JP6255382B2 - ヒトヒストンメチルトランスフェラーゼezh2阻害剤の塩形態 - Google Patents
ヒトヒストンメチルトランスフェラーゼezh2阻害剤の塩形態 Download PDFInfo
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- JP6255382B2 JP6255382B2 JP2015505912A JP2015505912A JP6255382B2 JP 6255382 B2 JP6255382 B2 JP 6255382B2 JP 2015505912 A JP2015505912 A JP 2015505912A JP 2015505912 A JP2015505912 A JP 2015505912A JP 6255382 B2 JP6255382 B2 JP 6255382B2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
本出願は、2012年4月13日出願の米国仮出願番号61/624,215号に対し優先権を主張し、参照によりその全体が本明細書に組み込まれる。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド臭化水素酸塩。
(項目2)
一臭化水素酸塩である、項目1に記載の化合物。
(項目3)
結晶性である、項目1〜2のいずれか1項に記載の化合物。
(項目4)
項目1〜3のいずれか1項に記載の化合物であって、実質的に不純物を含まない、化合物。
(項目5)
項目1〜4のいずれか1項に記載の化合物であって、非晶質N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド臭化水素酸塩を実質的に含まない結晶性固体である、化合物。
(項目6)
項目1〜5のいずれか1項に記載の化合物及び医薬的に許容され得る担体または希釈剤を含む、医薬組成物。
(項目7)
項目1に記載の化合物の製造方法であって、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドを臭化水素酸と化合することを含む、方法。
(項目8)
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド臭化水素酸塩の多形A。
(項目9)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、約17.5±0.3°及び約22.0±0.3°(2θ)に1個以上の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目10)
項目8〜9のいずれか1項に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、約17.5±0.3°及び約22.0±0.3°(2θ)に特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目11)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、約14.3±0.3°、約18.7±0.3°、約23.3±0.3°及び約23.6±0.3°(2θ)に1個以上の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目12)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも5個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目13)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも6個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目14)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも7個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目15)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも8個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目16)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも9個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目17)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも10個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目18)
