JP2019509286A - 結晶性(2s,4r)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸およびその使用 - Google Patents
結晶性(2s,4r)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸およびその使用 Download PDFInfo
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- JP2019509286A JP2019509286A JP2018546864A JP2018546864A JP2019509286A JP 2019509286 A JP2019509286 A JP 2019509286A JP 2018546864 A JP2018546864 A JP 2018546864A JP 2018546864 A JP2018546864 A JP 2018546864A JP 2019509286 A JP2019509286 A JP 2019509286A
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Abstract
Description
本出願は、2016年3月8日および2016年6月6日にそれぞれ出願された米国仮出願番号第62/305,393号および同62/346,336号の利益を主張しており、これら仮出願の全体の開示は、参考として本明細書中に援用される。
(発明の分野)
本発明は、ネプリライシン阻害活性を有する新規結晶性形態に関する。本発明はまた、化合物を含む薬学的組成物、化合物を調製するためのプロセス、ならびに高血圧、心不全、および腎疾患などの疾患を処置するために化合物を使用する方法に関する。
ネプリライシン(中性エンドペプチダーゼ、EC3.4.24.11)(NEP)は、脳、腎臓、肺、消化管、心臓、および末梢血管系を含めた多くの器官および組織に見出される内皮膜結合Zn2+メタロペプチダーゼである。NEPは、いくつかの内因性ペプチド、例えば、エンケファリン、循環ブラジキニン、アンジオテンシンペプチド、およびナトリウム利尿ペプチド(これらのうち後者は、例えば、血管拡張およびナトリウム排泄増加/利尿、ならびに心肥大および心室線維症の阻害を含めた、いくつかの作用を有する)を分解および不活化する。したがって、NEPは、血圧恒常性および心血管の健康において重要な役割を果たす。
本発明は、ネプリライシン(NEP)酵素阻害活性を保有することが判明した、化合物Iの新規結晶性形態を提供する。したがって、この化合物は、高血圧、肺高血圧、心不全および腎疾患などの状態を処置するための治療剤として有用および有利であると予期される。化合物Iの構造は、
一態様では、本発明は、結晶性の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I’)に関する。
本発明の化合物、組成物、方法およびプロセスを記載する場合、他に指摘されない限り以下の用語は、以下の意味を有する。さらに、本明細書で使用する場合、単数の形態「a」、「an」および「the」は、使用されている文脈が明らかに他を指示していない限り、対応する複数の形態を含む。「含む(comprising)」、「含む(including)」および「有する」という用語は、包括的であることが意図され、列挙した要素以外のさらなる要素も存在し得ることを意味する。本明細書中で使用された成分の量、特性、例えば分子量、反応条件などを表現するすべての数は、他に指摘されない限り、すべての場合において、「約」という用語で修飾されているものと理解されたい。したがって、本明細書中に記述された数は、本発明により得ようとされている所望の特性に応じて異なり得る近似値である。少なくとも、しかも特許請求の範囲の同等物の原理の適用を限定しようと試みることなく、各数は、少なくとも、報告された有効数字を考慮して、かつ普通の丸め技法を適用することによって解釈すべきである。
一般的合成手順
結晶特性
有用性
ナトリウム利尿ペプチドおよびブラジキニンのような血管作用性ペプチドの作用を増強することによって、化合物Iおよび結晶形態I’に、心血管疾患などの医学的状態を処置および/または予防することにおいて有用性が見出されると予期されている。例えば、Roquesら、(1993年)Pharmacol. Rev.45巻:87〜146頁およびDempseyら、(2009年)Amer. J. of Pathology、174巻(3号):782〜796頁を参照されたい。特に興味深い心血管疾患として、高血圧および心不全が挙げられる。高血圧は、例示として、これらに限定されずに、以下が挙げられる:原発性高血圧(これはまた本態性高血圧または特発性高血圧とも呼ばれる);続発性高血圧;付随的腎疾患を伴う高血圧;付随的腎疾患を伴う、または伴わない重症の高血圧;肺高血圧(肺動脈高血圧を含む);および治療抵抗性高血圧。心不全は、例示として、これらに限定されずに、以下が挙げられる:うっ血性心不全;急性心不全;慢性心不全、例えば左室駆出率の減少を有するもの(収縮期心不全とも呼ばれる)または左室駆出率が保たれているもの(拡張期心不全ともと呼ばれる);ならびに急性および慢性の非代償性心不全。したがって、本発明の一実施形態は、患者に化合物Iまたは結晶形態I’の治療有効量を投与することを含む、高血圧、特に原発性高血圧、肺動脈高血圧、慢性血栓塞栓性肺高血圧症(CTEPH)、または腎動脈狭窄を伴う高血圧を処置する方法に関する。
