JP2021519313A - Urat−1阻害剤の新規塩型 - Google Patents
Urat−1阻害剤の新規塩型 Download PDFInfo
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- JP2021519313A JP2021519313A JP2020551976A JP2020551976A JP2021519313A JP 2021519313 A JP2021519313 A JP 2021519313A JP 2020551976 A JP2020551976 A JP 2020551976A JP 2020551976 A JP2020551976 A JP 2020551976A JP 2021519313 A JP2021519313 A JP 2021519313A
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Abstract
Description
本出願は2018年3月28日に提出された国際出願番号PCT/CN2018/080889の優先権を主張し、その内容はすべて参照により本明細書に組み込まれる。
各種実施形態において、本発明は概して、URAT−1阻害剤の新規塩型、それを含む医薬組成物、並びにその製造及び使用方法に関する。
米国特許第9,809,580号には、URAT1の阻害に有効でありかつ痛風及び高尿酸血症などの疾患又は障害の治療に利用できる、チオ酪酸化合物などの様々なチオ置換カルボン酸が記載されている。各種の実施形態において、本発明は、例えば結晶形態及び/又は実質的に純粋な単離塩であるチオ置換カルボン酸及びその薬学的に許容される塩、それを含む医薬組成物、その製造方法、並びにその使用方法に関する。
様々な実施形態では、例えば結晶型又は実質的に純粋な化合物であるチオ置換カルボン酸化合物及び薬学的に許容される塩が提供される。また、医薬組成物、その製造方法、及びそれらを用いる方法を提供する。より具体的な実施形態は、2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸及びその薬学的に許容される塩、例えばナトリウム塩、カリウム塩、又はカルシウム塩に関する。
様々な実施形態では、本発明に係るチオ置換カルボン酸化合物の塩(例えば、ナトリウム塩、カリウム塩、又はカルシウム塩)は、URAT−1の有効な阻害剤であり、痛風又は高尿酸血症などの様々な疾患及び障害の治療に有用である。このようなカルボン酸化合物の例は、以前に米国特許第9,809,580号に記載されており、その内容は全体が参照により本明細書に組み込まれている。
いくつかの実施形態では、本発明は、1種又は複数種の本明細書に記載の化合物(例えば、化合物1、1−Na、1−K、又は1−Ca)を含む医薬組成物を提供する。典型的に、医薬組成物は、本明細書に記載の治療有効量の1種又は複数種の化合物(例えば、化合物1、1−Na、1−K、又は1−Ca)と、任意で薬学的に許容される賦形剤又は担体とを含む。いくつかの実施形態では、医薬組成物は、本明細書に記載の実質的に純粋な化合物1、1−Na、1−K、及び1−Caのうちの1種又は複数種を含む。いくつかの実施形態では、医薬組成物は、化合物1のI型、化合物1−NaのII型、化合物1−KのIII型、及び化合物1−CaのIV型から選択される1種又は複数種の結晶型を含む。医薬組成物は、任意の投与経路、例えば経口投与のために製剤化することができる。
本明細書に記載の化合物及び医薬組成物は、様々な疾患及び障害の治療に利用できる。米国特許第9,809,580号に示されているように、化合物1などのカルボン酸化合物はURAT−1の有効な阻害剤であり、尿酸レベル異常による各種疾患及び障害の治療に利用できる。
本明細書で使用されるように、本発明に関連する量を修飾する用語「約」は、例えば、通常の測定及び処理、このような測定及び処理中の意図しないエラー、本発明に用いる成分の製造、由来、又は純度の違いなどによって生じ得る数量のバリエーションを意味する。ここで使用するように、「約」特定の値は、この特定の値も含み、例えば、約10%は10%を含む。用語「約」で修飾されているかどうかにかかわらず、特許請求の範囲には記載された量の同等の形が含まれる。一実施形態では、用語「約」は報告された数値の20%以内を意味する。
実施形態1。化合物1、化合物1−Na、化合物1−K、又は化合物1−Caの結晶形態。
材料:出発材料、試薬、溶剤などは、概ね市販で入手できた。
粉末X線回折(XRPD):X線回折計(Bruker D8 advance)を用いて固体試料を検査した。システムにはLynxEye検出器が備えられている。X線の波長は1.5406Åである。試料は、3°から40°の2θで走査し、ステップサイズは0.02°の2θであった。チューブ電圧と電流はそれぞれ40KVと40mAであった。試料を試料容器からゼロバックグラウンドXRPDホルダーに移し、静かに接地した。
機器:Agilent 1260シリーズ
流速:1.2mL/min
移動相:A:0.1%TFA/水
