JP2018527339A - Lsd1阻害剤の塩 - Google Patents
Lsd1阻害剤の塩 Download PDFInfo
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- JP2018527339A JP2018527339A JP2018506930A JP2018506930A JP2018527339A JP 2018527339 A JP2018527339 A JP 2018527339A JP 2018506930 A JP2018506930 A JP 2018506930A JP 2018506930 A JP2018506930 A JP 2018506930A JP 2018527339 A JP2018527339 A JP 2018527339A
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Classifications
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Description
本開示は、LSD1阻害剤の酸塩及びその結晶形態に関する。具体的には、本明細書において、LSD1阻害剤のp−トルエンスルホン酸(トシル酸)塩及びその結晶形態が提供される。本明細書に記載される塩及び結晶形態は、多くの利点を有し、例えば、取り扱いの容易さ、処理の容易さ、貯蔵安定性、及び精製の容易さなどの望ましい特性を有する。さらに、塩及び結晶形態は、溶解プロファイル、貯蔵寿命、及び生物学的利用能などの医薬製品の性能特性を改善するために有用であり得る。
本明細書で使用される場合、単独でまたは他の用語との組み合わせで用いられる「Ci〜jアルキル」という用語は、i〜j個の炭素を有する、直鎖または分枝状であり得る飽和炭化水素基を指す。いくつかの実施形態では、アルキル基は、1〜6個の炭素原子、または1〜4個の炭素原子、または1〜3個の炭素原子を含有する。アルキル部分の例としては、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、s−ブチル、及びt−ブチルなどの化学基が挙げられるが、これらに限定されない。
一態様では、本開示は、1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸のp−トルエンスルホン酸(もしくはトシル酸)塩、またはその水和物もしくは溶媒和物を提供する。化合物Iは、下記式を有する1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸を指す。
いくつかの実施形態では、結晶性固体は、下記の実施例において記載される形態Iを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約4.9(例えば、4.9±0.3または4.9±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約6.2(例えば、6.2±0.3または6.2±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約7.7(例えば、7.7±0.3または7.7±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約22.7(例えば、22.7±0.3または22.7±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約4.9(例えば、4.9±0.3もしくは4.9±0.2)または約6.2(例えば、6.2±0.3もしくは6.2±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3もしくは4.9±0.2)、または約6.2(例えば、6.2±0.3もしくは6.2±0.2)度で少なくとも1つの特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3もしくは4.9±0.2)、約6.2(例えば、6.2±0.3または6.2±0.2)、約7.7(例えば、7.7±0.3または7.7±0.2)、及び約22.7(例えば、22.7±0.3または22.7±0.2)度から選択される2つ以上の特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3または4.9±0.2)、約6.2(6.2±0.3または6.2±0.2)、約7.7(例えば、7.7±0.3または7.7±0.2)、約22.7(例えば、22.7±0.3または22.7±0.2)、約8.9(例えば、8.9±0.3または8.9±0.2)、約10.0(例えば、10.0±0.3または10.0±0.2)、約11.5(例えば、11.5±0.3または11.5±0.2)、約14.3(例えば、14.3±0.3または14.3±0.2)、約15.0(例えば、15.0±0.3または15.0±0.2)、約15.5(例えば、15.5±0.3または15.5±0.2)、約16.3(例えば、16.3±0.3または16.3±0.2)、約17.8(例えば、17.8±0.3または17.8±0.2)、約19.1(例えば、19.1±0.3または19.1±0.2)、約19.8(例えば、19.8±0.3または19.8±0.2)、約20.9(例えば、20.9±0.3または20.9±0.2)、及び約22.2(例えば、22.2±0.3または22.2±0.2)度から選択される2つ以上の特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3または4.9±0.2)、約6.2(6.2±0.3または6.2±0.2)、約7.7(例えば、7.7±0.3または7.7±0.2)、約22.7(例えば、22.7±0.3または22.7±0.2)、約8.9(例えば、8.9±0.3または8.9±0.2)、約10.0(例えば、10.0±0.3または10.0±0.2)、約11.5(例えば、11.5±0.3または11.5±0.2)、約14.3(例えば、14.3±0.3または14.3±0.2)、約15.0(例えば、15.0±0.3または15.0±0.2)、約15.5(例えば、15.5±0.3または15.5±0.2)、約16.3(例えば、16.3±0.3または16.3±0.2)、約17.8(例えば、17.8±0.3または17.8±0.2)、約19.1(例えば、19.1±0.3または19.1±0.2)、約19.8(例えば、19.8±0.3または19.8±0.2)、約20.9(例えば、20.9±0.3または20.9±0.2)、及び約22.2(例えば、22.2±0.3または22.2±0.2)度から選択される3つ以上の特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、2θに関して、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3または4.9±0.2)、約6.2(6.2±0.3または6.2±0.2)、約7.7(例えば、7.7±0.3または7.7±0.2)、約22.7(例えば、22.7±0.3または22.7±0.2)、約8.9(例えば、8.9±0.3または8.9±0.2)、約10.0(例えば、10.0±0.3または10.0±0.2)、約11.5(例えば、11.5±0.3または11.5±0.2)、約14.3(例えば、14.3±0.3または14.3±0.2)、約15.0(例えば、15.0±0.3または15.0±0.2)、約15.5(例えば、15.5±0.3または15.5±0.2)、約16.3(例えば、16.3±0.3または16.3±0.2)、約17.8(例えば、17.8±0.3または17.8±0.2)、約19.1(例えば、19.1±0.3または19.1±0.2)、約19.8(例えば、19.8±0.3または19.8±0.2)、約20.9(例えば、20.9±0.3または20.9±0.2)、及び約22.2(例えば、22.2±0.3または22.2±0.2)度から選択される4つ以上の特徴的なXRPDピークを有する。