JP2021534076A - 新規脂質 - Google Patents
新規脂質 Download PDFInfo
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- JP2021534076A JP2021534076A JP2020569849A JP2020569849A JP2021534076A JP 2021534076 A JP2021534076 A JP 2021534076A JP 2020569849 A JP2020569849 A JP 2020569849A JP 2020569849 A JP2020569849 A JP 2020569849A JP 2021534076 A JP2021534076 A JP 2021534076A
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- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims description 7
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Abstract
Description
本出願は、2018年6月26日に出願された米国特許仮出願第62/690,196号に基づく優先権を主張するもので、その内容全体を参照により本明細書に組み込む。
なし
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、薬学的に許容されるカチオンの組込みは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心(stereogenic center)は独立に、R、S又はラセミである]
の新規脂質に関する。
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、薬学的に許容されるカチオンの組込みは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物を調製する方法であって、
(1)式II
の化合物のヒドロキシル基をエステル、カーボネート、カルバメート、又はまとめてアセタール若しくはケタールに変換するステップと、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む;あるいは
(1)式IIIの化合物を、リン酸ジエステル架橋の作製を通して式IVの化合物又は式Vの化合物に連結するステップ
と、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む、方法に関する。
本発明の少なくとも一実施形態は、式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、薬学的に許容されるカチオンの組込みは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の構造を提供する。
本発明の様々な実施形態の作製及び使用を以下に詳細に述べるが、本発明は、多種多様な具体的状況の中で具現化することができる多くの適用可能な発明概念を提供することが理解されよう。本明細書において述べられている具体的な実施形態は、本発明を作製及び使用する具体的な方式の例示にすぎず、本発明の範囲を限定するものではない。
一実施形態において、本発明は、式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、薬学的に許容されるカチオンの組込みは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物に関する。
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムであり、Li、Na及びKは、モノマー塩を形成し、Mg、Ca、Zn及びCsは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を形成し、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物に関する。
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、薬学的に許容されるカチオンの組込みは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物を調製する方法であって、
(1)式II
の化合物のヒドロキシル基をエステル、カーボネート、カルバメート、又はまとめてアセタール若しくはケタールに変換するステップと、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む;あるいは
(1)式IIIの化合物を、リン酸ジエステル架橋の作製を通して式IVの化合物又は式Vの化合物に連結するステップ
と、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む、方法に関する。
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムであり、Li、Na及びKは、モノマー塩を形成し、Mg、Ca、Zn及びCsは、塩、例えばモノマー塩、ダイマー塩、トリマー塩、又はマルチマー塩を形成し、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物を調製する方法であって、
(1)式II
の化合物のヒドロキシル基をエステル、カーボネート、カルバメート、又はまとめてアセタール若しくはケタールに変換するステップと、
(3)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む;あるいは
(1)式IIIの化合物を、リン酸ジエステル架橋の作製を通して式IVの化合物又は式Vの化合物に連結するステップ
と、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む、方法に関する。
