである。
いくつかの実施形態では、R2は、メトキシカルボニル、エトキシカルボニルおよびtert−ブトキシカルボニルから選択される。
いくつかの実施形態では、R2はカルボキシルである。
いくつかの実施形態では、R2はテトラゾリルである。
いくつかの実施形態では、R2は、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択される。
いくつかの実施形態では、R2はメトキシカルボニルである。
いくつかの実施形態では、R2はエトキシカルボニルである。
いくつかの実施形態では、R2はtert−ブトキシカルボニルである。
いくつかの実施形態では、R2は1H−テトラゾール−1−イルである。
いくつかの実施形態では、R2は2H−テトラゾール−2−イルである。
いくつかの実施形態では、R2は1H−テトラゾール−5−イルである。
いくつかの実施形態では、Wは、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびカルボニルから選択され、またはWは存在しない。
いくつかの実施形態では、Wは、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイル、シクロペンタン−1,1−ジイルおよびカルボニルから選択される。
いくつかの実施形態では、WはC1〜C4アルキレンである。
いくつかの実施形態では、Wは、メチレン、エタン−1,2−ジイル、プロパン−1,3−ジイルおよびプロパン−2,2−ジイルから選択される。
いくつかの実施形態では、WはC3〜C7シクロアルキレンである。
いくつかの実施形態では、Wはシクロペンタン−1,1−ジイルである。
いくつかの実施形態では、Wはカルボニルである。
いくつかの実施形態では、Wはメチレンである。
いくつかの実施形態では、Wはエタン−1,2−ジイルである。
いくつかの実施形態では、Wはプロパン−2,2−ジイルである。
いくつかの実施形態では、Wはプロパン−1,3−ジイルである。
いくつかの実施形態では、Wはカルボニルである。
いくつかの実施形態では、Wは存在しない。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
いくつかの実施形態では、Xは、−O−、−NHC=O−およびカルボニルから選択され、またはXは存在しない。
いくつかの実施形態では、Xは−O−である。
いくつかの実施形態では、Xは−NHC=O−である。
いくつかの実施形態では、Xはカルボニルである。
いくつかの実施形態では、Xは存在しない。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
いくつかの実施形態では、Yは、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレンから選択され、またはYは存在しない。
いくつかの実施形態では、Yは、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択される。
いくつかの実施形態では、YはC1〜C4アルキレンである。
いくつかの実施形態では、Yは、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイルおよびエタン−1,2−ジイルから選択される。
いくつかの実施形態では、YはC3〜C7シクロアルキレンである。
いくつかの実施形態では、Yはシクロヘキサン−1,2−ジイルである。
いくつかの実施形態では、Yはヘテロシクリレンである。
いくつかの実施形態では、Yは、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択される。
いくつかの実施形態では、Yはメチレンである。
いくつかの実施形態では、Yはプロパン−2,2−ジイルである。
いくつかの実施形態では、Yはプロパン−1,3−ジイルである。
いくつかの実施形態では、Yはエタン−1,1−ジイルである。
いくつかの実施形態では、Yはエタン−1,2−ジイルである。
いくつかの実施形態では、Yはピロリジン−1,2−ジイルである。
いくつかの実施形態では、Yはピペリジン−1,4−ジイルである。
いくつかの実施形態では、Yは存在しない。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
いくつかの実施形態では、WとXはどちらも存在しない。
いくつかの実施形態では、WとYはどちらも存在しない。
いくつかの実施形態では、XとYはどちらも存在しない。
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択されるある特定のビフェニル誘導体に関する。
末梢拘束性化合物
本発明のある特定の組合せ
R2が、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択され、
Wが、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイル、シクロペンタン−1,1−ジイルおよびカルボニルから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択され、または
Yが存在しない、
式(Ic)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
R2が、C1〜C4アルコキシカルボニル、カルボキシルおよびテトラゾリルから選択され、
Wが、C1〜C4アルキレンおよびC3〜C7シクロアルキレンから選択され、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレンから選択され、または
Yが存在しない、
式(Ic)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
R2が、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択され、
Wが、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイルおよびシクロペンタン−1,1−ジイルから選択され、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択され、または
Yが存在しない、
式(Ic)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
R2が、C1〜C4アルコキシカルボニルおよびカルボキシルから選択され、
Wが、C1〜C4アルキレンおよびC3〜C7シクロアルキレンから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、
Yが、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレンから選択される、
式(Ic)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
R2が、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニルおよびカルボキシルから選択され、
Wが、メチレン、エタン−1,2−ジイルおよびシクロペンタン−1,1−ジイルから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択される、
式(Ic)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
Wが、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイルおよびシクロペンタン−1,1−ジイルから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイルおよびピロリジン−1,2−ジイルから選択され、または
Yが存在しない、