いくつかの実施形態では、形態Iは、約3.6(例えば、3.6±0.3または3.6±0.2)、約4.9(例えば、4.9±0.3または4.9±0.2)、約6.2(6.2±0.3または6.2±0.2)、約7.7(例えば、7.7±0.3または7.7±0.2)、約22.7(例えば、22.7±0.3または22.7±0.2)、約8.9(例えば、8.9±0.3または8.9±0.2)、約10.0(例えば、10.0±0.3または10.0±0.2)、約11.5(例えば、11.5±0.3または11.5±0.2)、約14.3(例えば、14.3±0.3または14.3±0.2)、約15.0(例えば、15.0±0.3または15.0±0.2)、約15.5(例えば、15.5±0.3または15.5±0.2)、約16.3(例えば、16.3±0.3または16.3±0.2)、約17.8(例えば、17.8±0.3または17.8±0.2)、約19.1(例えば、19.1±0.3または19.1±0.2)、約19.8(例えば、19.8±0.3または19.8±0.2)、約20.9(例えば、20.9±0.3または20.9±0.2)、及び約22.2(例えば、22.2±0.3または22.2±0.2)度2θ、及びそれらの組み合わせから選択される1つ以上の特徴的なピークを含むX線粉末回折パターンを有する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態HIと称される化合物Iジトシル酸塩の結晶形態に関する。実験的証拠は、形態HIが、化合物Iジトシル酸塩の水和形態であることを示す。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態HIIと称される化合物Iジトシル酸塩の結晶形態に関する。実験的証拠は、形態HIIが、化合物Iジトシル酸塩の水和形態であることを示す。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態HIIIと称される化合物Iジトシル酸塩の結晶形態に関する。実験的証拠は、形態HIIIが、化合物Iジトシル酸塩の水和形態であることを示す。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態DHと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IIIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IIIaと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IVと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IVaと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態Vと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態VIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態VIIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態VIIIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態IXと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態Xと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態XIと称される化合物Iジトシル酸塩の結晶形態に関する。
いくつかの実施形態では、本出願は、下記及び実施例において記載される、形態XIIと称される化合物Iジトシル酸塩の結晶形態に関する。
別の態様では、本開示は、化合物Iのジトシル酸塩、すなわち、1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)の調製方法を提供する。この方法は、下記式を有する1−{[4−({(tert−ブトキシカルボニル)[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)−4−(メトキシメチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸(11)を、
ジトシル酸塩を含む本明細書に記載される化合物Iのトシル酸塩は、LSD1の活性を阻害することができ、したがってLSD1の活性と関連した疾患及び障害の治療において有用である。本開示は、個体(例えば、患者)におけるLSD1関連または媒介性疾患または障害の治療方法であって、そのような治療を必要とする個体に、治療有効量または用量の化合物Iトシル酸塩、またはその実施形態のうちのいずれか、またはその薬学的組成物を投与することによる治療方法を提供する。本開示はまた、LSD1関連または媒介性疾患または障害の治療に使用するための、化合物Iジトシル酸塩、またはその実施形態のうちのいずれか、またはその薬学的組成物を提供する。また、LSD1関連または媒介性疾患または障害を治療するための医薬品の製造における、化合物Ip−トルエンスルホン酸塩、またはその実施形態のうちのいずれか、またはその薬学的組成物が提供される。
癌細胞成長及び生存は、複数のシグナル伝達経路によって影響を受け得る。したがって、異なるキナーゼ阻害剤を組み合わせて(それらが活性を調節するキナーゼにおいて異なる選好を示す)、そのような病態を治療することが有用である。2つ以上のシグナル伝達経路(または所定のシグナル伝達経路に関与する2つ以上の生物学的分子)を標的とすることは、細胞集団において生じる薬物抵抗の可能性を低減し、かつ/または治療の毒性を低減することができる。
本開示の塩は、薬学的組成物の形態で投与され得る。したがって、本開示は、本発明の塩、またはその実施形態のうちのいずれか、及び少なくとも1つの薬学的に許容される担体を含む組成物を提供する。これらの組成物は、薬学的分野において周知の方法で調製され得、局所または全身治療が示されるかどうか、及び治療される領域に応じて様々な経路によって投与され得る。投与は、局所(経皮、上皮、眼を含む、及び粘膜(鼻腔内、膣、及び直腸送達を含む))、肺(例えば、粉末またはエアロゾルの吸入または吹送(噴霧器によるものを含む)、髄腔内または鼻腔内)、経口または非経口であり得る。非経口投与としては、静脈内、動脈内、皮下、腹腔内、筋肉内注射もしくは注入、または頭蓋内、例えば髄腔内もしくは心室内投与が挙げられる。非経口投与は、単回ボーラス用量の形態であり得るか、または例えば、連続かん流ポンプによるものであり得る。局所投与のための薬学的組成物及び製剤としては、経皮パッチ、軟膏、ローション、クリーム、ゲル、ドロップ、坐薬、スプレー、液体、及び粉末が挙げられ得る。従来の薬学的担体、水性、粉末、または油性基剤、増粘剤等は、必須であるか、または望ましい場合がある。
1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)(12)(化合物(I)ジトシル酸塩)の合成
スキーム1.
