JP2016522835A - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- JP2016522835A JP2016522835A JP2016516235A JP2016516235A JP2016522835A JP 2016522835 A JP2016522835 A JP 2016522835A JP 2016516235 A JP2016516235 A JP 2016516235A JP 2016516235 A JP2016516235 A JP 2016516235A JP 2016522835 A JP2016522835 A JP 2016522835A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- methyl
- fluoro
- pharmaceutically acceptable
- indol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 63
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 39
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07B2200/07—Optical isomers
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (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)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
R1およびR2は、それぞれ独立して、HまたはFであり;
R3は、Hまたはメチルであり;
a)R4は、Hであり、R5は、Fであるか;または
b)R4は、Fであり、R5は、Hであるか
のいずれかである]
の化合物またはそれらの医薬的に許容される塩が提供される。
a)Methods in Enzymology、42巻, 309-396頁、K. Widderら編(Academic Press、1985);
b)Design of Pro-drugs、H. Bundgaard編(Elsevier、1985);
c)A Textbook of Drug Design and Development、Krogsgaard-LarsenおよびH. Bundgaard編、第5章、「Design and Application of Pro-drugs」、H. Bundgaard著、113〜191頁(1991);
d)H. Bundgaard、Advanced Drug Delivery Reviews、8、1〜38(1992);
e)H. Bundgaardら、Journal of Pharmaceutical Sciences、77、285(1988);
f)N. Kakeyaら、Chem. Pharm. Bull.、32、692(1984);
g)T. HiguchiおよびV. Stella、「Pro-Drugs as Novel Delivery Systems」、A.C.S. Symposium Series、14巻;および
h)E. Roche(編集者)、「Bioreversible Carriers in Drug Design」、Pergamon Press、1987。
一形態において、R1は、水素である。別の形態において、R1は、フルオロである。
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3−フルオロ−4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸。
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4(1R)−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4(1R)−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4(1R)−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4(1R)−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3−フルオロ−4(1R)−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;および
(E)−3−[4−[(1R,3R)−1−ジュウテリオ−2−(2−フルオロ−2−メチル−プロピル)−3−メチル−4,9−ジヒドロ−3H−ピリド[3,4−b]インドール−1−イル]−3,5−ジフルオロ−フェニル]プロパ−2−エン酸。