項目8に記載の多形であって、°(2θ)で表示して、約3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に特徴的ピークを有するX線粉末回折パターンを示す、多形。
(項目19)
項目8〜18のいずれか1項に記載の多形であって、実質的に図1に従うX線粉末回折パターンを示す、多形。
(項目20)
項目8〜19のいずれか1項に記載の多形であって、実質的に表1に従うX線粉末回折パターンを示す、多形。
(項目21)
項目8〜20のいずれか1項に記載の多形であって、℃の単位で表示して、255±5℃の温度に特徴的ピークを有する示差走査熱量測定サーモグラムを示す、多形。
(項目22)
項目8〜21のいずれか1項に記載の多形であって、実質的に図3に従う示差走査熱量測定サーモグラムを示す、多形。
(項目23)
項目8〜22のいずれか1項に記載の多形の製造方法であって、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドを臭化水素酸と化合することを含む、方法。
(項目24)
項目8〜22のいずれか1項に記載の多形の再結晶化方法であって、(a)多形Aを第1溶媒に溶解するステップ、及び(b)第2溶媒を添加するステップを含み、それにより前記多形を再結晶化する、方法。
(項目25)
項目24に記載の方法であって、前記第1溶媒はエタノールであり、前記第2溶媒はMTBEである、方法。
(項目26)
項目16に記載の方法であって、(a)多形Aをエタノールに溶解し、(b)前記混合物を加熱し、(c)前記混合物にMTBEを添加し、前記多形を含む沈殿物を形成し、及び前記沈殿物を濾過することを含み、それにより前記多形を再結晶化する、方法。
(項目27)
項目8〜22のいずれか1項に記載の多形及び医薬的に許容され得る担体または希釈剤を含む、医薬組成物。
(項目28)
癌の治療方法であって、癌治療の必要がある被験者に治療有効量の項目1〜5のいずれかに記載の化合物、項目8〜22のいずれかに記載の多形、または項目6または27のいずれかに記載の医薬組成物を投与することを含む、方法。
(項目29)
前記癌が、非ホジキンリンパ腫または乳癌である、項目28に記載の方法。
(項目30)
被験者におけるEZH2のヒストンメチルトランスフェラーゼ活性の阻害方法であって、前記阻害の必要がある被験者に有効量の項目1〜5のいずれかに記載の化合物または項目8〜22のいずれかに記載の多形を投与することを含む、方法。
(項目31)
インビトロでのEZH2のヒストンメチルトランスフェラーゼ活性の阻害方法であって、項目1〜5のいずれかに記載の化合物または項目8〜22のいずれかに記載の多形を投与することを含む、方法。
(項目32)
項目1〜5のいずれかに記載の化合物または項目8〜22のいずれかに記載の多形の使用であって、癌治療医薬の必要がある被験者において癌を治療するための医薬を製造するための、使用。
(項目33)
5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボン酸(5)を、3−(アミノメチル)−4,6−ジメチル−ジヒドロ−ピリジン−2(1H)−オンの塩と反応させることを含む、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドの製造方法。
(項目34)
(5)は結晶形である、項目33に記載の方法。
本発明では、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド臭化水素酸塩:
化合物Iの臭化水素酸塩及び多形Aは公知技術を用いて製造され得る。従来、塩形態は溶液中で遊離塩基化合物を所望の塩形態のアニオンを含有している酸と化合した後、反応溶液から(結晶化、沈殿、蒸発等により)固体塩生成物を単離することにより製造されている。他の塩形成技術が使用され得る。
別の態様で、本発明では、化合物Iの臭化水素酸塩及び医薬的に許容され得る担体または希釈剤を含む医薬組成物が提供される。本発明では、多形A及び医薬的に許容され得る担体または希釈剤を含む医薬組成物が提供される。