本発明のいくつかの特徴を本明細書に図示及び説明してきたが、多くの修正、置換、変更、及び等価形態がここで当業者に思い浮かぶであろう。したがって、添付の特許請求の範囲は、本発明の真の精神の範囲内に入るような修正及び変更形態すべてを包含するように意図されていることを理解すべきである。
本発明の化合物の有効性の評価は、成熟雄性HartleyモルモットのECG測定を必要とし、PR、QRS、QT、QTc、JT、RRを記録した。典型的な実験において、登録時に体重300〜350gの成熟雄性Hartleyモルモットに、皮下Kaha TR50B生体電位テレメータを外科的に植え込んだ。あるリード線を心尖に縫合し、別のリード線を大動脈の側面に縫合した。動物は、試験群体に戻される前に5日間手術から回復させることができた。回復後に、動物を以下の通り2ラウンドの評価にかけた。
Claims (65)
- 式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、前記薬学的に許容されるカチオンの組込みは塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物。 - R4が、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムである、請求項1に記載の化合物。
- 単一体、溶媒和物、水和物、結晶、非晶質固体、液体又は油として存在する、請求項1〜32のいずれかに記載の化合物。
- 式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、前記薬学的に許容されるカチオンの組込みは塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物を調製する方法であって、
(1)式II
の化合物のヒドロキシル基をエステル、カーボネート、カルバメート、又はまとめてアセタール若しくはケタールに変換するステップと、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む;あるいは
(1)式IIIの化合物を、リン酸ジエステル架橋の作製を通して式IVの化合物又は式Vの化合物に連結するステップ
と、
(2)リンに結合したOH基をO−R4[式中、R4はHでない]に変換するステップと
を含む、前記方法。 - R4が、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムである、請求項34に記載の式Iの化合物を調製する方法。
- から選択される化合物を生成する、請求項34に記載の方法。
- 単一体、溶媒和物、水和物、結晶、非晶質固体、液体又は油として個別に存在する化合物を生成する、請求項34〜40のいずれかに記載の方法。
- 式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、前記薬学的に許容されるカチオンの組込みは塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物と薬学的に許容される希釈剤又は担体とを含む医薬組成物。 - 式Iの化合物のR4が、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムである、請求項41に記載の医薬組成物。
- 式Iの化合物が、単一体、溶媒和物、水和物、結晶、非晶質固体、液体又は油として存在する、請求項41に記載の医薬組成物。
- 心疾患を副作用として誘発する1又は2以上の薬剤をさらに含む、請求項41に記載の医薬組成物。
- 心疾患を副作用として誘発する薬剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルフィン、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、アンフェタミン、ジヒドロアルテミシニン及びピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバマート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レバルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、ペルフルトレン脂肪ミクロスフェア、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−スルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンを含む、請求項46に記載の医薬組成物。
- 1又は2以上の賦形剤、結合剤、粘着防止剤、コーティング剤、崩壊剤、充填剤、香料、染料、着色剤、流動化剤、滑沢剤、保存剤、収着剤、甘味剤、それらの誘導体、又はそれらの組合せをさらに含む、請求項41に記載の医薬組成物。
- 結合剤が、ヒドロキシプロピルメチルセルロース、エチルセルロース、ポビドン、アクリル酸及びメタクリル酸コポリマー、薬学的グレーズ、ガム、並びにミルク誘導体からなる群から選択される、請求項48に記載の医薬組成物。
- 式Iの化合物を単位用量当たり約1mg〜約1グラムの単位用量当たりの量で含む、請求項41に記載の医薬組成物。
- 経口、舌下、経皮、坐剤、髄腔内、経腸、非経口、静脈内、腹腔内、皮膚、皮下、局所、経肺、直腸、腟内、又は筋肉内投与用の製剤である、請求項41に記載の医薬組成物。
- 経口投与用の製剤が、錠剤、カプセル剤、カプレット剤、丸剤、散剤、トローチ剤、薬用キャンディー剤、スラリー剤、液体溶液剤、懸濁剤、乳剤、エリキシル剤又は経口フィルム剤(OTF)である、請求項51に記載の医薬組成物。
- 製剤が、固体形態、溶液剤、懸濁剤、又は軟質ゲル形態である、請求項51に記載の医薬組成物。
- ヒト又は動物対象において、心臓パターンの不規則性又は変化に起因する心臓チャネル病、心筋損傷、又は状態のうちの1又は2以上を低減又は除去する方法であって、前記ヒト又は動物対象に式I
R1は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R2は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC1−C20の分枝又は非分枝炭化水素であり、