a)ピクテ−スペングラー反応に好適な当業界において公知の条件下での(例えば、酸(例えば酢酸)の存在下、および好適な溶媒(例えばトルエン)中、および好適な温度(例えば80℃))での、式(III)の化合物と式(IV)の化合物との反応によって;または
工程2:トリフルオロメタンスルホン酸無水物/塩基、例えば2,6−ルチジン/DCM/0℃
工程2:トリフルオロメタンスルホン酸無水物/塩基、例えば2,6−ルチジン/DCM/−10℃
式(I)の化合物は、キラルである。当業者には、望ましい異性体を得るために立体選択的反応を使用できることが理解されると予想される。その代わりに、立体化学は、好適な手段によって、例えば、本明細書では実施例4で例示したように(および例えばJ. Org. Chem. 2009、74、2771〜2779で説明されているように)、保護されたアミン基での中間体の酸性化を介したシスからトランス異性体へのエピマー化によって調整することができる。
以下のアッセイを使用して、本発明の化合物の作用を測定した。
ランザスクリーン(LanthaScreen(商標))時間分解蛍光共鳴エネルギー移動(TR−FRET)検出のエンドポイントを使用した競合アッセイで、単離されたエストロゲン受容体アルファリガンド結合ドメイン(ERアルファ−LBD(GST))に結合する化合物の能力を評価した。ランザスクリーンTR−FRETのエンドポイントに関して、好適なフルオロフォア(フルオルモンES2(Fluormone ES2)、製品コードP2645)および組換えヒトエストロゲン受容体アルファリガンド結合ドメイン(製品コードPV4543)をインビトロジェン(Invitrogen)から購入し、化合物の結合を測定するのに使用した。アッセイの原理は、ERアルファ−LBD(GST)を蛍光リガンドに添加すると、受容体/フルオロフォア複合体が形成されることである。テルビウム標識抗GST抗体(製品コードPV3551)は、そのGSTタグに結合することにより受容体を間接的に標識するために使用され、競合結合は、蛍光リガンドを置き換えて、その結果としてTb−抗GST抗体とトレーサーとの間のTR−FRETシグナルの損失を引き起こす試験化合物の能力によって検出される。アッセイは以下のようにして行われ、ここで全ての試薬の添加は、ベックマン・コールター(Beckman Coulter)のBioRAPTR FRDマイクロフルイディックワークステーションを使用して実行された。
MCF−7ヒト腺管癌乳房細胞株を使用した細胞ベースの免疫蛍光アッセイで、エストロゲン受容体(ER)の数を下方調節する化合物の能力を評価した。2mMのL−グルタミンを含有するアッセイ培地(フェノールレッド非含有ダルベッコ改変イーグル培地(DMEM)(シグマ(Sigma)D5921)中のクライオバイアル(およそ5×106個の細胞)からMCF−7細胞を直接再生し、5%(v/v)チャコール/デキストラン処理したウシ胎児血清細胞を、滅菌した18G×幅1.5インチ(1.2×40mm)ゲージのニードルを使用して一回注入し、コールターカウンター(ベックマン(Beckman))を使用して細胞密度を測定した。細胞を、細胞3.75×104個/mlの密度にアッセイ培地でさらに希釈し、40μl/ウェルを、サーモ・サイエンティフィック(Thermo Scientific)のマトリックス・ウェルメイト(Matrix WellMate)またはサーモマルチドロップ(Thermo Multidrop)を使用して、底が透明な黒色の組織培養処理済み384ウェルプレート(コースター(Costar)、番号3712)に添加した。細胞を植え付けた後、37℃、5%CO2(リコニック(Liconic)回転式インキュベーター)で、プレートを一晩インキュベートした。自動化ワークセル(統合型のエコー2ワークセル)の一部であるラボサイト(LabCyte)のエコー(Echo(登録商標))モデル555化合物リフォーマッター(compound reformatter)を使用して試験データを作成した。試験化合物の10mMの化合物ストック溶液を使用して、384ウェルの化合物投入プレート(ラボサイトP−05525−CV1)を作製した。それぞれの10mMの化合物ストック溶液40μlを第一の四分円のウェルに分配し、次いで、ハイドラII(Hydra II)(MATRIX UK)液体操作ユニットを使用してDMSOでの1:100の段階的な連続希釈を行い、40μlの希釈化合物をそれぞれ四分円のウェル2(0.1mM)、3(1μM)および4(0.01μM)に入れた。源プレート上のP列中のウェルに40μlのDMSOを添加することにより、用量範囲全体のDMSOでの正規化が可能になる。対照ウェルに入れるために、化合物源プレート上の、O1列に40μlのDMSOを添加し、O3列にDMSO中の100μMファスロデックス(Faslodex(登録商標))40μlを添加した。