NEP阻害剤として、化合物Iまたは結晶形態I’は、内因性エンケファリンの分解を阻害することが予期され、したがってこのような化合物に、伝染性および分泌性/水様性の下痢を含めた下痢の処置に対しても有用性を見出すことができる。例えば、Baumerら、(1992年)Gut、33巻:753〜758頁;Farthing(2006年)Digestive Diseases、24巻:47〜58頁;およびMarcais−Collado(1987年)Eur. J. Pharmacol.144巻(2号):125〜132頁を参照されたい。下痢を処置するために使用する場合、化合物Iまたは結晶形態I’は、1つまたは複数の追加の止瀉薬と併用することができる。
ナトリウム利尿ペプチドおよびブラジキニンなどの血管作用性ペプチドの作用を増強させることによって、化合物Iまたは結晶性形態I’に、腎機能を向上させ(Chenら、(1999年)Circulation 100巻:2443〜2448頁;Lipkinら、(1997年)Kidney Int. 52巻:792〜801頁;およびDussauleら、(1993年)Clin. Sci. 84巻:31〜39頁を参照されたい)、腎障害のある対象における腎疾患の処置および/または予防における有用性を見出すことが予期されている。特に興味深い腎疾患として、糖尿病性腎症、慢性腎疾患、タンパク質尿、および特に急性腎臓傷害(例えば、心血管手術、化学療法、または医学的画像撮影における造影染料の使用により引き起こされる)または急性腎不全が挙げられる(Sharkovskaら、(2011年)Clin. Lab. 57巻:507〜515頁およびNewazら、(2010年)Renal Failure 32巻:384〜390頁を参照されたい)。特に興味深い他の腎疾患として、ネフローゼ症候群、巣状分節性糸球体硬化症(FSGS)および多発性嚢胞腎疾患(PKD)が挙げられる。
ナトリウム利尿ペプチドの作用を増強させることによって、化合物1はまた、予防療法において、ナトリウム利尿ペプチドの抗肥大性および抗線維性作用により(Potterら、(2009年)Handbook of Experimental Pharmacology、191巻:341〜366頁を参照されたい)、例えば心筋梗塞後の心機能不全の進行を予防すること、血管形成後の動脈再狭窄を予防すること、血管手術後の血管壁の増粘を予防すること、アテローム性動脈硬化症を予防すること、および糖尿病の脈管症を予防することにおいて有用であることも予期されている。
ナトリウム利尿ペプチドの作用を増強させることによって、化合物Iまたは結晶形態I’は、緑内障を処置するのに有用であると予期されている。例えば、Diestelhorstら、(1989年)International Ophthalmology、12巻:99〜101頁を参照されたい。緑内障を処置するために使用する場合、化合物1は、1つまたは複数の追加の抗緑内障剤と併用することができる。
NEP阻害剤として、化合物Iまたは結晶形態I’は、内因性エンケファリンの分解を阻害すると予期されており、したがってこのような化合物に、鎮痛剤としての有用性を見出すこともできる。例えば、Roquesら、(1980年)Nature、288巻:286〜288頁およびThanawalaら、(2008年)Current Drug Targets、9巻:887〜894頁を参照されたい。疼痛を処置するために使用する場合、化合物Iまたは結晶形態I’は、1つまたは複数の追加の抗侵害受容性薬物、例えばアミノペプチダーゼNまたはジペプチジルペプチダーゼIII阻害剤、非ステロイド性抗炎症剤、モノアミン再取り込み阻害剤、筋弛緩剤、NMDA受容体アンタゴニスト、オピオイド受容体アゴニスト、5−HT1Dセロトニン受容体アゴニストおよび三環式抗うつ剤などと併用することができる。
これらのNEP阻害特性に起因して、化合物Iまたは結晶形態I’はまた、鎮咳剤として有用であることも予期され、ならびに肝硬変に伴う門脈圧亢進症(Sansoeら、(2005年)J. Hepatol.43巻:791〜798頁を参照されたい)、がん(Vesely、(2005年)J. Investigative Med.53巻:360〜365頁を参照されたい)、うつ病(Nobleら、(2007年)Exp. Opin. Ther. Targets、11巻:145〜159頁を参照されたい)、月経障害、早期陣痛、子癇前症、子宮内膜症、繁殖障害(例えば、男性および女性の不妊、多嚢胞性卵巣症候群、着床不全)、ならびに男性の勃起不全および女性の性的興奮障害を含めた男性および女性の性機能不全の処置における有用性が見出されている。