本発明の化合物(すなわち、化合物Iの臭化水素酸塩及び多形A)はEZH2またはその変異体のヒストンメチルトランスフェラーゼ活性を阻害し、従って本発明の1つの態様で、本明細書中に開示されているある化合物はある状態及び疾患を治療または予防するための候補者である。本発明は、その過程がヒストンまたは他のタンパク質のメチル化状態をモジュレートすることにより影響され得る状態及び疾患を治療するための方法を提供し、前記メチル化状態は少なくとも部分的にEZH2の活性により媒介される。また、ヒストンのメチル化状態のモジュレーションは、メチル化により活性化される標的遺伝子及び/またはメチル化により抑制される標的遺伝子の発現レベルに影響を及ぼし得る。この方法はその治療を必要とする被験者に対して治療有効量の本発明の化合物を投与することを含む。
粉末X線回折
全てのサンプルについてのPXRDをRigaku MultiFlex(標的:Cu;管電圧:40kV;管電流:30mA)で取った。
全てのサンプルについてのDSCをMettler−Toledo DSC 1/700(ラン条件:初期温度35℃,最終温度325℃,加熱速度30℃/分)で取った。
0.28×0.22×0.06mmの寸法を有する無色板状結晶を非常に少量のパラトン油を用いてナイロンループに載せた。173Kで操作するOxford Cryostream低温装置を備えたブルカーCCD(電荷結合素子)に基づく回折計を用いてデータを集めた。データは0.5°/フレームのω及びφスキャンを用いて45秒間測定した。イメージの全数は、冗長度が4.0であると予測され、100%までの完全性が0.83ÅであるプログラムCOSMOからの結果に基づいていた。細胞パラメーターをAPEX IIソフトウェアを用いて検索し、全ての観察された反射についてSAINTを用いて精密化した。データ整理をLpについて補正するSAINTソフトウェアを用いて実施した。スケーリング及び吸収補正はGeorge Sheldrickから供給されるSADABSマルチスキャン技術を用いて適用した。構造をSHELXS−97プログラムを用いる直接方法により解析し、SHELXTL−PC V 6.10に取り込まれるF2,SHELXL−97を用いて最小二乗法により精密化した。
DVSはVTIモデルSGA−100システムを用いて測定した。測定方法:相対湿度(RH)を管理された方法で5.0%から95.0%まで5%ずつ変化させた後、重量測定水蒸気吸脱着システムを用いて5.0%に戻し、各段階でのサンプルの重量変化%(wt%)を測定した。
HPLCは、インライン脱ガス装置を有するAgilent 1200 HPLCクォータナリポンプ,低圧混合を用いて実施した。分析方法条件:8μLのサンプル(約0.4mg/mLの溶液を与えるように50mLのメタノールで希釈した20mgのER−581982−06)をAgilent Zorbax Eclipse XDB−C18(4.6×150mm,3.5um)に注入した。クロマトグラフィー条件:移動相A 水+5mM ギ酸アンモニウム;移動相B 50/45/5 アセトニトリル/メタノール/水中の5mM ギ酸アンモニウム;流速 1.5ml/分;勾配:0分から3分までは10% Bで無勾配;3分から7分までは70% Bに線形増加;7分から12分までは70% Bで無勾配;12分から15分までは100% Bに線形増加;15分から20分までは100% Bで無勾配;カラム温度35℃;検出 UV 230nm。化合物Iのおおよその保持時間=10.7分。
メチル5−ブロモ−3−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−2−メチルベンゾエート(580g,1.63mol)、4−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンジル)モルホリン(592g,1.95mol)、1,4−ジオキサン(3.86L)、炭酸ナトリウム(618g,5.83mol)及び水(771ml)の混合物に20℃で窒素を20分間通気することによりこの混合物を脱気し、テトラキス(トリフェニルホスフィン)パラジウム(0)(14.11g,12.21mmol)で処理した。生じた混合物を更に20分間脱気した後、87〜89℃に17時間加熱した。20℃に冷却した後、混合物を酢酸エチル(5.80L)及び(R)−2−アミノ−3−メルカプトプロピオン酸(232g)を水(2.320L)中に含む溶液で希釈した。20℃で1時間撹拌した後、有機層を分離し、(R)−2−アミノ−3−メルカプトプロピオン酸(232g)を水(2.320L)中に含む溶液で再び洗浄した。水性層を合わせ、酢酸エチル(5.80L)で抽出した。有機層を合わせ、水(2.32L)中に水酸化ナトリウム(93g)を含む溶液で洗浄し、真空下35℃で濃縮して、標記化合物をオレンジ色油状物(1.21kg,収率164%)として得た。
塩酸塩、臭化水素酸塩、半硫酸塩、ナトリウム塩、リン酸塩、硝酸塩、マレイン酸塩、マロン酸塩及びL−酒石酸塩を含めた化合物Iの多数の各種塩形態を製造し、スクリーニングした。これらの中で、臭化水素酸塩(HBr)塩が製造の容易さ及び吸湿性の点で最も有利な物理化学的特性を有していた。