エコーは、音響技術を使用して、アッセイプレートに対してDMSO化合物溶液の直接的なマイクロプレートからマイクロプレートへの移動を実行する。このシステムは、マイクロプレート間で2.5nLもの少ない体積を複数の増分で移動させ、その際にアッセイプレート中で化合物の連続希釈物を作製し、次いでこれを、希釈範囲全体でDMSO濃度を正規化するために充填し戻すようにプログラム化することができる。上記の通りに調製された化合物源プレートを含むセルプレート上に化合物を分配し、統合型エコー2ワークセルを使用して、3倍希釈物と1つの最終的な10倍希釈物とを含む12ポイントの重複する3μMから3pMの用量範囲を作製した。そこで、最大シグナルの対照ウェルにはDMSOを入れて0.3%の最終濃度を得て、最小シグナルの対照ウェルにはファスロデックス(登録商標)を入れて、100nMの最終濃度を得た。プレートを37℃、5%CO2で18〜22時間さらにインキュベートし、次いで20μlの11.1%(v/v)ホルムアルデヒド溶液(リン酸緩衝生理食塩水(PBS)中)の添加によって固定し、3.7%(v/v)の最終的なホルムアルデヒド濃度を得た。細胞を室温で20分間固定し、その後、バイオテック(BioTek)プレートウォッシャーを使用して、250μlのPBS/プロクリン(殺生保存剤を含むPBS)で2回洗浄し、次いで全てのウェルに40μlのPBS/プロクリンを添加し、プレートを4℃で保存した。統合型のエコー2ワークセルで上述した固定方法を実行した。自動化オートイライザ(AutoElisa)ワークセルを使用して免疫染色を行った。全てのウェルからPBS/プロクリンを吸い出し、0.5%トゥイーン(Tween(商標))20(v/v)を含有する40μlのPBSを用いて、細胞を室温で1時間透過化した。250μlのプロクリン(殺生保存剤を含むPBST)を含むPBS/0.05%(v/v)トゥイーン20中でプレートを3回洗浄し、次いで、20μlの、PBS/トゥイーン(商標)/3%(w/v)ウシ血清アルブミン中のERα(SP1)ウサギモノクローナル抗体(サーモフィッシャー(Thermofisher))1:1000を添加した。プレートを4℃で一晩インキュベートし(リコニック回転式インキュベーター)、次いで、250μlの、プロクリン(PBST)を含むPBS/0.05%(v/v)トゥイーン(商標)20中で3回洗浄した。次いで、PBS/トゥイーン(商標)/3%(w/v)ウシ血清アルブミン中の1:5000でヘキストを含む、20μl/ウェルのヤギ抗ウサギIgGアレクサフルオロ(AlexaFluor)594またはヤギ抗ウサギアレクサフルオロ488抗体(モレキュラープローブス(Molecular Probes))と共にプレートを室温で1時間インキュベートした。次いでプレートを、プロクリン(殺生保存剤を含むPBST)を含む250μlのPBS/0.05%(v/v)トゥイーン(商標)20中で3回洗浄した。各ウェルに20μlのPBSを添加し、プレートを黒色のプレートシールで覆い、読取り前に4℃で保存した。各ウェルのERα受容体レベルを測定するために、594nm(24時間のタイムポイント)または488nm(5時間のタイムポイント)の蛍光を読み取るセロミクス(Cellomics)のアレイスキャンを使用して、プレートを読み取った。平均合計強度を細胞数に正規化し、細胞1つ当たりの合計強度を得た。好適なソフトウェアパッケージ(例えばオリジン)にデータをエクスポートし、カーブフィッティング分析を行った。ERα受容体の下方調節をIC50値として表し、これは、平均の最大合計強度シグナルの50%低減を達成するのに必要な化合物濃度の計算によって決定された。
免疫不全(SCID)マウス後脇腹に0.5mg/21日のエストロゲンペレット(イノベーティブ・リサーチ(Innovative Research)、米国)を外科的に埋め込んだ次の日に、各マウスの皮下に、MCF7細胞(5×106個の細胞を100μlのRPMI細胞培地に懸濁した)を埋め込んだ。腫瘍を週2回測定し、腫瘍体積の変化および成長阻害を、両側に副尺が付いたノギスでの測定(長さ×幅)によって決定し、ここで長さを腫瘍全体で最長の直径とし、幅をそれに対応する垂線とした。腫瘍体積を、式(長さ×幅)×√(長さ×幅)×π/6)を使用して計算した。
好適な細胞培養期間の後、HCC1428LTED細胞(1×106)を、卵巣摘出術を受けた雌免疫不全NSGマウス(ジャクソン研究所(Jackson Labs)、米国)後脇腹の皮下に埋め込んだ。腫瘍を週2回測定して、腫瘍体積の変化および成長阻害を、両側に副尺が付いたノギスでの測定(長さ×幅)によって決定し、ここで長さを腫瘍全体で最長の直径とし、幅をそれに対応する垂線とした。腫瘍体積を、式(長さ×幅)×√(長さ×幅)×(π/6)を使用して計算した。細胞埋め込みの後に、平均サイズが150mm3に達するまで腫瘍を週1回測定し、それに達した時点で、各グループが10匹のマウスを含有する無作為化した試験グループにマウスを配した。その日の後に(この研究の62日目に)化合物での処置を始め、腫瘍を週1回測定し続けた。実施例1を、1日1回25mg/kgで毎日、0.1ml/10gの体積で経口(p.o.)投与した。別の動物グループにビヒクルをp.o.投与しては、対照として作用した。