B:0.1%TFA/メタノール
試料注入量:2μL
カラム:Agilent Eclipse plus C18,3.5um、4.6*100mm
カラム温度:40℃
検出:255nm
稼働時間:8分(次の注入まで2分間隔)
勾配(T/B%):0.0/30、6.0/70、及び8.0/90
N2雰囲気下、1,4−ジオキサン(10v)、3−ブロモ−4−クロロピリジン(1400.0g,1.0eq)、4−シアノフェニルボロン酸(1.02eq)、Na2CO3(2M aq、2.0eq)と、KOAc(1.0eq)を反応器に添加した。窒素で反応器を不活性化し、その後Pd(PPh3)4(0.02wt)を添加した。3−ブロモ−4−クロロピリジンの含有量が≦5.0%になるまで、得られた混合物を90±5℃で24時間加熱した。反応混合物を20±5℃に冷却し、ろ過してケーキを1,4−ジオキサン(2v)で洗浄した。合わせたろ液を10vまで減圧濃縮した後、H2O(20v)を加えると、白色固体が形成された。混合物をろ過し、ろ過ケーキをH2O(2v)で洗浄した。ケーキをDCM(5v)に溶解し、得られた混合物を分離し、残った水を除去した。3-メルカプトプロピルエチルスルフィドシリカ(0.15wt)を加え、混合物をろ過して、DCM(2v)で洗浄した。合わせたろ液に再度3-メルカプトプロピルエチルスルフィドシリカ(0.15wt)を加え、混合物をろ過して、DCM(2v)で洗浄した。得られたろ液を2〜3vに濃縮し、純水(8v)を加えた。混合物を、少なくとも30分間撹拌してからろ過した。ろ過ケーキを水(2v)で洗浄し、50±5℃の真空オーブンで乾燥させて、白色固体(純度:90.4%)として粗生成物が得られ、これは、さらに精製することなく次の反応に用いた。
N2雰囲気下、DMF(6v)を反応器に入れた後、化合物20−b(1313.6g,1.0eq)、2−(1−メルカプトメチル)シクロプロピル酢酸メチル(1.05eq)及びK2CO3(1.2eq)を加えた。化合物20bの含有量が≦1.0%になるまで、得られた混合物を80±5℃で3時間加熱した。反応混合物を20±5℃まで冷却し、ろ過してEA(2v)でケーキを洗浄した。合わせたろ液にH2O(10v)を加え、EA(5v)で抽出した。有機相を合わせ、飽和NaHCO3溶液とNaCl溶液で洗浄した。得られた有機相を2〜3vに減圧濃縮し、n−ヘプタン(10v)を加えた。混合物をろ過し、n−ヘプタン(2v)で洗浄した。ろ過したケーキをEA(10v)に溶解し、得られた有機相を、50±5℃(水温)で2〜3vまで減圧濃縮した。n−ヘプタン(10v)を混合物に加え、40±5℃で1時間撹拌した後に、ろ過によって固体を回収し、n−ヘプタン(2v)で洗浄した。ろ過したケーキを、50±5℃でMTBE(10v)に溶解し、3-メルカプトプロピルエチルスルフィドシリカ(0.20wt)を加えた。得られた混合物を、50±5℃で少なくとも5時間撹拌し、ろ過し、MTBE(2v)で洗浄した。合わせたろ液に、再度3-メルカプトプロピルエチルスルフィドシリカ(0.20wt)を加え、50±5℃で少なくとも5時間撹拌した。ろ過したケーキはMTBE(2v)で洗浄し、合わせた有機相を2〜3vに減圧濃縮した。n−ヘプタン(10v)を混合物に加えて、ろ過よって固体を回収した。ろ過したケーキを真空オーブンで50±5℃で乾燥させ、白色固体として粗化合物20−cが得られた(純度:95.2%)。
N2雰囲気下、THF(10v)における化合物20−c(1533.0g、1.0eq)の撹拌溶液を、LiOH水溶液(2M、1.1eq)に加えた。化合物20−cの含有量が≦1.0%になるまで、得られた混合物を25±3℃で2時間撹拌した。反応混合物をH2O(10v)でクエンチングした後、MTBEで抽出した。水相を0±5℃まで冷却し、20%HOAc水溶液を0±5℃でゆっくりと加え、pH 5.0〜6.0に調整した。得られた固体をろ過により回収し、H2O(5v)で洗浄して乾燥させ、オフホワイト固体として化合物1のI型が得られ、これを、XRPDにより特徴付けた(純度:99.6%)。
2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸(2.003g)をガラスフラスコに入れた。その後、THF(80mL)を加えて、清澄溶液を形成した。その後、NaOH(264.2mg)をフラスコに入れ、黄色沈殿が現れるまで、混合物を4時間撹拌した。ナトリウム塩固体をろ過し、THFで洗浄し、真空乾燥させた。
2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸(50.04mg)をバイアルに添加した。次いでTHF(2mL)を添加し、超音波後に清澄溶液を形成した。その後、KOHのメタノール溶液(0.1 mol/L、1.54mL)を加え、2時間撹拌した。溶媒を蒸発させてほぼ乾燥させ、酢酸エチル1.0mLを加えた。懸濁液を30分間撹拌し、黄色沈殿が現れた。固体をろ過し、回収し、真空で乾燥させた。