式(Ie)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
Wが、C1〜C4アルキレンおよびC3〜C7シクロアルキレンから選択され、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレンから選択され、または
Yが存在しない、
式(Ie)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
Wが、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイルおよびシクロペンタン−1,1−ジイルから選択され、
Xが、−O−、−NHC=O−およびカルボニルから選択され、または
Xが存在せず、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイルおよびピロリジン−1,2−ジイルから選択され、または
Yが存在しない、
式(Ie)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
Wが、C1〜C4アルキレンおよびC3〜C7シクロアルキレンから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、
Yが、C1〜C4アルキレン、C3〜C7シクロアルキレンおよびヘテロシクリレンから選択される、
式(Ie)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
Wが、メチレン、エタン−1,2−ジイルおよびシクロペンタン−1,1−ジイルから選択され、または
Wが存在せず、
Xが、−O−、−NHC=O−およびカルボニルから選択され、
Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイルおよびピロリジン−1,2−ジイルから選択される、
式(Ie)の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物に関する。
4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−カルボン酸;2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)酢酸;3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸;エチル2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)アセテート;2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)酢酸;2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エトキシ)酢酸;1−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール;2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−2H−テトラゾール;メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート;2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸;エチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート;tert−ブチル2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;tert−ブチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;エチル2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート;エチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;メチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート;2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸;2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸;1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボン酸;エチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート;メチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;tert−ブチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;tert−ブチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート;メチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート;メチル1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキシレート;tert−ブチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート;メチル2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)アセテート;メチル2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)酢酸;2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボン酸;tert−ブチル3−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;1−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピロリジン−2−カルボン酸;4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタン酸;tert−ブチル4−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)ブタノエート;エチル1−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピペリジン−4−カルボキシレート;4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)−4−オキソブタン酸;5−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メチル)−1H−テトラゾール;メチル2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート;メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート;メチル2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)アセテート;2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)酢酸;2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸;3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸;5−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール;4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタン酸;およびエチル4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタノエート
ならびにその薬学的に許容される塩、溶媒和物および水和物から選択される1つまたは複数の化合物のいずれの組合せも包含する。
予防および/または処置の適応症および方法
本発明のある特定の実施形態
医薬組成物
水和物および溶媒和物
同位体
他の有用性
A.Sandmeyerなどの反応:この手順は、アリールアミンまたはヘテロアリールアミンをジアゾニウムテトラフルオロホウ酸塩などのジアゾニウム塩に転換させ、続いてNa125Iを使用して125I標識化合物に転換させる。代表的な手順は、Zhu, G−Dおよび共同研究者によって、J. Org. Chem.、2002年、67巻、943〜948頁に報告された。
本発明の化合物の合成。
本発明の化合物の調製のための一般合成スキームを図1〜図4に例示する。ここで、記号は本開示を通して使用されるものと同じ定義を有する。
(実施例1.1)
(R)−4−(2−(2−メチルピロリジン−1−イル)エチル)フェニルボロン酸の調製。
ステップA:(R)−1−(4−ブロモフェネチル)−2−メチルピロリジンの調製。
ステップB:(R)−4−(2−(2−メチルピロリジン−1−イル)エチル)フェニルボロン酸の調製。
(実施例1.2)
(R)−2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エトキシ)酢酸(化合物6)の調製。
ステップA:(R)−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エタノールの調製。
ステップB:(R)−2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エトキシ)酢酸(化合物6)の調製。
(実施例1.3)
(R)−1−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール(化合物7)および(R)−2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−2H−テトラゾール(化合物8)の調製。
(実施例1.4)
(R)−メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート(化合物9)の調製。
(実施例1.5)
(R)−2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸(化合物10)の調製。
(実施例1.6)
(R)−エチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート(化合物11)の調製。
(実施例1.7)
(R)−tert−ブチル2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート(化合物12)の調製。
(実施例1.8)
(S)−tert−ブチル2−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート(化合物13)の調製。
(実施例1.9)
(1R,2R)−エチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート(化合物14)の調製。
(実施例1.10)
(R)−エチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート(化合物15)の調製。
(実施例1.11)
(R)−メチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート(化合物16)の調製。
(実施例1.12)
(R)−2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸(化合物17)の調製。
(実施例1.13)
(S)−2−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸(化合物18)の調製。
(実施例1.14)
(R)−1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボン酸(化合物19)の調製。
(実施例1.15)
(1R,2S)−エチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート(化合物20)の調製。
(実施例1.16)
(R)−メチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート(化合物21)の調製。
(実施例1.17)
(R)−tert−ブチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート(化合物22)の調製。
(実施例1.18)
(R)−tert−ブチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート(化合物23)の調製。
(実施例1.19)
(R)−メチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート(化合物24)の調製。
(実施例1.20)
(R)−メチル1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキシレート(化合物25)の調製。
(実施例1.21)
(R)−tert−ブチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート(化合物26)の調製。
(実施例1.22)
(R)−メチル2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)アセテート(化合物27)の調製。
(実施例1.23)
(S)−メチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート(化合物28)の調製。
(実施例1.24)
(R)−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)酢酸(化合物29)の調製。
(実施例1.25)
(1R,2R)−2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボン酸(化合物30)の調製。
(実施例1.26)
(R)−tert−ブチル3−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート(化合物31)の調製。
(実施例1.27)
(S)−1−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピロリジン−2−カルボン酸(化合物32)の調製。
(実施例1.28)
(R)−4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタン酸(化合物33)の調製。
(実施例1.29)
(R)−tert−ブチル4−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)ブタノエート(化合物34)の調製。
(実施例1.30)
(R)−エチル1−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピペリジン−4−カルボキシレート(化合物35)の調製。
(実施例1.31)
(R)−5−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メチル)−1H−テトラゾール(化合物37)の調製。
(実施例1.32)