さらに具体的には、化合物Iまたは結晶形態I’は、女性の性機能不全を処置するのに有用であると予期されており(Prydeら、(2006年)J. Med. Chem.49巻:4409〜4424頁を参照されたい)、この性機能不全とは、多くの場合、女性患者が、性的表現に満足を見出すことが困難であること、またはできないことと定義される。性機能不全は、様々な多様な女性の性的疾患をカバーし、例示として、これらに限定されずに、性的欲求低下障害、性的興奮障害、オルガスム障害および性的疼痛障害が挙げられる。このような疾患、特に女性の性機能不全を処置するために使用する場合、本発明の化合物は、以下の第2の剤のうちの1つまたは複数と併用してもよい:PDE−V阻害剤、ドーパミンアゴニスト、エストロゲン受容体アゴニストおよび/またはアンタゴニスト、アンドロゲン、ならびにエストロゲン。これらのNEP阻害特性に起因して、化合物Iまたは結晶形態I’はまた、抗炎症特性を有することが予期され、よって、特にスタチンと組み合わせて使用する場合、有用性を有することが予期される。
化合物Iまたは結晶形態I’は、NEP酵素阻害活性を有するので、これらは、NEP酵素を有する生物学的系または試料を調査または研究する、例えば、NEP酵素またはそのペプチド基質がある役割を果たしている疾患を研究するためのリサーチツールとしても有用である。NEP酵素を有する任意の適切な生物学的系または試料を、インビトロまたはインビボのいずれかで行うことができるような研究において利用することができる。このような研究に対して適切な代表的な生物学的系または試料として、これらに限定されないが、細胞、細胞抽出物、原形質膜、組織試料、単離した器官、哺乳動物(例えばマウス、ラット、モルモット、ウサギ、イヌ、ブタ、ヒトなど)などが挙げられ、哺乳動物が特に興味深い。本発明の1つの特定の実施形態では、哺乳動物におけるNEP酵素活性は、化合物Iまたは結晶形態I’のNEP阻害量を投与することによって阻害される。
化合物Iまたは結晶形態I’は通常、薬学的組成物または製剤の形態で患者に投与される。このような薬学的組成物は、これらに限定されないが、経口、直腸、経膣、鼻、吸入、局所用(経皮的を含む)、眼、および非経口モードの投与を含めた、任意の許容される投与経路で患者に投与され得る。さらに、化合物Iまたは結晶形態I’は、例えば経口的に、一日あたり複数回投与(例えば、毎日、2、3、または4回)するか、一日量を単回で投与するか、または週間用量を単回で投与することができる。特定のモードの投与に対して適切な化合物Iまたは結晶形態I’の任意の形態(すなわち、遊離塩基、遊離酸、薬学的に許容される塩、溶媒和物など)が、本明細書中で考察された薬学的組成物で使用することができることを理解されたい。
化合物Iまたは結晶形態I’は、疾患の単独処置として有用であってもよいし、または所望の治療効果を得るための1つもしくは複数の追加の治療剤と併用してもよい。したがって、一実施形態では、本発明の薬学的組成物は、化合物Iまたは結晶形態I’と共投与される他の薬物を含有する。例えば、組成物は、1つまたは複数の薬物(また「第2の剤(複数可)」とも呼ばれる)をさらに含んでもよい。このような治療剤は、当技術分野で周知であり、アデノシン受容体アンタゴニスト、α−アドレナリン受容体アンタゴニスト、β1−アドレナリン受容体アンタゴニスト、β2−アドレナリン受容体アゴニスト、二重作用性β−アドレナリン受容体アンタゴニスト/α1−受容体アンタゴニスト、進行糖化終末産物ブレーカー、アルドステロンアンタゴニスト、アルドステロンシンターゼ阻害剤、アミノペプチダーゼN阻害剤、アンドロゲン、アンジオテンシン変換酵素阻害剤および二重作用性アンジオテンシン変換酵素/ネプリライシン阻害剤、アンジオテンシン変換酵素2アクチベーターおよび刺激物質、アンジオテンシン−IIワクチン、抗凝血剤、抗糖尿病剤、下痢止剤、抗緑内障剤、抗脂質剤、抗侵害受容性剤、抗血栓剤、AT1受容体アンタゴニストおよび二重作用性AT1受容体アンタゴニスト/ネプリライシン阻害剤および多官能性アンジオテンシン受容体遮断剤、ブラジキニン受容体アンタゴニスト、カルシウムチャネル遮断剤、キマーゼ阻害剤、ジゴキシン、利尿剤、ドーパミンアゴニスト、エンドセリン変換酵素阻害剤、エンドセリン受容体アンタゴニスト、HMG−CoA還元酵素阻害剤、エストロゲン、エストロゲン受容体アゴニストおよび/またはアンタゴニスト、鉱質コルチコイド受容体アンタゴニスト、モノアミン再取り込み阻害剤、筋弛緩剤、ナトリウム利尿ペプチドおよびこれらの類似体、ナトリウム利尿ペプチドクリアランス受容体アンタゴニスト、ネプリライシン阻害剤、一酸化窒素ドナー、非ステロイド性抗炎症剤、N−メチルd−アスパラギン酸受容体アンタゴニスト、オピオイド受容体アゴニスト、ホスホジエステラーゼ阻害剤(例えば、PDE5およびPDE9)、プロスタグランジン類似体、プロスタグランジン受容体アゴニスト、レニン阻害剤、選択的セロトニン再取り込み阻害剤、ナトリウムチャネル遮断剤、可溶性グアニル酸シクラーゼ刺激物質およびアクチベーター、三環式抗うつ剤、バソプレッシン受容体アンタゴニスト、ならびにこれらの組合せが挙げられる。これら剤の具体例は、本明細書中で詳述されている。