2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸カリウム(79.92mg)をバイアルに添加し、塩化カルシウム溶液(12.27mg/1.0mL水)を加えた。混合物を2.5時間撹拌したところ、白い沈殿が現れた。カルシウム塩固体がろ過によって得られ、次いで水で洗浄し、真空下で乾燥させた。
1−Na、1−K、1−Ca、及び化合物1(遊離酸)の溶解度試験
試料固体(1−Ca塩又は化合物1)5mgをガラスバイアル8mLに秤量した後、pH6.8緩衝液又は水を1ml加えた。0.3〜0.5mLの懸濁液を、25℃、200rpmで、それぞれ0.5時間および2時間遠心した。それぞれの時点で懸濁液をろ過して固体を除去し、ろ液をHPLCで分析した。
20mgの塩(1−Na又は1−K又は1−Ca塩)を20mLのガラスに秤量し、加速条件下(40℃/75%RH)に置いた。1週間及び2週間の時点で、5mgの固体を10mLの容量フラスコに秤量し、希釈剤(メタノール:水=1:1)を加えて溶解し、希釈剤で目盛りまで希釈した。HPLC及びXRPDの分析はそれぞれ0、1、2週間目に行った。
Claims (20)
- 2θが8.8、15.2、16.2、17.2、17.6、18.6、20.2、20.9、21.7、22.2、23.1、25.2、25.9、及び26.4°±0.2°であるピークの1つ又は複数を有するX線粉末回折(XRPD)パターンを特徴とする、請求項1に記載の結晶型II。
- 2θが8.8、15.2、16.2、17.2、17.6、18.6、20.2、20.9、21.7、22.2、23.1、25.2、25.9、及び26.4°±0.2°であるピークの4つ以上を有するXRPDパターンを特徴とする、請求項1に記載の結晶型II。
- 2θが8.8、15.2、16.2、17.2、17.6、18.6、20.2、20.9、21.7、22.2、23.1、25.2、25.9、及び26.4°±0.2°であるピークの8つ以上を有するXRPDパターンを特徴とする、請求項1に記載の結晶型II。
- XRPDパターンが図2Aに示すものと実質的に同じであることを特徴とする、請求項1に記載の結晶型II。
- 示差走査熱量測定(DSC)パターンが図2Bに示すものと実質的に同じであることを特徴とする、請求項1〜5のいずれか一項に記載の結晶型II。
- 請求項1〜6のいずれか一項に記載の結晶型IIと、任意で薬学的に許容される賦形剤又は担体とを含む、医薬組成物。
- 2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸ナトリウムの他の固体形態を実質的に含まない、請求項7に記載の医薬組成物。
- 2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸を実質的に含まない、請求項7又は8に記載の医薬組成物。
- 腸溶コーティングされていない、請求項7〜9のいずれか一項に記載の医薬組成物。
- 錠剤又はカプセルの形態である、請求項7〜10のいずれか一項に記載の医薬組成物。
- 前記医薬組成物の活性成分が、本質的に2−(1−(((3−(4−シアノフェニル)ピリジン−4−イル)チオ)メチル)シクロプロピル)酢酸ナトリウムからなる、請求項7〜11のいずれか一項に記載の医薬組成物。
- その必要がある対象に、治療有効量の請求項1〜6のいずれか一項に記載の結晶型II又は請求項7〜12のいずれか一項に記載の医薬組成物を投与する工程を含む、痛風、痛風性関節炎、再発性痛風発作、高尿酸血症、関節の炎症、関節炎、尿路結石症、腎臓疾患、腎結石、腎不全、高血圧、心血管疾患、冠状動脈性心疾患、レッシュ・ナイハン症候群、ケリー・シーグミラー症候群、鉛毒症、副甲状腺機能亢進症、乾癬、及びサルコイドーシスから選ばれる1種又は複数種の疾患又は障害を治療する方法。
- その必要がある対象に、治療有効量の請求項1〜6のいずれか一項に記載の結晶型II又は請求項7〜12のいずれか一項に記載の医薬組成物を投与する工程を含む、高尿酸血症を治療する方法。
- その必要がある対象に、治療有効量の請求項1〜6のいずれか一項に記載の結晶型II又は請求項7〜12のいずれか一項に記載の医薬組成物を投与する工程を含む、痛風を治療する方法。
- 痛風を治療するのに有効な第2の薬剤を、前記対象に投与する工程をさらに含む、請求項15に記載の方法。
- 前記第2の薬剤が、キサンチンオキシダーゼ阻害剤、キサンチンデヒドロゲナーゼ阻害剤、キサンチンオキシドレダクターゼ阻害剤、又はそれらの組み合わせである、請求項16に記載の方法。
- 前記第2の薬剤が、アロプリノール、フェブキソスタット、又はそれらの組み合わせである、請求項17に記載の方法。
- その必要がある対象に、有効量の請求項1〜6のいずれか一項に記載の結晶型II又は請求項7〜12のいずれか一項に記載の医薬組成物を投与する工程を含む、血液中の尿酸レベルを低下させるか又は尿酸の排泄を促進する方法。
- 前記結晶型II又は医薬組成物を、前記対象に経口投与で投与する、請求項13〜19のいずれか一項に記載の方法。
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