(i)内科的腫瘍学において使用されるような、他の抗増殖/抗新生物剤およびそれらの組み合わせ、例えば、アルキル化剤(例えばシスプラチン、オキサリプラチン、カルボプラチン、シクロホスファミド、ナイトロジェンマスタード、メルファラン、クロラムブシル、ブスルファン、テモゾロミド(temozolamide)およびニトロソウレア);代謝拮抗物質(例えばゲムシタビンおよび抗葉酸剤、例えばフルオロピリミジン、例えば5−フルオロウラシルおよびテガフール、ラルチトレキセド、メトトレキセート、シトシンアラビノシド、ならびにヒドロキシ尿素);抗腫瘍抗生物質(例えばアントラサイクリン、例えばアドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン−C、ダクチノマイシンおよびミトラマイシン);細胞分裂抑制薬(例えばビンカアルカロイド、例えばビンクリスチン、ビンブラスチン、ビンデシンおよびビノレルビン、ならびにタキソイド、例えばタキソールおよびタキソテール、ならびにポロキナーゼ阻害剤);ならびにトポイソメラーゼ阻害剤(例えばエピポドフィロトキシン、例えばエトポシドおよびテニポシド、アムサクリン、トポテカンならびにカンプトテシン);
(ii)抗ホルモン剤、例えば抗エストロゲン剤(例えばタモキシフェン、フルベストラント、トレミフェン、ラロキシフェン、ドロロキシフェンおよびヨードキシフェン)、プロゲストゲン(例えば酢酸メゲストロール)、アロマターゼ阻害剤(例えばアナストロゾール、レトロゾール、ボロゾール(vorazole)およびエキセメスタン);
(iii)増殖因子の機能およびそれらの下流シグナル伝達経路の阻害剤:例えばあらゆる増殖因子または増殖因子受容体の標的のAbモジュレーターなど(Sternら、Critical Reviews in Oncology/Haematology、2005、54、11〜29頁で総論されている);さら例えばこのような標的の小分子阻害剤など、例えばキナーゼ阻害剤、例として、抗erbB2抗体であるトラスツズマブ[ハーセプチン(Herceptin(商標))]、抗EGFR抗体であるパニツムマブ、抗EGFR抗体であるセツキシマブ[セツキシマブ、C225]およびチロシンキナーゼ阻害剤、例えばerbB受容体ファミリーの阻害剤、例えば上皮増殖因子ファミリー受容体(EGFR/erbB1)チロシンキナーゼ阻害剤、例えばゲフィチニブまたはエルロチニブ、erbB2チロシンキナーゼ阻害剤、例えばラパチニブ、ならびに混合されたerb1/2阻害剤、例えばアファチニブ(afatanib)など;類似の方策、例えば増殖因子およびそれらの受容体の他のクラス、例えば、c−metおよびronなどの肝細胞増殖因子ファミリーまたはそれらの受容体の阻害剤なども利用可能;インスリンおよびインスリン増殖因子ファミリーまたはそれらの受容体(IGFR、IR)の阻害剤、血小板由来増殖因子ファミリーまたはそれらの受容体(PDGFR)の阻害剤、ならびにc−キット、AnLK、およびCSF−1Rなどの他の受容体チロシンキナーゼが介在するシグナル伝達の阻害剤;
また、PI3−キナーゼシグナル伝達経路におけるシグナル伝達タンパク質を標的とするモジュレーター、例えば、PI3K−α/β/γなどのPI3−キナーゼアイソフォーム、およびAKT、mTOR(例えばAZD2014)、PDK、SGK、PI4KまたはPIP5Kなどのser/thrキナーゼの阻害剤など;また、上記で列挙されていないセリン/スレオニンキナーゼの阻害剤、例えばraf阻害剤、例えばベムラフェニブ、MEK阻害剤、例えばセルメチニブ(AZD6244)、Abl阻害剤、例えばイマチニブまたはニロチニブ、Btk阻害剤、例えばイブルチニブ、Syk阻害剤、例えばフォスタマチニブ(fostamatinib)、オーロラキナーゼ阻害剤(例えばAZD1152)、JAK、STATおよびIRAK4などの他のser/thrキナーゼの阻害剤、およびサイクリン依存性キナーゼ阻害剤、例えばパルボシクリブ(palbociclib)など;
(iv)DNA損傷シグナル伝達経路のモジュレーター、例えばPARP阻害剤(例えばオラパリブ(Olaparib))、ATR阻害剤またはATM阻害剤;
(v)アポトーシスおよび細胞死経路のモジュレーター、例えばBclファミリーモジュレーター(例えばABT−263/ナビトクラックス(Navitoclax)、ABT−199);
(vi)抗血管新生剤、例えば血管内皮増殖因子の作用を阻害するもの[例えば抗血管内皮細胞増殖因子抗体であるベバシズマブ(アバスチン(Avastin(商標)))および例えば、VEGF受容体チロシンキナーゼ阻害剤、例えばソラフェニブ、アキシチニブ、パゾパニブ、スニチニブおよびバンデタニブ(および他のメカニズムによって作用する化合物(例えばリノマイド(linomide)、インテグリンαvβ3の機能およびアンギオスタチンの阻害剤)];