1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)(12)(532.9g、729.1mmol)を、2−ブタノン(7223mL)と混合した。混合物を、透明な溶液になるまで55℃(設定内部温度)に加熱した。熱い溶液を、インラインフィルターを通して濾過研磨し、55℃(設定内部温度)で加熱しながら、透明な溶液を、真空下で約4L量まで蒸留した。溶液に、ヘプタン(4676mL)を撹拌しながら添加した。添加後、混合物を55℃(設定内部温度)で4時間保持し、その後、室温まで冷ました。混合物を一晩撹拌した。固体を濾過し、ヘプタン(1000.0mL)及び2−ブタノン(1000.0mL)の混合物で洗浄した。再結晶化生成物1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)(12)を、フィルター上で一晩、その後、高真空下50℃で一晩乾燥させて純生成物を得た。LC−MS C37H50N2O9S2[M+H]+m/zに対する計算値:387.2、実測値387.2。1H NMR(400MHz,MeOD)δ 7.73(d,J=8.2Hz,4H),7.34−7.19(m,7H),7.15(d,J=7.2Hz,2H),3.70−3.51(m,4H),3.43(d,J=18.4Hz,7H),3.36−3.22(m,3H),3.13−2.97(m,1H),2.67−2.50(m,3H),2.38(s,6H),2.21(q,J=9.5,8.6Hz,2H),2.05(dt,J=28.5,11.6Hz,2H),1.94−1.78(m,1H),1.66−1.55(m,1H),1.32(d,J=8.0Hz,2H),0.92(t,J=6.8Hz,1H)。
形態IのX線粉末回折(XRPD)
形態Iは、XRPDによって特徴付けられた。X線粉末回折(XRPD)は、Rigaku MiniFlex X線粉末回折計(XRPD)から得られた。XRPDの一般的な実験手順は、以下のとおりであった。(1)1.054056ÅでのKβフィルターによる銅からのX線放射、(2)30KV、15mAでのX線パワー、及び(3)サンプル粉末を、ゼロバックグラウンドサンプルホルダー上に分散させた。XRPDの一般的な測定条件は、以下のとおりであった。開始角度3度、停止角度45度、サンプリング0.02度、及び走査速度2度/分。XRPDパターンを図1に示し、XRPDデータを表1に提供する。
形態Iの示差走査熱量測定(DSC)サーモグラム
形態Iは、DSCによって特徴付けられた。DSCは、オートサンプラーを有するTA Instruments視差走査熱量測定、モデルQ200から得られた。DSC計器の条件は、以下のとおりであった。10℃/分で30〜300℃、Tゼロアルミニウムサンプルパン及び蓋、ならびに50mL/分での窒素ガス流。DSCサーモグラムを図2に示す。DSCサーモグラムは、94.6℃の開始温度、103.1℃のピーク温度で主要な吸熱事象を明らかにし、これは化合物の溶融であると考えられる。
形態Iの熱重量分析(TGA)
形態Iは、TGAによって特徴付けられた。TGAは、TA Instrument熱重量分析器、モデルQ500を使用して得られた。TGAの一般的な実験条件は、以下のとおりであった。20℃から600℃まで20℃/分での傾斜;40mL/分での窒素パージガス流に続いてパージ流の均衡;60mL/分でのサンプルパージ流;白金サンプルパン。TGAサーモグラムを図3に示す。150℃までで約3.5%の重量喪失が観測され、水分及び残留溶媒の喪失と関連すると考えられた。化合物は、200℃以降で著しく分解し始めた。
形態Iの動的蒸気吸着(DVS)分析
形態Iは、DVSによって特徴付けられた。DVS分析は、TA Instruments蒸気吸着分析器、モデルVTI−SA+上で行った。サンプルをVTI上で、50℃で0%RH N2により1時間予備乾燥させた。その後、吸湿プロファイルは、0%RHから95%RHまで5%RH増分の吸着に続いて、95%から5%RHまで5%増分の脱着で1サイクルで完了した。平衡基準は、180分の最大平衡時間で5分以内に0.0050重量%であった。全ての吸着及び脱着は、25℃で行った。
形態HIの調製及び特徴付け
化合物Iジトシル酸塩の形態HIは、周囲温度条件下、化合物Iジトシル酸塩、形態Iのウェットサンプルを乾燥するプロセス中に調製した。形態Iは、大気中の水分をゆっくり吸収し、結晶形態HIへと徐々に変化した。25℃/60%RH及び40℃/75%RHの貯蔵条件下においても、形態Iは、形態HIに変換された。形態HIはまた、湿った空気(例えば、60〜85%RH)を形態Iの固体を通してパージすることによって生成され得る。
形態HIIの調製及び特徴付け
形態HIIは、室温で3日間、水中の形態Iのスラリー化によって調製した。結果として生じた懸濁液を濾過した。残渣固体を収集し、周囲条件で5〜7日間空気乾燥させた。
形態HIIIの調製及び特徴付け
形態HIIIは、蒸気吸着分析器(TA Instruments VTI−SA+)上の形態HIを、40℃で0%RH N2により3時間乾燥させ、その後、それを約30〜50%RHの湿度に25℃で1日間曝露することによって調製した。形態HIIIは、それが約60〜85%RHで高湿度に曝露されると、形態HIに変化し得る。
形態DHの調製及び特徴付け