(R)−5−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール(化合物44)の調製。
(実施例1.33)
(R)−4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタン酸(化合物45)の調製。
(実施例1.34)
HCl塩としての(R)−エチル4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタノエート(化合物46)の調製。
(実施例1.35)
(R)−エチル2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)アセテート(化合物4)の調製。
ステップA:エチル2−(4−ブロモベンジルオキシ)アセテートの調製。
ステップB:(R)−エチル2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)アセテートの調製。
(実施例1.36)
(R)−2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)酢酸(化合物5)の調製。
(実施例1.37)
(R)−4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)−4−オキソブタン酸(化合物36)の調製。
(実施例1.38)
(R)−メチル2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート(化合物38)の調製。
(実施例1.39)
(R)−メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート(化合物39)の調製。
(実施例1.40)
(R)−メチル2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)アセテート(化合物40)の調製。
(実施例1.41)
(R)−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)酢酸(化合物41)の調製。
(実施例1.42)
(R)−2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸(化合物42)の調製。
(実施例1.43)
(R)−3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸(化合物43)の調製。
(実施例1.44)
(R)−4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−カルボン酸(化合物1)の調製。
(実施例1.45)
(R)−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)酢酸(化合物2)の調製。
(実施例1.46)
(R)−3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸(化合物3)の調製。
(実施例2)
[3H]N−α−メチル−ヒスタミン競合的ヒスタミンH3受容体結合アッセイ。
(実施例3)
受容体結合アッセイ
(実施例3.1)
ヒトヒスタミンH3受容体結合アッセイ−MDS Pharma Services(Taiwan)。
(実施例3.2)
ラット皮質H3受容体放射性リガンド結合アッセイ。
(実施例3.3)
GPCR活性化または阻害の判定のためアッセイ。
1.膜[35S]GTPγS結合アッセイ。
ヒトH3受容体GTPγSアッセイ。
2.cAMPアッセイ。
ヒトH3受容体HTRF cAMPアッセイ。
3.ツメガエル(Xenopus)メラノフォアアッセイ。
H3受容体は恒常的に活性なGi共役受容体であるため、H3受容体を発現するメラノフォアは、静止状態で部分的な色素凝集を示すことになる。H3受容体アゴニストまたは逆アゴニストでの刺激は、さらなる色素の凝集または分散をそれぞれ引き起こす。H3受容体に対するニュートラルアンタゴニストは、選択的H3受容体アゴニストによって刺激される色素凝集を阻害するその能力によって検出される。
4.細胞内カルシウムおよびイノシトールリン酸アッセイ。
H3受容体などのGqのGタンパク質と通常共役しない受容体は、ないまぜの(promiscuous)Gタンパク質(G15およびG16)を使用することによってIP/カルシウムシグナル伝達経路と人工的に共役させることができる。これらのGタンパク質は、Gq経路を通してシグナル伝達し、したがって細胞内カルシウム放出を制御するが、それらがGqタンパク質と通常交互作用しない受容体と共役できるという意味でないまぜである。あるいは、キメラGタンパク質を使用することができる。これらのキメラタンパク質は、典型的には、カルボキシ末端のおよそ5個のアミノ酸がGiαサブユニット由来の対応するアミノ酸で置き換えられているGqαタンパク質を利用する。得られるキメラαサブユニットは、Gi共役受容体を認識しそのGi共役受容体によって活性化されるが、Gq経路を通してシグナル伝達して、細胞内カルシウムを放出する。
5.βアレスチンアッセイ。
アレスチン移動アッセイ
アレスチン−受容体相互作用アッセイ
6.レポーター遺伝子アッセイ。
RAMH誘発飲水の遮断アッセイ。
齧歯動物に投与した場合、(R)−α−メチル−ヒスタミン(RAMH)などのH3受容体アゴニストは、H3受容体阻害剤での逆転に敏感な飲水応答を誘発する。したがって、RAMH誘発飲水の遮断は、機能的H3受容体阻害活性についてのインビボでのアッセイとして利用することができる。このアッセイでは、雄のSprague Dawleyラット(250〜350g)をケージ当たり3匹収容し、逆転した12h光周期(1130hに光を切る)下に保持する。試験日の1030hに、ラットを個別に新しいケージに収容し、食物を取り除く。120分後、ラットに試験品(ビヒクルまたはH3受容体阻害剤、0.3mg/kg PO)を投与する。30分後、水を除去し、RAMH(ビヒクルまたはRAMH 3mg/kg塩 SC)を投与する。RAMHの投与10分後、計量した水の瓶をケージに入れ、20分間飲水を可能にする。各瓶を最近接の0.1gまで計量することによって、水の消費を各動物について測定する。データは、以下の式:
[((VEH/RAMH)−(アンタゴニスト/RAMH))/((VEH/RAMH)−(VEH/VEH))]*100
にしたがって、水摂取の減少率%で表される。
(実施例5)
掻痒のためのヒスタミン誘発モデル。
(実施例6)
掻痒のためのヒスタミン誘発モデル
(実施例7)
雄C57BL6マウスにおける化合物3の薬理学的試験、脳と血漿の比の測定。
(実施例8)
掻痒についてのアレルギーモデルにおけるH3Rアンタゴニスト
Claims (31)
- R1がメチルである、請求項1に記載の化合物。
- R2が、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択される、請求項1または2に記載の化合物。
- R2がC1〜C4アルコキシカルボニルである、請求項1または2に記載の化合物。
- R2が、メトキシカルボニル、エトキシカルボニルおよびtert−ブトキシカルボニルから選択される、請求項4に記載の化合物。
- R2がカルボキシルである、請求項1または2に記載の化合物。
- Wが、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイル、シクロペンタン−1,1−ジイルおよびカルボニルから選択される、請求項1〜6のいずれか一項に記載の化合物。
- WがC1〜C4アルキレンである、請求項1〜6のいずれか一項に記載の化合物。
- Wが、メチレン、エタン−1,2−ジイル、プロパン−1,3−ジイルおよびプロパン−2,2−ジイルから選択される、請求項8に記載の化合物。
- Wが存在しない、請求項1〜6のいずれか一項に記載の化合物。
- Xが存在しない、請求項1〜10のいずれか一項に記載の化合物。
- Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択される、請求項1〜11のいずれか一項に記載の化合物。
- YがC1〜C4アルキレンである、請求項1〜11のいずれか一項に記載の化合物。
- Yが、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイルおよびエタン−1,2−ジイルから選択される、請求項13に記載の化合物。
- Yが存在しない、請求項1〜11のいずれか一項に記載の化合物。
- 式(Ic):
R2は、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択され、
Wは、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイル、シクロペンタン−1,1−ジイルおよびカルボニルから選択され、または
Wは存在せず
、
Xは、−O−、−NHC=O−およびカルボニルから選択され、または
Xは存在せず、
Yは、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択され、または
Yは存在しない)
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択される、請求項1に記載の化合物。 - 式(Ic):
R2は、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、カルボキシル、1H−テトラゾール−1−イル、2H−テトラゾール−2−イルおよび1H−テトラゾール−5−イルから選択され、
Wは、メチレン、エタン−1,2−ジイル、プロパン−2,2−ジイル、プロパン−1,3−ジイルおよびシクロペンタン−1,1−ジイルから選択され、
Xは、−O−、−NHC=O−およびカルボニルから選択され、または
Xは存在せず、
Yは、メチレン、プロパン−2,2−ジイル、プロパン−1,3−ジイル、エタン−1,1−ジイル、エタン−1,2−ジイル、シクロヘキサン−1,2−ジイル、ピロリジン−1,2−ジイルおよびピペリジン−1,4−ジイルから選択され、または
Yは存在しない)
の化合物ならびにその薬学的に許容される塩、溶媒和物および水和物から選択される、請求項1に記載の化合物。 - 以下の化合物:
(R)−4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−カルボン酸;
(R)−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)酢酸;
(R)−3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸;
(R)−エチル2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)アセテート;
(R)−2−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メトキシ)酢酸;
(R)−2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エトキシ)酢酸;
(R)−1−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール;
(R)−2−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−2H−テトラゾール;
(R)−メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート;
(R)−2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパン酸;
(R)−エチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノエート;
(R)−tert−ブチル2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;
(S)−tert−ブチル2−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;
(1R,2R)−エチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート;
(R)−エチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;
(R)−メチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート;
(R)−2−メチル−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸;
(S)−2−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパン酸;
(R)−1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボン酸;
(1R,2S)−エチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボキシレート;
(R)−メチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;
(R)−tert−ブチル3−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;
(R)−tert−ブチル4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタノエート;
(R)−メチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート;
(R)−メチル1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキシレート;
(R)−tert−ブチル2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)アセテート;
(R)−メチル2−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)アセテート;
(S)−メチル2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)プロパノエート;
(R)−2−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)酢酸;
(1R,2R)−2−(1−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)シクロヘキサンカルボン酸;
(R)−tert−ブチル3−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)プロパノエート;
(S)−1−(3−(4’−(2−((R)−2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピロリジン−2−カルボン酸;
(R)−4−(1−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)シクロペンタンカルボキサミド)ブタン酸;
(R)−tert−ブチル4−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパンアミド)ブタノエート;
(R)−エチル1−(3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)プロパノイル)ピペリジン−4−カルボキシレート;
(R)−4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)−4−オキソブタン酸;