本発明の化合物(50g)、スプレー乾燥したラクトース440gおよびステアリン酸マグネシウム10gを十分にブレンドする。次いで得られた組成物を硬質ゼラチンカプセルに充填する(カプセル剤1個あたり組成物500mg)。あるいは、化合物Iまたは結晶形態I’(20mg)をデンプン(89mg)、微結晶性セルロース(89mg)およびステアリン酸マグネシウム(2mg)と十分にブレンドする。次いでこの混合物を米国製の45番メッシュの篩に通し、硬質ゼラチンカプセルに充填する(カプセル剤1個あたり組成物200mg)。
化合物Iまたは結晶形態I’(100mg)を、ポリオキシエチレンソルビタンモノオレエート(50mg)およびデンプン粉末(250mg)と十分にブレンドする。次いでこの混合物をゼラチンカプセル剤に充填する(カプセル剤1個あたり組成物400mg)。あるいは、化合物I(70mg)および第2の剤(30mg)をポリオキシエチレンソルビタンモノオレエート(50mg)およびデンプン粉末(250mg)と十分にブレンドし、得られた混合物をゼラチンカプセル剤に充填する(カプセル剤1個あたり組成物400mg)。
化合物Iまたは結晶性形態I’(50mgまたは100mg)を、HPMCカプセルに直接充填する。
化合物Iまたは結晶形態I’(10mg)、デンプン(45mg)および微結晶性セルロース(35mg)を米国製20番メッシュの篩に通し、十分混合する。こうして生成された粒剤を50〜60℃で乾燥させ、米国製16番メッシュの篩に通す。ポリビニルピロリドン溶液(4mgを滅菌水中の10%溶液として)を、カルボキシメチルデンプンナトリウム(4.5mg)、ステアリン酸マグネシウム(0.5mg)、およびタルク(1mg)と混合し、次いでこの混合物を、米国製16番メッシュの篩に通す。次いでカルボキシメチルデンプンナトリウム、ステアリン酸マグネシウムおよびタルクをこの粒剤に加える。混合後、この混合物を錠剤機上で圧縮して、重さ100mgの錠剤を生成する。
適切な液体製剤は、カルボン酸ベースの緩衝剤、例えばクエン酸緩衝液、乳酸緩衝液およびマレイン酸緩衝液などを用いたものである。例えば、化合物Iまたは結晶形態I’(DMSOと予備混合しておいてもよい)を、100mMクエン酸アンモニウム緩衝剤とブレンドし、pHをpH5に調整するか、または100mMクエン酸溶液とブレンドし、pHをpH2に調整する。このような溶液はまた、シクロデキストリンなどの可溶化賦形剤を含んでもよく、例えば溶液は、10重量%のヒドロキシプロピル−β−シクロデキストリンを含んでもよい。
化合物Iまたは結晶形態I’(0.2g)を、0.4M酢酸ナトリウム緩衝液(2.0mL)とブレンドする。必要に応じて、0.5N水性の塩酸または0.5N水性の水酸化ナトリウムを使用して、得られた溶液のpHをpH4に調整し、次いで注射のための十分な水を加えて、総容量を20mLとする。次いでこの混合物を、無菌フィルター(0.22ミクロン)を通す濾過をして、注射による投与に対して適切な無菌溶液を得る。
製剤例A
製剤例B
製剤例C
化合物IまたはI’(0.2mg)を微粉化し、次いでラクトース(25mg)とブレンドする。次いでこのブレンドした混合物をゼラチン吸入カートリッジに充填する。カートリッジの内容物を、例えばドライパウダー吸入器を使用して投与する。
ACN=アセトニトリル
CPME=シクロペンチルメチルエーテル
d=日
DCC=N,N’−ジシクロヘキシルカルボジイミド
DCM=ジクロロメタンまたは塩化メチレン
DIPE=ジイソプロピルエーテル
DIPEA=N,N−ジイソプロピルエチルアミン
DMF=N,N−ジメチルホルムアミド
EDTA=エチレンジアミン四酢酸
EtOH=エタノール
EtOAc=酢酸エチル
g=グラム
h=時間
H2=水素ガス
H2O2=過酸化水素
HCTU=2−(6−クロロ−1H−ベンゾ[d][1,2,3]トリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート(V)
HATU=N,N,N’,N’−テトラメチル−O−(7−アザ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
HCl=塩化水素
NaBH4=水素化ホウ素ナトリウム
NaCl=塩化ナトリウム
NaHCO3=重炭酸ナトリウム
Na2CO3=炭酸ナトリウム
NaHMDS=ナトリウムビス(トリメチルシリル)アミドまたはナトリウムヘキサメチルジシラジド
NaOH=水酸化ナトリウム
Na2SO4=硫酸ナトリウム
NH4Cl=塩化アンモニウム
NMM=n−メチルモルホリン
MeI=ヨウ化メチル
MeOH=メタノール
min=分
MgSO4=硫酸マグネシウム
Pd(PPh3)4=テトラキス(トリフェニルホスフィン)パラジウム(0)
Pd/C=パラジウム担持活性炭、担持率10%
PE=石油エーテル
SiO2=二酸化ケイ素またはシリカ
TFA=トリフルオロ酢酸
THF=テトラヒドロフラン