形態DHは、蒸気吸着分析器(TA Instruments VTI−SA+)上の形態HIを、25℃で0%RH N2により2日間乾燥させることによって調製した。形態DHが湿度に曝露されると、水を吸収して、約30〜50%RHで形態HIIIに変化し得るか、または約60〜85%RHの高湿度で形態HIに変化し得る。
形態HIの物理的安定性
形態HIの物理的安定性を、異なる湿度条件下で研究した。湿度は、蒸気吸着分析器(TA Instruments、モデルVTI−SA+)を使用して25℃で制御した。サンプルホルダー中のおよそ20mgの形態HIを、計器の湿度チャンバ内に置き、一定の湿度下で保持した。また、オープンガラスバイアル内のサンプルは、周囲条件下で設定した。ある特定の期間後、サンプルを除去し、XRPD、DSC、及びTGAによって特徴付けた。TGAによる重量喪失は、大部分が水の喪失と関連していた。XRPD、DSC、及びTGAの実験パラメータは、形態HIの実施例6におけるものと同様である。
25℃及び50℃での相平衡
クロロホルム、ジメチルホルムアミド(DMF)、1,4−ジオキサン、メチルイソブチルケトン(MIBK)、テトラヒドロフラン(THF)、アセトン、n−BuOH、酢酸イソブチル、酢酸イソプロピル(IPAc)、イソプロピルアルコール(IPA)、水、メチルエチルケトン(MEK)、メタノール、2−メトキシエタノール、EtOH、酢酸エチル(EtOAc)、ギ酸エチル、酢酸イソブチル、ヘプタン、または1−プロパノールなどの溶媒に、白濁溶液が得られるまで化合物Iジトシル酸を添加し、その後、約30mgの化合物Iジトシル酸塩を白濁溶液に添加した。混合物を25℃で3日間、50℃で2日間撹拌した。固体を濾過し、XRPDによって分析し、DSC及びTGAによって特徴付けた。25℃での相平衡は、形態II(n−BuOH)、形態III(IPA)、形態IV(水)、及び非晶質(1,4−ジオキサン)をもたらした。
25℃及び50℃での蒸発
化合物Iジトシル酸塩溶液の蒸発研究は、アセトニトリル(MeCN)、クロロホルム、ジクロロメタン、DMF、1,4−ジオキサン、メタノール、2−メトキシエタノール、MIBK、THF、アセトン、n−BuOH、メチルt−ブチルエーテル(MTBE)、ジメチルスルホキシド(DMSO)、EtOH、EtOAc、ギ酸エチル、酢酸イソブチル、IPAc、1−プロパノール、水、及びMEKなどの様々な溶媒中、25±1℃で実行した。形態IV(水)、形態V(MeCN、1−プロパノール)、形態VI(CH2Cl2)、及び形態VII(EtOH)が発見された。上記溶媒中の50±1℃での蒸発は、形態V(MeCN、EtOH、及び1−プロパノール)、形態VI(2−メトキシエタノール及びIPA)、ならびに形態VIII(n−BuOH)をもたらした。
貧溶媒添加
化合物Iジトシル酸塩の飽和またはほぼ飽和した溶液は、化合物Iジトシル酸塩を下記表7の溶媒に添加することによって調製した。MTBE、IPAc、ヘプタン、及びヘキサンなどの貧溶媒を添加して沈殿を誘導した。結果を表7に提示する。貧溶媒添加は、形態II(n−BuOH/IPAc)、形態III(IPA/ヘキサン、IPA/MTBE、及びIPA/ヘプタン)、形態IIIa(EtOH/IPAc)、形態V(MeCN/MTBE及びMeCN/IPAc)、形態IX(n−BuOH/MTBE及びn−BuOH/ヘプタン)、形態X(EtOH/ヘプタン)、ならびに非晶質(THF/MTBE、THF/ヘプタン、THF/ヘキサン、MEK/ヘプタン、及びMEK/ヘキサン)をもたらした。
**約50mg/mLのn−BuOH溶液
***約60mg/mLのエタノール溶液
****25分撹拌でスラリーを得る
逆添加
化合物Iジトシル酸塩の飽和溶液は、表8に列挙した溶媒中で調製し、より大量の混和性貧溶媒に添加した。逆添加は、形態II(n−BuOH/IPAc)、形態III(IPA/ヘキサン、IPA/MTBE、及びIPA/ヘプタン)、形態IIIa(EtOH/IPAc)、形態V(MeCN/MTBE及びMeCN/IPAc)、形態IX(n−BuOH/MTBE及びn−BuOH/ヘプタン)、ならびに形態X(EtOH/ヘプタン)をもたらした。
**約50mg/mLのn−BuOH溶液
***約60mg/mLのエタノール溶液
****25分撹拌でスラリーを得る
飽和溶液の急冷
35℃で調製された飽和溶液を、約−20℃〜約25℃まで急冷した。結果を表9に示す。急冷は、形態II(n−BuOH)、形態III(IPA)、形態V(MeCN)、及び形態XI(1−プロパノール)をもたらした。
加熱及び冷却サイクルによる飽和溶液の結晶化
化合物Iジトシル酸塩の飽和溶液は、50℃で調製し、プログラムした循環浴を使用することによって浴中でゆっくり冷却した。化合物Iジトシル酸塩の透明溶液に、約20〜30mgの化合物Iジトシル酸塩形態Iを添加してスラリーを得た。その後、形成されたスラリーを50℃で2時間にわたって加熱し、その後、5℃まで2時間にわたって冷却した。このプロセスは、3日間繰り返し、結果として生じる固体をさらなる分析のために濾過した。結果を表10に示す。加熱及び冷却は、形態I(EtOAc、MEK、及びMEK/ヘプタン)、形態IV(水)、及び形態XII(アセトン及びIPA)をもたらした。
形態IIの調製及び特徴付け