一般的材料
S−アデノシルメチオニン(SAM)、S−アデノシルホモシステイン(SAH)、ビシン、KCl、トゥイーン20、ジメチルスルホキシド(DMSO)及び牛皮ゼラチン(BSG)はSigma−Aldrichからできるだけ最高純度のものを購入した。ジチオトレイトール(DTT)はEMDから購入した。3H−SAMはAmerican Radiolabeled Chemicalsから80Ci/mmolの比放射能のものを購入した。384ウェルのストレプトアビジンフラッシュプレートはPerkinElmerから購入した。
無修飾リシン27(H3K27me0)またはジメチル化リシン27(H3K27me2)のいずれかを含有しているヒトヒストンH3残基21−44を代表するペプチドを21st Century BiochemicalsによりC末端G(K−ビオチン)リンカー親和性タグモチーフ及びC末端アミドキャップを用いて合成した。これらのペプチドを高速液体クロマトグラフィー(HPLC)にかけて純度95%以上に精製し、液体クロマトグラフィー質量分析法(LC−MS)により確認した。配列を以下にリストする:
H3K27me0:ATKAARKSAPATGGVKKPHRYRPGGK(ビオチン)−アミド(配列番号1)
H3K27me2:ATKAARK(me2)SAPATGGVKKPHRYRPGGK(ビオチン)−アミド(配列番号2)
ニワトリ赤血球オリゴヌクレオゾームは定型手順に従ってニワトリ血液から精製した。
ヒトPRC2複合体をスポドプテラ・フルギペルダ(Spodoptera frugiperda)(sf9)細胞においてバキュロウイルス発現系を用いて共発現させた四成分酵素複合体として精製した。発現させたサブユニットは、野生型EZH2(NM_004456)、または野生型EZH2構築物から作成したEZH2 Y641F、N、H、SまたはC変異体、EED(NM_003797)、Suz12(NM_015355)及びRbAp48(NM_005610)であった。EEDサブユニットは、sf9細胞ライゼート由来の全四成分複合体を精製するために使用したN末端FLAGタグを含んでいた。複合体の純度はSDS−PAGE及びアジレントバイオアナライザー分析により調べて95%以上であった。酵素ストック濃厚物の濃度(通常0.3〜1.0mg/mL)はウシ血清アルブミン(BSA)標準に対してブラッドフォードアッセイを用いて測定した。
アッセイはすべて、使用当日に調製した20mM ビシン(pH=7.6)、0.5mM DTT、0.005% BSG及び0.002% トゥイーン20から構成した緩衝液中で実施した。100% DMSO(1μL)中の化合物を384チャネルピペットヘッド(Thermo)を取り付けたPlatemate 2×3を用いてポリプロピレン384ウェルV底プレート(Greiner)にスポッティングした。最大シグナルコントロールのためにDMSO(1μL)を列11、12、23、24の行A〜Hに添加し、最小シグナルコントロールのために公知化合物でありPRC2の阻害剤のSAH(1μL)を列11、12、23、24の行I〜Pに添加した。野生型PRC2酵素及びH3K27me0ペプチド、またはY641変異体酵素及びH3K27me2ペプチドを含有しているカクテル(40μL)をMultidrop Combi(Thermo)により添加した。化合物をPRC2と25℃で30分間インキュベートした後、反応を開始させるために非放射性及び3H−SAMの混合物を含有しているカクテル(10μL)を添加した(最終容量=51μL)。いずれの場合も、最終濃度は以下の通りであった:野生型または変異体PRC2酵素は4nMであり、最小シグナルコントロールウェル中のSAHは1mMであり、DMSO濃度は1%であった。残りの成分の最終濃度を下表2に示す。3H−SAMをペプチド基質への取り込みがもはや検出されなくなるレベルに希釈する600μMの最終濃度まで非放射性SAM(10μL)を添加することによりアッセイを停止した。次いで、384ウェルポリプロピレンプレート中の反応物50μLを384ウェルフラッシュプレートに移し、ビオチニル化ペプチドをストレプトアビジン表面に少なくとも1時間結合させた後、Biotek ELx405プレート洗浄装置を用いて0.1% トゥイーン20で3回洗浄した。次いで、プレートを毎分壊変数(dpm)として測定される、または毎分カウント数(cpm)と称されるフラッシュプレート表面に結合した3H標識ペプチドの量を測定するためにPerkinElmerトップコートプレートリーダーを用いて調べた。