R3は、
R4は、H又は薬学的に許容されるカチオンであり、前記薬学的に許容されるカチオンの組込みは塩を生じさせ、
R5は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R6は、OH、OAc、OMe、NH2、NHAc、NHMe、N(Me)2、SH、CN、COOH、CONH2、Cl、Br及びIから選択される1又は2以上の基で置換されていてもよいC1−C10の分枝又は非分枝炭化水素であり、
R7は、0〜10の二重結合、0〜10の三重結合又は0〜10の二重及び三重結合の組合せを有するC0−C20の分枝又は非分枝炭化水素であり、
R8は、H、又は0〜10の二重結合、0〜10の三重結合若しくは0〜10の二重及び三重結合の組合せを有するC0−C20の分枝若しくは非分枝炭化水素であり、
Xは、直接結合、CH2、O又はNHであり、
Yは、直接結合、CH2、O又はNHであり、
各不斉中心は独立に、R、S又はラセミである]
の化合物の1又は2以上を投与するステップを含む、前記方法。 - 式Iの化合物のR4が、H、Li、Na、K、Mg、Ca、Zn、Cs、アンモニウム又はテトラアルキルアンモニウムである、請求項54に記載の方法。
- 式Iの化合物が、単一体、溶媒和物、水和物、結晶、非晶質固体、液体又は油として存在する、請求項54に記載の方法。
- 式Iの化合物が、疾患を治療するために使用される活性薬剤によって引き起こされる心臓パターンの不規則性又は変化に起因する心臓チャネル病又は状態のうちの1又は2以上を低減又は除去する、請求項54に記載の方法。
- 式Iの化合物が、約1mg〜約1グラムの単位用量当たりの量で投与される、請求項54に記載の方法。
- 式Iの化合物が、経口、舌下、経皮、坐剤、髄腔内、経腸、非経口、静脈内、腹腔内、皮膚、皮下、局所、経肺、直腸、腟内、又は筋肉内投与用に製剤化されている、請求項54に記載の方法。
- 式Iの化合物が、経口投与用に錠剤、カプセル剤、カプレット剤、丸剤、散剤、トローチ剤、薬用キャンディー剤、スラリー剤、液体溶液剤、懸濁剤、乳剤、エリキシル剤又は経口フィルム剤(OTF)として製剤化されている、請求項59に記載の方法。
- 式Iの化合物が、固体形態、溶液剤、懸濁剤、又は軟質ゲル形態として製剤化されている、請求項54に記載の方法。
- 固体形態が、1又は2以上の賦形剤、結合剤、粘着防止剤、コーティング剤、崩壊剤、充填剤、香料、染料、着色剤、流動化剤、滑沢剤、保存剤、収着剤、甘味剤、それらの誘導体、又はそれらの組合せをさらに含む、請求項61に記載の方法。
- 式Iの化合物が、心疾患を副作用として誘発する1又は2以上の薬剤と共投与される、請求項54に記載の方法。
- 心疾患を副作用として誘発する1又は2以上の活性薬剤が、アルブテロール、アルフゾシン、アマンタジン、アミオダロン、アミスルプリド、アミトリプチリン、アモキサピン、アンフェタミン、アナグレリド、アポモルフィン、アルフォルモテロール、アリピプラゾール、三酸化ヒ素、アステミゾール、アタザナビル、アトモキセチン、アジスロマイシン、ベダキリン、ベプリジル、ボルテゾミブ、ボスチニブ、抱水クロラール、クロロキン、クロルプロマジン、シプロフロキサシン、シサプリド、シタロプラム、クラリスロマイシン、クロミプラミン、クロザピン、コカイン、クルクミン、クリゾチニブ、ダブラフェニブ、ダサチニブ、デシプラミン、デクスメデトミジン、デクスメチルフェニデート、デキストロアンフェタミン、アンフェタミン、ジヒドロアルテミシニン及びピペラキン、ジフェンヒドラミン、ジソピラミド、ドブタミン、ドフェチリド、ドラセトロン、ドンペリドン、ドーパミン、ドキセピン、ドロネダロン、ドロペリドール、エフェドリン、エピネフリン、アドレナリン、エリブリン、エリスロマイシン、エスシタロプラム、ファモチジン、フェルバマート、フェンフルラミン、フィンゴリモド、フレカイニド、フルコナゾール、フルオキセチン、ホルモテロール、ホスカルネット、ホスフェニトイン、フロセミド、フルセミド、ガランタミン、ガチフロキサシン、ゲミフロキサシン、グラニセトロン、ハロファントリン、ハロペリドール、ヒドロクロロチアジド、イブチリド、イロペリドン、イミプラミン、メリプラミン、インダパミド、イソプロテレノール、イスラジピン、イトラコナゾール、イバブラジン、ケトコナゾール、ラパチニブ、レバルブテロール、レボフロキサシン、レボメタジル、リスデキサンフェタミン、リチウム、メソリダジン、メタプロテレノール、メサドン、メタンフェタミン、メチルフェニデート、ミドドリン、ミフェプリストン、ミラベグロン、ミルタザピン、モエキシプリル/HCTZ、モキシフロキサシン、ネルフィナビル、ニカルジピン、ニロチニブ、ノルエピネフリン、ノルフロキサシン、ノルトリプチリン、オフロキサシン、オランザピン、オンダンセトロン、オキシトシン、パリペリドン、パロキセチン、パシレオチド、パゾパニブ、ペンタミジン、ペルフルトレン、フェンテルミン、フェニレフリン、フェニルプロパノールアミン、ピモジド、ポサコナゾール、プロブコール、プロカインアミド、プロメタジン、プロトリプチリン、プソイドエフェドリン、クエチアピン、キニジン、硫酸キニーネ、ラノラジン、リルピビリン、リスペリドン、リトドリン、リトナビル、ロキシスロマイシン、サルブタモール、サルメテロール、サキナビル、セルチンドール、セルトラリン、セボフルラン、シブトラミン、ソリフェナシン、ソラフェニブ、ソタロール、スパルフロキサシン、スルピリド、スニチニブ、タクロリムス、タモキシフェン、テラプレビル、テラバンシン、テリスロマイシン、テルブタリン、テルフェナジン、テトラベナジン、チオリダジン、チザニジン、トルテロジン、トレミフェン、トラゾドン、トリメトプリム−スルファ、トリミプラミン、バンデタニブ、バルデナフィル、ベムラフェニブ、ベンラファキシン、ボリコナゾール、ボリノスタット、又はジプラシドンのうちの少なくとも1種から選択される、請求項63に記載の方法。
- 式Iの化合物が、薬物誘発性である又は疾患若しくは状態によって引き起こされる、QT延長、心筋損傷、又はAVブロックなどの心疾患を低減又は除去する、請求項54に記載の方法。
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