一実験では、形態IIは、約60mgの形態Iをn−ブタノール中3mLの形態Iの飽和または白濁溶液に添加することによって調製した。結果として生じる混合物を、25±1℃で3日間撹拌した。結果として生じる固体を濾過した。形態IIはまた、実施例13、14、及び15に記載される手順に従い、それぞれn−BuOH/IPAc、n−BuOH/IPAc、及びn−BuOH中で調製した。
形態IIIの調製及び特徴付け
一実験では、形態IIIは、約50mgの形態Iを、IPA中約3mLの形態Iの飽和または白濁溶液に添加することに続いて、25±1℃で3日間撹拌することによって調製した。結果として生じる固体を濾過した。形態IIIはまた、実施例13、14、及び15に記載される手順に従い、IPA/ヘキサン、IPA/ヘプタン、またはIPA/MTBEを貧溶媒添加における溶媒対として、IPA/ヘキサン、IPA/MTBE、またはIPA/ヘプタンを逆添加における溶媒対として、及びIPAを急冷において使用して調製した。
形態IIIaの調製及び特徴付け
一実験では、形態IIIaは、エタノール(60mg/mL)中0.4mLの形態Iの飽和溶液を、3.0mLのIPAcに添加することによって調製した。結果として生じる固体を濾過した。形態IIIaはまた、実施例13に記載される手順に従い、EtOH/IPAcを溶媒対として使用して調製した。
形態IVの調製及び特徴付け
一実験では、形態IVは、約50mgの形態Iを、水中約3mLの形態Iの飽和または白濁溶液に添加することに続いて、25±1℃で3日間撹拌することによって調製した。結果として生じる固体を濾過し、フード内で4日間空気乾燥させた。形態IVはまた、実施例12及び16に記載される手順に従い、水を溶媒として使用して調製した。
形態IVaの調製及び特徴付け
形態IVaは、形態IVを真空下、45〜50℃で一晩乾燥させることによって調製し、28日間空気乾燥させた。
形態Vの調製及び特徴付け
一実験では、形態Vは、アセトニトリル中およそ2mLの形態Iの飽和溶液を、25±1℃で撹拌することなく空気下で蒸発させることによって調製した。形態Vはまた、実施例11に記載される手順に従い、MeCN、EtOH、または1−プロパノール中の化合物Iの溶液を50℃で蒸発させることによって調製した。他の実験では、形態Vは、実施例13、14、及び15に記載される手順に従い、MeCN/MTBEまたはMeCN/IPAcを貧溶媒添加における溶媒対として、MeCN/MTBE、MeCN/IPAcを逆添加における溶媒対として、及びMeCNを急冷において使用して調製した。
形態VIの調製及び特徴付け
一実験では、形態VIは、ジクロロメタン中およそ2mLの形態Iの飽和溶液を、25±1℃で撹拌することなく空気下で蒸発させることによって調製した。形態VIはまた、実施例11に記載される手順に従い、2−メトキシエタノールまたはIPA中の化合物Iの溶液を50℃で蒸発させることによって調製した。
形態VIIの調製及び特徴付け
形態VIIは、エタノール中およそ2mLの形態Iの飽和溶液を、25±1℃で撹拌することなく空気下で蒸発させることによって調製した。
形態VIIIの調製及び特徴付け
形態VIIIは、n−ブタノール中およそ2mLの形態Iの飽和溶液を、50±1℃で撹拌することなく空気下で蒸発させることによって調製した。
形態IXの調製及び特徴付け
一実験では、形態IXは、n−ブタノール(50mg/mL)中約0.3mLの形態Iの溶液を、2.0mLのヘプタンに添加することに続いて、約5分間撹拌することよって調製した。結果として生じる固体を濾過した。形態IXはまた、実施例13に記載される手順に従い、n−BuOH/MTBEまたはn−BuOH/ヘプタンを溶媒対として使用して調製した。
形態Xの調製及び特徴付け
一実験では、形態Xは、エタノール(60mg/mL)中0.3mLの形態Iの飽和溶液を、2.5mLのヘプタンに添加することによって調製した。結果として生じる固体を濾過した。形態Xはまた、実施例13に記載される手順に従い、EtOH/ヘプタンを溶媒対として使用して調製した。
形態XIの調製及び特徴付け
形態XIは、以下のとおり調製した。n−プロパノール中約2.0mLの形態Iの飽和溶液を、−20℃まで冷却し、−20℃で1時間保持してスラリーを得た。結果として生じる固体を濾過し、1時間空気乾燥させた。
形態XIIの調製及び特徴付け
形態XIIは、以下のとおり調製した。アセトン中およそ7mLの形態Iの飽和溶液は、約30℃で調製し、プログラムした循環浴を使用することによって浴中で25℃まで冷却した。結果として生じる溶液を、50℃まで2時間にわたって加熱し、その後、5℃まで2時間にわたって冷却し、このプロセスを80時間繰り返した。結果として生じる固体を濾過し、空気乾燥させた。
非晶質固体の調製及び特徴付け
一実験では、化合物Iジトシル酸塩の非晶質固体は、以下のとおり調製した。1,4−ジオキサン中約3mLの形態Iの飽和または白濁溶液に、約30mgの形態Iを添加し、続いて25±1℃で2日間撹拌した。結果として生じる固体を濾過した。化合物Iジトシル酸塩の非晶質形態はまた、実施例13に記載される手順に従い、THF/ヘプタン、THF/MTBE、THF/ヘキサン、MEK/ヘプタン、またはMEK/ヘキサンを溶媒対として使用して調製した。
多形形態の安定性