(vii)血管障害剤、例えばコンブレタスタチンA4;
(viii)抗浸潤剤、例えばc−Srcキナーゼファミリー阻害剤、例えばダサチニブ(J. Med. Chem.、2004、47、6658〜6661)およびボスチニブ(SKI−606)、ならびにメタロプロテイナーゼ阻害剤、例えばマリマスタット、ウロキナーゼ型プラスミノゲン活性化因子受容体機能の阻害剤またはヘパラナーゼに対する抗体];
(ix)免疫療法アプローチ、例えば患者の腫瘍細胞の免疫原性を高めるエクスビボおよびインビボのアプローチ、例えばインターロイキン2、インターロイキン4または顆粒球マクロファージコロニー刺激因子などのサイトカインでのトランスフェクション、T細胞のアネルギーを減少させるアプローチ、サイトカインでトランスフェクトされた樹状細胞などのトランスフェクトされた免疫細胞を使用するアプローチ、サイトカインでトランスフェクトされた腫瘍細胞株を使用するアプローチ、および抗イディオタイプ抗体を使用するアプローチなど、具体的な例としては、PD−1(例えばBMS−936558)またはCTLA4(例えばイピリムマブおよびトレメリムマブ)を標的とするモノクローナル抗体など;
(x)アンチセンスまたはRNAiベースの療法、例えば、列挙した標的を対象とする療法;
(xi)遺伝子治療アプローチ、例えば、異常なp53または異常なBRCA1もしくはBRCA2などの異常な遺伝子を置き換えるアプローチ、GDEPT(遺伝子指向性酵素プロドラッグ療法)アプローチ、例えばシトシンデアミナーゼ、チミジンキナーゼまたは細菌のニトロレダクターゼ酵素を使用するアプローチ、ならびに化学療法または放射線治療、例えば多剤耐性遺伝子治療に対する患者の耐性を高めるアプローチなど。
a)第一の単位剤形の、式(I)の化合物またはそれらの医薬的に許容される塩;
b)第二の単位剤形の、本明細書で上記された(i)〜(xi)に列挙されたものから選択される抗腫瘍剤;および
c)前記第一および第二の剤形を収容するための容器手段
を含むキットが提供される。
a)第一の単位剤形の、式(I)の化合物またはそれらの医薬的に許容される塩;
b)第二の単位剤形の、本明細書で上記された(i)〜(ii)に列挙したものから選択される抗腫瘍剤;および
c)前記第一および第二の剤形を収容するための容器手段
を含むキットが提供される。
a)第一の単位剤形の、実施例1またはそれらの医薬的に許容される塩;
b)第二の単位剤形の、本明細書で上記された(i)〜(xi)に列挙されたものから選択される抗腫瘍剤;および
c)前記第一および第二の剤形を収容するための容器手段
を含むキットが提供される。
a)第一の単位剤形の、実施例1またはそれらの医薬的に許容される塩;
b)第二の単位剤形の、本明細書で上記された(i)〜(ii)に列挙したものから選択される抗腫瘍剤;および
c)前記第一および第二の剤形を収容するための容器手段
を含むキットが提供される。
a)第一の単位剤形の、実施例1またはそれらの医薬的に許容される塩;
b)第二の単位剤形の、AZD2014、PI3Kα−阻害剤(例えば、本発明者らの同時係属中のPCT出願PCT/GB2014/050163に記載のPI3Kα/δ阻害剤)およびパルボシクリブから選択される抗腫瘍剤;および
c)前記第一および第二の剤形を収容するための容器手段
を含むキットが提供される。
本発明の別の形態は、ERαをコードする遺伝子の状態と、式(I)の化合物での処置に対する潜在的な感受性との関連を同定することに基づく。詳細に言えば、いくつかのERα突然変異は、現行の処置に対する耐性メカニズムとして発生すると考えられていることに少なくとも一部起因して、ERα遺伝子の状態は、患者が、現行のホルモン療法(例えばアロマターゼ阻害剤)に応答する可能性が低いことの指標となる可能性がある。次いで、SERD、特に、過剰な不利益なくより多くの用量で経口投与することができるSERDは、他の療法に対して耐性である可能性があるERα突然変異を有する患者を処置するのに有利に使用することができる。したがってそれにより、式(I)の化合物で処置するための患者、特にがん患者を選択するための、機会、方法およびツールがもたらされる。本発明は、患者選択ツールおよび方法(個別化医薬など)に関する。選択は、処置しようとする腫瘍細胞が、野生型または突然変異ERα遺伝子を有するかどうかに基づく。それゆえにERα遺伝子の状態は、SERDでの処置を選択することが有利であり得ることを示すバイオマーカーとして使用することができる。誤解を避けるために、本明細書で説明されるような式(I)の化合物は、野生型および突然変異ERα遺伝子に対して同様に活性であると考えられ、ここで少なくともこれらの突然変異は、本出願の出願日の時点で確認されたERα遺伝子である。