アッセイは、使用当日に調製した20mM ビシン(pH=7.6)、0.5mM DTT、0.005% BSG、100mM KCl及び0.002% トゥイーン20から構成される緩衝液中で実施した。100% DMSO(1μL)中の化合物を384チャネルピペットヘッド(Thermo)を取り付けたPlatemate 2×3を用いてポリプロピレン384ウェルV底プレート(Greiner)にスポッティングした。最大シグナルコントロールのためにDMSO(1μL)を列11、12、23、24の行A〜Hに添加し、最小シグナルコントロールのために公知化合物でありPRC2の阻害剤のSAH(1μL)を列11、12、23、24の行I〜Pに添加した。野生型PRC2酵素及びニワトリ赤血球オリゴヌクレオゾームを含有しているカクテル(40μL)をMultidrop Combi(Thermo)により添加した。化合物をPRC2と25℃で30分間インキュベートした後、反応を開始させるために非放射性及び3H−SAMの混合物を含有しているカクテル(10μL)を添加した(最終容量=51μL)。最終濃度は以下の通りであった:野生型PRC2酵素は4nMであり、非放射性SAMは430mMであり、3H−SAMは120nMであり、ニワトリ赤血球オリゴヌクレオゾームは120nMであり、最小シグナルコントロールウェル中のSAHは1mMであり、DMSO濃度は1%であった。3H−SAMをニワトリ赤血球オリゴヌクレオゾームへの取り込みがもはや検出されなくなるレベルに希釈する600μMの最終濃度まで非放射性SAM(10μL)を添加することによりアッセイを停止した。次いで、384ウェルポリプロピレンプレート中の反応物50μLを384ウェルフラッシュプレートに移し、ニワトリ赤血球オリゴヌクレオゾームをプレートの表面に固定化し、次いでBiotek ELx405プレート洗浄装置を用いて0.1% トゥイーン20で3回洗浄した。次いで、プレートを毎分壊変数(dpm)として測定される、または毎分カウント数(cpm)と称されるフラッシュプレート表面に結合した3H標識ニワトリ赤血球オリゴヌクレオゾームの量を測定するためにPerkinElmerトップコートプレートリーダーを用いて調べた。
WSU−DLCL2懸濁細胞はDSMZ(German Collection of Microorganisms and Cell Cultures,独国ブラウンシュヴァイク)から購入した。RPMI/Glutamax培地、ペリシリン−ストレプトマイシン、熱失活したウシ胎児血清及びD−PBSはLife Technologies(米国ニューヨーク州グランドアイランド)から購入した。抽出緩衝液及び中和緩衝液(5×)はActive Motif(米国カリフォルニア州カールスバッド)から購入した。家兔抗ヒストンH3抗体はAbcam(米国マサチューセッツ州ケンブリッジ)から購入した。家兔抗H3K27me3及びHRPコンジュゲートした抗家兔IgGはCell Signaling Technology(米国マサチューセッツ州ダンバース)から購入した。TMB「スーパーセンシティブ」基質はBioFX Laboratories(米国メリーランド州オーウィング・ミルズ)から提供された。IgG非含有ウシ血清アルブミンはJackson ImmunoResearch(米国ペンシルベニア州ウェスト・グローブ)から購入した。トゥイーンを含むPBSはKPL(米国マサチューセッツ州ゲイザースバーグ)(10×PBST)から購入した。硫酸はRicca Chemical(米国テキサス州アーリントン)から購入した。Immulon ELISAプレートはThermo(米国ニューヨーク州ロチェスター)から購入した。V底細胞培養プレートはCorning Inc.(米国ニューヨーク州コーニング)から購入した。V底ポリプロピレンプレートはGreiner Bio−One(米国ノースカロライナ州モンロー)から購入した。
WSU−DLCL2懸濁細胞はDSMZ(German Collection of Microorganisms and Cell Cultures,独国ブラウンシュヴァイク)から購入した。RPMI/Glutamax培地、ペニシリン−ストレプトマイシン、熱失活したウシ胎児血清はLife Technologies(米国ニューヨーク州グランドアイランド)から購入した。V底ポリプロピレン384ウェルプレートはGreiner Bio−One(米国ノースカロライナ州モンロー)から購入した。細胞培養384ウェル乳白色プレートはPerkin Elmer(米国マサチューセッツ州ウォーザン)から購入した。Cell−Titer Glo(登録商標)はPromega Corporation(米国ウィスコンシン州マディソン)から購入した。SpectraMax M5プレートリーダーはMolecular Devices LL(米国カリフォルニア州サニーベール)から購入した。