様々な化合物Iジトシル酸塩多形形態の相対安定性関係を評価するために、形態I、II、III、及びIIIa〜形態XIIの混合物による競合スラリー実験を、ブタノン−ヘプタン中50℃で下記手順1に従って行い、またブタノン中25℃で下記手順2に従って行った。13個の多形の混合物は、ブタノン/ヘプタン(1:1)中50℃で6〜18時間撹拌した後、及びブタノン中25℃で6〜18時間撹拌した後に形態Iに変換された。これらの結果は、形態Iが、ブタノン及びブタノン/ヘプタン(1:1)中で最も安定な多形形態であることを示す。
手順1 50℃でのブタノン−ヘプタン中の競合実験:
手順2 25℃でのブタノン中の競合実験:
LANCE LSD1/KDM1A脱メチル化酵素アッセイ−アッセイ緩衝液(50mM Tris、pH7.5、0.01% Tween−20、25mM NaCl、5mM DTT)中10μLの1nM LSD−1酵素(ENZO BML−SE544−0050)を、25℃で1時間、黒色384ウェルポリスチレンプレートに滴下させた0.8μL化合物/DMSOでプレインキュベートした。0.4μMビオチン標識化ヒストンH3ペプチド基質:ART−K(Me1)−QTARKSTGGKAPRKQLA−GGK(ビオチン)配列番号1(AnaSpec 64355)を含有する10μLのアッセイ緩衝液を添加することによって反応を開始し、25℃で1時間インキュベートした。1.5nM Eu−抗非修飾H3K4抗体(PerkinElmer TRF0404)及び225nM LANCE Ultraストレプトアビジン(PerkinElmer TRF 102)で補充した10μLの1×LANCE検出緩衝液(PerkinElmer CR97−100)を、0.9mM トラニルシプロミン−HCl(Millipore 616431)と共に添加することによって、反応を止めた。反応を止めた後、プレートを30分間インキュベートし、PHERAstar FSプレートリーダー(BMG Labtech)上で読み取った。本開示の塩を試験し、100nM未満のIC50でLSD1に対して活性であることが見出された。
Claims (73)
- 1−((4−(メトキシメチル)−4−(((1R,2S)−2−フェニルシクロプロピルアミノ)メチル)ピペリジン−1−イル)メチル)シクロブタンカルボン酸のp−トルエンスルホン酸塩である塩、またはその水和物もしくは溶媒和物。
- 前記塩が、1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)である、請求項1に記載の塩、またはその水和物もしくは溶媒和物。
- 前記塩が、実質的に結晶性である、請求項1または2に記載の塩。
- 前記塩が、結晶性である、請求項1または2に記載の塩。
- 水和物である、請求項1〜4のいずれか1項に記載の塩。
- 形態Iを有する、請求項1〜4のいずれか1項に記載の塩。
- 前記塩が、約94.6℃の開始温度及び約103.1℃のピーク温度を持つ吸熱を有する示差走査熱量測定サーモグラムを示す、請求項6に記載の塩。
- 前記塩が、約3.6±0.3度2θで特徴的なピークを含むX線粉末回折パターンを有する、請求項6に記載の塩。
- 前記塩が、約4.9±0.3度2θで特徴的なピークを含むX線粉末回折パターンを有する、請求項6に記載の塩。
- 前記塩が、約6.2±0.3度2θで特徴的なピークを含むX線粉末回折パターンを有する、請求項6に記載の塩。
- 前記塩が、約7.7±0.3度2θで特徴的なピークを含むX線粉末回折パターンを有する、請求項6に記載の塩。
- 前記塩が、約22.7±0.3度2θで特徴的なピークを含むX線粉末回折パターンを有する、請求項6に記載の塩。
- 前記塩が、約3.6±0.3、約4.9±0.3、約6.2±0.3、約7.7±0.3、及び約22.7±0.3度2θから選択される少なくとも2つの特徴的ピークを含むX線粉末回折パターンを有する、請求項8〜12のいずれか1項に記載の塩。
- 前記塩が、約8.9±0.3、約10.0±0.3、約11.5±0.3、約14.3±0.3、約15.0±0.3、約15.5±0.3、約16.3±0.3、約17.8±0.3、約19.1±0.3、約19.8±0.3、約20.9±0.3、約22.2±0.3度2θから選択される位置、及びそれらの組み合わせで1つ以上の特徴的なピークをさらに含むX線粉末回折パターンを有する、請求項13に記載の塩。
- 実質的に図1に示される特徴的なピークを持つX線粉末回折パターンを有する、請求項6に記載の塩。
- 実質的に図2に描かれるDSCサーモグラムを有する、請求項6に記載の塩。
- 実質的に図3に描かれるTGAサーモグラムを有する、請求項6に記載の塩。
- 前記塩が、約94.6℃の開始温度及び約103.1℃のピーク温度を持つ吸熱を有する示差走査熱量測定サーモグラム、ならびに約3.6±0.3、約4.9±0.3、約6.2±0.3、約7.7±0.3、または約22.7±0.3度2θで特徴的なピークを含むX線粉末回折パターンを示す、請求項6に記載の塩。
- 前記塩が、約103.1℃の融点を有する、請求項1〜4のいずれか1項に記載の塩。
- 形態HI、形態HII、形態HIII、及び形態DHから選択される形態を有する、請求項1〜4のいずれか1項に記載の塩。
- 前記塩が、形態HIを有し、約80℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラムを示す、請求項20に記載の塩。