この個別化医療の章において:
「対立遺伝子」は、その特定のヌクレオチドまたはアミノ酸配列によって他の形態とは区別される遺伝子座の特定の形態を指す。
遺伝子状態に関して試験しようとする患者のサンプルは、個体から得られた、または個体から得ることができる、あらゆる腫瘍組織または腫瘍細胞を含有するサンプルであり得る。試験サンプルは、都合のよい形態としては、個体から得られた、血液、口腔スワブ、生検、または他の体液もしくは組織のサンプルである。特定の例としては、血漿または血清中の循環腫瘍細胞、循環DNA、卵巣がん患者の腹水から単離した細胞、肺に腫瘍を有する患者の場合は肺の痰、乳がん患者からの穿刺吸引物、尿、末梢血液、細胞の掻き取り検体(cell scraping)、毛包、皮膚パンチまたは頬側サンプルが挙げられる。
突然変異ERα核酸の検出は、本発明の内容において、薬物処置を選択するために採用することができる。これらの遺伝子における突然変異はDNAレベルで起こるため、本発明の方法は、ゲノムDNA、同様に転写物およびタンパク質それ自身における突然変異または変化の検出に基づくものであってもよい。検出された突然変異が実際に対象で発現されることを確認するために、転写物および/またはポリペプチドの分析によりゲノムDNAにおける突然変異を確認することが望ましい可能性がある。
図1は、実施例7の形態AのX線粉末回折パターンを示す。
図2は、実施例1の形態BのX線粉末回折パターンを示す。
図3は、実施例1の形態BのDSCサーモグラムを示す。
図4は、実施例1の形態AのX線粉末回折パターンを示す。
図5は、実施例1の形態AのTGAサーモグラムを示す。
図6は、実施例1の形態CのX線粉末回折パターンを示す。
図7は、実施例1の形態CのTGAサーモグラムを示す。
図8は、実施例11のX線粉末回折パターンを示す。
図9は、実施例11のDSCトレースを示す。
図10は、実施例1およびAZD2014を用いたMCF−7異種移植片研究の結果を示す。
図11は、実施例1を用いたHCC1428長期エストロゲン枯渇(LTED)異種移植片の効能研究の結果を示す。
図12は、実施例1を用いたHCC1428長期エストロゲン枯渇(LTED)異種移植片の効能研究の結果を示す。
(i)操作は、特に他の指定がない限り、周囲温度、すなわち17〜25℃の範囲で、窒素などの不活性ガスの雰囲気下で実行された。
(vi)収量が示される場合、それは必ずしも最大の到達可能な収量ではない。
aq. 水溶液
CDCl3 重水素化クロロホルム
Conc. 濃
DCM ジクロロメタン
DMA N,N−ジメチルアセトアミド
DMSO ジメチルスルホキシド
DSC 示差走査熱量測定,
EtOH エタノール
EtOAc 酢酸エチル
IPA/iPrOH イソプロピルアルコール
MeCN アセトニトリル
MTBE メチルtertブチルエーテル
rt/RT 室温
sat. 飽和
sol. 溶液
THF テトラヒドロフラン
TFA トリフルオロ酢酸
TGA 熱重量分析。
1H NMR (500 MHz, DMSO, 27℃) 1.02 - 1.09 (3H, m), 1.17 (6H, dd), 2.37 (1H, dd), 2.59 (1H, dd), 2.8 - 2.98 (2H, m), 3.47 - 3.58 (1H, m), 5.24 (1H, s), 6.68 (1H, d), 6.9 - 7.06 (2H, m), 7.20 (1H, d), 7.38 - 7.51 (3H, m), 7.55 (1H, d), 10.59 (1H, s), 12.60 (1H, br)。また結晶性形態Bは、エタノール/水の混合物およびエタノール/MTBEの混合物からも単離することができる。
1H NMR (400 MHz, CDCl3, 27℃) δ 1.46 (6H, d), 4.41 (2H, d)。
1H NMR (400 MHz, DMSO, 30℃) δ 0.50 (3H, d), 1.02 (3H, s), 1.30 (3H, s), 2.11 (1H, dd), 2.62 (2H, d), 2.80 (1H, d), 2.99 (1H, dd), 3.74 (3H, s), 4.09 - 4.23 (1H, m), 4.29 (1H, d), 5.09 (1H, s), 6.81 (1H, d), 6.97 (2H, dt), 7.16 (1H, d), 7.39 (1H, d), 7.53 (2H, d), 7.64 (1H, d), 10.44 (1H, s). m/z: ES+ [M+H]+ 471。
1H NMR (400 MHz, CDCl3, 30℃) δ 3.83 (3H, s), 6.53 (1H, d), 7.31 (1H, dd), 7.41 (1H, d), 7.65 (1H, d), 7.79 - 8 (1H, m), 10.25 - 10.41 (1H, m)。LCMSにおいて質量イオンは観察されなかった。