マウス
雌Fox Chase SCID(登録商標)マウス(CB17/Icr−Prkdcscid/IcrIcoCrl,Beijing Vitalriver Laboratory Animal Co.,LTD)は6〜8週齢であり、研究の1日目には16.0〜21.1gの体重(BW)を有していた。動物は自由に水(滅菌)及び放射線滅菌したドライ顆粒状餌を摂取した。マウスをスタティックマイクロアイソレーター中のトウモロコシ穂軸わらに20〜22℃(68〜72°F)及び40〜60% 湿度で12時間光サイクルで入れた。全ての手順は拘束、畜産、外科手順、飼料及び流体規制並びに獣医ケアに関して実験動物の管理及び使用に関するガイドの推奨に従っている。
ヒトリンパ腫細胞株SUDHL10はDSMZから入手し、100単位/mLのペニシリンGナトリウム塩、100g/mLのストレプトマイシン及び10% ウシ胎児血清を含有しているRPMI−1640培地中の懸濁培養物としてCROで維持した。細胞を加湿インキュベーター内の組織培養フラスコにおいて37℃、5% CO2及び95% 空気の雰囲気中で培養した。移植のためには経代12以下の培養物のみを使用した。
SUDHL10ヒトリンパ腫細胞株を対数増殖中期中に採取し、50% マトリゲル(商標)(BD Biosciences)を含むPBS中に再懸濁した。各マウスの右脇腹に1×107細胞(0.2mL細胞懸濁液)を皮下投与した。所望の80〜120mm3範囲に近づいた平均容積として増殖をモニターするために腫瘍を2寸法でカリパスを用いて計った。腫瘍大きさ(単位mm3)は
から計算した。腫瘍重量は、1mgは1mm3の腫瘍容積に等しいと仮定して推定され得る。10日後、72〜256mm3の腫瘍を有するマウスを173〜179mm3の平均腫瘍容積を有する4つの群(n=16匹/群)に分けた。
化合物Iの臭化水素酸塩を室温で保存し、遮光した。各治療日に、粉末を脱イオン水中0.5% ナトリウムカルボキシメチルセルロース(NaCMC)及び0.1% トゥイーン(登録商標)80中に懸濁することにより新鮮な化合物処方物を調製した。同一スケジュールで対照群を治療するためにビヒクル、脱イオン水中0.5% NaCMC及び0.1% トゥイーン(登録商標)80を使用した。処方物は投与前4℃で遮光して保存した。
マウスに125〜500mg/kgの用量の化合物Iの臭化水素酸塩を用いてBID(12時間毎に1日2回)スケジュールで28日間強制経口投与した。各用量を0.2mL/20g マウス(10mL/kg)の容量でデリバリーし、各動物の最後に記録された体重に対して調節した。25日目に、8匹/群の最小の腫瘍を有するマウスを腫瘍増殖遅延エンドポイント(60日まで観察)のために選択した。残りの動物は腫瘍採取のために28日目に最後の投与から3時間後に安楽死させた。
治療効率を治療最終日に調べた。最終日に評価可能な動物数nに対するMTV(n)メディアン腫瘍容積を群毎に調べた。腫瘍増殖抑制パーセント(%TGI)は幾つかの方法で規定され得る。第1に、指定された対象群のMTV(n)と薬物治療群のMTV(n)間の差は対象群のMTV(n)のパーセントとして表示される。
腫瘍増殖遅延分析のために、8匹/群のマウスを最終治療日後も生存させた。腫瘍を1週間に2回カリパスを用いて計り、新生物が2000mm3のエンドポイント容積に達したかまたは研究の予め特定した最終日のいずれか早い日に各試験動物を安楽死させた。カプランマイヤー生存分析を実施した。
動物の体重を1〜5日目に毎日測定した後、研究が完了するまで1週間に2回測定した。治療に関連する副作用の明らかな兆候についてマウスをしばしば観察し、文書に残した。最大耐量(MTD)に対する許容され得る毒性は、試験中群平均BW減少20%未満及びTR死に起因する死亡率10%以下と定義された。死亡が臨床兆候及び/または検死により立証される治療副作用に起因したかまたは投与期間中の原因不明のためであったならば、死亡はTRと分類することとした。死亡が治療副作用に関連していなかったならば、死亡はNTRと分類することとした。投与間隔中のNTR死は典型的にはNTRa(事故またはヒューマンエラーに起因する)またはNTRm(侵襲及び/または転移による検死で確認された腫瘍播種に起因する)と分類される。投与期間中原因不明で死亡した経口治療を受けた動物は、投与エラーを除外するために群パフォーマンスがTR分類及び検死を裏付けず、利用不可能のときにはNTRuと分類され得る。
28日目に、腫瘍の標的抑制を評価するために最大の腫瘍を有する8匹のマウスを予め規定した方法でサンプリングした。腫瘍を特定したマウスからRNAseのない条件下で採取し、二分した。全腫瘍重量を測定した。各動物からの凍結腫瘍組織を液体N2中で瞬間凍結し、乳鉢及び乳棒を用いて粉砕した。