- 形態HI及び約7.0、約10.4、約13.6、約15.5、約17.3、約22.2、及び約24.0度2θから選択される特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HI及び約7.0、約10.4、約13.6、約15.5、約17.3、約22.2、及び約24.0度2θから選択される2つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HI及び約7.0、約10.4、約13.6、約15.5、約17.3、約22.2、及び約24.0度2θから選択される3つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HI及び実質的に図4に示されるX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HI及び実質的に図5に描かれるDSCサーモグラムを有する、請求項20に記載の塩。
- 形態HI及び実質的に図6に描かれるTGAサーモグラムを有する、請求項20に記載の塩。
- 前記塩が、形態HIを有し、約80℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラム、ならびに約7.0、約10.4、約13.6、約15.5、約17.3、約22.2、及び約24.0度2θから選択される特徴的なピークを含むX線粉末回折パターンを示す、請求項20に記載の塩。
- 前記塩が、形態HIIを有し、約52℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラムを示す、請求項20に記載の塩。
- 形態HII及び約8.7、約10.1、約14.8、約21.3、約22.0、約22.7、及び約24.3度2θから選択される特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HII及び約8.7、約10.1、約14.8、約21.3、約22.0、約22.7、及び約24.3度2θから選択される2つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HII及び約8.7、約10.1、約14.8、約21.3、約22.0、約22.7、及び約24.3度2θから選択される3つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HII及び実質的に図7に示されるX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HII及び実質的に図8に描かれるDSCサーモグラムを有する、請求項20に記載の塩。
- 形態HII及び実質的に図9に描かれるTGAサーモグラムを有する、請求項20に記載の塩。
- 前記塩が、形態HIIを有し、約52℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラム、ならびに約8.7、約10.1、約14.8、約21.3、約22.0、約22.7、及び約24.3度2θから選択される特徴的なピークを含むX線粉末回折パターンを示す、請求項20に記載の塩。
- 前記塩が、形態HIIIを有し、約67℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラムを示す、請求項20に記載の塩。
- 前記塩が、形態HIIIを有し、約98℃の温度で吸熱ピークをさらに示す、請求項37に記載の塩。
- 形態HIII及び約7.0、約9.0、約9.2、約10.2、約17.9、約20.3、約22.0、及び約23.8度2θから選択される特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HIII及び約7.0、約9.0、約9.2、約10.2、約17.9、約20.3、約22.0、及び約23.8度2θから選択される2つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HIII及び約7.0、約9.0、約9.2、約10.2、約17.9、約20.3、約22.0、及び約23.8度2θから選択される3つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HIII及び実質的に図10に示されるX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態HIII及び実質的に図11に描かれるDSCサーモグラムを有する、請求項20に記載の塩。
- 形態HIII及び実質的に図12に描かれるTGAサーモグラムを有する、請求項20に記載の塩。
- 前記塩が、形態HIIIを有し、約67℃及び約98℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラム、ならびに約7.0、約9.0、約9.2、約10.2、約17.9、約20.3、約22.0、及び約23.8度2θから選択される特徴的なピークを含むX線粉末回折パターンを示す、請求項20に記載の塩。
- 前記塩が、形態DHを有し、約98℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラムを示す、請求項20に記載の塩。