実施例1の例示的な組成物を、75gスケールで、湿式造粒法を使用して製造した。活性成分、マンニトール、微結晶性セルロースおよびデンプングリコール酸ナトリウムを以下に要約した量に量りとり、ディオズナ(Diosna)P1−6ミキサー−グラニュレーターに移し、600rpmで6分間(細断しながら)混合した。組成物Aの場合、およそ1mL/秒の速度で2つのアリコートに30mLの水を添加しながら混合を続け、アリコートとアリコートとの合間では混合を中断し、一方で組成物Bの場合、必要な量のEDTAおよびアスコルビン酸を20mLの水と共に50℃で20分(遮光)攪拌することによって調製された溶液が、類似のプロセスを使用して添加され、このケースにおける第二のアリコートはおよそ10mLの濯ぎ用溶液を含む。湿式混合を合計1.5分続けた。湿った顆粒を1.5mmの篩に通過させ、次いで50〜60℃で2%w/w未満の含水量になるまで真空中で乾燥させた。結果得られた顆粒を1mmの篩を使用して磨砕し、次いでターブラーブレンダーを使用して潤滑剤と共に32rpmで5分間混合した。6mmの一般的な凹面加工用具を備えたリバ(Riva)のミニプレスを使用して、名目上100mgの圧縮重量に顆粒を圧縮することによって、活性成分10mgを含有する錠剤を形成した。
メタノール(1045mL)中の1−(4−(5−(5−アミノ−6−(5−tert−ブチル−1,3,4−オキサジアゾール−2−イル)ピラジン−2−イル)−1−エチル−1H−1,2,4−トリアゾール−3−イル)ピペリジン−1−イル)−3−(テトラヒドロ−2H−ピラン−2−イルオキシ)プロパン−1−オン(131.9g、0.2382mol)の懸濁液に、N2下で、ピリジニウムp−トルエンスルホネート(11.97g、47.7mmol)を添加した。反応混合物を、60℃で5.5時間、次いで50℃で一晩攪拌した。反応混合物を0℃に冷却し、固体をろ過して除いた。生成物を、水(250mL)中、室温で20分環スラリー化し、ろ過して除き、水(3×40mL)で洗浄し、真空中、50℃で乾燥させた。それにより、1−(4−(5−(5−アミノ−6−(5−tert−ブチル−1,3,4−オキサジアゾール−2−イル)ピラジン−2−イル)−1−エチル−1H−1,2,4−トリアゾール−3−イル)ピペリジン−1−イル)−3−ヒドロキシプロパン−1−オン(21.4g)を形態Aとして得た(以下参照)。
IPA(12vol)中の1−(4−(5−(5−アミノ−6−(5−tert−ブチル−1,3,4−オキサジアゾール−2−イル)ピラジン−2−イル)−1−エチル−1H−1,2,4−トリアゾール−3−イル)ピペリジン−1−イル)−3−ヒドロキシプロパン−1−オン(例えば上記で概説した方法によって作製された形態B)の懸濁液を、固体が溶解するまで加熱還流した。この溶液を加熱ろ過し、次いで室温に冷却した。それにより、形態Cとして、1−(4−(5−(5−アミノ−6−(5−tert−ブチル−1,3,4−オキサジアゾール−2−イル)ピラジン−2−イル)−1−エチル−1H−1,2,4−トリアゾール−3−イル)ピペリジン−1−イル)−3−ヒドロキシプロパン−1−オンを薄黄色の固体として得た(99.3g、97%)。
10Lのフランジ付きフラスコ中に、MIBK(7900mL)中の形態C(377.8g、1部)を110〜115℃に加熱して、溶液を得た。この溶液ををそのまま97〜103℃に冷却させ、即座にアセトニトリル(8220mL)中の形態Bの種(0.8g)を含有する50Lの容器にポリッシュろ過し、−15℃で攪拌した。添加中、50Lの容器中の温度をジャケット冷却手段によって−15から25℃の間に維持した。MIBKに溶解させた追加の3部の化合物を、類似の方法で添加した。結果得られたスラリーに、形態Bの種(0.8g)を添加し、次いで混合物を10〜20℃で一晩攪拌した。工程内分析により、目に見える形態Cまたは非晶質がない望ましい形態(形態B)であることを確認した。混合物をろ過し、アセトニトリル(3340mL)で洗浄した。固体を、一定重量が得られるまでオーブンで2日間乾燥させた(固体は、乾燥中に、粉末と約1mmから約3〜4mmのサイズの小さい塊の混合物に崩壊した)。収量=1532.8g(93.5%)。
メタノール(2.4L)および濃硫酸(44.4mL、832.61mmol)の攪拌溶液に、0℃、窒素下で、ベータ−プロピオラクトン(175mL、2.78mol)を一滴ずつ添加した。この溶液をそのまま室温で2日攪拌した。反応混合物を10℃に冷却し、その後、重炭酸ナトリウム(145g、1.72mol)を一部ずつ添加し、結果得られた懸濁液をそのまま室温で75分攪拌させておいた。この溶液をろ過し、ろ過ケークをメタノール(800mL)で洗浄した。ろ液を蒸発させて油状物を得て、これをジクロロメタン(1.2L)中に再溶解させ、60分間攪拌し、その後再度ろ過した。この溶液をろ過し、その後蒸発させて、メチル3−ヒドロキシプロパノエート(219g、76%)を油状物として得た。 1 H NMRスペクトル:(CDCl3) 2.50 (2H, t), 3.63 (3H, s), 3.78 (2H, t)。