(R)−5−((4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)メチル)−1H−テトラゾール;
(R)−メチル2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート;
(R)−メチル3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパノエート;
(R)−メチル2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)アセテート;
(R)−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)酢酸;
(R)−2−メチル−2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸;
(R)−3−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イルカルボキサミド)プロパン酸;
(R)−5−(2−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)エチル)−1H−テトラゾール;
(R)−4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタン酸;および
(R)−エチル4−(4’−(2−(2−メチルピロリジン−1−イル)エチル)ビフェニル−4−イル)ブタノエート
ならびにその薬学的に許容される塩、溶媒和物および水和物から選択される、請求項1に記載の化合物。 - 請求項1〜23のいずれか一項に記載の化合物および薬学的に許容される担体を含む医薬組成物。
- 覚醒状態を誘発するための医薬品の製造における、請求項1〜23のいずれか一項に記載の化合物の使用。
- H3受容体関連障害の処置のための医薬品の製造における、請求項1〜23のいずれか一項に記載の化合物または請求項24に記載の医薬組成物の使用。
- 認知障害、てんかん、脳損傷、うつ病、肥満、睡眠および覚醒状態の障害、ナルコレプシー、交代勤務睡眠障害、脱力発作、過眠症、傾眠症候群、時差ぼけ、睡眠時無呼吸、日中の過剰な眠気、注意欠陥多動性障害(ADHD)、統合失調症、アレルギー、上気道におけるアレルギー反応、アレルギー性鼻炎、鼻閉、認知症、アルツハイマー病、疼痛および掻痒の群から選択される障害の処置のための医薬品の製造における、請求項1〜23のいずれか一項に記載の化合物または請求項24に記載の医薬組成物の使用。
- アレルギー性鼻炎の処置のための医薬品の製造における、請求項1〜23のいずれか一項に記載の化合物または請求項24に記載の医薬組成物の使用。
- 掻痒の処置のための医薬品の製造における、請求項1〜23のいずれか一項に記載の化合物または請求項24に記載の医薬組成物の使用。
- 前記掻痒が、湿疹、アトピー性湿疹様皮膚炎、脂漏性皮膚炎、アトピー性皮膚炎、接触性皮膚炎、刺激性皮膚炎、乾燥症(ドライスキン)、乾癬、真菌感染症、足白癬、イースト菌感染症、おむつ皮膚炎、膣のかゆみ、寄生虫感染症、疥癬およびシラミを含む寄生虫の繁殖、扁平苔癬、単純苔癬、慢性単純性苔癬、硬化性苔癬、投薬に後続するかゆみ、老人性かゆみ、尿毒症、特発性かゆみ、肝硬変に関連するかゆみ、炎症に関連するかゆみ、アレルギーに関連するかゆみ、がんに関連するかゆみ、化学療法に関連するかゆみ、腎疾患に関連するかゆみ、血液透析に関連するかゆみ、熱傷、やけど、日焼け、創傷治癒、刺虫症に関連するかゆみ、ノミ咬傷に関連するかゆみ、虫刺されに関連するかゆみ、蚊による刺されに関連するかゆみ、ダニ咬傷に関連するかゆみ、じん麻疹、植物によって引き起こされるじん麻疹、ツタウルシによって引き起こされるじん麻疹、イラクサによって引き起こされるじん麻疹、汗腺異常、水疱性類天疱瘡、光線皮膚症、皮膚疱疹、成人座瘡、水疱瘡および疱疹状皮膚炎から選択される障害に関連する、請求項29に記載の化合物または医薬組成物の使用。
- 請求項1〜23のいずれか一項に記載の化合物と薬学的に許容される担体とを混合する工程を含む、医薬組成物を調製するためのプロセス。
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PCT/US2014/010632 WO2014110103A1 (en) | 2013-01-09 | 2014-01-08 | Biphenyl-ethyl-pyrrolidine derivatives as histamine h3 receptor modulators for the treatment of cognitive disorders |
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US5869479A (en) | 1997-08-14 | 1999-02-09 | Schering Corporation | Treatment of upper airway allergic responses |
WO2002074758A2 (en) * | 2001-03-16 | 2002-09-26 | Abbott Laboratories | Novel amines as histamine-3 receptor ligands and their therapeutic applications |
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US20050245543A1 (en) * | 2004-04-30 | 2005-11-03 | Pfizer Inc | Histamine-3 receptor antagonists |
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US20060014733A1 (en) * | 2004-07-19 | 2006-01-19 | Pfizer Inc | Histamine-3 agonists and antagonists |
WO2008005338A1 (en) * | 2006-06-29 | 2008-01-10 | Arena Pharmaceuticals, Inc. | Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto |
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CN105263914B (zh) | 2017-10-27 |
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US20150353488A1 (en) | 2015-12-10 |
DK3309150T3 (da) | 2021-08-30 |
WO2014110103A1 (en) | 2014-07-17 |
PT3309150T (pt) | 2021-08-31 |
EP2943473A1 (en) | 2015-11-18 |
LT3309150T (lt) | 2021-10-25 |
JP2016504388A (ja) | 2016-02-12 |
CN105263914A (zh) | 2016-01-20 |
US9365511B2 (en) | 2016-06-14 |
HK1219953A1 (zh) | 2017-04-21 |
EP3889141A1 (en) | 2021-10-06 |
EP2943473B1 (en) | 2017-08-23 |
HK1253019A1 (zh) | 2019-06-06 |
ES2647965T3 (es) | 2017-12-27 |
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