A.分析用HPLC条件−方法A
測定技法
粉末X線回折
示差走査熱量測定
熱重量分析
偏光顕微鏡法
動的水分収着評価
合成反応スキーム
(実施例1)
(3S,5R)−5−[[4−(5−クロロ−2−フルオロフェニル)フェニル]メチル]−3−(ヒドロキシメチル)−3−メチルピロリジン−2−オン(A)の合成
ステップA−1:
ステップA−2:
ステップA−3:
ステップA−4:
ステップA−5:
ステップA−6およびA−7:
ステップA−8およびA−9:
(実施例2)
(2S,4R)−ベンジル4−アミノ−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−2−メチルペンタノエート(B)の合成
ステップB−1:
ステップB−2:
ステップB−3:
ステップB−4:
ステップB−5:
ステップB−6:
ステップB−7:
ステップB−8:
(実施例3)
(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(化合物I)
ステップ2:
(実施例4)
結晶性の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(化合物I’)の調製
(実施例5)
結晶性の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(化合物I’)の代替的調製
(実施例6)
結晶性の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I’)の安定性研究
アッセイ
アッセイ1:ラット、イヌおよびサルにおけるIV/PO薬動学研究
アッセイ2:ラット、イヌおよびサルの種における化合物Iの腎排泄
アッセイ3:第1相単回漸増用量研究
アッセイ3.1:ヒトにおけるNEP活性(cGMP)
アッセイ3.2 ヒトにおける化合物I’のPKプロファイル、経口生物学的利用能および腎排泄
アッセイ3.3:標準的処置との区別
アッセイ4:第1相複数回漸増用量研究
アッセイ4.1:ヒトにおけるNEP活性(cGMP)、および標準的処置との区別
本発明の実施形態の一部の例として、以下の項目が挙げられる。
(項目1)
(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I’)の結晶性遊離酸形態。
(項目2)
6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、および23.28±0.20の2θ値に回折ピークを含む粉末X線回折パターンによって特徴付けられる、項目1に記載の結晶性形態。
(項目3)
6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、17.12±0.20、23.28±0.20、および26.19±0.20の2θ値に回折ピークを含む粉末X線回折パターンによって特徴付けられる、項目1に記載の結晶性形態。
(項目4)
6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、15.72±0.20、17.12±0.20、20.79±0.20、21.10±0.20、23.28±0.20、24.48±0.20、25.81±0.20、および26.19±0.20から選択される2θ値に1つまたは複数の追加の回折ピークを有することによって特徴付けられる、項目1に記載の結晶性形態。
(項目5)
ピーク位置が図1に示すパターンのピーク位置と実質的に一致する粉末X線回折パターンによって特徴付けられる、項目1に記載の結晶性形態。
(項目6)
毎分10℃の加熱速度で記録した示差走査熱量測定トレースが、約214℃〜約218℃の間の温度で吸熱熱流の最大値を示すことによって特徴付けられる、項目1に記載の結晶性形態。
(項目7)
図2に示すものと実質的に一致する示差走査熱量測定トレースによって特徴付けられる、項目1に記載の結晶性形態。
(項目8)
項目1から7のいずれか一項に記載の結晶性形態と、薬学的に許容される担体とを含む薬学的組成物。
(項目9)
前記薬学的に許容される担体が、ステアリン酸マグネシウムである、項目8に記載の薬学的組成物。
(項目10)
項目1から7のいずれか一項に記載の結晶性形態と、AT 1 受容体アンタゴニスト、ホスホジエステラーゼ阻害剤、レニン阻害剤、可溶性グアニル酸シクラーゼ阻害剤、ミネラルコルチコイド受容体アンタゴニスト、利尿剤、またはこれらの組合せとを含む薬学的組成物。
(項目11)
薬学的に許容される担体をさらに含む、項目10に記載の薬学的組成物。
(項目12)
カプセル剤、錠剤、または懸濁液剤中に、項目1から7のいずれか一項に記載の結晶性形態を含む経口投与剤形。
(項目13)
対象における前記結晶性形態の放出が、即時性放出、制御性放出、または遅延性放出である、項目12に記載の経口投与剤形。
(項目14)
前記カプセル剤の材料が、ゼラチン、多糖、キトサン、または合成ポリマーである、項目12に記載の経口投与剤形。
(項目15)