全ての統計及びグラフィカル分析をPrism 3.03(GraphPad)for Windows(登録商標)を用いて実施した。全治療期間にわたり対照群と治療群間の統計上有意を調べるために、反復測定ANOVAテストの後に、ダネット多重比較ポストテストを使用した。Prismは、結果をP>0.05で有意でない(ns)、0.01<P<0.05で有意である(“*”の記号で表す)、0.001<P<0.01で非常に有意である(“**”)、P<0.001で特に有意である(“***”)と報告している。研究の腫瘍増殖遅延アームの場合、研究で残っている各群中の動物のパーセント対時間をカプラン・マイヤー生存プロットで表す。
ヒストンを単離するために、60〜90mgの腫瘍組織を1.5mlの核抽出緩衝液(10mM トリスHCl,10mM MgCl2,25mM KCl,1% トリトンX−100,8.6% スクロース+Rocheプロテアーゼ阻害剤錠剤1836145)中でホモジナイズし、氷上で5分間インキュベートした。核を4℃で600gで5分間遠心することにより収集し、PBSで1回洗浄した。上清を取り除き、15分毎に渦流撹拌しながらヒストンを0.4N 冷硫酸で1時間抽出した。抽出物を4℃で10000gで10分間遠心することにより清澄化し、10×容量の氷冷アセトンを収容している新しい微量遠心管に移した。ヒストンを−20℃で2時間〜一晩沈殿させ、10000gで10分間遠心することによりペレット化し、水中に再懸濁した。
ヒストンを0.5ng/ul−サンプルを生ずるようにコーティグ緩衝液(PBS+0.05% BSA)中に当量濃度で作成し、100ulのサンプルまたは標準物質を2つの96ウェルELISAプレート(Thermo Labsystems,Immulon 4HBX #3885)に対して2通りで添加した。プレートを密封し、4℃で一晩インキュベートした。翌日、プレートをBioTekプレート洗浄装置を用いて300ul/ウェルのPBST(PBS+0.05% トゥイーン20;10×PBST,KPL #51−14−02)で3回洗浄した。プレートを300ul/ウェルの希釈剤(PBS+2%BSA+0.05% トゥイーン20)でブロックし、室温で2時間インキュベートし、PBSTで3回洗浄した。全ての抗体を希釈剤で希釈した。100ul/ウェルの抗H3K27me3(CST #9733,50% グリセロールストック 1:1,000)または抗全H3(Abcam ab1791,50% グリセロール 1:10,000)を各プレートに添加した。プレートを室温で90分間インキュベートし、PBSTで3回洗浄した。100ul/ウェルの抗Rb−IgG−HRP(Cell Signaling Technology,7074)をH3K27Me3プレートに対して1:2,000で添加し、H3プレートに対しては1:6,000で添加し、室温で90分間インキュベートした。プレートをPBSTで4回洗浄した。検出のために、100ul/ウェルのTMB基質(BioFx Laboratories,#TMBS)を添加し、プレートを暗所、室温で5分間インキュベートした。反応を100ul/ウェルの1N H2SO4で停止させた。450nmの吸光度をSpectaMax M5マイクロプレートリーダーを用いて測定した。
SUDHL10腫瘍異種移植片を有しているマウスを化合物Iの臭化水素酸塩を用いて500mg/kg BIDの最大耐量及びMTDの分量(1/2及び1/4 MTD)で治療した。全ての用量は明白な体重減少を示すことなく28日間十分耐性を示した。500mg/kgの群では、投与エラーのために15日目に1例の治療関連死が見られた。全ての用量で、28日目でビヒクルと比較して腫瘍増殖抑制が生じ(表4)、250mg/kg及び500mg/kg BID群は退縮を誘発した(TGI>100%)。
化合物Iの一臭化水素酸塩の抗癌活性をヒトびまん性大細胞型B細胞リンパ腫異種移植片モデルであるファイファーマウス異種移植片モデルで調べた。雌5週令のNSGマウス(Jackson Labs,メイン州バー・ハーバー)に20〜25mgの腫瘍断片を皮下移植した。平均腫瘍が約365mm3に達した腫瘍移植から約31日目に治療を開始した。治療スキームを表5に示す。
Claims (22)
- N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド一臭化水素酸塩。
- 結晶性である、請求項1に記載の化合物。
- 請求項1〜2のいずれか1項に記載の化合物であって、0.1重量%未満の全不純物を含む、化合物。