- 形態DHならびに約7.5、約9.6、約10.7、約14.8、約20.1、約20.7、約21.6、約22.9、及び約24.7度2θから選択される特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態DHならびに約7.5、約9.6、約10.7、約14.8、約20.1、約20.7、約21.6、約22.9、及び約24.7度2θから選択される2つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態DHならびに約7.5、約9.6、約10.7、約14.8、約20.1、約20.7、約21.6、約22.9、及び約24.7度2θから選択される3つ以上の特徴的なピークを含むX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態DH及び実質的に図13に示されるX線粉末回折パターンを有する、請求項20に記載の塩。
- 形態DH及び実質的に図14に描かれるDSCサーモグラムを有する、請求項20に記載の塩。
- 形態DH及び実質的に図15に描かれるTGAサーモグラムを有する、請求項20に記載の塩。
- 前記塩が、形態DHを有し、約98℃の温度で吸熱ピークを有する示差走査熱量測定サーモグラム、ならびに約7.5、約9.6、約10.7、約14.8、約20.1、約20.7、約21.6、約22.9、及び約24.7度2θから選択される特徴的なピークを含むX線粉末回折パターンを示す、請求項20に記載の塩。
- 請求項1〜53のいずれか1項に記載の塩、及び薬学的に許容される担体または賦形剤を含む、薬学的組成物。
- 請求項54に記載の薬学的組成物を含む、固体経口剤形。
- リジン特異的脱メチル化酵素1(LSD1)の阻害方法であって、前記LSD1を請求項1〜53のいずれか1項に記載の塩と接触させることを含む、前記方法。
- 癌の治療方法であって、治療有効量の請求項1〜53のいずれか1項に記載の塩または請求項54に記載の組成物を、治療を必要とする患者に投与することを含む、前記方法。
- 前記癌が、血液癌、肉腫、肺癌、胃腸癌、泌尿生殖路癌、肝臓癌、骨癌、神経系癌、婦人科癌、及び皮膚癌から選択される、請求項57に記載の方法。
- 前記血液癌が、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、急性前骨髄球性白血病(APL)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、びまん性大細胞型B細胞リンパ腫(DLBCL)、マントル細胞リンパ腫、非ホジキンリンパ腫、ホジキンリンパ腫、原発性骨髄線維症(PMF)、真性多血症(PV)、本態性血小板増加症(ET))、骨髄異形成症候群(MDS)、及び多発性骨髄腫から選択される、請求項58に記載の方法。
- 式(II)を有する化合物であって、
R2が、ハロ、CN、C1〜6アルキル、C1〜6アルコキシ、C1〜4ハロアルキル、またはC1〜4ハロアルコキシであり、
R3が、Hまたは不安定基であり、
下付き文字nが、0、1、2、または3である、前記化合物。 - R1が、CH3である、請求項60に記載の化合物。
- nが0である、請求項60または61に記載の化合物。
- R3が、H、p−トルエンスルホニル、メタンスルホニル、またはトリフルオロメタンスルホニルである、請求項60〜62のいずれか1項に記載の化合物。
- R1がCH3であり、R3がHであり、nが0である、請求項60または63に記載の化合物。
- 式(III)を有する化合物であって、
R5が、ハロ、CN、C1〜6アルキル、C1〜6アルコキシ、C1〜4ハロアルキル、またはC1〜4ハロアルコキシであり、
R6が、Hまたはハロであり、
下付き文字mが、0、1、2、または3である、前記化合物。 - R4がCH3である、請求項65に記載の化合物。
- mが0である、請求項65または66に記載の化合物。
- R6が、H、Cl、またはBrである、請求項65〜67のいずれか1項に記載の化合物。
- R4がCH3であり、R6がHであり、mが0である、請求項65に記載の化合物。
- 1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)の調製方法であって、
下記式を有する1−{[4−({(tert−ブトキシカルボニル)[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)−4−(メトキシメチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸を、
- 1−{[4−(メトキシメチル)−4−({[(1R,2S)−2−フェニルシクロプロピル]アミノ}メチル)ピペリジン−1−イル]メチル}シクロブタンカルボン酸ビス(4−メチルベンゼンスルホナート)を再結晶化することをさらに含む、請求項70に記載の方法。
- 前記反応が、約50〜60℃の温度で実行される、請求項70または71に記載の方法。
- 前記溶媒が、テトラヒドロフラン(THF)である、請求項70〜72のいずれか1項に記載の方法。
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