硬質カプセル剤が、ゼラチン、多糖、または合成ポリマーを含む、項目12に記載の経口投与剤形。
(項目16)
前記カプセル剤が、ヒドロキシプロピルメチルセルロースを含む、項目12に記載の経口投与剤形。
(項目17)
療法での使用のための、項目1から7のいずれか一項に記載の結晶性形態。
(項目18)
高血圧、心不全、または腎疾患の処置における使用のための、項目17に記載の結晶性形態。
(項目19)
高血圧、心不全、または腎疾患を処置するための医薬の製造のための、項目1から7のいずれか一項に記載の化合物の使用。
(項目20)
高血圧、心不全、または腎疾患を処置するための方法であって、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、項目1から7のいずれか一項に記載の化合物を、患者に1日1回投与するステップを含む方法。
(項目21)
高血圧が、原発性高血圧、肺動脈高血圧、慢性血栓塞栓性肺高血圧、または腎動脈狭窄を伴う高血圧である、項目20に記載の方法。
(項目22)
腎疾患が、糖尿病性腎症、慢性腎疾患、タンパク質尿、急性腎臓傷害、ネフローゼ症候群、巣状分節性糸球体硬化症、または多発性嚢胞腎疾患である、項目20に記載の方法。
(項目23)
腎障害のある患者における高血圧、心不全、または腎疾患を処置する方法であって、前記(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、項目1から7のいずれか一項に記載の化合物の治療有効量を、前記患者に1日1回投与するステップを含む方法。
(項目24)
前記腎障害のある患者が、推定糸球体濾過量(eGFR)が60mL/分/1.73m 2 〜15mL/分/1.73m 2 の間である慢性腎臓病を有する、項目23に記載の方法。
(項目25)
ヒトにおいて少なくとも24時間、心房性ナトリウム利尿ペプチド(ANP)または環状グアノシン一リン酸(cGMP)のレベルを増加させる方法であって、前記ヒトに、ANPまたはcGMPを増加させる量の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、項目1から7のいずれか一項に記載の化合物を1日1回投与するステップを含む方法。
(項目26)
ANPおよびcGMPのレベルが、前記ヒトにおける尿中もしくは血漿中のいずれか、またはその両方で測定される、項目25に記載の方法。
(項目27)
(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、項目1から7のいずれか一項に記載の化合物が、非経口的に投与される、項目20、23または25のいずれか一項に記載の方法。
(項目28)
(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)を調製するためのプロセスであって、
(a)ベンジル(2S,4R)−4−アミノ−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−2−メチルペンタノエート塩酸塩を、溶媒中で、およそ1:1のモル比で3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボン酸とカップリングして、ベンジル(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボキサミド)−2−メチルペンタノエートを得るステップと、
(b)ベンジル(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボキサミド)−2−メチルペンタノエートを脱保護して、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)を形成するステップと
を含むプロセス。
(項目29)
ステップ(a)が、ペプチドカップリング剤および塩基を、およそ1:3:1:1のカップリング剤対塩基対ベンジル(2S,4R)−4−アミノ−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−2−メチルペンタノエート塩酸塩対3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボン酸のモル比でさらに含む、項目28に記載のプロセス。
(項目30)
前記カップリング剤が、2−(6−クロロ−1H−ベンゾ[d][1,2,3]トリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート(V)であり、前記塩基が、N,N−ジイソプロピルエチルアミンである、項目29に記載のプロセス。
(項目31)
前記脱保護ステップ(b)が、パラジウム触媒および水素ガスを用いて実施される、項目28に記載のプロセス。
(項目32)
項目1に記載の結晶性形態を調製するためのプロセスであって、
(a)必要に応じて金属捕集剤と共に、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸および溶媒を含む溶液を高温で形成するステップと、