- 請求項1〜3のいずれか1項に記載の化合物であって、非晶質N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド一臭化水素酸塩を含まない結晶性固体である、化合物。
- 請求項4に記載の化合物であって、ここで、前記結晶性固体が、°(2θ)で表示して、3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも10個の特徴的ピークを有するX線粉末回折パターンを示す、少なくとも95重量%の結晶性多形Aを含む、化合物。
- 請求項1〜5のいずれか1項に記載の化合物及び医薬的に許容され得る担体または希釈剤を含む、医薬組成物。
- 請求項1に記載の化合物の製造方法であって、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドを臭化水素酸と化合することを含む、方法。
- N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミド臭化水素酸塩の多形Aであって、ここで、該多形は、°(2θ)で表示して、3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に少なくとも10個の特徴的ピークを有するX線粉末回折パターンを示す、多形。
- 請求項8に記載の多形であって、°(2θ)で表示して、3.9±0.3°、10.1±0.3°、14.3±0.3°、17.5±0.3°、18.7±0.3°、20.6±0.3°、20.9±0.3°、21.8±0.3°、22.0±0.3°、23.3±0.3°及び23.6±0.3°(2θ)に特徴的ピークを有するX線粉末回折パターンを示す、多形。
- 請求項8〜9のいずれか1項に記載の多形であって、図1:
に従うX線粉末回折パターンを示す、多形。 - 請求項8〜10のいずれか1項に記載の多形であって、表1:
に従うX線粉末回折パターンを示す、多形。 - 請求項8〜11のいずれか1項に記載の多形であって、℃の単位で表示して、255±5℃の温度に特徴的ピークを有する示差走査熱量測定サーモグラムを示す、多形。
- 請求項8〜12のいずれか1項に記載の多形であって、図3:
に従う示差走査熱量測定サーモグラムを示す、多形。 - 請求項8〜13のいずれか1項に記載の多形の製造方法であって、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドを臭化水素酸と化合することを含む、方法。
- 請求項8〜13のいずれか1項に記載の多形及び医薬的に許容され得る担体または希釈剤を含む、医薬組成物。
- 癌の治療のための組成物であって、治療有効量の請求項1〜5のいずれかに記載の化合物、請求項8〜13のいずれかに記載の多形、または請求項6または15のいずれかに記載の医薬組成物を含む、組成物。
- 前記癌が、非ホジキンリンパ腫または乳癌である、請求項16に記載の組成物。
- EZH2のヒストンメチルトランスフェラーゼ活性の阻害を必要とする被験者におけるEZH2のヒストンメチルトランスフェラーゼ活性の阻害のための組成物であって、有効量の請求項1〜5のいずれかに記載の化合物または請求項8〜13のいずれかに記載の多形を含む、組成物。
- インビトロでのEZH2のヒストンメチルトランスフェラーゼ活性の阻害方法であって、請求項1〜5のいずれかに記載の化合物または請求項8〜13のいずれかに記載の多形を投与することを含む、方法。
- 請求項1〜5のいずれかに記載の化合物または請求項8〜13のいずれかに記載の多形の使用であって、癌治療医薬の必要がある被験者において癌を治療するための医薬を製造するための、使用。
- 5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボン酸(5)を、3−(アミノメチル)−4,6−ジメチル−ジヒドロ−ピリジン−2(1H)−オンの塩と反応させることを含む、N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(エチル(テトラヒドロ−2H−ピラン−4−イル)アミノ)−4−メチル−4’−(モルホリノメチル)−[1,1’−ビフェニル]−3−カルボキサミドの製造方法。
- (5)は結晶形である、請求項21に記載の方法。
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JP2018002742A (ja) * | 2012-04-13 | 2018-01-11 | エピザイム,インコーポレイティド | ヒトヒストンメチルトランスフェラーゼezh2阻害剤の塩形態 |
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