イソニペコチン酸(858g、3.74mol)をDMA(25.3L)中に溶解させ、4−メチルモルホリン(393mL、3.74mol)を添加した。5分間攪拌し、クロロギ酸イソブチル(489mL、3.74mol)を添加した。反応混合物を25℃で2時間攪拌し、15℃に冷却し、その後(Z)−5−アミノ−6−(5−tert−ブチル−1,3,4−オキサジアゾール−2−イル)ピラジン−2−カルボヒドラゾンアミド(940g、3.4mol)を10分かけて一部ずつ添加した。反応混合物を15℃で1〜2時間攪拌した。水(20.5L)を1時間かけて一部ずつ添加し、さらに1時間攪拌し、その後ろ過した。次いでろ過ケークを水(4×4L)で洗浄し、フィルター上で吸引乾燥し、その後、乾燥するまで真空オーブン中50℃で乾燥させ、望ましい生成物を得た。
Claims (16)
- 式(I)
R1およびR2は、それぞれ独立して、HまたはFであり;
R3は、Hまたはメチルであり;
a)R4は、Hであり、R5は、Fであるか;または
b)R4は、Fであり、R5は、Hであるか
のいずれかである]
の化合物またはその医薬的に許容される塩。 - 前記化合物が、式(IA)
- R3が水素である、請求項1または2に記載の化合物またはその医薬的に許容される塩。
- R3がメチルである、請求項1または2に記載の化合物またはその医薬的に許容される塩。
- R4が水素であり、R5がフルオロである、請求項1〜4のいずれか一項に記載の化合物またはその医薬的に許容される塩。
- R5が、水素であり、R4が、フルオロである、請求項1〜4のいずれか一項に記載の化合物またはその医薬的に許容される塩。
- 前記化合物が、
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−((1R,3R)−2−((S)−3−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3,5−ジフルオロ−4−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(4−(2−(2−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;
(E)−3−(3−フルオロ−4−(2−((S)−3−フルオロ−2−メチルプロピル)−3,3−ジメチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸;および
(E)−3−[4−[(1R,3R)−1−ジュウテリオ−2−(2−フルオロ−2−メチル−プロピル)−3−メチル−4,9−ジヒドロ−3H−ピリド[3,4−b]インドール−1−イル]−3,5−ジフルオロ−フェニル]プロパ−2−エン酸
から選択される、請求項1に記載の化合物またはそれらの医薬的に許容される塩。 - (E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸またはその医薬的に許容される塩である、請求項7に記載の化合物。
- 実質的に図2で示されるようなXRPDを有する結晶性形態の、化合物(E)−3−(3,5−ジフルオロ−4−((1R,3R)−2−(2−フルオロ−2−メチルプロピル)−3−メチル−2,3,4,9−テトラヒドロ−1H−ピリド[3,4−b]インドール−1−イル)フェニル)アクリル酸。
- 医薬品として使用するための、請求項1〜9のいずれか一項に記載の化合物またはその医薬的に許容される塩。
- ヒトなどの温血動物におけるがんの予防または処置に使用するための、請求項1〜9のいずれか一項に記載の化合物またはその医薬的に許容される塩。
- 乳がんまたは婦人科系がんの処置で使用するための、請求項1〜9のいずれか一項に記載の式(I)の化合物またはその医薬的に許容される塩。
- 処置が必要なヒトなどの温血動物においてがんを予防または処置するための方法であって、前記動物に、請求項1〜9のいずれか一項に記載の式(I)の化合物またはその医薬的に許容される塩の有効量を投与することを含む、上記方法。
- 請求項1〜9のいずれか一項に記載の式(I)の化合物またはその医薬的に許容される塩と、医薬的に許容される希釈剤またはキャリアーとを含む医薬組成物。
- 式(I)の化合物が、請求項8または9に記載の化合物であり、前記組成物が、抗酸化剤をさらに含み、金属−キレート剤をさらに含んでいてもよい、請求項14に記載の医薬組成物。
- 請求項1〜9のいずれか一項に記載の式(I)の化合物またはその医薬的に許容される塩と、別の抗腫瘍剤とを含む、がんの処置での使用に好適な組み合わせ。
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