(b)前記溶液を約−20℃〜5℃の間の温度に冷却するステップと、
(c)前記結晶性形態を得るために、得られた固体を単離するステップと
を含むプロセス。
(項目33)
ステップ(a)における前記溶媒が、極性溶媒である、項目32に記載のプロセス。
(項目34)
前記溶媒が、酢酸エチルと水との混合物、酢酸エチル、またはエタノールである、項目33に記載のプロセス。
(項目35)
ステップ(a)における前記温度が、約60℃〜95℃の間である、項目32に記載のプロセス。
(項目36)
前記温度が、約70℃〜85℃の間である、項目35に記載のプロセス。
(項目37)
ステップ(c)において前記固体を単離するステップが、濾過すること、1種もしくは複数の溶媒で洗浄すること、空気中もしくは減圧下で乾燥させること、またはこれらの組合せを含む、項目29に記載のプロセス。
(項目38)
前記溶媒が、酢酸エチルおよび水、酢酸エチル、またはエタノールである、項目37に記載のプロセス。
(項目39)
減圧下で乾燥させることが、25℃〜70℃の間の温度で実施される、項目37に記載のプロセス。
Claims (39)
- (2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I’)の結晶性遊離酸形態。
- 6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、および23.28±0.20の2θ値に回折ピークを含む粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶性形態。
- 6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、17.12±0.20、23.28±0.20、および26.19±0.20の2θ値に回折ピークを含む粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶性形態。
- 6.51±0.20、11.62±0.20、13.05±0.20、15.07±0.20、15.72±0.20、17.12±0.20、20.79±0.20、21.10±0.20、23.28±0.20、24.48±0.20、25.81±0.20、および26.19±0.20から選択される2θ値に1つまたは複数の追加の回折ピークを有することによって特徴付けられる、請求項1に記載の結晶性形態。
- ピーク位置が図1に示すパターンのピーク位置と実質的に一致する粉末X線回折パターンによって特徴付けられる、請求項1に記載の結晶性形態。
- 毎分10℃の加熱速度で記録した示差走査熱量測定トレースが、約214℃〜約218℃の間の温度で吸熱熱流の最大値を示すことによって特徴付けられる、請求項1に記載の結晶性形態。
- 図2に示すものと実質的に一致する示差走査熱量測定トレースによって特徴付けられる、請求項1に記載の結晶性形態。
- 請求項1から7のいずれか一項に記載の結晶性形態と、薬学的に許容される担体とを含む薬学的組成物。
- 前記薬学的に許容される担体が、ステアリン酸マグネシウムである、請求項8に記載の薬学的組成物。
- 請求項1から7のいずれか一項に記載の結晶性形態と、AT1受容体アンタゴニスト、ホスホジエステラーゼ阻害剤、レニン阻害剤、可溶性グアニル酸シクラーゼ阻害剤、ミネラルコルチコイド受容体アンタゴニスト、利尿剤、またはこれらの組合せとを含む薬学的組成物。
- 薬学的に許容される担体をさらに含む、請求項10に記載の薬学的組成物。
- カプセル剤、錠剤、または懸濁液剤中に、請求項1から7のいずれか一項に記載の結晶性形態を含む経口投与剤形。
- 対象における前記結晶性形態の放出が、即時性放出、制御性放出、または遅延性放出である、請求項12に記載の経口投与剤形。
- 前記カプセル剤の材料が、ゼラチン、多糖、キトサン、または合成ポリマーである、請求項12に記載の経口投与剤形。
- 硬質カプセル剤が、ゼラチン、多糖、または合成ポリマーを含む、請求項12に記載の経口投与剤形。
- 前記カプセル剤が、ヒドロキシプロピルメチルセルロースを含む、請求項12に記載の経口投与剤形。
- 療法での使用のための、請求項1から7のいずれか一項に記載の結晶性形態。
- 高血圧、心不全、または腎疾患の処置における使用のための、請求項17に記載の結晶性形態。
- 高血圧、心不全、または腎疾患を処置するための医薬の製造のための、請求項1から7のいずれか一項に記載の化合物の使用。
- 高血圧、心不全、または腎疾患を処置するための方法であって、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、請求項1から7のいずれか一項に記載の化合物を、患者に1日1回投与するステップを含む方法。
- 高血圧が、原発性高血圧、肺動脈高血圧、慢性血栓塞栓性肺高血圧、または腎動脈狭窄を伴う高血圧である、請求項20に記載の方法。
- 腎疾患が、糖尿病性腎症、慢性腎疾患、タンパク質尿、急性腎臓傷害、ネフローゼ症候群、巣状分節性糸球体硬化症、または多発性嚢胞腎疾患である、請求項20に記載の方法。
- 腎障害のある患者における高血圧、心不全、または腎疾患を処置する方法であって、前記(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、請求項1から7のいずれか一項に記載の化合物の治療有効量を、前記患者に1日1回投与するステップを含む方法。
- 前記腎障害のある患者が、推定糸球体濾過量(eGFR)が60mL/分/1.73m2〜15mL/分/1.73m2の間である慢性腎臓病を有する、請求項23に記載の方法。
- ヒトにおいて少なくとも24時間、心房性ナトリウム利尿ペプチド(ANP)または環状グアノシン一リン酸(cGMP)のレベルを増加させる方法であって、前記ヒトに、ANPまたはcGMPを増加させる量の(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、請求項1から7のいずれか一項に記載の化合物を1日1回投与するステップを含む方法。
- ANPおよびcGMPのレベルが、前記ヒトにおける尿中もしくは血漿中のいずれか、またはその両方で測定される、請求項25に記載の方法。
- (2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)、例えば、請求項1から7のいずれか一項に記載の化合物が、非経口的に投与される、請求項20、23または25のいずれか一項に記載の方法。
- (2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)を調製するためのプロセスであって、
(a)ベンジル(2S,4R)−4−アミノ−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−2−メチルペンタノエート塩酸塩を、溶媒中で、およそ1:1のモル比で3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボン酸とカップリングして、ベンジル(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボキサミド)−2−メチルペンタノエートを得るステップと、
(b)ベンジル(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボキサミド)−2−メチルペンタノエートを脱保護して、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸(I)を形成するステップと
を含むプロセス。 - ステップ(a)が、ペプチドカップリング剤および塩基を、およそ1:3:1:1のカップリング剤対塩基対ベンジル(2S,4R)−4−アミノ−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−2−メチルペンタノエート塩酸塩対3−((4−メトキシベンジル)オキシ)イソオキサゾール−5−カルボン酸のモル比でさらに含む、請求項28に記載のプロセス。
- 前記カップリング剤が、2−(6−クロロ−1H−ベンゾ[d][1,2,3]トリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート(V)であり、前記塩基が、N,N−ジイソプロピルエチルアミンである、請求項29に記載のプロセス。
- 前記脱保護ステップ(b)が、パラジウム触媒および水素ガスを用いて実施される、請求項28に記載のプロセス。
- 請求項1に記載の結晶性形態を調製するためのプロセスであって、
(a)必要に応じて金属捕集剤と共に、(2S,4R)−5−(5’−クロロ−2’−フルオロ−[1,1’−ビフェニル]−4−イル)−2−(エトキシメチル)−4−(3−ヒドロキシイソオキサゾール−5−カルボキサミド)−2−メチルペンタン酸および溶媒を含む溶液を高温で形成するステップと、
(b)前記溶液を約−20℃〜5℃の間の温度に冷却するステップと、
(c)前記結晶性形態を得るために、得られた固体を単離するステップと
を含むプロセス。 - ステップ(a)における前記溶媒が、極性溶媒である、請求項32に記載のプロセス。
- 前記溶媒が、酢酸エチルと水との混合物、酢酸エチル、またはエタノールである、請求項33に記載のプロセス。
- ステップ(a)における前記温度が、約60℃〜95℃の間である、請求項32に記載のプロセス。
- 前記温度が、約70℃〜85℃の間である、請求項35に記載のプロセス。
- ステップ(c)において前記固体を単離するステップが、濾過すること、1種もしくは複数の溶媒で洗浄すること、空気中もしくは減圧下で乾燥させること、またはこれらの組合せを含む、請求項29に記載のプロセス。
- 前記溶媒が、酢酸エチルおよび水、酢酸エチル、またはエタノールである、請求項37に記載のプロセス。
- 減圧下で乾燥させることが、25℃〜70℃の間の温度で実施される、請求項37に記載のプロセス。
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